Highly efficient and broad-scope protocol for the preparation of 7-substituted 6-halopurines via N 9-Boc-protected 7,8-dihydropurines

Article abstract of DOI:10.1055/s-0031-1290068

9-Boc-6-chloropurine, which can be obtained in high yield, is nearly quantitatively reduced with the THFBH₃ complex. The obtained 9-Boc-7,8-dihydropurine derivative is more stable compared to the corresponding 9-tritylpurine and can be smoothly

Full text of DOI:10.1055/s-0031-1290068

610
PAPER
Highly Efficient and Broad-Scope Protocol for the Preparation of
7-Substituted 6-Halopurines via N9-Boc-Protected 7,8-Dihydropurines
P
reparation of 7-S
l
ubstitut
a
e
d
6-Halop
d
urines islav Kotek, Tomáš Tobrman, Dalimil Dvořák*
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5, 2166, 28 Prague 6, Czech Republic
Fax +42(224)354288; E-mail: dvorakd@vscht.cz
Received 26 October 2011; revised 2 December 2011
rines,9,10 we have developed a new practical route to the
synthesis of N7-alkyl-6-halo and N7-alkyl-2,6-dihalopu-
rines based on the reaction of 9-tritylated-7,8-dihydropu-
rines with alkyl halide in the presence of a base.11 One
Abstract: 9-Boc-6-chloropurine, which can be obtained in high
yield, is nearly quantitatively reduced with the THF·BH3 complex.
The obtained 9-Boc-7,8-dihydropurine derivative is more stable
compared to the corresponding 9-tritylpurine and can be smoothly
N7-alkylated, acylated, or it can serve as an N-nucleophile in conju- complication of the reported procedure is that the solu-
gate additions. Deprotection with trifluoroacetic acid followed by
tions of 9-benzyl-6-chloro-7,8-dihydropurine and 6-chlo-
MnO2 oxidation affords the N7-substituted purines in high yields.
ro-9-trityl-7,8-dihydropurine turned out to be prone to
The whole sequence of alkylation, deprotection, and oxidation can
spontaneous oxidation to the corresponding purines in the
be done with crude intermediates using chromatography only for
presence of air. Since the 7,8-dihydropurines bearing
electron-withdrawing substituents at the 2-, 6-, or 8-posi-
tions were reported to be more stable to oxidation,12 we
envisioned that the introduction of an electron-withdraw-
ing group to the N9-position of 7,8-dihydropurines could
lower the electron density and thus increase the overall
stability of 7,8-dihydropurines to the oxidation as well.
the purification of the final N7-substituted purine.
Key words: alkylation, acylation, Michael addition, nucleobases,
reduction
Due to the wide occurrence of purine scaffolds in biolog-
ical systems, many substituted purines are biologically ac-
tive compounds. A vast number of purine derivatives have
therefore been synthesised, and a number of them have
been found to be biologically active.1 Many synthetic
methodologies, including C–C cross coupling reactions at
the 2-, 6- and 8-positions, substitution of halogens by nu-
cleophiles or N9-alkylation, and arylation have been de-
veloped for the synthesis of purine derivatives.2
Therefore, the Boc protecting group was chosen; this can
be quantitatively introduced at the N9-position and is eas-
ily cleaved under acidic conditions. Thus, following liter-
ature procedures,13 6-chloro-9H-purine and 6-iodo-9H-
purine were converted into the 9-tert-butoxycarbonyl-6-
chloro-9H-purine (1a) and 9-tert-butoxycarbonyl-6-iodo-
9H-purine (1b) by reaction with Boc2O in the presence of
triethylamine in 92% isolated yield. Contrary to the above
discussed benzyl and trityl derivatives, DIBAL-H failed
to reduce 1a,b. From other reported reagents suitable for
the preparation of 7,8-dihydropurines, the THF·BH3 or
DMS·BH3 complex turned out to be the reagent of choice,
giving 7,8-dihydropurines 2a,b in quantitative isolated
yield. Thus, dihydropurines 2a,b can be obtained accord-
ingly in 92% isolated yield in two steps starting from 6-
chloro or 6-iodopurine. Since the previous study11 re-
vealed that the reactivity of 6-iodopurines was very simi-
lar to that of 6-chloro derivatives, the easier accessible 6-
chloro derivative 2a was used in the reactions mentioned
here.14
However, a simple and reliable methodology for the syn-
thesis of N7-substituted purines, despite their reported bi-
ological activity,3 was absent until very recently. Direct
alkylation of purine bases usually leads to the formation
of both N7 and N9 isomers of which, with the exception of
a few 2- and 6-aminopurines,4 the latter predominates.
Thus, N7-substituted purines were mostly prepared by la-
boured cyclisation of diaminopyrimidine derivatives.5 A
more convenient method has been recently described in-
volving cyclisation of N-substituted 5-amido-4-iodo-6-
benzylsulfanylpyrimidines, which is based on copper-
catalysed amidation.6 Additionally, methodology using
Co-complexes of chloropurines7 and temporary protec-
tion of the N9-position by reversible Michael addition
of acrylonitrile in the synthesis of asmarines8 have also
been used for the N7-alkylation of purines. Solvent depen-
dent, preferential N7-arylation was also observed in the
arylation of N2-[(dimethylamino)methylene]guanine and
N6-[(dimethylamino)methylene]adenine.9
The ability of 2a to undergo spontaneous oxidation in so-
lution was also tested. A solution of 2a in anhydrous
DMSO-d6 was kept in an air atmosphere for a prolonged
period of time. 1H NMR analysis showed no conversion of
2a into 1a within 32 days. In contrast, a solution of 6-chlo-
ro-9-benzyl-7,8-dihydropurine in DMSO-d6 was convert-
ed into 9-benzyl-6-chloropurine quantitatively during the
same period of time. Prolonged storage of the above solu-
tion of 2a did not show substantial progress of oxidation,
and a 95:5 ratio of 2a:1a was observed after four months.
Recently, as a part of our ongoing project to develop a
new selective synthesis of C- and N7-substituted pu-
SYNTHESIS 2012, 44, 610–618
x
x
.x
x
.2
0
1
1
Deprotonation of 2a was advantageously accomplished
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290068; Art ID: Z101411SS
by LiHMDS in a mixture of THF and DMF at –78 °C.15
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of 7-Substituted 6-Halopurines
611
Addition of an alkylating agent and warming the resulting
mixture to room temperature led to the formation of the
N7-alkylated product 3 in high yield (Scheme 1, Table 1).
This showed a lower tendency of deprotonated 2a to de-
hydrohalogenation compared to the trityl and benzyl de-
rivatives, where simultaneous addition of the base and the
alkylating agent had to be used to suppress dehydrohalo-
genation.11,16 Thus, methyl iodide, propyl iodide, and ben-
zyl bromide gave excellent yields of the alkylated
products (Table 1, entries 1–3). Also, allyl bromide and
the troublesome propargyl bromide11 reacted smoothly
under the above conditions (entries 4, 5). Secondary
alkyls could also be smoothly introduced, which was
demonstrated by the example of the isopropyl group. In
this case, the isopropyl triflate gave a noticeably better re-
sult compared to the isopropyl iodide (entries 6, 7). More-
over, ester functionality was introduced by the reaction of
2a with methyl bromoacetate and methyl 2-bromopropi-
onate (entries 8, 9). Phenacyl bromide turned out to be a
sensitive substrate under these reaction conditions, and
transmetalation to zinc had to be performed before the ad-
dition of phenacyl bromide (entry 10). Alkylation reaction
conditions do not tolerate a free hydroxy group. However,
alkylation with TMS protected 3-iodopropan-1-ol was
easy, furnishing the unprotected alcohol 3j (as the result
of acidic deprotection in situ) in 65% isolated yield (entry
11). In this case, the dihydropurine 3j showed low stabil-
ity and substantial decomposition within a couple of days
upon standing at room temperature.
Table 1 Alkylation of 9-tert-Butoxycarbonyl-6-chloro-7,8-dihy-
dropurine (2a) with Alkyl Halidesa
Entry
RX
Product
3a
Yield (%)b
1
2
MeI
91
84
91
91
91
53
88
90
84
87
65
MeCH2CH2I
PhCH2Br
3b
3
3c
4
CH2=CHCH2Br
HC≡CCH2Br
Me2CHI
3d
5
3e
6
3f
7
Me2CHOTf
MeCO2CCH2Br
MeCO2CH(Br)Me
PhCOCH2Brc
TMSOCH2CH2CH2I
3f
8
3g
9
3h
10
11
3i
3jd,e
a Reaction conditions: LiHMDS (1.05 equiv, 1 M solution in THF)
was added to a solution of dihydropurine 2a (1.0 equiv) in anhyd
DMF (4 mL/mmol) and THF (1.3 mL/mmol) at –78 °C. The resulting
mixture was stirred for 1 min at –78 °C, followed by the addition of
alkyl halide (1.5 equiv). The mixture was then stirred for 20 min at r.t.
b Isolated yields.
c Li to Zn transmetalation was performed before phenacyl bromide
was added.
d Compound partially decomposed upon standing at r.t. within a cou-
ple of days.
e After acidic deprotection.
Cl
Cl
R
H
N
1. LiHMDS
2. RX
N
O
N
N
Cl
N
Cl
N
R
H
N
N
N
N
N
N
N
RCOX
N
N
Boc
Boc
3
2a
DMAP, DIPEA
N
Boc
Boc
Scheme 1 Alkylation of 9-tert-butoxycarbonyl-6-chloro-7,8-dihy-
dropurine (2a)
2a
4
Scheme 2 Acylation of 6-chloro-7,8-dihydropurine 2a
With the purpose of protecting the N7-position for further
potential synthetic transformations, acylation of the dihy-
dropurine 2a was also performed (Scheme 2, Table 2).
Thus, the reaction of 2a with acetic anhydride in the pres-
ence of DMAP gave the 7-acetylated product 4a in 97%
yield (Table 2, entry 1). Also, acetic acid in the presence
of N,N-diisopropylcarbodiimide (DIC) and diisopropyl-
ethylamine (DIPEA) could be used for acetylation. This
reaction was relatively slow and required 20% DMAP to
be completed within 24 hours (entry 2). For the introduc-
tion of other acyl groups, the reaction with acyl chlorides
in the presence of DMAP and DIPEA was used. The reac-
tion proceeded smoothly with pivaloyl chloride and
anisoyl chloride, while 2,2,2-trichloroethyl chloroformate
reacted slower and the reaction with tosyl chloride re-
quired 24 hours to reach completion (entries 3–6). The
yields, however, were excellent in all cases.
tron-withdrawing groups at the b-position, was addressed
next (Scheme 3). Initial screening of the reactivity of 2a
with methyl acrylate in the presence of LiHMDS failed to
give any isolable amount of 5a and decomposition of the
starting compound 2a was observed. A similar reactivity
pattern, involving decomposition of the starting dihydro-
purine 2a, was also observed when NaH or K2CO3 was
used as the base (Table 3, entries 1–3). Triethylamine did
not give any expected product and the unreacted starting
compound was detected in the reaction mixture (entry 4).
However, when 1.2 equivalents of DBU in anhydrous
DMF at room temperature was used, 2a was readily con-
verted into 5a within two hours in 92% isolated yield
(Table 3, entry 5). Surprisingly, this reaction required
more than one equivalent of DBU. With 0.1 equivalent of
DBU, the reaction proceeded incompletely (entry 6). The
reactions became catalytic when DMF was replaced with
acetonitrile, giving 97% isolated yield of 5a using 0.1
equivalent of DBU (entry 7). In contrast, only 65% con-
Michael addition, which in principle enables the introduc-
tion of various functionalised alkyl chains bearing elec-
© Thieme Stuttgart · New York
Synthesis 2012, 44, 610–618

612
V. Kotek et al.
PAPER
Table 2 Preparation of N7-Acyl-6-chloro-7,8-dihydropurinesa
Time (h) Product Yield (%)b
Table 3 Reaction of Michael Acceptors with 2a in the Presence of
a Basea
Entry RCOX
Entry Alkene
Base
(amount)
Solvent
Product
(Yield, %)b
1
2
3
4
5
6
Ac2O
2
24
2
4a
4a
4b
4c
4d
4e
97
92
97
96
95
95
AcOH, DIC, DMAPc
t-BuCOCl
1
2
3
4
5
6
7
8
9
CH2=CHCO2Me LiHMDS
CH2=CHCO2Me NaH
CH2=CHCO2Me K2CO3
CH2=CHCO2Me Et3N
DMF–THF –c
c
DMF
–
–
–
c
4-MeOC6H4COCl
Cl3CCH2OCOCl
4-MeC6H4SO2Cl
10
15
24
DMF
d
DMSO
CH2=CHCO2Me DBU (1.2 equiv) DMF
CH2=CHCO2Me DBU (0.1 equiv) DMF
CH2=CHCO2Me DBU (0.1 equiv) MeCN
CH2=CHCO2Me DBU (0.1 equiv) THF
5a (92)
5ae
a Reaction conditions: acyl halide or anhydride (2 equiv) was added
to a solution of 7,8-dihydropurine 2a (1.0 equiv), DMAP (10 mol%),
and DIPEA (3 equiv) in anhyd CH2Cl2 (5 mL/mmol) cooled to 0 °C.
The resultant mixture was stirred at r.t.
5a (97)
5ae
b Isolated yields.
c Reaction conditions: to the suspension of 2a and DMAP (25 mol%)
in anhyd CH2Cl2 (5 mL/mmol) cooled to 0 °C were added AcOH (1.5
equiv) and DIC (1.5 equiv). The resultant mixture was stirred at r.t.
CH2=CHCN
DBU (0.1 equiv) MeCN
DBU (0.1 equiv) MeCN
DBU (0.1 equiv) MeCN
5b (97)
5c (95)
10 CH2=CHCOMe
11 CH2=CHCHO
f
–
version was observed in THF (entry 8). This phenomenon
can be explained by the change of relative pKa values of
the reagents in different solvents. Similar results as with
methyl acrylate in acetonitrile were obtained using acry-
lonitrile as the Michael acceptor. Also, but-3-en-2-one re-
acted catalytically and smoothly in acetonitrile (entries 9,
10). In contrast, with acrolein, a complex reaction mixture
was formed in which the expected product was not ob-
served (Table 3, entry 11).
a Reaction conditions: alkene (2.0 equiv) and the base were added to
a solution of 7,8-dihydropurine (1.0 equiv) in an anhyd solvent (4 mL/
mmol), and the reaction mixture was stirred for 2 h at r.t.
b Isolated yields.
c Decomposition of 2a was observed.
d No reaction was observed.
e Incomplete conversion of 2a into 5a was noted even at elevated tem-
perature.
f Complex mixture was formed.
ester, ketone, and nitrile functionality were introduced to
position 7 in high yields starting from 7,9-disubstituted
7,8-dihydropurines 3a, 3c, 3d, 3e, and 5a–c. In the case of
the derivatives 6b, 6e, and 6g, a three-step procedure start-
ing from 2a including alkylation, deprotection and reoxi-
dation with chromatographic purification of the final
product 6 was also performed. Thus, 7-alkylated purines
6b, 6e, and 6g were isolated in 81, 75, and 92% yield, re-
spectively (Table 4, entries 2, 5, and 6).
EWG
Cl
N
Cl
N
H
N
N
N
conditions
N
N
+
EWG
N
Boc
Boc
2a
5
Scheme 3 Reaction of Michael acceptors with 2a
In summary, we have demonstrated that a Boc protecting
group is suitable for the synthesis of 7-substituted purines
via 7,8-dihydropurines. Compared to the earlier reported
9-trityl derivatives, the 9-Boc-7,8-dihydropurines are less
prone to the oxidation and therefore significantly expand
the synthetic possibilities of 7,8-dihydropurines. Thus, 6-
chloro-9-Boc-9H-purine is reduced quantitatively with
THF·BH3 in anhydrous THF. The obtained 7,8-dihydro-
purine derivative is more stable compared to the corre-
sponding trityl and benzyl derivatives and can be readily
alkylated, acylated, or it can serve as an N-nucleophile in
conjugate additions. The 7-substituted purines can then be
easily obtained by Boc-deprotection with trifluoroacetic
acid followed by MnO2 oxidation in overall yields ranging
from 79–89%. Moreover, the described protocol can be
further simplified, and it is possible to perform alkylation
or Michael addition followed by deprotection and oxida-
tion on the crude isolated intermediates using chromatog-
raphy only for the isolation of the final 7-substituted 6-
Finally, the conversion of representative examples of the
7-substituted 9-Boc-dihydropurine derivatives 3 and 5
into the corresponding 7-substituted purines 6 was accom-
plished (Scheme 4). The Boc-protective group was
smoothly removed by treatment with trifluoroacetic acid
in dichloromethane and the obtained N7-substituted pu-
rine was then, without purification, oxidised by MnO2 in
the same solvent. The summarised results in Table 4 show
uniformly high overall yields after both the deprotection
and oxidation steps. Thus, substituents bearing alkynyl,
Cl
Cl
R
R
N
N
1. TFA, CH2Cl2
N
N
2. MnO2, CH2Cl2
N
N
N
N
Boc
3 or 5
6
Scheme 4 Preparation of 7-substituted 6-chloropurines 6
Synthesis 2012, 44, 610–618
© Thieme Stuttgart · New York

PAPER
Preparation of 7-Substituted 6-Halopurines
613
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydropurine (2a)
Table 4 Preparation of 7-Substituted 6-Chloropurines 6
THF·BH3 (110 mL, 0.11 mol, 1 M solution in THF) was added to a
solution of 1a (25.5 g, 0.10 mol) in anhyd THF (300 mL) cooled to
–78 °C. Then, the mixture was warmed to 0 °C, stirred 30 min, di-
luted with CH2Cl2 (500 mL), quenched by the addition of aq NH4Cl
(500 mL), and extracted with CH2Cl2 (2 × 500 mL). Collected or-
ganic layers were dried (Na2SO4), concentrated in vacuo, and the
isolated crude product was filtered through silica gel (300 g) using
EtOAc–CH2Cl2 (1:3) mixture. The solvents were evaporated in vac-
uo and the title compound was isolated as a white solid; yield: 25.3
g (99%); mp >185 °C (dec.).
Entry Starting
material
R
Product
Yield (%)
(yield, %)a,b starting from 2ac
1
2
3
4
5
6
7
3a
3c
3d
3e
5a
5b
5c
Me
6a (92)
6b (94)
6c (93)
6d (91)
6e (97)
6f (87)
6g (91)
84
CH2Ph
86, (81)d
85, (90)d
83
CH2CH=CH2
CH2C≡CH
CH2CH2CO2Me
CH2CH2CN
CH2CH2COMe
IR (ATR): 3297, 2981, 2909, 1730, 1596, 1569, 1504, 1463, 1423,
1358, 1292, 1257, 1218, 1154, 1126, 1092, 1061, 907, 848, 769,
660 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.47 [s, 9 H, C(CH3)3], 5.18 (s,
2 H, CH2), 6.98 (br s, 1 H, NH), 7.91 (s, 1 H, H-2).
89 (93)d
79
79 (92)d
a Reaction conditions: N7-substituted dihydropurine 3 or 5 (1.0 equiv)
was added to a solution of trifluoroacetic acid (1 mL/mmol) in anhyd
CH2Cl2 (1 mL/mmol). The mixture was stirred for 90 min at r.t., and
after workup (see experimental), the crude isolated product was
mixed with MnO2 (5.0 equiv) and CH2Cl2 (5 mL/mmol) and stirred
for 1 h at r.t.
13C NMR (75 MHz, DMSO-d6): d = 28.4, 65.1, 82.9, 132.0, 132.7,
147.8, 148.8, 154.8.
HRMS (EI): m/z calcd for C10H13ClN4O2: 256.0727; found:
256.0724.
b Isolated yield starting from pure 3 or 5 after two steps.
c Overall isolated yield starting from 2a after three steps with isolation
of the intermediate 3 or 5.
9-tert-Butoxycarbonyl-7,8-dihydro-6-iodopurine (2b)
THF·BH3 (11 mL, 11 mmol, 1 M solution in THF) was added to a
solution of 1b (3.46 g, 0.10 mol) in anhyd THF (30 mL) cooled to
–78 °C. Then the mixture was warmed to 0 °C, stirred 30 min, di-
luted with CH2Cl2 (50 mL), quenched by the addition of aq NH4Cl
(500 mL), and extracted with CH2Cl2 (2 × 500 mL). Collected or-
ganic layers were dried (Na2SO4), concentrated in vacuo, and the
isolated crude product was filtered through silica gel (300 g) using
EtOAc–CH2Cl2 (1:3) mixture. The solvents were evaporated in vac-
uo and the title compound was isolated as a yellow solid; 3.44 g
(99%); mp >165 °C (dec.).
d Overall isolated yield starting from 2a after three steps using column
chromatography only for the isolation of final product 6.
chloro-7H-purines. Further studies on the reactivity of
7,8-dihydropurines and their applications in the synthesis
of novel purine derivatives are ongoing in our laboratory.
IR (ATR): 3238, 2979, 2902, 1732, 1593, 1564, 1456, 1392, 1367,
1307, 1287, 1257, 1207, 1152, 1126, 1058, 884, 842, 787, 766 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 [s, 9 H, C(CH3)3], 4.31 (br s,
1 H, NH), 5.31 (s, 2 H, CH2), 8.03 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.3, 63.6, 84.1, 99.7, 138.2,
148.8, 149.8, 151.5.
All reactions were performed under an argon atmosphere. NMR
spectra were measured on a Varian Gemini 300 (1H, 300.07 MHz;
13C, 75.46 MHz) spectrometer at 298 K. IR spectra were recorded
on Nicolet 6700 with continuum microscope. High-resolution mass
spectra were recorded on LTQ Orbitrap Velos spectrometer (Ther-
mo Scientific). The solvents were dried and degassed by standard
procedures; silica gel (Merck, Silica Gel 60, 40–63 mm) was used
for column chromatography. 9-tert-Butoxycarbonyl-6-chloro-9H-
purine (1a),13 isopropyl triflate,17 and 1-[(trimethylsilyl)oxy]-3-
iodopropane18 were prepared by the reported procedures; other
compounds were purchased.
HRMS (EI): m/z calcd for C10H13IN4O2: 348.0083; found: 348.
0070.
Alkylation of Dihydropurine 2a; General Procedure
LiHMDS (1.05 equiv, 1 M solution in THF) was added to a solution
of dihydropurine 2a (1.0 equiv) in anhyd DMF (4 mL/mmol) and
THF (1.3 mL/mmol) at –78 °C. The resultant mixture was stirred
for 1 min at –78 °C, followed by the addition of alkyl halide (1.5
equiv). Then, the mixture was warmed to r.t., stirred 20 min,
quenched by the addition of aq NH4Cl (10 mL), and diluted with
EtOAc (35 mL). The organic layer was separated, washed with
brine (3 × 35 mL), and dried (Na2SO4). The solvents were evaporat-
ed in vacuo and column chromatography of the residue gave the fi-
nal product.
9-tert-Butoxycarbonyl-6-iodo-9H-purine (1b)
Anhyd THF (200 mL) was added to a mixture of 6-iodo-9H-purine
(24.6 g, 0.1 mol) and Boc2O (22.9 g, 0.105 mol). The mixture was
vigorously stirred followed by the addition of Et3N (10 mL, 0.072
mol). Then the mixture was stirred 1 h at r.t., concentrated in vacuo,
dissolved in CH2Cl2 (80 mL), and filtered (hexane–EtOAc, 1:2)
through silica gel (200 g). Subsequent crystallisation from hexane–
EtOAc (1:2) gave the title compound as a white solid; yield: 31.9 g
(92%); mp >110 °C (dec.).
IR (ATR): 3119, 3010, 2975, 2933, 1785, 1759, 1581, 1550, 1488,
1436, 1374, 1344, 1330, 1293, 1258, 1218, 1203, 1163, 1088, 913,
838, 821, 764 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.70 [s, 9 H, C(CH3)3], 8.55 (s, 1
H, Pu-H), 8.77 (s, 1 H, Pu-H).
13C NMR (75 MHz, CDCl3): d = 28.1, 88.2, 123.1, 139.5, 143.4,
145.8, 147.6, 154.1.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-methylpurine
(3a)
Following the general procedure, starting from 2a (0.771 g, 3.0
mmol), LiHMDS (3.15 mL, 3.15 mmol, 1 M solution in THF), MeI
(0.639 g, 4.5 mmol), anhyd DMF (12 mL), and anhyd THF (3.9
mL), the title compound was obtained after column chromatogra-
phy (silica gel, hexane–EtOAc, 1:1) as a white solid; yield: 0.739 g
(91%); mp 88–90 °C.
HRMS (EI): m/z calcd for C10H11IN4O2: 345.9927; found:
IR (ATR): 2975, 2931, 2855, 1744, 1709, 1587, 1568, 1476, 1438,
1412, 1393, 1366, 1329, 1311, 1299, 1260, 1149, 1080, 977, 888,
852, 816, 761, 727 cm–1.
345.9924.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 610–618

614
V. Kotek et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.55 [s, 9 H, C(CH3)3], 3.13 (s, 3
H, CH3), 5.11 (s, 2 H, CH2), 8.11 (s, 1 H, H-2).
HRMS (EI): m/z calcd for C13H17ClN4O2: 296.1040; found:
296.1035.
13C NMR (75 MHz, CDCl3): d = 28.3, 35.1, 70.8, 84.0, 131.2,
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-propargylpu-
rine (3e)
133.0, 148.2, 148.5, 155.2.
HRMS (EI): m/z calcd for C11H15ClN4O2: 270.0884; found:
270.0887.
Following the general procedure, starting from 2a (0.514 g, 2.0
mmol), LiHMDS (2.1 mL, 2.1 mmol, 1 M solution in THF), prop-
argyl bromide (0.357 g, 3.0 mmol), anhyd DMF (8 mL), and anhyd
THF (2.6 mL), the title compound was obtained after column chro-
matography (silica gel, hexane–EtOAc, 1:1) as a white solid; yield:
0.536 g (91%); mp 92–94 °C.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-propylpurine
(3b)
Following the general procedure, starting from 2a (0.257 g, 1.0
mmol), LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF), pro-
pyl iodide (0.255 g, 1.5 mmol), anhyd DMF (4 mL), and anhyd THF
(1.3 mL), the title compound was obtained after column chromatog-
raphy (silica gel, hexane–EtOAc, 1:1) as a colourless amorphous
solid; yield: 0.251 g (84%).
IR (ATR): 3297, 3071, 2987, 2855, 1703, 1570, 1503, 1472, 1453,
1437, 1416, 1371, 1343, 1297, 1266, 1225, 1183, 1159, 1098, 1013,
920, 891, 850, 815, 764, 734, 682, 659 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.57 [s, 9 H, C(CH3)3], 2.28 (t,
J = 2.4 Hz, 1 H, CH), 4.25 (d, J = 2.4 Hz, 2 H, NCH2), 5.18 (s, 2 H,
CH2), 8.21 (s, 1 H, H-2).
IR (ATR): 2964, 2933, 2873, 1749, 1705, 1566, 1503, 1469, 1446,
1420, 1392, 1367, 1344, 1290, 1256, 1224, 1201, 1165, 1146, 1103,
1086, 988, 889, 760, 732 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.5 Hz, 3 H, CH3),
1.52 [s, 9 H, C(CH3)3], 1.59 (m, 2 H, CH2), 3.40 (t, J = 7.4 Hz, 2 H,
NCH2), 5.11 (s, 2 H, CH2), 8.03 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.3, 68.5, 74.5, 77.2, 84.2, 29.5,
136.2, 148.3, 150.5, 156.2.
HRMS (EI): m/z calcd for C13H15ClN4O2: 294.0884; found:
294.0884.
13C NMR (75 MHz, CDCl3): d = 11.2, 21.5, 28.3, 49.4, 69.1, 84.0,
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-isopropylpurine
(3f)
130.7, 132.3, 148.1, 148.3, 155.2.
HRMS (EI): m/z calcd for C13H19ClN4O2: 298.1197; found:
298.1199.
Following the general procedure, starting from 2a (0.257 g, 1.0
mmol), LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF), iso-
propyl triflate (1.5 mL of freshly prepared 1 M solution in CCl4), an-
hyd DMF (4 mL), and anhyd THF (1.3 mL), the title compound was
obtained after column chromatography (silica gel, hexane–EtOAc,
1:1) as a white solid; yield: 0.263 g (88%). The same procedure us-
ing isopropyl iodide (0.15 mL, 1.5 mmol) instead of isopropyl tri-
flate afforded the same product; yield: 0.158 g (53%); mp 88–90 °C.
9-tert-Butoxycarbonyl-7-benzyl-6-chloro-7,8-dihydropurine
(3c)
Following the general procedure, starting from 2a (1.29 g, 5.0
mmol), LiHMDS (5.25 mL, 5.25 mmol, 1 M solution in THF), ben-
zyl bromide (0.941 g, 5.5 mmol), anhyd DMF (20 mL), and anhyd
THF (6.5 mL), the title compound was obtained after column chro-
matography (silica gel, hexane–EtOAc, 1:1) as a white solid; yield:
1.574 g (91%); mp 93–95 °C.
IR (ATR): 2981, 2970, 2933, 1710, 1564, 1474, 1445, 1415, 1393,
1368, 1322, 1294, 1271, 1249, 1211, 1152, 1032, 972, 762 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (d, J = 9.9 Hz, 6 H, 2 CH3),
1.51 [s, 9 H, C(CH3)3], 4.57 (m, 1 H, CH), 5.08 (s, 1 H, CH2), 8.01
(s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 19.4, 28.3, 47.0, 63.2, 84.0, 130.1,
132.8, 148.3, 148.5, 155.8.
IR (ATR): 2984, 2930, 2869, 1704, 1596, 1473, 1444, 1423, 1392,
1367, 1334, 1300, 1261, 1157, 1083, 1018, 999, 915, 887, 849, 816,
775, 761, 728, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51 [s, 9 H, C(CH3)3], 4.73 (s, 2
H, CH2), 5.04 (s, 2 H, CH2), 7.26–7.40 (m, 5 H, C6H5), 8.13 (s, 1 H,
H-2).
HRMS (ES): m/z [M + Na]+ calcd for C13H19ClN4O2 + Na:
321.10942; found: 321.10867.
13C NMR (75 MHz, CDCl3): d = 28.3, 51.5, 68.6, 84.2, 128.0,
128.4, 129.2, 130.5, 132.9, 136.1, 148.3, 148.7, 155.2.
Methyl (9-tert-Butoxycarbonyl-6-chloro-7,8-dihydropurin-7-
yl)acetate (3g)
HRMS (EI): m/z calcd for C17H19ClN4O2: 346.1197; found:
246.1194.
Following the general procedure, starting from 2a (0.257 g, 1.0
mmol), LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF),
methyl bromoacetate (0.230 g, 1.5 mmol), anhyd DMF (4 mL), and
anhyd THF (1.3 mL), the title compound was obtained column
chromatography (silica gel, hexane–EtOAc, 1:1) as a white solid;
yield: 0.296 g (90%); mp 125–129 °C.
7-Allyl-9-tert-butoxycarbonyl-6-chloro-7,8-dihydropurine (3d)
Following the general procedure, starting from 2a (0.514 g, 2.0
mmol), LiHMDS (2.1 mL, 2.1 mmol, 1 M solution in THF), allyl
bromide (0.363 g, 3.0 mmol), anhyd DMF (8 mL), and anhyd THF
(2.6 mL), the title compound was obtained after column chromatog-
raphy (silica gel, hexane–EtOAc, 1:1) as a white solid; yield: 0.543
g (91%); mp 76–80 °C.
IR (ATR): 2978, 2958, 2935, 2875, 1750, 1711, 1698, 1570, 1501,
1468, 1420, 1396, 1369, 1349, 1297, 1263, 1237, 1222, 1181, 1157,
1101, 1028, 983, 927, 891, 850, 818, 779, 766, 741, 701, 656 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 [s, 9 H, C(CH3)3], 3.76 (s, 3
H, OCH3), 4.29 (s, 2 H, CH2), 5.21 (s, 2 H, CH2), 8.14 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.3, 48.0, 52.8, 69.4, 84.2, 129.9,
133.2, 148.1, 149.3, 155.4, 167.5.
IR (ATR): 2982, 2934, 2864, 1709, 1569, 1503, 1471, 1440, 1420,
1393, 1370, 1335, 1301, 1268, 1191, 1154, 1090, 991, 936, 912,
887, 849, 817, 763, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 [s, 9 H, C(CH3)3], 4.10 (d,
J = 6.3 Hz, 2 H, NCH2), 5.10 (s, 2 H, CH2), 5.28 (d, J = 11.1 Hz, 1
H, =CH2), 5.29 (d, J = 16.5 Hz, 1 H, =CH2), 5.82 (m, 1 H, =CH),
8.10 (s, 1 H, H-2).
HRMS (EI): m/z calcd for C13H17ClN4O4: 328.0938; found:
328.0938.
13C NMR (75 MHz, CDCl3): d = 28.3, 50.2, 68.5, 84.1, 119.4,
130.2, 132.1, 133.2, 148.4, 148.8, 155.5.
Synthesis 2012, 44, 610–618
© Thieme Stuttgart · New York

PAPER
Preparation of 7-Substituted 6-Halopurines
615
Methyl (9-tert-Butoxycarbonyl-6-chloro-7,8-dihydropurin-7-
yl)propionate (3h)
HRMS (ES): m/z [M + Na]+ calcd for C13H19ClN4O3 + Na:
337.10435; found: 337.10324.
Following the general procedure, starting from 2a (0.257 g, 1.0
mmol), LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF),
methyl 2-bromopropionate (0.169 g, 1.5 mmol), anhyd DMF (4
mL), and anhyd THF (1.3 mL), the title compound was obtained af-
ter column chromatography (silica gel, hexane–EtOAc, 1:1) as a
white solid; yield: 0.288 g (84%); mp 90–93 °C.
Acylation of 7,8-Dihydropurine 2a; General Procedure
Acyl halide (2.0 equiv) was added to a solution of 7,8-dihydropu-
rine 2a (1.0 equiv), DMAP (10 mol%), DIPEA (3 equiv) in anhyd
CH2Cl2 (5 mL/mmol) cooled to 0 °C. The resultant mixture was
stirred at r.t. and concentrated in vacuo. The product was purified
by column chromatography.
IR (ATR): 2982, 2958, 1738, 1709, 1564, 1500, 1456, 1418, 1392,
1369, 1334, 1297, 1263, 1221, 1196, 1155, 1111, 1065, 975, 960,
883, 847, 817, 763, 723 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.49 (m, 3 H, CHCH3), 1.51 [s, 9
H, C(CH3)3], 3.68 (s, 3 H, OCH3), 5.10 (q, J = 7.2 Hz, 1 H, CHCH3),
5.18 (m, 2 H, CH2), 8.08 (s, 1 H, H-2).
7-Acetyl-9-tert-butoxycarbonyl-6-chloro-7,8-dihydropurine
(4a)
Following the general procedure, a mixture of 2a (0.257 g, 1.0
mmol), DMAP (0.012 g, 0.1 mmol), DIPEA (0.51 mL, 3.0 mmol),
and Ac2O (0.19 mL, 2.0 mmol) was stirred for 2 h at r.t. and con-
centrated in vacuo. Column chromatography of the residue (silica
gel, hexane–EtOAc, 1:1) gave the title compound as a white solid;
yield: 0.289 g (97%); mp 157–161 °C.
13C NMR (75 MHz, CDCl3): d = 18.0, 28.2, 53.0, 54.1, 65.9, 84.1,
130.1, 133.9, 148.1, 149.6, 155.7, 172.1.
HRMS (EI): m/z calcd for C14H19ClN4O4: 342.1095; found:
342.1094.
IR (ATR): 2984, 2930, 1745, 1695, 1586, 1563, 1468, 1416, 1384,
1372, 1306, 1256, 1215, 1199, 1155, 1138, 1090, 1037, 1006, 905,
884, 848, 813, 756, 719 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.58 [s, 9 H C(CH3)3], 2.34 (s, 3
H, CH3), 5.56 (s, 2 H, CH2), 8.49 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 23.8, 28.3, 65.6, 85.1, 123.1,
144.1, 147.6, 154.7, 157.6, 169.4.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-phenacylpurine
(3i)
LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF) was added to
a solution dihydropurine 2a (0.257 g, 1.0 mmol) in anhyd DMF (4
mL) and anhyd THF (1.3 mL) at –78 °C. The resultant mixture was
stirred 1 min at –78 °C, followed by the addition of ZnBr2 (1.0 mL,
1.0 mmol, 1 M solution in THF). Then, the reaction mixture was
stirred 30 min at –78 °C, followed by the addition of phenacyl bro-
mide (0.22 g, 1.1 mmol). The mixture was then warmed to r.t.,
stirred for 20 min, quenched with aq NH4Cl (10 mL), and diluted
with EtOAc (35 mL). The organic layer was washed with brine (3 ×
35 mL) and dried (Na2SO4). The solvents were evaporated in vacuo
and column chromatography of the residue (silica gel, hexane–
EtOAc, 1:1) gave the final product as a yellow solid; yield: 0.325 g
(87%); mp 159–161 °C.
HRMS (EI): m/z calcd for C12H15ClN4O3: 298.0833; found;
298.0836.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-pivaloylpurine
(4b)
Following the general procedure, a mixture of 2a (0.257 g, 1.0
mmol), DMAP (0.012 g, 0.1 mmol), DIPEA (0.51 mL, 3.0 mmol),
and pivaloyl chloride (0.25 mL, 2.0 mmol) was stirred for 2 h at r.t.
and concentrated in vacuo. Column chromatography of the residue
(silica gel, hexane–EtOAc, 1:1) gave the title compound as a white
solid; yield: 0.33 g (97%); mp 141–144 °C.
IR (ATR): 2973, 2947, 1744, 1689, 1585, 1473, 1434, 1396, 1370,
1316, 1290, 1256, 1232, 1180, 1153, 1088, 1019, 986, 911, 888,
847, 832, 754, 686 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.57 [s, 9 H, C(CH3)3], 4.99 (s, 2
H, CH2), 5.25 (s, 2 H, CH2), 7.5–7.7 (m, 3 H, C6H5), 7.94 (dd,
J = 1.5, 8.4 Hz, 2 H, C6H5), 8.15 (s, 1 H, H-2).
IR (ATR): 2985, 1708, 1687, 1591, 1565, 1449, 1383, 1370, 1330,
1286, 1251, 1190, 1141, 1074, 1038, 894, 876, 840, 771, 749, 694
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 9 H, C(CH3)3], 1.59 [s, 9
H, C(CH3)3], 5.57 (s, 2 H, CH2), 8.74 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.2, 28.3, 40.9, 65.5, 84.9, 125.2,
146.4, 148.1, 154.4, 156.1, 177.5.
13C NMR (75 MHz, CDCl3): d = 28.3, 52.7, 69.7, 84.1, 128.1,
129.3, 130.7, 132.6, 134.2, 134.5, 148.8, 149.4, 155.5, 193.9.
HRMS (EI): m/z calcd for C18H19ClN4O3: 374.1146; found:
374.1132.
HRMS (EI): m/z calcd for C15H21ClN4O3: 340.1302; found:
340.1303.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-(3-hydroxypro-
pyl)purine (3j)
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-(4-methoxyben-
zoyl)purine (4c)
Following the general procedure, starting from 2a (0.257 g, 1.0
mmol), LiHMDS (1.05 mL, 1.05 mmol, 1 M solution in THF), tri-
methyl(3-iodopropyloxy)silane (0.387 g, 1.5 mmol), anhyd DMF (4
mL), anhyd THF (1.3 mL), and acidic deprotection (1 M AcOH–
MeOH/silica gel), the title compound was obtained after column
chromatography (silica gel, hexane–EtOAc, 1:1) as a colourless oil;
0.219 g (65%).
Following the general procedure, a mixture of 2a (0.257 g, 1.0
mmol), DMAP (0.012 g, 0.1 mmol), DIPEA (0.51 mL, 3.0 mmol),
and 4-methoxybenzoyl chloride (0.27 g, 2.0 mmol) was stirred for
15 h at r.t., and concentrated in vacuo. Column chromatography of
the residue (silica gel, hexane–EtOAc, 1:1) gave the title compound
as a white solid; yield: 0.371 g (95%); mp 162–165 °C.
IR (ATR): 3401, 2978, 2931, 2874, 1739, 1709, 1589, 1567, 1589,
1567, 1468, 1450, 1421, 1369, 1323, 1291, 1255, 1142, 1079, 888,
761 cm–1.
IR (ATR): 2978, 1742, 1668, 1604, 1579, 1564, 1513, 1447, 1422,
1384, 1369, 1302, 1257, 1236, 1188, 1133, 1089, 1019, 884, 862,
843, 809, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48 [s, 9 H, C(CH3)3], 1.80 (m, 2
H, CH2), 3.55 (t, J = 7.2 Hz, 2 H, CH2), 3.69 (t, J = 6.0 Hz, 2 H,
CH2), 5.12 (s, 2 H, CH2), 7.98 (s, 1 H, H-2).
1H NMR (300 MHz, CDCl3): d = 1.44 [s, 9 H, C(CH3)3], 3.80 (s, 3
H, CH3), 5.45 (s, 2 H, CH2), 6.91 (d, J = 8.7 Hz, 2 H, ArH), 7.61 (d,
J = 8.7 Hz, 2 H, ArH), 8.39 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.3, 31.0, 45.1, 59.7, 69.3, 84.2,
130.7, 132.2, 148.1, 148.2, 155.4.
13C NMR (75 MHz, CDCl3): d = 28.3, 55.8, 67.5, 85.0, 114.6,
124.4, 124.8, 131.2, 145.7, 150.0, 154.7, 157.2, 163.8, 168.4.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 610–618

616
V. Kotek et al.
PAPER
HRMS (EI): m/z calcd for C18H19ClN4O4: 390.1095; found:
HRMS (ESI): m/z calcd for C14H19ClN4O4: 342.1095; found:
390.1091.
342.1098.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-(2,2,2-trichloro-
ethoxycarbonyl)purine (4d)
3-(9-tert-Butoxycarbonyl-6-chloro-7,8-dihydropurin-7-yl)pro-
panenitrile (5b)
Following the general procedure, starting from 2a (1.285 g, 5.0
mmol), acrylonitrile (0.530 g, 10.0 mmol), DBU (0.912 g, 6.0
mmol), and anhyd MeCN (20 mL), the title compound was obtained
after column chromatography (silica gel, hexane–EtOAc, 1:1) as a
white solid; yield: 1.347 g (97%); mp 93–96 °C.
Following the general procedure, a mixture of 2a (0.257 g, 1.0
mmol), DMAP (0.012 g, 0.1 mmol), DIPEA (0.51 mL, 3.0 mmol),
and 2,2,2-trichloroethyl chloroformate (0.28 mL, 2.0 mmol) was
stirred for 10 h at r.t., and concentrated in vacuo. Column chroma-
tography of the residue (silica gel, hexane–EtOAc, 1:1) gave the ti-
tle compound as a beige solid; 0.41 g (97%); mp 138–142 °C.
IR (ATR): 2979, 2935, 2880, 1709, 1598, 1569, 1476, 1454, 1426,
1395, 1371, 1342, 1300, 1258, 1154, 1095, 1050, 886, 835, 762,
728 cm–1.
IR (ATR): 2986, 1736, 1590, 1562, 1472, 1416, 1400, 1309, 1288,
1216, 1160, 1138, 1087, 1036, 944, 887, 812, 754, 713 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.58 [s, 9 H, C(CH3)3], 4.92 (s, 2
1H NMR (300 MHz, CDCl3): d = 1.56 [s, 9 H, C(CH3)3], 2.73 (t,
J = 6.6 Hz, 2 H, CH2), 3.82 (t, J = 6.6 Hz, 2 H, CH2), 5.31 (s, 2 H,
CH2), 8.17 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 18.6, 28.3, 44.6, 69.7, 84.5, 117.7,
129.5, 133.4, 148.0, 149.5, 155.3.
H, CH2), 5.59 (s, 2 H, CH2), 8.50 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 28.3, 65.5, 76.0, 85.2, 94.5, 122.4,
144.6, 147.6, 150.3, 154.8, 156.9.
HRMS (EI): m/z calcd for C13H14Cl4N4O4: 429.9769; found:
429.9756.
HRMS (EI): m/z calcd for C13H16ClN5O2: 309.0993; found:
309.0994.
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-(4-toluenesulfo-
nyl)purine (4e)
9-tert-Butoxycarbonyl-6-chloro-7,8-dihydro-7-(3-oxobutyl)pu-
rine (5c)
Following the general procedure, starting from 2a (1.285 g, 5.0
mmol), but-3-en-2-one (0.70 g, 10.0 mmol), DBU (0.912 g, 6.0
mmol), and anhyd MeCN (20 mL), the title compound was obtained
after column chromatography (silica gel, hexane–EtOAc, 1:1) as a
white solid; yield: 1.418 g (95%); mp 115–118 °C.
Following the general procedure, a mixture of 2a (0.257 g, 1.0
mmol), DMAP (0.012 g, 0.1 mmol), DIPEA (0.51 mL, 3.0 mmol),
and 4-toluenesulfonyl chloride (0.381 g, 2.0 mmol) was stirred for
24 h at r.t., and concentrated in vacuo. Column chromatography of
the residue (silica gel, hexane–EtOAc, 1:1) gave the title compound
as a white solid; 0.390 g (95%); mp 154–157 °C.
IR (ATR): 2980, 2931, 1715, 1590, 1567, 1484, 1449, 1396, 1373,
1348, 1301, 1244, 1175, 1160, 1087, 1057, 1017, 975, 896, 870,
845, 817, 802, 784, 762, 708, 671 cm–1.
IR (ATR): 2984, 2939, 2860, 1706, 1667, 1598, 1573, 1499, 1465,
1425, 1370, 1352, 1295, 1251, 1167, 1154, 1096, 1068, 1050, 986,
927, 888, 851, 760, 728 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47 [s, 9 H, C(CH3)3], 2.38 (s, 3
H, CH3), 5.41 (s, 2 H, CH2), 7.24 (d, J = 8.8 Hz, 2 H, ArH), 7.53 (d,
J = 8.8 Hz, 2 H, ArH), 8.45 (s, 1 H, H-2).
1H NMR (300 MHz, CDCl3): d = 1.56 [s, 9 H, C(CH3)3], 2.22 (s, 3
H, CH3), 2.85 (t, J = 6.0 Hz, 2 H, CH2), 3.71 (t, J = 6.0 Hz, 2 H,
CH2), 5.20 (s, 2 H, CH2), 8.09 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 21.9, 28.2, 67.1, 84.9, 123.5,
127.7, 130.3, 132.6, 146.2, 149.2, 156.3, 159.6.
13C NMR (75 MHz, CDCl3): d = 28.3, 30.5, 42.6, 43.2, 69.9, 84.0,
130.4, 132.1, 148.1, 148.4, 155.3, 206.8.
HRMS: m/z calcd for C17H19ClN4O4S: 410.0816; found: 410.0807.
HRMS (EI): m/z calcd for C14H19ClN4O3: 326.1146; found:
326.1146.
Michael Addition Reactions of 7,8-Dihydropurine 2a; General
Procedure
Michael acceptor (2.0 equiv) and DBU (0.1 equiv) were added to a
suspension of 7,8-dihydropurine 2a (1.0 equiv) in anhyd MeCN (4
mL/mmol). The reaction mixture was then stirred for 2 h at r.t., con-
centrated in vacuo, and the product was purified by column chroma-
tography.
Deprotection and Oxidation of N7-Substituted Dihydropurines
3 and 5; General Procedure
N7-Substituted dihydropurine 3 or 5 (1 mmol, 1.0 equiv) was added
to a solution of trifluoroacetic acid (1 mL/mmol) in anhyd CH2Cl2
(1 mL/mmol). The mixture was stirred for 90 min at r.t., and con-
centrated in vacuo. Subsequently, CH2Cl2 (20 mL/mmol) was add-
ed and the organic layer was washed with sat. aq KHCO3 (20 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), the com-
bined organic layers were dried (Na2SO4), and concentrated in vac-
uo. The crude product was mixed with MnO2 (5 mmol, 5.0 equiv)
and CH2Cl2 (5 mL/mmol), stirred for 1 h at r.t., concentrated in vac-
uo, and the product was purified by column chromatography.
Methyl 3-(9-tert-Butoxycarbonyl-6-chloro-7,8-dihydropurin-7-
yl)propionate (5a)
Following the general procedure, starting from 2a (1.285 g, 5.0
mmol), methyl acrylate (0.860 g, 10.0 mmol), DBU (0.912 g, 6.0
mmol), and anhyd MeCN (20 mL), the title compound was obtained
after column chromatography (silica gel, hexane–EtOAc, 1:1) as a
white solid; 1.593 g (97%); mp 89–92 °C.
Simplified Preparation of N7-Substituted Purines from 9-tert-
Butoxycarbonyl-6-chloro-7,8-dihydropurine (2a) without Puri-
fication of Intermediates; General Procedure
IR (ATR): 3073, 2985, 2954, 2866, 1799, 1736, 1702, 1667, 1594,
1571, 1504, 1470, 1440, 1424, 1384, 1372, 1341, 1328, 1316, 1303,
1269, 1255, 1234, 1196, 1177, 1138, 1099, 1056, 994, 976, 885,
852, 819, 784, 764, 740, 710 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.56 [s, 9 H, C(CH3)3], 2.70 (t,
J = 6.2 Hz, 2 H, CH2), 3.78 (t, J = 6.2 Hz, 2 H, CH2), 3.71 (s, 3 H,
CH3), 5.20 (s, 2 H, CH2), 8.10 (s, 1 H, H-2).
N7-Substituted dihydropurines 3 and 5 were prepared following the
general procedures for the alkylation and the Michael addition of
2a. Crude N7-alkylated-7,8-dihydropurine 3 or 5, obtained by evap-
oration of the solvents, was dissolved in anhyd CH2Cl2 (1 mL/
mmol) followed by the addition of trifluoroacetic acid (1 mL/
mmol). The mixture was then stirred for 90 min at r.t., and concen-
trated in vacuo. Subsequently, CH2Cl2 (20 mL/mmol) was added
and the organic layer was washed with sat. aq KHCO3 (20 mL), the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL), the com-
13C NMR (75 MHz, CDCl3): d = 28.3, 34.0, 44.0, 53.2, 68.7, 84.1,
130.2, 132.7, 148.2, 148.7, 155.3, 172.0.
Synthesis 2012, 44, 610–618
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Preparation of 7-Substituted 6-Halopurines
617
bined organic layers were dried (Na2SO4) and concentrated in vac-
uo. The crude product obtained was mixed with MnO2 (5.0 equiv)
and CH2Cl2 (5 mL/mmol), stirred for 1 h at r.t., and concentrated in
vacuo. Column chromatography of the residue gave the desired N7-
substituted purine 6.
(6-Chloro-7H-purin-7-yl)propanenitrile (6f)
Following the general procedure, starting from 5b (0.310 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a white solid; yield: 0.189 g (91%); mp 160–163 °C.
IR (ATR): 3106, 2962, 2927, 1672, 1595, 1537, 1485, 1453, 1422,
1382, 1368, 1326, 1284, 1249, 1213, 1181, 1165, 1080, 1002, 975,
924, 903, 847, 822, 796, 731 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.20 (t, J = 6.6 Hz, 2 H, CH2),
4.77 (t, J = 6.6 Hz, 2 H, CH2), 8.82 (s, 1 H, Pu-H), 8.86 (s, 1 H, Pu-
6-Chloro-7-methyl-7H-purine (6a)
Following the general procedure, starting from 3a (0.271 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a white solid; yield: 0.157 g (92%); mp 200–202 °C (Lit.19
mp 198–199 °C).
H).
13C NMR (75 MHz, DMSO-d6): d = 20.5, 42.7, 118.7, 122.6, 143.0,
151.6, 152.5, 162.2.
1H NMR (300 MHz, DMSO-d6): d = 4.10 (s, 3 H, CH3), 8.74 (s, 1
H, Pu-H), 8.80 (s, 1 H, Pu-H); in accordance with the literature.20
HRMS (EI): m/z calcd for C8H6ClN5: 207.0312; found: 207.0305.
7-Benzyl-6-chloro-7H-purine (6b)
Following the general procedure, starting from 3c (0.347 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a white solid; yield: 0.229 g (94%); mp 150–152 °C (Lit.21
mp 153–154 °C).
6-Chloro-7-(3-oxobutyl)-7H-purine (6g)
Following the general procedure, starting from 5c (0.327 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a yellow solid; yield: 0.195 g (87%); mp 122–124 °C.
1H NMR (300 MHz, DMSO-d6): d = 5.75 (s, 2 H, CH2), 7.1–7.2 (m,
2 H, C6H5) 7.3–7.4 (m, 3 H, C6H5), 8.81 (s, 1 H, Pu-H), 9.00 (s, 1 H,
Pu-H); in accordance with the literature.21
IR (ATR): 3242, 3143, 3075, 2952, 2765, 1680, 1662, 1643, 1616,
1543, 1501, 1456, 1437, 1423, 1364, 1345, 1316, 1278, 1215, 1192,
1163, 1134, 1061, 1014, 983, 833, 799, 780, 764, 720, 689 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 3.10 (t, J = 7.1
Hz, 2 H, CH2), 4.74 (t, J = 7.1 Hz, 2 H, CH2), 8.41 (s, 1 H, Pu-H),
8.86 (s, 1 H, Pu-H).
13C NMR (75 MHz, CDCl3): d = 30.4, 41.5, 44.3, 122.3, 142.7,
151.1, 152.5, 162.2, 205.1.
7-Allyl-6-chloro-7H-purine (6c)
Following the general procedure, starting from 3d (0.297 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a white solid; yield: 0.181 g (93%); mp 93 °C (Lit.7 mp 93–
94 °C).
1H NMR (300 MHz, CDCl3): d = 5.13 (m, 2 H, CH2), 5.1–5.3 (m, 2
H, CH2), 6.08 (m, 1 H, =CH), 8.31 (s, 1 H, Pu-H), 8.75 (s, 1 H, Pu-
H); in accordance with the literature.22
HRMS (EI): m/z calcd for C9H9ClN4O: 224.0465; found: 224.0460.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra of 1b, 2a, 2b, 3a–j, 4a–e, 5a–c, 6a–g.
6-Chloro-7-propargyl-7H-purine (6d)
Following the general procedure, starting from 3e (0.295 g, 1.0
mmol) and MnO2 (0.435 g, 5.0 mmol), the title compound was ob-
tained after column chromatography (silica gel, EtOAc–MeOH,
20:1) as a yellow solid; yield: 0.175 g (91%); mp 108–111 °C (Lit.11
white foam, no mp given).
1H NMR (300 MHz, CDCl3): d = 2.68 (t, J = 1.2 Hz, 1 H, ≡CH),
5.29 (d, J = 1.2 Hz, 2 H, CH2), 8.48 (s, 1 H, Pu-H), 8.90 (s, 1 H, Pu-
Acknowledgment
This project was supported by the Research Centre ‘The Structure
and Synthetic Applications of Transition Metal Complexes–
LC06070’ of the Ministry of Education, Youth, and Sports of the
Czech Republic, by the Grant Agency of the Czech Republic (grant
no. 203/09/1552), and by Specific University Research (MSMT No.
21/2011).
H).
13C NMR (75 MHz, CDCl3): d = 37.5, 75.3, 77.6, 122.4, 143.4,
148.7, 152.9, 162.3; in accordance with the literature.11
References
Methyl 3-(6-Chloro-7H-purin-7-yl)propionate (6e)
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HRMS (EI): m/z calcd for C9H9ClN4O2: 240.0414; found:
240.0417.
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618
V. Kotek et al.
PAPER
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Synthesis 2012, 44, 610–618
© Thieme Stuttgart · New York