Synthesis of 8-bromo-N-benzylpurines via 8-lithiated purines: Scope and limitations

Article abstract of DOI:10.1080/00397910903318708

9-Benzylpurines have been lithiated in the 8-position and subsequently brominated when trapped with BrCCl₂CCl₂Br. The 8-bromopurines were isolated in excellent yields when the benzyl group carried an alkoxy or alkyl group in the ortho or para position. Without these substituents, the conversion was generally less, and formation of 8,8'-purinyl dimers was observed. There was also evidence of debenzylation in some instances. Bromination of 7-benzylpurines employing the same set of reaction conditions has also been achieved.

Full text of DOI:10.1080/00397910903318708

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Synthesis of 8-Bromo-N-benzylpurines
via 8-Lithiated Purines: Scope and
Limitations
Thywill Gamadeku a & Lise-Lotte Gundersen a
a Department of Chemistry , University of Oslo , Oslo, Norway
Published online: 09 Aug 2010.
To cite this article: Thywill Gamadeku & Lise-Lotte Gundersen (2010) Synthesis of 8-Bromo-N-
benzylpurines via 8-Lithiated Purines: Scope and Limitations, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:18, 2723-2735,
DOI: 10.1080/00397910903318708
To link to this article: http://dx.doi.org/10.1080/00397910903318708
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Synthetic Communications1, 40: 2723–2735, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318708
SYNTHESIS OF 8-BROMO-N-BENZYLPURINES VIA
8-LITHIATED PURINES: SCOPE AND LIMITATIONS
Thywill Gamadeku and Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, Oslo, Norway
9-Benzylpurines have been lithiated in the 8-position and subsequently brominated when
trapped with BrCCl2CCl2Br. The 8-bromopurines were isolated in excellent yields when
the benzyl group carried an alkoxy or alkyl group in the ortho or para position. Without
these substituents, the conversion was generally less, and formation of 8,80-purinyl dimers
was observed. There was also evidence of debenzylation in some instances. Bromination
of 7-benzylpurines employing the same set of reaction conditions has also been achieved.
Keywords: Bromination; debenzylation; dimerization; lithiation; purine
Purines and purine nucleosides have been subjected to direct lithiation in the
8-position when treated with BuLi, or preferably lithium diisopropylamide (LDA),
and the metallated purines have been trapped with a variety of electrophiles
including halogen sources, simple alkyl halides, and aldehydes.[1] We established a
convenient procedure for halogenation of 9-tetrahydropyrane (THP)-purines and
purine nucleosides, where the 8-lithiated species were trapped with appropriate halo-
gen donors (CCl3CCl3, BrCCl2CCl2Br, BrCN, or ICN),[2] but we were not able to
synthesize 8-halogenated 6-chloro-9-benzylpurines employing this protocol.[3] How-
ever, later we managed to lithiate 6-chloro-9-(4-methoxybenzyl)purine and trap this
intermediate with MeI and CCl3CCl3, and both the 8-methyl- and 8-chloropurines
were isolated in excellent yields.[4]
9-Benzylated purines are of great interest because of their potent biological
activities. For instance, they may be selective adenosine A2A receptor antagonists,[5]
selective inhibitors of Mycobacterium tuberculosis,[4,6] inhibitors of 15-lipoxygenase
(non-antioxidant inhibitors)[7] or they may have potential as antiviral[8] or antican-
cer[9] compounds. The continuous need for efficient syntheses of various 9-benzy-
lated purines with potential biological activities led us to explore the scope and
limitations of C-8 functionalization of such compounds via 8-lithiated intermediates.
The model reaction chosen in this study was treatment of the purines 1 with
LDA followed by bromination with BrCCl2CCl2Br (Scheme 1; Table 1). The purines
were treated with LDA for 1 h, and the lithiated purine allowed to react with
Received August 3, 2009.
Address correspondence to Lise-Lotte Gundersen, Department of Chemistry, University of Oslo,
Oslo, Norway. E-mail: l.l.gundersen@kjemi.uio.no
2723

2724
T. GAMADEKU AND L.-L. GUNDERSEN
Scheme 1. (i) (1) LDA; (2) BrCCl2CCl2Br, THF, ꢀ78 ꢁC.
BrCCl2CCl2Br for approximately 2–3 h to compare reactivity with the previously
studied purine nucleosides and THP-protected purines.[2] 9-Benzyl-6-chloropurine
1
(1a) was quite unreactive, but a careful analysis of the H NMR spectrum of the
crude product showed that some desired product 2a was formed, and the compound
Table 1. Lithiation–bromination of 9-benzylpurines 1
Reaction
time (h)a
Ratio
1:2:3b
Yield
(%) 2
Yield
(%) 3
Yield
(%) 4
Entry
X
R1
R2
R3
R4
c
1
2
H
H
H
H
H
H
H
Me
Me
OMe
OMe
OMe
OBn
OMe
H
H
H
2.25
1.25
2.00
3.00
2.50
2.75
1.50
2.00
2.75
2.30
1.75
3.00
2.25
2.50
2.00
2.00
2.50
73:13:14
0:100:0
3:96:1d
0:100:0
0:100:0
75:18:7f
0:100:0
0:100:0
15:56:29
16:75:9
6:94:0
2, 2a
76, 2b
75, 2c
83, 2d
80, 2e
6, 2f
11, 3a
–
–
c
–
e
c
3
Cl
H
H
H
H
–
–
c
4
H
H
H
–
–
–
c
5
Cl
NO2
H
H
H
H
–
g
–
h
6
H
H
H
þ
h
7
H
H
H
84, 2g
78, 2h
25, 2i
51, 2j
80, 2k
8, 2l
–
–
þ
8
H
H
OMe
OMe
OMe
H
OMe
H
8, 4h
h
9
H
H
26, 3i
8, 3j
–
þ
h
10
11
12
13
14
15
16
17
Cl
Cl
H
H
H
H
þ
c
OMe
H
H
H
–
c
H
CF3
F
H
76:19:5
24:69:7
62:18:20e
25:75:0
29:71:0
74:13:13
7, 3l
5, 3m
–
c
H
H
H
H
19, 2m
17, 2n
34, 2o
19, 2p
15, 2q
–
i
–
h
H
F
H
H
Cl
H
þ
g
Cl
H
H
H
Cl
H
–
–
þ
c
–
H
Cl
H
H
H
H
Cl
H
6, 3q
–
aAfter adding BrCCl2CCl2Br.
bMolecular ratio taken from the 1H NMR spectra of the crude products.
cNo aldehyde present in the crude product according to 1H NMR.
dBased on the presence of a signal at 6.10 ppm in the crude 1H NMR spectrum, which may be assigned
to the CH2 in the dimer.
eNot isolated.
fMolecular ratio 1:2:5.
gDimer 5 (Fig. 1) isolated in 4%.
hA signal was present in the 1H NMR spectrum of the crude product, which corresponded well with the
reported ppm value for the CHO proton in the aldehyde 4.
iBased on the presence of a signal at 6.27 ppm in the crude 1H NMR spectrum, which may be assigned to
the CH2 in the dimer.

LITHIATION–BROMINATION OF N-BENZYLPURINES
2725
was isolated in very poor yield (Table 1, entry 1). A second product was also formed
and isolated. This turned out to be the symmetrical dimer 3a. Purine nucleoside
8,80-dimers have been formed as a result of oxidative DNA damage,[10] but synthetic
routes leading to such dimers are limited to Cu-mediated homodimerization of
8-iodopurines.[11] Also, dimerization of 8-unsubstituted purines in the presence of
CuI and air has been observed.[12] However, introduction of carbon substituents
in the purine 8-position by reacting phenyllithium[13] or allylic cuprates[14] with a
C-8 unsubstituted purine have been achieved, probably by an addition–oxidation
mechanism. Hence, the dimers 3 may have been formed by addition of lithiated
purine to unreacted compound 1. Alternatively, the dimers may have been formed
by an attack from the lithiated purine on the 8-brominated products 2, but the dif-
ference in reactivity between 6- and 8-halopurines toward nucleophiles are generally
not very profound,[15] and exchange of the chloride was not observed for any of the
6-chloropurines 1 examined in this study.
As suspected, the substitution pattern in the benzylic substituent turned out
to be important for the outcome of lithiation–bromination of compounds 1. Com-
pounds carrying a methyl or an alkoxy group in the para position (Table 1, entries
2–5 and 7–8) gave the desired 8-bromopurines 2 in excellent yields and with no or
minimal dimer formation. The same was true for the 2-methoxybenzylpurine 2k
(Table 1, entry 11). A chlorine in the purine 2-position did not affect the outcome
of the reaction (Table 1, entries 3 and 5), but in the case of the 2-nitropurine 1f
(Table 1, entry 6), the yield of the desired product 2f was poor and substitution in
the purine 2-position had taken place, giving the unsymmetrical dimer 5 (Fig. 1).
There are also other examples of facile nucleophilic displacement of a nitro group
at the purine C-2.[4,16]
In the reaction of the trimethoxybenzylpurine 1h, 3,4,5-trimethoxybenzalde-
hyde (4h)[17] was isolated in 8% yield in addition to the desired product 2h. Indoles
has been debenzylated by initial deprotonation in the benzylic a-position, and the
reaction was sometimes followed by benzaldehyde formation.[18] We were only able
to isolate an aldehyde in the reaction of 1h, but debenzylation may be partly respon-
sible for reduced yields of the desired product 2 in several cases. In some instances,
1
the H NMR spectrum of the crude product indicated the presence of an aldehyde
(Table 1, entries 6–10, 14, and 15), but formation of aldehydes may be difficult to
detect because of volatility and=or because they are easily oxidized to acids.
Figure 1. Structure of the dimer 5, formed in the synthesis of compound 2f.

2726
T. GAMADEKU AND L.-L. GUNDERSEN
The purines not carrying an electron-donor substituent (methyl, alkoxy) in the
benzylic ortho or para position reacted more sluggishly in the lithiation–bromination
reaction (Table 1, entries 9, 10, and 12–17). The conversions of the starting materials 1
were lower and, except for the 4-chlorobenzylpurines 2p and 2q (Table 1, entries 16
and 17), some dimer formation took place in all these reactions. The isolated yields of
1
the desired compounds 2 were poor, even in the cases where the H NMR spectrum
of the crude product indicated that more than 50% of the starting material was con-
verted. This can be explained by loss of material during tedious chromatographic separ-
ation of product 2, dimer 3, and unconverted starting material 1 but may also (in part) be
due to undetected debenzylation reactions giving polar products that were not isolated.
The reason why alkyl or alkoxy substituents in the benzylic ortho or para pos-
ition is favorable in the reaction studied is not totally clear. These substituents may
reduce the acidity of the benzylic CH2 and hence prevent extensive aldehyde forma-
tion. However, it is more difficult to explain why other substitution patterns lead to
dimer formation and=or poor conversion of the starting material.
Compound 2m has been synthesized and isolated in a somewhat better yield
(55%), employing almost the same set of reaction conditions.[19] It may be that the
outcome of the reactions is also very sensitive to concentration, exact reaction tem-
perature, rate of addition, and other factors. Also 6-bromo-9-benzylpurine has been
lithiated and trapped with a brominating agent, BrCN, and the product was isolated
in 34% yield.[20] Again, it is difficult to know at the present stage if the difference in
reactivity between the 6-bromopurine and the 6-chloropurine 1a studied herein is
due to slight variations in reaction conditions and=or the identity of the substituent
in the purine 6-position.
Finally, we examined lithiation–bromination of the 7-benzylated purines 6a
and 6b (Scheme 2). In the reaction of 6a, the conversion was ca. 40% according to
1
the crude product H NMR spectrum, and both conversion and isolated yield of
the product 7a were better than for the 9-benzylated isomer 1a. In the reaction of
compound 6b, no unreacted starting material could be detected in the crude product
1H NMR spectrum, but the isolated yield of product 7b was only moderate. This
may have been a result of debenzylation; there were indications of aldehyde
formation in the crude product NMR spectra of both compounds 7a and 7b. Dimer
formation was not observed in the reactions of the 7-benzylated purines 6.
In summary, 9-benzylpurines can be lithiated in the 8-position and
subsequently brominated when trapped with BrCCl2CCl2Br. The 8-bromopurines
Scheme 2. (i) (1) LDA; (2) BrCCl2CCl2Br, THF, ꢀ78 ꢁC.

LITHIATION–BROMINATION OF N-BENZYLPURINES
2727
were isolated in excellent yields when the benzyl group carried an alkoxy or alkyl
group in the ortho or para position. With other substitution patterns in the benzyl
group, the conversion was generally less, and formation of 8,80-purinyl dimers was
observed. There was also evidence of debenzylation in some instances. Bromination
of 7-benzylpurines employing the same set of reaction conditions has also been
achieved. Here, no dimer formation was observed, and the outcome of the reaction
appeared to be less dependant on the presence of electron-donating groups in the
benzylic ortho=para positions. In this study, lithiation with LDA followed by reac-
tion with BrCCl2CCl2Br was chosen as a model reaction. We believe that the out-
come of the reactions are mainly dependent on the ease of lithiation and=or
stability of the 8-lithiated species and that the compounds reacting well under these
set of reaction conditions also may be halogenated when the lithiated species is
trapped with other sources of electrophilic halogens.
EXPERIMENTAL
1H NMR spectra were recorded at 500 MHz with a Bruker Avance DRX 500
instrument, at 300 MHz with a Bruker Avance DPX 300, instrument or at 200 MHz
with a Bruker Avance DPX 200 instrument. Decoupled 13C NMR spectra were
recorded at 125, 75, or 50MHz using the instruments mentioned. Mass spectra under
electron-impact conditions were recorded with a VG Prospec instrument at 70eV
ionizing voltage and are presented as m=z (% rel. int.). Melting points were determined
with a Buchi melting-point B-545 apparatus and are uncorrected. Tetrahydrofuran
¨
(THF) was purified by a solvent purification system, MB SPS-800 from MBraun, or
by distillation from Na=benzophenone. Diisopropylamine was distilled from CaH2
˚
and stored over molecular sieves (4 A). Silica gel for flash chromatography was pur-
chased from Merck, Darmstadt, Germany (Merck No. 09385). Starting materials were
created using literature methods: 1a,[19] 1b–e,[6c] 1f,[16b] 1g–q,[6c] 6a,[21] and 6b.[6c] All
other reagents were commercially available and used as received.
General Procedure
A solution of the purine 1 or 6 (0.50 mmol) in THF (2.0 mL) was added drop-
wise over 10 min to a stirred solution of LDA (ca. 0.5 M in THF, prepared in situ
from butyllithium and diisopropylamine, 1.4 mL) under N2 at ꢀ78 ꢁC. After stirring
for 1 h, a solution of BrCCl2CCl2Br (326 mg, 1.00 mmol) in THF (1.0 ml) was added
dropwise over 10 min. The resulting mixture was stirred at ꢀ78 ꢁC, for the time given
in Table 1, before sat. aq. NH4Cl (15 mL) was added. The mixture was warmed to
ambient temperature and extracted with EtOAc (3 ꢂ 25 mL). The combined EtOAc
extracts were washed with brine (20 mL), dried (MgSO4), and evaporated in vacuo.
The product was purified by flash chromatography on silica gel.
8-Bromo-6-chloro-9-(phenylmethyl)-9H-purine (2a)
Hexane, followed by EtOAc–hexane (1:5) and EtOAc–hexane (1:2), was used
1
for flash chromatography; yield 4 mg (2%), off-white wax. H NMR (300 MHz,
CDCl3) d 5.47 (s, 2H, CH2), 7.29–7.36 (m, 5H, Ph), 8.74 (s, 1H, H-2); MS EI m=z

2728
T. GAMADEKU AND L.-L. GUNDERSEN
(rel. %) 324=322 (Mþ, 9=7), 287 (6), 280 (5), 278 (8), 245 (6), 243 (18), 91 (100);
HRMS (EI) calcd. for C12H8BrClN4 321.9616, found 321.9621.
6,6’-Dichloro-9,9’-di(phenylmethyl)-9H,9’H-[8,8’]-bipurinyl (3a)
Isolated in the synthesis of 2a; yield 14 mg (11%), off-white solid, mp
1
228–230 ꢁC. H NMR (500 MHz, CDCl3) d 6.24 (s, 4H, CH2), 7.13–7.17 (m, 6H,
Ph), 7.28–7.30 (m, 4H, Ph), 8.88 (s, 2H, H-2); MS EI m=z (rel. %) 488=486 (Mþ,
30=44), 397 (66), 396 (22), 395 (100), 91 (93); HRMS (EI) calcd. for C24H16Cl2N8
486.0875; found 486.0880.
8-Bromo-6-chloro-9-[(4-methylphenyl)methyl]-9H-purine (2b)
Hexane, followed by EtOAc–hexane (1:8) and EtOAc–hexane (1:4), was used
1
for flash chromatography; yield 127 mg (76%), yellow solid, mp 131–132 ꢁC. H
NMR (300 MHz, CDCl3) d 2.29 (s, 3H, CH3), 5.42 (s, 2H, CH2), 7.11 (d, J ¼ 7.9 Hz,
Hz, 2H, Ar), 7.22 (d, J ¼ 7.9 Hz, 2H, Ar), 8.72 (s, 1H, H-2); 13C NMR (75 MHz,
CDCl3) d 21.1, 48.1, 127.9, 129.6, 131.1, 131.8, 134.2, 138.6, 149.4, 152.1, 152.9;
MS EI m=z (rel. %) 340=338=336 (Mþ, 3=11=8), 259 (5), 257 (16), 106 (9), 105
(100); HRMS (EI) calcd. for C13H10BrClN4 335.9777; found 335.9775.
8-Bromo-2,6-dichloro-9-[(4-methylphenyl)methyl]-9H-purine (2c)
Hexane, followed by EtOAc–hexane (1:6) and EtOAc–hexane (1:3), was used
1
for flash chromatography; yield 129 mg (75%), yellow solid, mp 178–179 ꢁC. H
NMR (300 MHz, CDCl3) d 2.34 (s, 3H, CH3), 5.42 (s, 2H, CH2), 7.16 (d, J ¼ 8.0 Hz,
Hz, 2H, Ar), 7.25 (d, J ¼ 8.0 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3) d 21.1, 48.3,
128.0, 129.7, 130.6, 130.8, 134.7, 138.8, 150.1, 153.2, 153.9; MS EI m=z (rel. %)
374=372=370 (Mþ, 5=11=7), 293 (3), 291 (5), 185 (2), 105 (100); HRMS (EI) calcd.
for C13H9BrCl2N4 369.9388; found 369.9393.
8-Bromo-6-chloro-9-[(4-methoxyphenyl)methyl]-9H-purine (2d)
The reaction was performed on a 0.99-mmol scale, and EtOAc–hexane (1:2)
1
was used for flash chromatography; yield 293 mg (83%), off-white wax. H NMR
(200 MHz, CDCl3) d 3.76 (s, 3H, OCH3), 5.41 (s, 2H, CH2), 6.83 (d, J ¼ 8.4 Hz,
2H, Ar), 7.33 (d, J ¼ 8.4 Hz, 2H, Ar), 8.74 (s. 1H, H-2); 13C NMR (50 MHz, CDCl3)
d 47.8, 55.1, 114.1, 126.0, 129.4, 131.6, 133.9, 149.1, 151.8, 152.6, 159.4; MS EI m=z
(rel. %) 354=352 (Mþ, 13=10), 275 (3), 273 (11), 122 (8), 121 (100), 78 (6), 77 (6);
HRMS (EI) calcd. for C13H10BrClN4O 351.9727; found 351.9727.
8-Bromo-2,6-dichloro-9-[(4-methoxyphenyl)methyl]-9H-purine (2e)
Hexane, followed by EtOAc–hexane (1:6) and EtOAc–hexane (1:2), was used
for flash chromatography; yield 154 mg (80%), pale yellow solid, mp 143–145 ꢁC.
1H NMR (300 MHz, CDCl3) d 3.75 (s, 3H, OCH3), 5.35 (s, 2H, CH2), 6.82 (d,
J ¼ 8.8 Hz, 2H, Ar), 7.30 (d, J ¼ 8.8 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3)
d 48.1, 55.3, 114.4, 125.7, 129.7, 130.8. 134.6, 150.1, 153.1, 159.9; MS EI m=z

LITHIATION–BROMINATION OF N-BENZYLPURINES
2729
(rel. %) 390=388=386 (Mþ, 3=7=4), 309 (1), 122 (11), 121 (100), 78 (8), 77 (7); HRMS
(EI) calcd. for C13H9BrCl2N4O 385.9337; found 385.9334.
8-Bromo-6-chloro-9-[(4-methylphenyl)methyl]-2-nitro-9H-purine (2f)
Hexane, followed by EtOAc–hexane (1:1) and EtOAc, was used for flash chro-
1
matography; yield 12 mg (6%), yellow solid. H NMR (300 MHz, CDCl3) d 3.76 (s,
3H, OCH3), 5.49 (s, 2H, CH2), 6.85 (d, J ¼ 8.7 Hz, 2H, Ar), 7.39 (d, J ¼ 8.7 Hz, 2H,
Ar); MS EI m=z (rel. %) 399=397 (Mþ, 11=9), 122 (12), 121 (100), 91 (5), 78 (8), 77
(8); HRMS (EI) calcd. for C13H9BrCl2N5O3 396.9577; found 396.9575.
6,6’-Dichloro-9,9’-di[(4-methoxyphenyl)methyl]-2-nitro-9H,9’H-[8,2’]-
bipurinyl (5)
Isolated in the synthesis of 2f; yield 6 mg (4%), yellow solid. 1H NMR
(500 MHz, CDCl3) d 3.68 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 5.45 (s, 2H, CH2),
6.20 (s, 2H, CH2), 6.69 (d, J ¼ 8.8 Hz, 2H, Ar), 6.87 (d, J ¼ 8.8 Hz, 2H, Ar), 7.15
(d, J ¼ 8.8 Hz, 2H, Ar), 7.22 (d, J ¼ 8.8 Hz, 2H, Ar), 8.17 (s, 1H, H-80); 13C NMR
(125 MHz, CDCl3) d 48.1, 48.9. 55.2, 55.3, 114.2, 114.8, 125.5, 127.1, 129.3, 129.7,
132.2, 132.7, 147.4, 149.3, 151.3, 152.1, 153.1, 153.7, 153,8, 159.5, 160.2; MS EI
m=z (rel. %) 593=591 (Mþ, 5=9), 122 (9), 121 (100), 77 (9); HRMS (EI) calcd. for
C26H19Cl2N9O4 591.0937; found 591.0955.
9-[(4-Benzyloxyphenyl)methyl]-8-bromo-6-chloro-9H-purine (2g)
Hexane, followed by EtOAc–hexane (1:6) and EtOAc–hexane (1:2), was used
for flash chromatography; yield 182 mg (84%), pale yellow solid, mp 103–105 ꢁC.
1H NMR (300 MHz, CDCl3) d 5.01 (s, 2H, CH2), 6.89–7.39 (m, 9H, Ar), 8.73 (s,
1H, H-2); 13C NMR (75 MHz, CDCl3) d 47.9, 70.0, 115.3, 126.5, 127.4, 128.1,
128.6, 129,7, 131.9, 134.2, 136.6, 149.5, 152.1, 152.9, 159.0; MS EI m=z (rel. %)
432=430=428 (Mþ, 2=8=6), 386 (2), 384 (4), 92 (11), 91 (100); HRMS (EI) calcd.
for C19H14BrClN4O 428.0040; found 428.0030.
8-Bromo-6-chloro-9-[(3,4,5-trimethoxyphenyl)methyl]-9H-purine (2h)
Hexane, followed by EtOAc–hexane (1:3) and EtOAc–hexane (1:1), was used
1
for flash chromatography; yield 127 mg (76%), off-white solid, mp 145–148 ꢁC. H
NMR (300 MHz, CDCl3) d 3.77 (s, 6H, 2 ꢂ OCH3), 3.78 (s, 3H, OCH3), 5.37 (s,
2H, CH2), 6.62 (s, 2H, Ar), 8.72 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3) d 48.7,
56.1, 60.8, 105.5, 129.5, 131.8, 134.1, 138.3, 149.6, 152.1, 152.8, 153.5; MS EI m=z
(rel. %) 416=414=412 (Mþ, 10=49=30), 399 (6), 335 (8), 333 (23), 181 (100); HRMS
(EI) calcd. for C15H14BrClN4O3 411.9938; found 411.9918.
3,4,5-Trimethoxybenzaldehyde (4h)
Isolated in the synthesis of 2h; yield 8 mg (8%), yellow solid, spectral data in
accordance with those reported before.[17]

2730
T. GAMADEKU AND L.-L. GUNDERSEN
8-Bromo-6-chloro-9-[(3-methoxyphenyl)methyl]-9H-purine (2i)
Hexane, followed by EtOAc–hexane (1:6) and EtOAc–hexane (1:3), was used
for flash chromatography; yield 44 mg (25%), pale yellow solid, mp 103–106 ꢁC.
1H NMR (300 MHz, CDCl3) d 3.78 (s, 3H, OCH3), 5.47 (s, 2H, CH2), 6.84–6.93
(m, 3H, Ar), 7.27–7.29 (m, 1H, Ar), 8.76 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3)
d 48.2, 55.2, 113.6, 113.9, 120.0, 130.1, 131.8, 134.2, 135.5, 149.5, 152.1, 152.9, 159.9;
MS EI m=z (rel. %) 356=354=352 (Mþ, 8=30=24), 275 (34), 274 (17), 273 (100), 121
(68); HRMS (EI) calcd. for C13H10BrClN4O 351.9727; found 351.9718.
6,6’-Dichloro-9,9’-di[(3-methoxyphenyl)methyl]-9H,9’H-
[8,8’]-bipurinyl (3i)
Isolated in the synthesis of 2i; yield 35 mg (26%), colorless solid, mp
218–220 ꢁC. 1H NMR (300 MHz, CDCl3) d 3.65 (s, 6H, OCH3), 6.21 (s, 4H,
CH2), 6.68–7.08 (m, 8H, Ar), 8.87 (s, 2H, H-2); 13C NMR (75 MHz, CDCl3) d
48.4, 55.1, 113.6, 114.0, 120.4, 129.6, 130.8, 137.2, 143.3, 152.2, 153.1, 153.4,
159.6; MS EI m=z (rel. %) 550=548=546 (Mþ, 5=36=53), 429 (11), 427 (66), 425
(100), 240 (31), 121 (93); HRMS (EI) calcd. for C26H20Cl2N8O2 546.1086; found
546.1080.
8-Bromo-2,6-dichloro-9-[(3-methoxyphenyl)methyl]-9H-purine (2j)
Hexane, followed by EtOAc–hexane (1:6) and EtOAc–hexane (1:2), was used
for flash chromatography; yield 108 mg (56%), pale yellow solid, mp 144–147 ꢁC.
1H NMR (300 MHz, CDCl3) d 3.76 (s, 3H, OCH3), 5.40 (s, 2H, CH2), 6.81–6.87
(m, 3H, Ar), 7.21–7.26 (m, 1H, Ar); 13C NMR (75 MHz, CDCl3) d 48.4, 55.3,
113.9, 114.0, 120.0, 130.2, 130.7, 134.7, 135.0, 150.2, 153.2, 154.0, 160.0; MS EI
m=z (rel. %) 390=388=386 (Mþ, 11=24=14), 307 (67), 122 (9), 121 (100), 91 (19);
HRMS (EI) calcd. for C13H9BrCl2N4O 385.9337; found 385.9338.
9,9’-Di[(3-methoxyphenyl)methyl]-2,2’,6,6’-tetrachloro-9H,9’H-
[8,8’]-bipurinyl (3j)
Isolated in the synthesis of 2j; yield 13 mg (8%), colorless solid, mp 251–254 ꢁC.
1H NMR (300 MHz, CDCl3) d 3.68 (s, 6H, OCH3), 6.14 (s, 4H, CH2), 6.72–7.07 (m,
8H, Ar); 13C NMR (75 MHz, CDCl3) d 48.8, 55.2, 113.8, 114.1, 120.4, 129.8, 130.0,
136.7, 143.6, 153.1, 154.3, 154.8, 159.7; MS EI m=z (rel. %) 618=616=614 (Mþ, 7=13=
10), 497 (15), 495 (34), 493 (26), 240 (36), 121 (100); HRMS (EI) calcd. for
C26H18Cl4N8O2 614.0307; found 614.0323.
8-Bromo-2,6-dichloro-9-[(2-methoxyphenyl)methyl]-9H-purine (2k)
Hexane, followed by EtOAc–hexane (1:2), was used for flash chromatography;
yield 154 mg (80%), yellow solid, mp 190–192 ꢁC. 1H NMR (300 MHz, CDCl3) d 3.80
(s, 3H, OCH3), 5.45 (s, 2H, CH2), 6.83–6.95 (m, 3H, Ar), 7.25–7.32 (m, 1H, Ar); 13
C
NMR (75 MHz, CDCl3) d 44.5, 55.2, 110.5, 120.5, 121.5, 128.7, 129.9, 130.8, 135.5,

LITHIATION–BROMINATION OF N-BENZYLPURINES
2731
149.9, 152.9, 154.3, 156.9; MS EI m=z (rel. %) 390=388=386 (Mþ, 5=11=6), 309 (23),
307 (35), 122 (9), 121 (100), 91 (48); HRMS (EI) calcd. for C13H9BrCl2N4O
385.9337; found 385.9335.
8-Bromo-6-chloro-9-[(4-trifluoromethylphenyl)methyl]-9H-purine (2l)
Hexane, followed by EtOAc–hexane (1:2) and EtOAc–hexane (1:1), was used
1
for flash chromatography; yield 16 mg (8%), pale yellow solid, mp 173–175 ꢁC. H
NMR (300 MHz, CDCl3) d 5.52 (s, 2H, CH2), 7.45 (d, J ¼ 8.1 Hz, 2H, Ar), 7.60
(d, J ¼ 8.1 Hz, 2H, Ar), 8.74 (s, 1H, H-2); MS EI m=z (rel. %) 392=390 (Mþ,
31=24), 313 (25), 311 (73), 159 (100), 109 (24); HRMS (EI) calcd. for C13H7BrClF3N4
389.9495; found 389.9484.
6,6’-Dichloro-9,9’-di[(4-trifluoromethylphenyl)methyl]-9H,9’H-
[8,8’]-bipurinyl (3l)
Isolated in the synthesis of 2l; yield 7 mg (4%), yellow wax. 1H NMR
(300 MHz, CDCl3) d 6.29 (s, 4H, CH2), 7.46 (d, J ¼ 8.3 Hz, 4H, Ar), 7.54 (d,
J ¼ 8.3 Hz, 4H, Ar), 8.91 (s, 2H, H-2); MS EI m=z (rel. %) 624=622 (Mþ, 36=54),
465 (65), 463 (100), 159 (26), 109 (9); HRMS (EI) calcd. for C26H14Cl3F6N8
622.0623; found 622.0609.
8-Bromo-6-chloro-9-[(4-fluorophenyl)methyl]-9H-purine (2m)
Hexane, followed by EtOAc–hexane (2:3) and EtOAc, was used for flash chro-
matography; yield 21 mg (19%), pale yellow solid, mp 143–144 ꢁC (lit.[19]
1
143–144 ꢁC). H NMR (200 MHz, CDCl3) d 5.43 (s, 2H, CH2), 6.95–7.05 (m, 2H,
Ar), 7.33–7.40 (m, 2H, Ar), 8.73 (s, 1H, H-2); MS EI m=z (rel. %) 342=340 (Mþ,
17=13), 263 (9), 261 (28), 110 (10), 109 (100); HRMS (EI) calcd. for C12H7BrClFN4
339.9527; found 339.9528.
6,6’-Dichloro-9,9’-di[(4-fluorophenyl)methyl]-9H,9’H-[8,8’]-
bipurinyl (3m)
1
Isolated in the synthesis of 2m; yield 6 mg (5%), colorless solid. H NMR
(500 MHz, CDCl3) d 6.20 (s, 4H, CH2), 6.84–6.88 (m, 4H, Ar), 7.41–7.44 (m, 4H,
Ar), 8.90 (s, 2H, H–2); MS EI m=z (rel. %) 524=522 (Mþ, 20=29), 417 (9), 415
(50), 413 (75), 216 (7), 109 (100); HRMS (EI) calcd. for C24H14Cl2F2N8 522.0687;
found 522.0700.
8-Bromo-6-chloro-9-[(2-fluorophenyl)methyl]-9H-purine (2n)
Hexane, followed by EtOAc–hexane (1:2) and EtOAc, was used for flash chro-
matography; yield 32 mg (17%), pale yellow solid, mp 133–134 ꢁC. 1H NMR
(300 MHz, CDCl3) d 5.55 (s, 2H, CH2), 7.04–7.08 (m, 3H, Ar), 7.27–7.31 (m, 1H,
Ar), 8.72 (s, 1H, H-2); MS EI m=z (rel. %) 342=340 (Mþ, 22=17), 110 (9), 109
(100), 83 (15); HRMS (EI) calcd. for C12H7BrClFN4 339.9527; found 339.9537.

2732
T. GAMADEKU AND L.-L. GUNDERSEN
8-Bromo-2,6-dichloro-9-[(4-chlorophenyl)methyl]-9H-purine (2o)
Hexane, followed by EtOAc–hexane (1:8), EtOAc–hexane (1:2), and EtOAc,
was used for flash chromatography; yield 64 mg (34%), yellow solid, mp
203–204 ꢁC. 1H NMR (300 MHz, DMSO-d6) d 5.46 (s, 2H, CH2), 7.29 (d, J ¼ 8.5 Hz,
Hz, 2H, Ar), 7.42 (d, J ¼ 8.5 Hz, 2H, Ar); 13C NMR (50 MHz, DMSO-d6) d 47.0,
128.7, 129.1, 130.8, 132.7, 133.6, 136.3, 148.2, 151.4, 154.4; MS EI m=z (rel. %)
394=392=390 (Mþ, 11=17=9), 313 (10), 311 (11), 127 (42), 125 (100); HRMS (EI)
calcd. for C12H6BrCl3N4 389.8841; found 389.8832.
8-Bromo-6-chloro-9-[(3,4-dichlorophenyl)methyl]-9H-purine (2p)
Hexane, followed by EtOAc–hexane (1:8) and EtOAc–hexane (1:4), was used
for flash chromatography; yield 37 mg (19%), yellow solid, mp 138–140 ꢁC. 1H
NMR (300 MHz, CDCl3) d 5.41 (s, 2H, CH2), 7.16–7.20 (m, 1H, Ar), 7.30–7.46
(m, 2H, Ar), 8.73 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3) d 47.1, 127.3, 130.0,
131.1, 131.8, 133.3, 133.7, 134.0, 149.8, 152.3, 152.8; MS EI m=z (rel. %) 394=392=
390 (Mþ, 18=27=14), 315 (15), 313 (45), 311 (47), 163 (11), 161 (65), 159 (100);
HRMS (EI) calcd. for C12H6BrCl3N4 389.8841; found 389.8834.
8-Bromo-6-chloro-9-[(3-chlorophenyl)methyl]-9H-purine (2q)
Hexane, followed by EtOAc–hexane (1:2) and EtOAc, was used for flash chro-
1
matography; yield 26 mg (15%), yellow wax. H NMR (300 MHz, CDCl3) d 5.44 (s,
2H, CH2), 7.23–7.34 (m, 4H, Ar), 8.74 (s, 1H, H-2); MS EI m=z (rel. %) 360=358=356
(Mþ, 9=20=12), 281 (6), 279 (34), 277 (52), 127 (35), 125 (100); HRMS (EI) calcd. for
C12H7BrCl2N4 355.9231; found 355.9227.
6,6’-Dichloro-9,9’-di[(3-chlorophenyl)methyl]-9H,9’H-[8,8’]-
bipurinyl (3q)
Isolated in the synthesis of 2q; yield 8 mg (6%), colorless solid, mp 245–246 ꢁC.
1H NMR (500 MHz, CDCl3) d 6.19 (s, 4H, CH2), 7.12–7.33 (m, 5H, Ar), 7.56 (br s,
2H, Ar), 8.91 (s, 2H, H-2); 13C NMR (125 MHz, CDCl3) d 48.1, 126.7, 128.5, 129.0,
130.9, 134.4, 137.5, 143.0, 152.6, 153.1, 153.7; MS EI m=z (rel. %) 558=556=554 (Mþ,
20=40=30), 433 (32), 432 (20), 431 (97), 430 (21), 429 (100), 127 (28), 125 (79); HRMS
(EI) calcd. for C24H14Cl4N8 554.0096; found 554.0096.
8-Bromo-6-chloro-7-(phenylmethyl)-7H-purine (7a)
The reaction time after the addition of BrCCl2CCl2Br was 2.30 h. Hexane, fol-
lowed by EtOAc–hexane (1:3) and EtOAc–hexane (1:1), was used for flash chroma-
tography, and the reaction was run in a 2-mmol scale; yield 148 mg (23%), yellow
1
solid, mp 108–110 ꢁC. H NMR (200 MHz, CDCl3) d 5.75 (s, 2H, CH2), 7.05–7.07
(m, 2H, Ph), 7.30–7.36 (m, 3H, Ph), 8.84 (s, 1H, H-2); 13C NMR (50 MHz, CDCl3)
d 50.5, 126.2, 126.3, 128.5, 129.2, 134.4, 140.1, 142.0, 152.9, 161.6; MS EI m=z (rel. %)

LITHIATION–BROMINATION OF N-BENZYLPURINES
2733
324=322 (Mþ, 14=11), 280 (8), 278 (12), 245 (3), 91 (100); HRMS (EI) calcd. for
C12H8BrClN4 321.9616; found 321.9618.
8-Bromo-2,6-dichloro-7-[4-methoxyphenyl)methyl]-7H-purine (7b)
The reaction time after the addition of BrCCl2CCl2Br was 2.25 h. Hexane,
followed by EtOAc–hexane (1:4) and EtOAc–hexane (1:1), was used for flash chro-
1
matography; yield 80 mg (41%), yellow solid, mp 142–144 ꢁC. H NMR (300 MHz,
CDCl3) d 3.77 (s, 3H, OCH3), 5.65 (s, 2H, CH2), 6.85 (d, J ¼ 8.6 Hz, 2H, Ar), 7.03
(d, J ¼ 8.6 Hz, 2H, Ar); 13C NMR (50 MHz, CDCl3) d 50.2, 55.3, 114.5, 123.5,
126.0, 127.9, 141.4, 142.6, 153.6, 159.7, 162.3; MS EI m=z (rel. %) 390=388=386
(Mþ, 3=6=3), 344 (5), 342 (6), 122 (17), 121 (100), 78 (11), 77 (8); HRMS (EI) calcd.
for C13H9BrCl2N4O 385.9337; found 385.9340.
ACKNOWLEDGMENTS
The Quota scholarship to T. G. is gratefully acknowledged. The authors also
thank the Norwegian Research Council for the partial financing of the Bruker
Avance NMR instruments used in this study.
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