2
D. Bliman et al. / Tetrahedron Letters xxx (2014) xxx–xxx
In an ongoing study of 2,6,8,9-tetrasubstituted purines we
after 55 h at room temperature (entry 5). Therefore, compounds
lacking a substituent at the 9-position did not react or provided
unsatisfactory yields.
needed a protocol that would allow selective bromination at the
8-position of purines in the presence of aromatic substituents.
We turned first to the commonly used methods for purine deriva-
tives. In our model reaction, bromination of 1a (Table 1, entry 1)
using NBS in acetonitrile at room temperature30 resulted in only
a 25% isolated yield of 2a; para-bromination of the phenyl also
occurred in trace amounts according to 1H NMR spectroscopy.
Reaction of purine 1a with Br2 in NaOAc/HOAc buffer in THF/
MeOH12,31 resulted in a 30% yield of 2a. However, when 1a was
treated with PyrBr3 in CH2Cl2 at room temperature for 5 h, 2a
was isolated in 93% yield (Table 1, entry 1).32 In addition to the
higher yield, the workup, and purification of the PyrBr3 reactions
are more convenient than for reactions involving elemental Br2.
These results encouraged us to explore the scope of PyrBr3 as a
brominating reagent for the 8-bromination of purines. The results
are summarized in Table 1. Initially, we wanted to investigate if the
method was applicable to purines lacking substituents at the 9-po-
sition. This is of interest since it allows insertion of bromine early
in a reaction sequence and paves the way for subsequent diversifi-
cation. Treating 6-chloropurine (1b) and 2-amino-6-chloropurine
(1c) with PyrBr3 in CH2Cl2 did not result in any or only a trace
amount of bromination (entries 2 and 3). Since these compounds
are largely insoluble in CH2Cl2, the reactions were also run in
DMF, but without success (results not shown). Bromination of 1d
in DMF gave the product in 38% yield (entry 4). Although 1d was
poorly soluble in CH2Cl2, 2d was obtained in 46% isolated yield
Next, we introduced substituents at the 9-position. Bromination
of purines not substituted at the 2-position (1e–h) was unsuccess-
ful using PyrBr3 in CH2Cl2 at room temperature (entries 6–9). The
bromination of 9-benzyladenine (1f) was also performed in DMF
at both room temperature and 60 °C, but no product was observed.
Lewis acids (TMS-triflate and BBr3) have been reported to increase
the rate of bromination reactions on similar substrates,20 but failed
to result in more than a trace amount of brominated material (as
observed by LCMS) in this case.
2,6-Diaminopurines (1i,j and 1l,m) were brominated in high
yields (80–91%) with PyrBr3 in CH2Cl2 at room temperature
(entries 10, 11, 13, and 14). 2,6-Diaminopurine 1k has poor
solubility in CH2Cl2, but can be brominated in DMF, although with
a significantly lower yield (27%, entry 12) compared to the
bromination of electron-rich purines soluble in CH2Cl2 (1i,j and
1l,m). When a tert-butyloxycarbamoyl group was introduced at
the C2 position (entry 15) as in 1n, treatment with PyrBr3 gave
2n in 36% isolated yield. The conversion was however not complete
after 3 h and the protecting group was partially cleaved under
these conditions. For 9-substituted 2,6-diaminopurines (1i and
1a), changing the solvent to DMF resulted in lower yields (entries
16 and 17) compared to CH2Cl2 (entries 10 and 1). In addition,
acetonitrile as the solvent resulted in a comparable yield to
reactions in CH2Cl2, but the reaction was slower (entry 18).
Table 1
8-Bromination of purines using PyrBr3
R6
R6
PyrBr3
CH2Cl2, r.t.
N
N
N
N
N
Br
R2
N
R2
N
N
R9
R9
1
2
Entry
Substratea
R6
R2
R9
Solvent
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1b
1c
1d
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1i
1a
1i
N(Me)2
Cl
Cl
N(Me)2
N(Me)2
NH2
NH2
H
NH2
NH2
NH2
H
H
H
H
NH2
NH2
NH2
NH2
NHBn
NHBoc
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Phenethyl
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
i-Bu
Phenethyl
Bn
Bn
CH2Cl2
CH2Cl2
CH2Cl2
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
5
24
o.nd
6
55
48
o.n
o.n
o.n
3
3
5
2.5
1
3
2a
2b
2c
2d
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2i
2a
2i
93
nrc
Tracee
38
46
nr
nr
nr
Trace
90
87
27
80
91
36
47
59
Cl
OMe
N(Me)2
N(Me)2
NHBn
NH2
N(Me)2
N(Me)2
NHBn
N(Me)2
N(Me)2
N(Me)2
OMe
CH2Cl2
CH2Cl2
CH2Cl2
DMF
3
3
Phenethyl
DMF
Bn
Bn
Bn
Bn
Bn
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
o.n
o.n
o.n
16
4
80
1o
1o
1p
1i
2o
2o
2p
2i
37
OMe
Cl
N(Me)2
43f
nr
93g
a
Protocols for brominations, synthesis of non-commercially available starting materials, and data from product characterization are available in the Supporting
Information.
b
Isolated yield.
c
d
e
f
nr = no reaction, that is, only starting material was observed by LCMS and/or TLC.
o.n = overnight.
Only a trace amount of the product was observed by LCMS.
3 equiv of PyrBr3 were used.
g
Polymer supported PyrBr3 was used.