Preparation of a diverse purine-scaffold library via one-step palladium catalyzed cross-coupling

Article abstract of DOI:10.3987/COM-12-12613

In our ongoing efforts to prepare Hsp90 inhibitors, various cross-coupling reactions (Suzuki, Stille, Heck, and Sonogashira) were used to construct a diverse library of substituted purines in a single step from PU-H71 (1). We show that these reactions, pa

Full text of DOI:10.3987/COM-12-12613

HETEROCYCLES, Vol. 87, No. 1, 2013
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HETEROCYCLES, Vol. 87, No. 1, 2013, pp. 91 - 113. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 28th October, 2012, Accepted, 16th November, 2012, Published online, 27th November, 2012
DOI: 10.3987/COM-12-12613
PREPARATION OF A DIVERSE PURINE-SCAFFOLD LIBRARY VIA
ONE-STEP PALLADIUM CATALYZED CROSS-COUPLING
Tony Taldone,a,* Danuta Zatorska,a Hardik J. Patel,a Weilin Sun,a Maulik R.
Patel,a and Gabriela Chiosisa,b,c
a. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute,
New York, NY, U.S.A. Email: taldonet@mskcc.org
b. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,
NY, U.S.A.
c. Department of Pharmacology, Weill Cornell Medical College, New York, NY
U.S.A.
Abstract – In our ongoing efforts to prepare Hsp90 inhibitors, various
cross-coupling reactions (Suzuki, Stille, Heck, and Sonogashira) were used to
construct a diverse library of substituted purines in a single step from PU-H71 (1).
We show that these reactions, particularly Suzuki coupling, are highly efficient,
do not require protection of the pendant amine, and due to the wide variety of
commercially available substrates, allow for the rapid development of a diverse
purine library. The products derived from these reactions will enable us to explore
the chemical space occupied by the key 6’-iodine of PU-H71 through molecules
with diverse physical and chemical properties with the potential to be useful for
diseases in which Hsp90 is implicated.
INTRODUCTION
The biological significance of purines and their derivatives as the endogenous ligand to a multitude of
receptors, kinases, and ATPases implicated in disease has made it an attractive scaffold for chemical
modification.1 As a result of this, as well as its ease of access to structural diversity, the purine ring has
become a privileged structure in medicinal chemistry. Towards this goal, cross-coupling reactions have
been used extensively to directly attach C-substituents (i.e. aryl, heteroaryl, alkenyl, alkyl) at positions 2,
6, or 8 of the purine-scaffold starting from the corresponding halopurine.2-4 In addition, these reactions
may also be used to introduce diversity to purine-scaffolds whereby the purine ring remains unmodified.
A protein of significant interest to us that requires ATP for its function is heat shock protein 90 (Hsp90).
Hsp90 is a molecular chaperone which assists in the conformational activation of its client proteins. Many
of its clients (i.e. HER2, EGFR, mutant ER, HIF1α, Raf-1, AKT and mutant p53) function in the

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development and progression of cancer. As a result of this, as well as the ability to simultaneously inhibit
multiple oncogenic signals, Hsp90 has emerged as an intriguing target in cancer and potentially in
neurodegenerative diseases.5,6 One class of Hsp90 inhibitor discovered through rational design is based
on the purine-scaffold, and in particular on 8-substituted adenines, as exemplified by the prototype PU3
(Scheme 1).7 Extensive medicinal chemistry efforts aimed at optimizing the potency and pharmacokinetic
properties of PU3 have resulted in a number of agents currently in clinical trials for cancer including
PU-H71 (1), MPC-3100 andCUDC-305(Scheme 1).8 Each of these molecules have in common a purine or
Scheme 1. Development of clinical agents targeting Hsp90 derived from PU3 and modifications to the
6'-position of 1 through Pd-catalyzed cross-coupling

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93
purine-like core attached to a benzo[d][1,3]dioxolyl moiety at the 8-position through a sulfur linker. The
benzo[d][1,3]dioxolyl moiety is substituted with a relatively small hydrophobic group in the 6'-position
such as iodine, bromine or dimethylamine, which combined occupies a hydrophobic pocket of Hsp90
where it makes many critical interactions.9 The 6'-position, key for high-affinity binding to Hsp90 for this
scaffold, has largely been unexplored because chemistry has not yet been developed. The presence of
iodine in the 8-thioaryl substituent of 1 offered to us the intriguing possibility of performing single-step
metal catalyzed cross-coupling reactions in an attempt to create a targeted and diverse library exploring
the chemical space around the 6’-position (2; Scheme 1). In this paper we show that the Suzuki, Stille,
Heck and Sonogashira coupling reactions can be used with great effect to generate a focused library of
6’-substituted 8-(benzo[d][1,3]dioxol-5-yl)thio purine analogs of the potent Hsp90 inhibitor PU-H71 (1)
in a single step without the need for wasteful protection-deprotection steps (Scheme 1).
RESULTS AND DISCUSSION
Palladium catalyzed cross-coupling reactions have revolutionized the field of organic synthesis by
enabling for the efficient construction of carbon-carbon bonds under mild conditions and with high
functional group tolerance.10 Suzuki, Stille, Heck and Sonogashira coupling are some of the most
commonly applied palladium-catalyzed cross-coupling reactions and their usefulness extends to the
synthesis of complex natural products and of biologically active molecules. In this regard, these reactions
have been used to construct novel scaffolds and to investigate structure activity relationships (SARs)
through the rapid development of diverse molecular libraries. While there are numerous palladium
catalyzed cross-coupling reactions available, we have chosen to focus on the Suzuki, Stille, Heck and
Sonogashira reactions. Combined, these reactions complement one another and have enabled us access to
a wide variety of derivatives of PU-H71 (1) through the direct substitution of the 6’-iodine on the 8-aryl
ring (Tables 1-4). We show that these reactions are applicable to a complex heterocycle such as 1 and that
they are tolerant of the secondary amine, thereby avoiding the necessity of tedious
protection-deprotection steps.
Our general conditions for Suzuki coupling were heating a mixture of 1 with boronic acid (1.5-3 eq.),
PdCl2(PPh3)2 (10-20 mol%) and NaHCO3 (3 eq.) in DMF/H2O at 90 °C for 2-24 h (Table 1). For the most
part, 1.5 eq. of boronic acid and 10 mol% of PdCl2(PPh3)2 were sufficient, however, in cases where the
reaction was noticeably sluggish, additional catalyst and/or boronic acid was added to ensure complete
consumption of 1. Progress of the reaction was monitored by LC-MS as TLC proved inadequate for many
ofthe reactions. Accordingly, it wasessentialtoensure complete reaction in order to efficiently isolate pure
product. Therefore, the conditions reported including reaction time have not been optimized for yield, but
rather reflect our requirement for complete consumption of starting material. As can be seen in Table 1, a

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Table 1. Suzuki-Miyaura coupling of 1
Compound
3
R
conditions yield (%)
90 °C, 4 h
90 °C, 3 h
90 °C, 4 h
73
83
71
4
5
6
7
90 °C, 9 h
90 °C, 9 h
71
77
MeO
OMe
8
90 °C, 3 h
90 °C, 4 h
90 °C, 4 h
85
66
44
9
10
11
12
13
90 °C, 20 h
90 °C, 20 h
90 °C, 24 h
64
69
54

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95
14
90 °C, 3 h
70
15
16
17
18
19
20
90 °C, 20 h
90 °C, 4 h
90 °C, 5 h
90 °C, 4 h
30a
55
45
72
90 °C, 4 h
42b
34
O
90 °C, 4 h
90 °C, 4 h
CHO
21
22
90
90 °C, 4 h
90 °C, 4 h
22c
23
24
25
26
30b,c
90 °C, 4 h
90 °C, 4 h
90 °C, 2 h
8
53b,c
74b
27
28
rt, 24 h
43d
49d
-CH2CN
90 °C, 4 h

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29
90 °C, 7 h
66
a. The primary amino formyl product (-CH2NHCHO) was also obtained in 17% yield.
b. from boronic acid pinacol ester
c. from Boc protected boronic acid or pinacol ester
d. from reaction with 4-isoxazoleboronic acid pinacol ester
large number of products were obtained from the reaction of 1 with 5- and 6-membered aromatic and
heteroaromatic boronic acids as well as with an alkenyl boronic acid.
Reaction of 1 with phenylboronic acid and 4-tert-butylphenylboronic acid yielded 3 and 4, respectively,
in good yields. The reaction was tolerant to a wide variety of functional groups and was unaffected by the
presence of electron donating or withdrawing groups on the phenyl ring. The 4-methoxy, 3-methoxy,
2,3-dimethoxy and 4-dimethylamino derivatives 5-8 were each prepared in good yield. The 4-formyl and
4-bromo derivatives 9-10, as well as the strongly electron withdrawing 3-cyano, 3-nitro, 3-trifluoromethyl
and 3,5-di-trifluoromethyl derivatives 11-14 were formed in moderate to good yields. The reaction of 1
with 4-aminomethylphenylboronic acid yielded 15 in 30% and its N-formyl derivative in 17% as a
by-product from the further reaction of the primary amine with the DMF solvent. Heterocyclic boronic
acids also reacted with 1 to give pyridine 16, thiophene 17, furans 18-21, pyrroles 22-23, and pyrazoles
24-26. Under the general conditions employed, the product 27 desired in the reaction with
4-isoxazoleboronic acid pinacol ester was not obtained. Instead, nitrile 28 was isolated, presumably as a
result of CO elimination from isoxazole 27, in 49% yield. A similar occurrence has been mentioned
previously in the coupling of 4-isoxazoleboronic acid pinacol ester with a fused 2-bromoimidazole.11
Furthermore, acetonitrile and CO were identified as the major products from the thermal decomposition
of isoxazole.12 In an attempt to isolate isoxazole 27, the reaction temperature was lowered to 60 °C,
however, an inseperable mixture of isoxazole 27 and nitrile 28 was obtained in a ratio of 71:29,
respectively, as determined by LC-MS. However, conducting the reaction at rt for 24 h yielded 27 in 43%
yield with no formation of nitrile 28.
While reaction of 1 with a substituted alkenyl boronic acid yielded vinylic compound 29 in 66% yield,
alkyl boronic acids failed to react under our general conditions. Reactions with methylboronic acid,
2-methylpropylboronic acid, phenethylboronic acid and cyclopropylboronic acid resulted in no product as
determined by LC-MS. Using conditions previously described as optimal for the coupling of
cyclopropylboronic acid with aryl bromides ((Pd(OAc)2, tricyclohexylphosphine, toluene, H2O, K3PO4,
100 °C)13 resulted in no reaction after 3 h. Prolonged heating for 24-48 h with excess cyclopropylboronic
acid (3 eq.), Pd(OAc)2, (20 mol%) and tricyclohexylphosphine (0.2 eq.) resulted in an inseparable mixture
of unreacted starting material 1, product and deiodinated reduced material.

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Although Stille coupling accomplishes similar transformations to Suzuki coupling, they complement each
other through the availability of respective starting materials and hence expand the scope of products that
may be obtained in one-step reactions. Our initial attempts of Stille coupling aryl tin compounds with 1 or
even Boc-protected 1 were unsuccessful and resulted in significant protodestannylation as well as
Table 2. Stille coupling of 1
compound
30
R
conditions
yield (%)
100 °C, 18 h
42
31
32
100 °C, 18 h
100 °C, 18 h
48
33
33
100 °C, 18 h
46
34
35
90 °C, 18 h
90 °C, 18 h
78
64
36
90 °C, 18 h
31
37
38
90 °C, 18 h
90 °C, 18 h
68
72

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unreacted starting material, with only very minor amount of product detectable. However, the addition of
LiCl to the reaction resulted in smooth conversion to product with no detectable protodestannylation and
was the key to the success of this reaction. LiCl is commonly used to promote Stille couplings14,15 and is
believed to function through the exchange of chloride ion with the coordinated iodide ion in the oxidative
addition product. The resulting chloro complex facilitates transmetalation with arylstannane through the
formation of stable Bu3SnCl. The general conditions we adopted ((n-Bu)3SnR (4 eq.), LiCl (2 eq.),
Pd(PPh3)4 (10-20 mol%), DMF, 90-100 °C, 18 h) were used to prepare a number of 5- and 6-membered
aromatics as well as the vinyl and allyl derivatives (Table 2). In order to demonstrate the usefulness of
Stille coupling and to expand the diversity of our library, the compounds formed (Table 2) were chosen to
be distinct from those produced by Suzuki coupling (Table 1).
The 4-benzyloxy and 4-morpholine substituted phenyl derivatives 30 and 31, respectively, as well as
pyrimidine 32 and pyrazine 33 were obtained by reaction with respective tri-n-butyltin compounds in
moderate yields. Other heterocycles including oxazole 34, thiazole 35, and imidazole 36 were similarly
prepared. The vinyl and allyl groups can also be added through Stille coupling by reaction with
tri-n-butylvinyltin or tri-n-butylallyltin to give 37 or 38, respectively. Although Stille and Suzuki
reactions complement each other well, a major disadvantage of the Stille reaction is the use of toxic
organotin compounds. In comparison to the boronic acids used in Suzuki coupling, organotin compounds
are much more toxic and must be handled with great care.
Our general conditions for Heck coupling consisted of heating a mixture of purine 1 with alkene (1.1-20
eq.), Pd(PPh3)4 (10-20 mol%) and N,N-diisopropylethylamine (1.2-2 eq.) in NMP at 55-100 °C for 20-24
h (Table 3). Reaction with methyl acrylate and acrylonitrile yielded the trans-substituted products 39 and
40, respectively. As expected, reaction with each of the cyclic alkenes occurred with migration of the
double bond.16,17 The major isolatable product obtained from the reaction with cyclopentene is the
2,3-alkene 41, whereas in the reaction with 2,5-dihydrofuran, the double bond flips to the 2,3-position to
give 42. In the case of the unsymmetrical alkenes, enol ether 2,3-dihydrofuran and N-protected enamine
2,3-dihydropyrrole, reaction occurs at the carbon adjacent to the heteroatom. 43 was obtained as the
major product from reaction with 2,3-dihydrofuran, while reaction with N-Boc-2,3-dihydropyrrole results
in the double bond flipping to the 3,4-position of the pyrrolidine ring, yielding 44 as the major product
following deprotection.
1 can also undergo the Sonogashira reaction with a variety of alkynes without protection of the amine in
moderate to good yields (Table 4). Our general conditions consisted of heating a mixture of purine 1 with
alkyne (2-2.5 eq.), PdCl2(PPh3)2 (15 mol%), CuI (0.5 eq.) and triethylamine (5 eq.) in DMF at 90-100 °C
for 24 h (Table 4). The unsubstituted alkyne derivative 45 was prepared from trimethylsilanylacetylene

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99
Table 3. Heck coupling of 1
compound
39
R
conditions
yield (%)
100 °C, 24 h
35
40
41
42
43
100 °C, 24 h
100 °C, 20 h
55 °C, 20 h
55 °C, 20 h
100 °C, 20 h
51
35a
19b
26c
23d
44
a. from cyclopentene
b. from 2,5-dihydrofuran
c. from 2,3-dihydrofuran
d. from N-Boc-2,3-dihydro-1H-pyrrole
following removal of the trimethylsilyl group. Other acetylene derivatives of 1 obtained in moderate to
good yields using our general conditions include n-butyl 46, t-butyl 47, cyclopentyl 48, cyclohexyl 49 and
phenyl 50.
CONCLUSION
WehaveshownthatPd-catalyzedcross-couplingreactions can be used to prepare a library of derivatives of
PU-H71 (1) in a single step with commercially available reagents. These reactions occur on an “advanced
intermediate” without the need of protecting groups and enable for late stage introduction of chemical
diversity to generate a focused library of 6’-substituted 8-(benzo[d][1,3]dioxol-5-yl)thio purines. Suzuki

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Table 4. Sonogashira coupling of 1
compound
45
R
conditions
yield (%)
H
90 °C, 24 h
69a
46
47
48
49
50
100 °C, 24 h
90 °C, 24 h
100 °C, 24 h
100 °C, 24 h
100 °C, 24 h
66
77
55
46
61
a. from trimethylsilylacetylene
and Stille coupling were used to introduce a variety of aryl or alkenyl groups to 1. Heck coupling enabled
for the reaction with a variety of olefins, while Sonogashira coupling was used to introduce a variety of
alkynes. In general, Suzuki coupling occurred with smooth conversion to the desired product and only in
the case of 4-isoxazoleboronic acid pinacol ester was the expected product 27 not isolated using the
general conditions. However, performing the reaction at rt allowed for the isolation of 27 and prevented
its decomposition to nitrile 28. In the case of Stille coupling, the addition of LiCl was found to be
essential for the success of the reaction by enabling efficient transmetalation. The wide variety and ready
availability of boronic acids, as well as their non-toxic nature, has made Suzuki coupling the most useful
reaction of those reported here to construct the library of substituted purines in a single step from PU-H71
(1). Because of the significance of 1 as a potent Hsp90 inhibitor which has entered clinical trials as an

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anticancer agent,8 we believe that this library has significant value for biological investigations which
Hsp90 has been associated with.
EXPERIMENTAL
GENERAL METHODS
13
1H and C NMR spectra were recorded on a Bruker 500 or 600 MHz instrument. Chemical shifts are
reported in δ values in ppm downfield from TMS as the internal standard. 1H data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),
13
coupling constant (Hz), integration. C chemical shifts are reported in δ values in ppm downfield from
TMS as the internal standard. High resolution mass spectra (HRMS) were recorded on a Waters LCT
Premier system. Low resolution mass spectra were obtained on a Waters Acquity Ultra Performance LC
with electrospray ionization and SQ detector. High-performance liquid chromatography analyses were
performed on a Waters Autopurification system with PDA, MicroMass ZQ, and ELSD detector, and a
reversed phase column (Waters X-Bridge C18, 4.6 x 150 mm, 5 µm) using a gradient of; method A (a)
H2O + 0.1% TFA and (b) CH3CN + 0.1% TFA, 5 to 95% b over 10 min at 1.2 mL/min; method B (a)
H2O + 0.1% TFA and (b) CH3CN + 0.1% TFA, 20 to 90% b over 16 min at 1.0 mL/min. PU-H71 was
prepared as previously reported.18 All reagents were purchased from Aldrich, Acros, Combi-blocks or
Frontier Scientific.
SUZUKI-MIYAURA COUPLING
General conditions. Boronic acid or pinacol ester (1.5-3 eq.) was added to 1 (30 mg, 0.0585 mmol, 1
eq.) and NaHCO3 (3 eq.) in a 10 mL RBF equipped with a magnetic stir bar and rubber septum. DMF (0.5
mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated
four times then nitrogen was bubbled through the reaction mixture for 10 min. Then H2O (0.1 mL) and
PdCl2(PPh3)2 (10-20 mol%) were added and the reaction mixture was heated under nitrogen at 90 °C for
2-24 h. Solvent was removed under reduced pressure and the resulting residue was purified by
preparatory TLC to yield compounds 3-26, 28 and 29. 27 was obtained by performing the reaction at rt as
is described below.
9-(3-(Isopropylamino)propyl)-8-(6-phenylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (3). 1H
NMR (500 MHz, MeOH-d4) δ 8.14 (s, 1H), 7.28-7.34 (m, 3H), 7.17-7.21 (m, 2H), 7.12 (s, 1H), 6.90 (s,
1H), 6.09 (s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.27 (septet, J = 6.6 Hz, 1H), 2.72 (t, J = 6.6 Hz, 2H), 2.13 (m,
2H), 1.40 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 156.0, 153.4, 152.1, 151.1, 150.3, 149.4,
142.3, 141.8, 130.4, 129.1, 128.7, 120.3, 119.8, 115.7, 112.2, 103.8, 52.2, 43.2, 41.1, 27.6, 19.3; HRMS
(ESI) m/z [M+H]+ calcd. for C24H27N6O2S, 463.1916; found 463.1905; HPLC: method A Rt = 6.50,

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method B Rt = 7.40.
8-(6-(4-tert-Butylphenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (4). 1H NMR (500 MHz, MeOH-d4) δ 8.11 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7.12 (d,
J = 8.4 Hz, 2H), 6.86 (s, 1H), 6.06 (s, 2H), 3.93 (t, J = 6.9 Hz, 2H), 2.92 (septet, J = 6.5 Hz, 1H), 2.61 (t,
J = 7.3 Hz, 2H), 1.86 (m, 2H), 1.28 (s, 9H), 1.12 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ
155.9, 153.3, 151.9, 151.8, 150.9, 150.2, 149.2, 141.9, 138.8, 130.0, 125.9, 120.4, 120.3, 115.4, 112.3,
103.6, 50.6, 44.0, 41.8, 35.4, 31.8, 29.3, 21.1; HRMS (ESI) m/z [M+H]+ calcd. for C28H35N6O2S, 519.
2542; found 519.2545; HPLC: method A Rt = 7.43, method B Rt = 9.45.
9-(3-(Isopropylamino)propyl)-8-(6-(4-methoxyphenyl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-
amine (5). 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.95 (s, 1H), 6.86 (d, J =
8.7 Hz, 2H), 6.82 (s, 1H), 6.00 (s, 2H), 5.92 (br s, 2H), 4.01 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 2.75 (septet,
13
J = 6.3 Hz, 1H), 2.43 (t, J = 6.7 Hz, 2H), 1.85 (m, 2H), 1.07 (d, J = 6.3 Hz, 6H); C NMR (125 MHz,
CDCl3) δ 159.2, 154.3, 152.5, 151.5, 148.6, 147.8, 147.5, 139.0, 132.5, 130.4, 120.6, 119.8, 113.5, 113.0,
111.0, 101.8, 55.3, 49.1, 43.2, 40.9, 29.2, 22.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H29N6O3S,
493.2022; found 493.2010; HPLC: method A Rt = 6.57, method B Rt = 7.55.
9-(3-(Isopropylamino)propyl)-8-(6-(3-methoxyphenyl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-
1
amine (6). H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.73-6.81
(m, 3H), 6.70 (s, 1H), 5.93 (s, 2H), 5.82 (br s, 2H), 3.91 (t, J = 6.9 Hz, 2H), 3.63 (s, 3H), 2.59 (septet, J =
6.2 Hz, 1H), 2.32 (t, J = 6.8 Hz, 2H), 1.66-1.75 (m, 2H), 0.93 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 159.9, 154.9, 153.2, 152.1, 149.2, 148.3, 142.1, 139.8, 129.7, 122.3, 121.4, 120.5, 115.5, 113.9,
111.5, 102.6, 55.8, 49.4, 44.2, 41.8, 30.5, 23.4; HRMS (ESI) m/z [M+H]+ calcd. for C25H29N6O3S,
493.2022; found 493.2036.
8-(6-(2,3-Dimethoxyphenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (7). 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 6.88-6.94 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.74
(s, 1H), 6.62 (d, J = 7.5 Hz, 1H), 5.92 (s, 2H), 5.88 (br s, 2H), 3.75-4.05 (m, 2H), 3.82 (s, 3H), 3.54 (s,
3H), 2.59 (septet, J = 6.2 Hz, 1H), 2.30 (t, J = 6.6 Hz, 2H), 1.64-1.74 (m, 2H), 0.93 (d, J = 6.1 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 155.0, 153.4, 153.2, 152.2, 148.8, 148.4, 148.3, 147.3, 135.5, 134.9, 124.3,
123.3, 122.9, 120.5, 113.5, 112.9, 111.6, 102.5, 61.4, 56.5, 49.4, 44.2, 41.7, 30.4, 23.3; HRMS (ESI) m/z
[M+H]+ calcd. for C26H31N6O4S, 523.2128; found 523.2107.
8-(6-(4-(Dimethylamino)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-
1
purin-6-amine (8). H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.93 (s, 1H),
6.83 (s, 1H), 6.67 (d, J = 8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J = 6.7 Hz, 2H), 2.97 (s, 6H),
2.78 (septet, J = 6.3 Hz, 1H), 2.44 (t, J = 6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J = 6.3 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 154.4, 152.4, 151.5, 149.9, 148.5, 148.0, 147.1, 139.6, 130.0, 127.8, 120.5, 119.7,

HETEROCYCLES, Vol. 87, No. 1, 2013
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112.8, 111.7, 111.0, 101.7, 49.3, 43.1, 40.9, 40.4, 28.9, 21.9; HRMS (ESI) m/z [M+H]+ calcd. for
C26H32N7O2S, 506.2338; found 506.2330; HPLC: method A Rt = 5.72, method B Rt = 5.12.
4-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)benzalde-
hyde (9). 1H NMR (500 MHz, MeOH-d4) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.47 (d,
J = 8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.13 (s, 2H), 4.05 (t, J = 6.8 Hz, 2H), 2.99 (septet, J = 6.4 Hz,
1H), 2.62 (t, J = 6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J = 6.4 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ
192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0, 117.7, 115.0,
110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H27N6O3S, 491.1865;
found 491.1877; HPLC: method A Rt = 6.23, method B Rt = 6.83.
8-(6-(4-Bromophenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine
(10). 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.01
(s, 1H), 6.81 (s, 1H), 6.05 (s, 2H), 5.69 (br s, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.91 (m, 1H), 2.50 (t, J = 5.9
Hz, 2H), 1.98 (m, 2H), 1.20 (d, J = 6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.0,
151.2, 149.8, 149.1, 148.2, 139.8, 139.1, 131.2, 131.0, 122.0, 119.0, 117.9, 115.0, 111.1, 102.4, 50.1, 42.1,
40.2, 27.3, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C24H26BrN6O2S, 541.1021/543.1001; found
541.1016/543.1004; HPLC: method A Rt = 6.93, method B Rt = 8.30.
3-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)benzo-
nitrile (11). 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.55 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45 (d, J
= 7.9 Hz, 1H), 7.31-7.36 (m, 1H), 6.95 (s, 1H), 6.73 (s, 1H), 5.97 (s, 2H), 5.74 (br s, 2H), 3.97 (t, J = 6.9
Hz, 2H), 2.63 (septet, J = 6.2 Hz, 1H), 2.39 (t, J = 6.7 Hz, 2H), 1.72-1.81 (m, 2H), 0.96 (d, J = 6.3 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 154.8, 153.2, 152.2, 149.8, 149.0, 148.0, 142.0, 138.0, 134.4, 133.6,
131.8, 129.5, 120.8, 120.5, 119.1, 114.8, 112.9, 111.4, 102.9, 49.5, 44.1, 41.8, 30.4, 23.3; HRMS (ESI)
m/z [M+H]+ calcd. for C25H26N7O2S, 488.1869; found 488.1878.
9-(3-(Isopropylamino)propyl)-8-(6-(3-nitrophenyl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
1
(12). H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7.5
Hz, 1H), 7.37-7.43 (m, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 5.99 (s, 2H), 5.77 (br s, 2H), 3.97 (t, J = 6.7 Hz,
2H), 2.60 (septet, J = 6.1 Hz, 1H), 2.37 (t, J = 6.6 Hz, 2H), 1.70-1.80 (m, 2H), 0.94 (d, J = 6.2 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 154.8, 153.2, 152.2, 149.9, 149.1, 148.5, 148.0, 142.3, 138.0, 136.1, 129.6,
125.1, 123.1, 120.7, 120.4, 115.0, 111.4, 102.9, 49.5, 44.1, 41.8, 30.5, 23.2; HRMS (ESI) m/z [M+H]+
calcd. for C24H26N7O4S, 508.1767; found 508.1772.
9-(3-(Isopropylamino)propyl)-8-(6-(3-(trifluoromethyl)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9H-
1
purin-6-amine (13). H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.45-7.51 (m, 2H), 7.32-7.40 (m, 2H),
6.99 (s, 1H), 6.76 (s, 1H), 5.98 (s, 2H), 5.70 (br s, 2H), 3.91 (t, J = 6.9 Hz, 2H), 2.60 (septet, J = 6.3 Hz,
1H), 2.34 (t, J = 6.7 Hz, 2H), 1.68-1.76 (m, 2H), 0.94 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ

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154.8, 153.2, 152.2, 149.7, 148.8, 148.2, 141.5, 138.9, 133.3, 131.1 (q, J = 33 Hz), 129.1, 126.8 (q, J = 4
Hz), 125.0 (q, J = 4 Hz) 124.6 (q, J = 271 Hz), 120.9, 120.4, 114.8, 111.6, 102.8, 49.5, 44.1, 41.7, 30.4,
23.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H26F3N6O2S, 531.1790; found 531.1780.
8-(6-(3,5-Bis(trifluoromethyl)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-
1
9H-purin-6-amine (14). H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.79 (s, 3H), 7.12 (s, 1H), 6.86 (s,
1H), 6.09 (s, 2H), 5.71 (br s, 2H), 4.07 (t, J = 6.6 Hz, 2H), 2.82 (septet, J = 6.2 Hz, 1H), 2.49 (t, J = 6.5
13
Hz, 2H), 1.95 (m, 2H), 1.12 (d, J = 6.3 Hz, 6H); C NMR (125 MHz, CDCl3) δ 154.1, 152.3, 151.5,
149.6, 148.6, 147.5, 142.1, 137.2, 131.2 (q, J = 33 Hz), 129.6, 123.1 (q, J = 270 Hz), 121.3, 119.6, 119.4,
114.9, 110.8, 102.4, 49.5, 42.8, 40.6, 28.8, 21.7; HRMS (ESI) m/z [M+H]+ calcd. for C26H25F6N6O2S,
599.1664; found 599.1653; HPLC: method A Rt = 7.45, method B Rt = 9.38.
8-(6-(4-(Aminomethyl)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-
purin-6-amine (15). 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0
Hz, 2H), 6.91 (s, 1H), 6.75 (s, 1H), 5.95 (s, 2H), 5.59 (br s, 2H), 3.90 (t, J = 6.9 Hz, 2H), 3.81 (s, 2H),
13
2.60 (septet, J = 6.3 Hz, 1H), 2.33 (t, J = 6.8 Hz, 2H), 1.65-1.74 (m, 2H), 0.94 (d, J = 6.2 Hz, 6H); C
NMR (125 MHz, CDCl3) δ 154.9, 153.3, 152.2, 149.2, 148.29, 148.26, 143.4, 139.7, 139.3, 130.1, 127.5,
121.4, 120.6, 113.8, 111.6, 102.6, 49.4, 46.8, 44.2, 41.9, 30.5, 23.3; HRMS (ESI) m/z [M+H]+ calcd. for
C25H30N7O2S, 492.2182; found 492.2170.
From above reaction 4.8 mg (17%) of N-formyl derivative of 15 was also obtained.
N-(4-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)benzyl)
1
formamide. H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.15 (s, 1H), 7.11 (d, J = 7.9 Hz, 2H), 7.08 (s,
1H), 7.02 (d, J = 7.9 Hz, 2H), 6.73 (s, 1H), 5.98 (s, 2H), 5.59 (br s, 2H), 4.40 (d, J = 6.0 Hz, 2H), 3.73 (t,
J = 6.8 Hz, 2H), 2.75 (septet, J = 6.3 Hz, 1H), 2.37 (t, J = 6.8 Hz, 2H), 1.64-1.73 (m, 2H), 1.04 (d, J = 6.3
13
Hz, 6H); C NMR (125 MHz, CDCl3) δ 162.0, 154.9, 153.0, 151.8, 149.7, 148.9, 148.3, 140.4, 140.2,
138.3, 130.2, 128.2, 121.0, 120.5, 115.2, 111.7, 102.7, 50.0, 43.7, 42.3, 41.5, 29.7, 22.6; HRMS (ESI) m/z
[M+H]+ calcd. for C26H30N7O3S, 520.2131; found 520.2145.
9-(3-(Isopropylamino)propyl)-8-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
1
(16). H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.53 (dd, J = 1.6, 4.8 Hz, 2H), 8.19 (s, 1H), 7.25 (dd, J =
1.6, 4.5 Hz, 2H), 7.11 (s, 1H), 6.89 (s, 1H), 6.11 (s, 2H), 4.07 (t, J = 6.8 Hz, 2H), 2.82 (m, 1H), 2.51 (t, J
13
= 6.8 Hz, 2H), 1.91 (m, 2H), 1.13 (d, J = 6.3 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.1,
152.0, 151.2, 150.0, 148.90, 148.85, 148.69, 137.9, 124.5, 119.1, 117.7, 115.3, 110.6, 102.5, 49.2, 42.8,
40.7, 28.4, 21.2; HRMS (ESI) m/z [M+H]+ calcd. for C23H26N7O2S, 464.1869; found 464.1848; HPLC:
method A Rt = 5.13, method B Rt = 2.57.
9-(3-(Isopropylamino)propyl)-8-(6-(thiophen-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
1
(17). H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.33 (dd, J = 1.4, 4.9 Hz, 1H), 7.07 (s, 1H),

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7.04 (s, 1H), 7.00-7.02 (m, 2H), 6.09 (s, 2H), 4.12 (t, J = 6.6 Hz, 2H), 2.95 (septet, J = 6.6 Hz, 1H), 2.62
13
(t, J = 6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J = 6.6 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ
154.2, 152.0, 151.1, 149.4, 148.8, 148.4, 140.5, 132.9, 127.8, 126.9, 126.3, 119.2, 119.0, 114.6, 111.8,
102.3, 49.6, 42.5, 40.6, 27.8, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O2S2, 469.1480; found
469.1461; HPLC: method A Rt = 6.38, method B Rt = 7.18.
8-(6-(Furan-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (18).
1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H),
6.71 (d, J = 3.3 Hz, 1H), 6.47 (dd, J = 1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J = 7.0 Hz, 2H), 2.87 (m,
1H), 2.61 (t, J = 6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz,
CDCl3/MeOH-d4) δ 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5,
111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S,
453.1709; found 453.1705; HPLC: method A Rt = 6.23, method B Rt = 6.82.
9-(3-(Isopropylamino)propyl)-8-(6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-
1
amine (19). H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.19 (s, 1H), 6.84 (s, 1H), 6.63 (d, J = 3.1 Hz,
1H), 6.07 (d, J = 2.5 Hz, 1H), 5.98 (s, 2H), 5.93 (br s, 2H), 4.22 (t, J = 6.6 Hz, 2H), 2.94 (m, 1H), 2.59 (t,
J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.05 (m, 2H), 1.20 (d, J = 6.3 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for
C23H27N6O3S, 467.1865; found 467.1869; HPLC: method A Rt = 6.49, method B Rt = 7.53.
5-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)furan-2-
1
carbaldehyde (20). H NMR (500 MHz, CDCl3/MeOH-d4) δ 9.57 (s, 1H), 8.18 (s, 1H), 7.36 (d, J = 3.8
Hz, 1H), 7.32 (s, 1H), 7.07 (s, 1H), 6.98 (d, J = 3.8 Hz, 1H), 6.12 (s, 2H), 4.32 (t, J = 6.7 Hz, 2H), 3.31
(septet, J = 6.6 Hz, 1H), 2.93 (t, J = 6.8 Hz, 2H), 2.30 (m, 2H), 1.42 (d, J = 6.6 Hz, 6H); 13C NMR (125
MHz, CDCl3/MeOH-d4) δ 177.5, 156.8, 154.5, 152.2, 151.9, 151.4, 150.1, 149.7, 148.1, 127.5, 124.3,
119.2, 118.7, 115.7, 112.7, 109.9, 102.9, 51.3, 41.8, 40.4, 26.4, 19.2; HRMS (ESI) m/z [M+H]+ calcd. for
C23H25N6O4S, 481.1658; found 481.1657; HPLC: method A Rt = 5.87, method B Rt = 5.93.
8-(6-(Furan-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (21).
1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.07 (s, 1H), 6.97 (s,
1H), 6.49 (s, 1H), 6.08 (s, 2H), 4.17 (t, J = 6.9 Hz, 2H), 2.93 (septet, J = 6.4 Hz, 1H), 2.64 (t, J = 7.1 Hz,
2H), 2.02 (m, 2H), 1.17 (d, J = 6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.1, 151.8, 151.0,
149.7, 149.0, 147.8, 142.6, 140.4, 131.7, 124.2, 118.9, 117.8, 114.8, 111.5, 110.7, 102.1, 49.2, 42.6, 40.6,
28.0, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found 453.1711; HPLC: method
A Rt = 6.18, method B Rt = 6.67.
8-(6-(1H-Pyrrol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine
(22). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.88 (m, 1H), 6.27
(m, 1H), 6.21 (m, 1H), 6.03 (s, 2H), 4.17 (t, J = 6.8 Hz, 2H), 3.29 (septet, J = 6.6 Hz, 1H), 2.80 (t, J = 6.7

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Hz, 2H), 2.15 (m, 2H), 1.41 (d, J = 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C22H26N7O2S,
452.1869; found 452.1872; HPLC: method A Rt = 6.13, method B Rt = 6.43.
8-(6-(1H-Pyrrol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine
(23). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.16 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 6.86 (m, 1H), 6.76
(m, 1H), 6.21 (m, 1H), 6.02 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H), 2.95 (septet, J = 6.4 Hz, 1H), 2.59 (t, J = 7.1
Hz, 2H), 1.96 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.4, 152.1,
152.0, 151.0, 149.4, 146.7, 135.9, 131.6, 122.1, 119.1, 117.8, 117.5, 114.6, 111.0, 109.2, 101.9, 53.6, 42.6,
40.6, 27.8, 20.6; HRMS (ESI) m/z [M+H]+ calcd. for C22H26N7O2S, 452.1869; found 452.1862; HPLC:
method A Rt = 6.02, method B Rt = 6.27.
8-(6-(1H-Pyrazol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (24). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H),
7.07 (s, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.08 (s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.31 (septet, J = 6.6 Hz, 1H),
2.89 (t, J = 7.2 Hz, 2H), 2.10 (m, 2H), 1.39 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ
154.5, 152.2, 152.1, 150.7, 149.5, 148.5, 148.3, 119.3, 119.1, 114.6, 114.5, 111.0, 110.9, 106.1, 102.3,
51.1, 41.7, 40.3, 26.0, 18.7; HRMS (ESI) m/z [M+H]+ calcd. for C21H25N8O2S, 453.1821; found
453.1826; HPLC: method A Rt = 5.65, method B Rt = 4.83.
8-(6-(1H-Pyrazol-4-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (25). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.58 (s, 2H), 7.10 (s, 1H), 6.95 (s, 1H),
6.06 (s, 2H), 4.08 (t, J = 6.9 Hz, 2H), 2.89 (septet, J = 6.4 Hz, 1H), 2.57 (t, J = 7.2 Hz, 2H), 1.91 (m, 2H),
13
1.14 (d, J = 6.4 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.0, 152.1, 151.2, 149.7, 148.9,
147.5, 133.6, 132.0, 119.8, 119.1, 117.9, 115.3, 110.9, 102.1, 49.2, 42.9, 40.8, 28.3, 21.3; HRMS (ESI)
m/z [M+H]+ calcd. for C21H25N8O2S, 453.1821; found 453.1819; HPLC: method A Rt = 5.60, method B
Rt = 4.87.
9-(3-(Isopropylamino)propyl)-8-(6-(1-methyl-1H-pyrazol-5-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-
1
purin-6-amine (26). H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.05 (s, 1H),
6.80 (s, 1H), 6.08 (s, 2H), 6.06 (d, J = 1.8 Hz, 1H), 5.91 (br s, 2H), 4.10 (t, J = 6.7 Hz, 2H), 3.67 (s, 3H),
2.85 (septet, J = 6.3 Hz, 1H), 2.53 (t, J = 6.7 Hz, 2H), 1.97 (m, 2H), 1.13 (d, J = 6.3 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 154.4, 152.7, 151.7, 149.3, 149.0, 147.0, 140.6, 138.5, 127.7, 123.3, 120.0, 113.8,
111.7, 107.4, 102.5, 49.6, 43.2, 41.1, 37.1, 29.1, 22.0; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N8O2S,
467.1978; found 467.1985; HPLC: method A Rt = 5.74, method B Rt = 5.20.
9-(3-(Isopropylamino)propyl)-8-(6-(isoxazol-4-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
(27). 4-Isoxazoleboronic acid pinacol ester (34.2 mg, 0.1755 mmol) was added to 1 (30 mg, 0.0585
mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was
evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through

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the reaction mixture for 10 min. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added
and the reaction mixture was stirred at rt for 24 h. Solvent was removed under reduced pressure and the
resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 4:7:2:1) to
1
give 11.5 mg (43%) of 27. H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s,
1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.13 (s, 2H), 4.37 (t, J = 7.0 Hz, 2H), 3.27 (septet, J = 7.1 Hz, 1H), 2.89 (t,
J = 7.1 Hz, 2H), 2.22 (m, 2H), 1.38 (d, J = 6.5 Hz, 6H); MS (ESI) m/z [M+H]+ 454.1; HPLC: method A
Rt = 5.87; method B Rt = 5.57.
2-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)acetonitrile
(28). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.10 (s, 2H), 4.35
(t, J = 6.9 Hz, 2H), 3.99 (s, 2H), 3.08 (septet, J = 6.5 Hz, 1H), 2.82 (t, J = 7.0 Hz, 2H), 2.25 (m, 2H), 1.27
13
(d, J = 6.5 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.1, 152.0, 151.5, 150.8, 148.6,
147.7, 129.5, 119.2, 117.6, 116.2, 110.3, 102.7, 49.8, 42.5, 40.7, 27.7, 22.9, 20.4; HRMS (ESI) m/z
[M+H]+ calcd. for C20H24N7O2S, 426.1712; found 426.1712; HPLC: method A Rt = 5.69, method B Rt =
4.57.
9-(3-(Isopropylamino)propyl)-8-(6-(3-methylbut-2-en-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-
1
6-amine (29). H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.22 (s, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 5.99 (s,
2H), 4.24 (t, J = 6.8 Hz, 2H), 2.77 (septet, J = 6.2 Hz, 1H), 2.54 (t, J = 6.8 Hz, 2H), 2.02 (m, 2H), 1.85 (s,
3H), 1.74 (s, 3H), 1.36 (s, 3H), 1.09 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.3,
152.3, 151.3, 149.0, 148.5, 147.2, 142.3, 130.7, 128.2, 119.3, 119.1, 112.6, 110.1, 101.9, 43.2, 41.1, 29.2,
21.9, 21.8, 20.1, 19.9; HRMS (ESI) m/z [M+H]+ calcd. for C23H31N6O2S, 455.2229; found 455.2215;
HPLC: method A Rt = 6.66, method B Rt = 8.07.
STILLE COUPLING
General conditions. A mixture of 1 (30 mg, 0.0585 mmol, 1 eq.), (n-Bu)3SnR (4 eq.), LiCl (2 eq.) and
Pd(PPh3)4 (10-20 mol%) in DMF (1 mL) in a 10 mL RBF equipped with a magnetic stir bar and rubber
septum was evacuated and back filled with nitrogen. This was repeated four times then the reaction
mixture was heated under nitrogen at 90-100 °C for 18 h. Solvent was removed under reduced pressure
and the resulting residue was purified by preparatory TLC to yield compounds 30-38.
8-(6-(4-(Benzyloxy)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (30). 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H),
7.36 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.93-6.98 (m, 3H), 6.84 (s, 1H), 6.02 (s, 2H), 5.79 (br s,
2H), 5.09 (s, 2H), 4.03 (t, J = 6.7 Hz, 2H), 2.73 (septet, J = 6.1 Hz, 1H), 2.44 (t, J = 6.6 Hz, 2H),
13
1.79-1.88 (m, 2H), 1.06 (d, J = 6.2 Hz, 6H); C NMR (125 MHz, CDCl3) δ 159.1, 154.9, 153.2, 152.2,
149.2, 148.4, 148.1, 139.6, 137.5, 133.4, 131.1, 129.3, 128.7, 128.2, 121.2, 120.5, 115.0, 113.7, 111.7,

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HETEROCYCLES, Vol. 87, No. 1, 2013
102.5, 70.7, 49.6, 44.0, 41.7, 30.2, 23.1; HRMS (ESI) m/z [M+H]+ calcd. for C31H33N6O3S, 569.2335;
found 569.2352.
9-(3-(Isopropylamino)propyl)-8-(6-(4-morpholinophenyl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-
amine (31). 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 6.87 (d, J
= 8.5 Hz, 2H), 6.84 (s, 1H), 6.01 (s, 2H), 5.81 (br s, 2H), 4.02 (t, J = 6.8 Hz, 2H), 3.85-3.92 (m, 4H),
3.16-3.24 (m, 4H), 2.71 (septet, J = 6.2 Hz, 1H), 2.43 (t, J = 6.7 Hz, 2H), 1.78-1.86 (m, 2H), 1.04 (d, J =
6.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.9, 153.2, 152.2, 151.2, 149.2, 148.4, 148.0, 139.7, 132.0,
130.8, 121.4, 120.5, 115.4, 113.6, 111.6, 102.5, 67.5, 49.56, 49.51, 44.1, 41.8, 30.3, 23.2; HRMS (ESI)
m/z [M+H]+ calcd. for C28H34N7O3S, 548.2444; found 548.2454.
9-(3-(Isopropylamino)propyl)-8-(6-(pyrimidin-5-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
1
(32). H NMR (600 MHz, CDCl3) δ 9.07 (s, 1H), 8.68 (s, 2H), 8.17 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H),
6.05 (s, 2H), 5.45 (br s, 2H), 4.07 (t, J = 6.7 Hz, 2H), 2.68-2.77 (m, 1H), 2.45 (t, J = 6.6 Hz, 2H),
13
1.80-1.88 (m, 2H), 1.04 (d, J = 6.0 Hz, 6H); C NMR (150 MHz, CDCl3) δ 157.6, 156.7, 153.9, 152.3,
151.7, 149.9, 149.0, 147.8, 134.1, 133.4, 119.7, 119.5, 115.6, 110.8, 102.5, 49.3, 43.1, 40.9, 29.7, 22.1;
HRMS (ESI) m/z [M+H]+ calcd. for C22H25N8O2S, 465.1821; found 465.1820.
9-(3-(Isopropylamino)propyl)-8-(6-(pyrazin-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
(33). 1H NMR (600 MHz, CDCl3) δ 8.79 (d, J = 1.5 Hz, 1H), 8.56 (dd, J = 1.5, 2.5 Hz, 1H), 8.46 (d, J =
2.5 Hz, 1H), 8.21 (s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 5.98 (s, 2H), 5.74 (br s, 2H), 4.05 (t, J = 7.0 Hz, 2H),
13
2.60 (septet, J = 6.2 Hz, 1H), 2.38 (t, J = 6.8 Hz, 2H), 1.72-1.80 (m, 2H), 0.94 (d, J = 6.2 Hz, 6H); C
NMR (150 MHz, CDCl3) δ 154.3, 153.2, 152.8, 151.6, 149.2, 148.9, 147.2, 145.2, 143.4, 143.0, 133.9,
122.2, 119.9, 113.6, 110.4, 102.3, 48.8, 43.7, 41.4, 30.0, 22.8; HRMS (ESI) m/z [M+H]+ calcd. for
C22H25N8O2S, 465.1821; found 465.1798.
9-(3-(Isopropylamino)propyl)-8-(6-(oxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (34).
1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.25 (s, 1H), 7.75 (s, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 6.71 (s,
1H), 6.06 (s, 2H), 4.26 (t, J = 6.9 Hz, 2H), 2.75 (septet, J = 6.3 Hz, 1H), 2.53 (t, J = 6.9 Hz, 2H), 1.98 (m,
2H), 1.06 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 160.0, 154.7, 152.8, 151.3, 150.1,
148.5, 146.8, 139.0, 128.3, 123.7, 122.3, 120.0, 112.1, 109.7, 102.7, 43.2, 41.5, 29.3, 22.0; HRMS (ESI)
m/z [M+H]+ calcd. for C21H24N7O3S, 454.1661; found 454.1650; HPLC: method A Rt = 5.77, method B
Rt = 5.28.
9-(3-(Isopropylamino)propyl)-8-(6-(thiazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine
(35). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.20 (s, 1H), 7.87 (d, J = 3.3 Hz, 1H), 7.45 (s, 1H), 7.44 (d,
J = 3.3 Hz, 1H), 6.98 (s, 1H), 6.11 (s, 2H), 4.21 (t, J = 6.9 Hz, 2H), 2.78 (septet, J = 6.3 Hz, 1H), 2.55 (t,
J = 6.9 Hz, 2H), 1.98 (m, 2H), 1.09 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.5,
152.5, 152.4, 151.4, 149.75, 149.69, 148.0, 142.7, 121.13, 121.07, 120.1, 119.4, 114.6, 110.9, 102.9, 43.2,

HETEROCYCLES, Vol. 87, No. 1, 2013
109
41.3, 29.2, 21.9; HRMS (ESI) m/z [M+H]+ calcd. for C21H24N7O2S2, 470.1433; found 470.1438; HPLC:
method A Rt = 5.86, method B Rt = 5.66.
9-(3-(Isopropylamino)propyl)-8-(6-(1-methyl-1H-imidazol-5-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-
purin-6-amine (36). 1H NMR (600 MHz, CDCl3) δ 8.21 (s, 1H), 7.40 (s, 1H), 6.93 (s, 1H), 6.82 (s, 1H),
6.73 (s, 1H), 6.00 (s, 2H), 5.53 (br s, 2H), 4.04 (t, J = 6.8 Hz, 2H), 3.38 (s, 3H), 2.66 (septet, J = 6.2 Hz,
1H), 2.42 (t, J = 6.8 Hz, 2H), 1.76-1.84 (m, 2H), 0.98 (d, J = 6.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ
153.0, 151.7, 150.6, 148.0, 147.5, 145.9, 137.2, 129.2, 128.1, 124.8, 123.6, 118.8, 112.0, 111.1, 101.2,
47.9, 42.5, 40.2, 30.8, 28.6, 21.4; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N8O2S, 467.1978; found
467.1957.
8-(6-Vinylbenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (37). 1H
NMR (CDCl3, 500 MHz) δ 8.29 (s, 1H), 7.23 (dd, J = 17.3, 10.9 Hz, 1H), 7.10 (s, 1H), 6.92 (s, 1H), 5.99
(s, 2H), 5.64 (br s, 2H), 5.61 (d, J = 17.3 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 4.26 (t, J = 7.1 Hz, 2H), 2.73
(septet, J = 6.3 Hz, 1H), 2.57 (t, J = 6.8 Hz, 2H), 1.97 (m, 2H), 1.05 (d, J = 6.3Hz, 6H); 13C NMR (CDCl3,
125 MHz) δ 154.1, 152.6, 148.0, 133.7, 115.7, 113.6, 106.0, 101.9, 48.8, 47.2, 43.8, 41.5, 30.0, 29.7, 22.7,
19.2; MS (ESI) m/z 412.9 [M+H]+.
8-(6-Allylbenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (38). 1H
NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.99 (s, 2H), 5.84-5.91 (m, 1H), 5.59
(br s, 2H), 4.98-5.07 (m, 2H), 4.28 (t, J = 6.9 Hz, 2H), 3.54 (m, 2H), 2.77 (septet, J = 6.3 Hz, 1H), 2.58 (t,
J = 6.8 Hz, 2H), 1.94-2.04 (m, 2H), 1.07 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 154.0, 152.4,
151.9, 147.8, 146.9, 136.9, 136.2, 119.5, 116.6, 113.9, 110.3, 101.7, 48.9, 43.5, 41.2, 38.3, 29.7, 22.5; MS
(ESI) m/z 426.8 [M+H]+.
HECK COUPLING
General conditions. A solution of 1 (30 mg, 0.0585 mmol, 1 eq.) in NMP (1.5 mL) in a 10 mL RBF
equipped with a magnetic stir bar and rubber septum was evacuated and back filled with nitrogen. This
was repeated four times, then N,N-diisopropylethylamine (1.2-2 eq.), alkene (1.1-20 eq.) and Pd(PPh3)4
(10-20 mol%) were added and the reaction mixture was heated under nitrogen at 55-100 °C for 20-24 h.
Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC
to yield compounds 39-43. 44 was similarly prepared and obtained following Boc removal as is described
below.
(E)-Methyl-3-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-
yl)acrylate (39). 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 8.17 (d, J = 15.8 Hz, 1H), 7.14 (s, 1H), 7.03
(s, 1H), 6.27 (d, J = 15.8 Hz, 1H), 6.05 (s, 2H), 5.66 (br s, 2H), 4.37 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H),
13
2.99-3.08 (m, 1H), 2.73 (t, J = 6.5 Hz, 2H), 2.27-2.33 (m, 2H), 1.27 (d, J = 6.1 Hz, 6H); C NMR (125

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HETEROCYCLES, Vol. 87, No. 1, 2013
MHz, CDCl3) δ 167.0, 154.2, 152.5, 151.7, 149.9, 149.7, 147.0, 141.1, 131.6, 123.3, 119.8, 119.0, 114.5,
106.6, 102.4, 51.9, 49.4, 43.2, 41.1, 31.9, 22.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N6O4S,
471.1815; found 471.1808; HPLC: method A Rt = 6.07, method B Rt = 6.39.
(E)-3-(6-(6-Amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d][1,3]dioxol-5-yl)-
acrylonitrile (40). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.94 (d, J = 16.5 Hz, 1H), 7.19
(s, 1H), 7.08 (s, 1H), 6.12 (s, 2H), 5.86 (d, J = 16.5 Hz, 1H), 4.30 (t, J = 6.4 Hz, 2H), 2.88 (m, 1H), 2.68 (t,
J = 6.7 Hz, 2H), 2.27-2.33 (m, 2H), 1.14 (d, J = 6.1 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for
C21H24N7O2S, 438.1712; found 438.1725; HPLC: method A Rt = 5.83, method B Rt = 5.64.
8-(6-(Cyclopent-2-enyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (41). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.16 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 6.01 (s, 2H),
5.98 (m, 1H), 5.63 (m, 1H), 4.41 (t, J = 6.4 Hz, 2H), 3.39 (m, 1H), 3.34 (septet, J = 6.6 Hz, 1H), 2.95 (t, J
13
= 6.4 Hz, 2H), 2.22-2.52 (m, 5H), 1.50-1.59 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H); C NMR (125 MHz,
CDCl3/MeOH-d4) δ 154.3, 151.9, 151.5, 150.7, 149.9, 147.0, 145.6, 133.4, 129.8, 119.1, 116.0, 115.2,
108.5, 102.1, 50.9, 42.2, 41.9, 40.5, 39.9, 29.9, 26.9, 19.6; HRMS (ESI) m/z [M+H]+ calcd. for
C23H29N6O2S, 453.2073; found 453.2064; HPLC: method A Rt = 6.51, method B Rt = 7.79.
8-(6-(2,3-Dihydrofuran-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-
6-amine (42). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.02 (s, 1H), 7.00 (s, 1H), 6.55 (m,
1H), 6.04 (s, 2H), 4.99 (m, 1H), 4.64-4.69 (m, 1H), 4.45 (m, 1H), 4.31 (t, J = 6.8 Hz, 2H), 4.05 (dd, J =
6.2, 9.2 Hz, 1H), 3.40 (m, 1H), 2.67 (t, J = 6.4 Hz, 2H), 2.14 (m, 2H), 1.16 (d, J = 6.1 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 153.8, 152.4, 152.0, 150.2, 148.1, 147.4, 146.9, 142.6, 119.7, 117.6, 114.5, 108.6,
13
104.0, 101.9, *, 48.9, 45.3, 43.7, 41.3, 30.0, 22.8, *signal overlaps with solvent; C NMR (125 MHz,
CD2Cl2) δ 154.4, 152.64, 152.61, 150.7, 148.8, 147.9, 147.4, 143.3, 120.2, 118.3, 115.0, 109.0, 104.4,
102.6, 77.6, 49.7, 45.8, 43.9, 41.7, 30.2, 22.6; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N6O3S,
455.1865; found 455.1862; HPLC: method A Rt = 6.04, method B Rt = 6.32.
8-(6-(2,3-Dihydrofuran-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-
6-amine (43). 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 6.43 (m, 1H), 6.01
(s, 2H), 5.94 (dd, J = 8.1, 10.8 Hz, 1H), 5.72 (br s, 2H), 4.93 (m, 1H), 4.35 (t, J = 6.8 Hz, 2H), 2.95-3.55
13
(m, 2H), 2.70 (t, J = 6.5 Hz, 2H), 2.39-2.47 (m, 1H), 2.22 (m, 2H), 1.25 (d, J = 6.2 Hz, 6H); C NMR
(125 MHz, CDCl3) δ 154.1, 152.1, 151.8, 150.0, 147.8, 147.6, 145.1, 141.3, 119.5, 116.3, 114.5, 106.9,
102.0, 99.3, 79.7, 50.1, 42.4, 40.6, 37.9, 29.7, 20.9; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N6O3S,
455.1865; found 455.1865; HPLC: method A Rt = 6.07, method B Rt = 6.49.
8-(6-(2,5-Dihydro-1H-pyrrol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-
purin-6-amine (44). A solution of 1 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro-1H-pyrrole (19.8 mg,
20.2 µL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated

HETEROCYCLES, Vol. 87, No. 1, 2013
111
four times, then N,N-diisopropylethylamine (15.1 mg, 21 µL, 0.117 mmol) and Pd(PPh3)4 (13.5 mg,
0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 100 °C for 20 h. Solvent
was removed under reduced pressure and the resulting residue was purified by preparatory TLC
(CH2Cl2:MeOH-NH3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of CH2Cl2:TFA (4:1)
and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by
1
preparatory TLC (CH2Cl2:MeOH-NH3 (7N), 10:1) to give 6.0 mg (23%) of 44. H NMR (500 MHz,
CDCl3/MeOH-d4) δ 8.19 (s, 1H), 6.98 (s, 2H), 6.04 (m, 1H), 6.01 (s, 2H), 5.74 (m, 1H), 5.62 (d, J = 2.0
Hz, 1H), 4.31 (t, J = 6.9 Hz, 2H), 3.81-3.88 (m, 1H), 3.89-3.95 (m, 1H), 2.87 (septet, J = 6.3 Hz, 1H),
2.68 (t, J = 6.7 Hz, 2H), 2.14 (m, 2H), 1.15 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ
154.0, 152.0, 151.7, 150.7, 149.4, 147.8, 142.8, 131.0, 129.8, 119.2, 116.8, 115.3, 108.7, 102.2, 66.1, 53.6,
43.4, 41.2, 40.4, 29.8, 22.2; HRMS (ESI) m/z [M+H]+ calcd. for C22H28N7O2S, 454.2025; found
454.2046; HPLC: method A Rt = 5.27, method B Rt = 2.72.
SONOGASHIRA COUPLING
General conditions. To a solution of 1 (20 mg, 0.039 mmol, 1 eq.) in DMF (2 mL) in a sealed tube
flushed with argon was added CuI (0.5 eq.), PdCl2(PPh3)2 (15 mol%), alkyne (2-2.5 eq.) and
triethylamine (5 eq.). The reaction mixture was heated at 90-100 °C for 24 h. Solvent was removed under
reduced pressure and the resulting residue was purified by preparatory TLC to yield compounds 46-50. 45
was similarly prepared and obtained following trimethylsilyl removal as is described below.
8-(6-Ethynyl-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylamino-propyl)-9H-purin-6-ylamine (45).
To a solution of 1 (20 mg, 0.039 mmol) in 2 ml of DMF in a sealed tube, was added CuI (3.8 mg, 0.019
mmol), PdCl2(PPh3)2 (4.2 mg, 0.006 mmol), trimethylsilylacetylene (14 µL, 0.098 mmol) and
triethylamine (13.7 µL, 0.1866 mmol). The reaction mixture was heated at 90 °C for 24 h. The reaction
mixture was concentrated under reduced pressure to give a white solid to which was added MeOH (1 mL)
and KOH (10 mg) and was stirred at rt for 2 h. Solvent was removed under reduced pressure and the
resulting residue was purified by preparatory TLC (CH2Cl2: n-hexane: EtOAc: MeOH-NH3 (7N), 4:4:2:1)
to give 11 mg (69%) of 45. 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 6.00 (s,
2H), 5.61 (br s, 2H), 4.31 (t, J = 7 Hz, 2H), 3.31 (s, 1H), 2.71 (m, 1H), 2.56 (t, J = 7 Hz, 2H), 1.97 (m,
2H), 1.02 (d, J = 6.5 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C20H23N6O2S, 411.1603; found
411.1605.
8-((6-(Hex-1-yn-1-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine
(46). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.23 (s, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 5.87 (s, 2H), 4.24
(t, J = 6.9 Hz, 2H), 2.66 (septet, J = 6.2 Hz, 1H), 2.48 (t, J = 6.2 Hz, 2H), 2.31 (t, J = 6.9 Hz, 2H), 1.90
(quintet, J = 7.6 Hz, 2H), 1.44 (quintet, J = 6.2 Hz, 2H), 1.34 (sextet, J = 7.6 Hz, 2H), 0.98 (d, J = 6.2 Hz,

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6H), 0.82 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.4, 152.8, 151.6, 148.1, 147.9,
146.6, 127.8, 119.8, 114.8, 112.5, 111.4, 101.9, 96.1, 77.9, 48.8, 43.6, 41.5, 30.6, 29.9, 22.6, 21.9, 19.3,
13.6; HRMS (ESI) m/z [M+H]+ calcd. for C24H31N6O2S, 467.2229; found 467.2227.
8-[6-(3,3-Dimethylbut-1-ynyl)benzo[1,3]dioxol-5-ylsulfanyl]-9-(3-isopropylamino-propyl)-9H-purin-
6-ylamine (47). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.25 (s, 1H), 6.99 (s, 1H), 6.97 (s, 1H), 6.05 (s,
2H), 4.41 (t, J = 7 Hz, 2H), 3.29 (m, 1H), 2.98 (t, J = 7.5 Hz, 2H), 2.24 (m, 2H), 1.34 (d, J = 6.5 Hz, 6H),
1.18 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C24H31N6O2S, 467.2229; found 467.2233.
8-((6-(Cyclopentylethynyl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (48). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.16 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.92 (s, 2H),
4.27 (t, J = 6.2 Hz, 2H), 2.81 (septet, J = 6.9 Hz, 1H), 2.69 (quintet, J = 6.9 Hz, 1H), 2.56 (t, J = 6.2 Hz,
2H), 2.03 (quintet, J = 6.2 Hz, 2H), 1.79-1.85 (m, 2H), 1.60-1.63 (m, 2H), 1.48-1.53 (m, 4H), 1.09 (d, J =
13
6.2 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.5, 152.5, 151.5, 148.6, 148.2, 147.6, 124.2,
121.2, 119.5, 112.7, 112.5, 102.2, 100.5, 77.7, 49.7, 42.8, 41.1, 33.9, 30.9, 28.8, 25.1, 21.4; HRMS (ESI)
m/z [M+H]+ calcd. for C25H31N6O2S, 479.2229; found 479.2235.
8-((6-(Cyclohexylethynyl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-
amine (49). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.13 (s, 1H), 6.87 (s, 1H), 6.78 (s, 1H), 5.94 (s, 2H),
4.29 (t, J = 6.9 Hz, 2H), 2.98 (septet, J = 6.6 Hz, 1H), 2.66 (t, J = 6.6 Hz, 2H), 2.48 (quintet, J = 4.6 Hz,
1H), 2.11 (quintet, J = 6.6 Hz, 2H), 1.57-1.67 (m, 4H), 1.30-1.36 (m, 2H), 1.22-1.26 (m, 2H), 1.19 (d, J =
13
5.9 Hz, 6H); C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.5, 152.6, 151.6, 148.1, 148.0, 146.8, 125.4,
119.9, 112.5, 111.3, 101.9, 101.8, 100.2, 77.9, 49.6, 42.8, 41.1, 33.6, 32.5, 29.7, 25.9, 25.1, 24.7; HRMS
(ESI) m/z [M+H]+ calcd. for C26H33N6O2S, 493.2386; found 493.2381.
9-(3-Isopropylaminopropyl)-8-(6-phenylethynylbenzo[1,3]dixool-5-ylsulfanyl)-9H-purin-6-yl-
amine (50). 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.2 (s, 1H), 7.30-7.40 (m, 5H), 7.08 (s, 1H), 6.96 (s,
1H), 6.06 (s, 2H), 4.27 (m, 2H), 2.69 (m, 1H), 2.51 (m, 2H), 1.97 (m, 2H), 1.01 (d, J = 6.5 Hz, 6H); 13C
NMR (125 MHz, CDCl3/MeOH-d4) δ 154.3, 152.3, 151.1, 148.8, 147.3, 131.3, 128.7, 128.3, 124.4, 122.4,
120.4, 119.3, 112.9, 112.4,102.3, 94.2, 86.6, 50.5, 43.1, 41.3, 29.2, 21.7; HRMS (ESI) m/z [M+H]+ calcd.
for C26H27N6O2S, 487.1903; found 487.1913.
ACKNOWLEDGEMENTS
T.T. is funded by Susan G. Komen for the Cure (KG091313) and the Department of Defense, Breast
Cancer Research Program (PDF-BC093421) and H.P. and W.S. by the National Institutes of Health
grants 1U01AG032969, 1R01CA155226 and 1R21AI090501. We also thank Dr. George Sukenick and
Dr. Hui Liu of the NMR Analytical Core Facility at MSKCC for expert mass spectral analysis.

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