Regioselective functionalization of purine derivatives at positions 8 and 6 using hindered TMP-amide bases of Zn and Mg

Article abstract of DOI:10.1055/s-0033-1338524

A broad range of purine derivatives were efficiently metalated at positions 8 and 6 using TMP-amide bases. This provided polysubstituted purines in good to very good yields after subsequent trapping of the zinc or magnesium intermediates with various elec

Full text of DOI:10.1055/s-0033-1338524

PAPER
▌3029
paper
Regioselective Functionalization of Purine Derivatives at Positions 8 and 6
Using Hindered TMP-Amide Bases of Zn and Mg
Regioselective Functionalization of Purine Derivatives
François Crestey,1 Silvia Zimdars, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität, Butenandtstrasse 5–13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received: 05.08.2013; Accepted: 09.08.2013
of purine 1i and 1j with 1,2-dibromo-1,1,2,2-tetrachloro-
Abstract: A broad range of purine derivatives were efficiently
ethane proceeded under Barbier reaction conditions13 at
metalated at positions 8 and 6 using TMP-amide bases. This provid-
0 °C using bisamide zinc base TMP2Zn·2MgCl2·2LiCl.14
ed polysubstituted purines in good to very good yields after subse-
The 8-brominated compounds 3d and 3e were obtained
after 15 minutes in 82% and 75% yield, respectively (en-
tries 4, 5). Remarkably, using the same conditions as de-
scribed above compound 1f was brominated to furnish the
2,6,8-trihalogenopurine 3f bearing three different halo-
gens in 87% yield (entry 6). Similarly, derivative 1i react-
ed with S-phenyl benzenesulfonothioate under Barbier
reaction conditions at 0 °C affording 8-phenylthiopurine
3g in 60% yield (entry 7). Copper(I)-catalyzed allylation15
(10 mol% CuCN·2LiCl) of derivative 1f with 3-bromocy-
clohexene (–65 °C to 25 °C, 2 h) led to the allylated pu-
rine 3h in 84% yield (entry 8).
quent trapping of the zinc or magnesium intermediates with various
electrophiles.
Key words: purine derivatives, metalation, Negishi cross-cou-
pling, magnesium, zinc
As a result of the large variety of biologically active com-
pounds bearing a purine unit this scaffold became an im-
portant class of pharmacophores that has been extensively
studied in the last decades.2 Diverse combinatorial librar-
ies of functionalized purines have been synthesized by di-
rect C–H arylations3 or heterocylizations.4 Moreover, Pd-
and Fe-mediated reactions can allow access to several
simple 6,8-disubstituted and 2,6,8-trisubstituted purines.5
In addition, the more challenging approach, that is, cou-
pling of metalated purine derivatives with appropriate
electrophiles, have been developed via magnesiation,6
zincation,7 or lithiation.8 Recently, our group has de-
scribed for the first time the successive and selective gen-
eration of magnesium and zinc organometallic
intermediates at positions 6, 8, and 2 to furnish a large col-
lection of novel and highly designed purine derivatives.9
In the present work, we extend the study in the regioselec-
tive functionalization of purine scaffolds to the develop-
ment of an efficient metalation protocol at positions 8 and
6 of a wide range of purine derivatives using hindered
TMP-amide bases10 (TMP = 2,2,6,6-tetramethylpiperi-
dide).
R1
R1
R1
Cl
N
N
N
N
N
N
N
N
N
N
N
N
R2
N
S
N
N
N
MOM
MOM
Bn
THP
1i R1 = H
1j R1 = Cl
1a R1 = Cl, R2 = H
1b R1 = H, R2 = Cl
1c R1 = R2 = H
1h
1k
OMe
1d R1 = R2 = Cl
1e R1 = Cl, R2 = TMS
1f R1 = Cl, R2 = I
1g R1 = H, R2 = TMS
Figure 1 Array of protected purines examined in the study
R
N
R
N
R
N
N
N
N
i
ii
N
N
N
N
N
MetX
E
R'
R'
R'
N
PG
PG
PG
First, the starting materials 1 used in this study were bear-
ing a protecting group (PG) such as a methoxymethyl
(MOM), a benzyl (Bn), or a 2,2,3,3-tetrahydropyranyl
(THP) group (see Figure 1). Thus, a selective deproton-
ation at position 8 using either zinc- or magnesium-amide
bases generated a metalated species of type 2 as depicted
in Scheme 1. For example, purines 1a, 1i, and 1k were
readily zincated by using TMPZnCl·LiCl11 within 30 min-
utes at 25 °C. Subsequent trapping with iodine (1.2 equiv)
provided the corresponding iodinated compounds 3a–c in
60–98% yields (Table 1, entries 1–3). Notably, if organo-
magnesium reagent TMPMgCl·LiCl12 was used at –60 °C
the yield was only slightly affected (entry 2). Bromination
1
2
3
Scheme 1 General reaction scheme for the selective metalation of
purine derivatives of type 1 at position 8 and subsequent reaction with
an electrophile: Reagents and conditions: (i) TMP-amide base; (ii)
electrophile, 60–98%. See Table 1 for more details.
As shown in Scheme 2, the 8-zincated intermediates of
type 4 underwent Pd-catalyzed Negishi cross-coupling
reactions16 with Pd(dba)2 (2 mol%), (o-furyl)3P (4 mol%),
and various aryl iodides (1.2 equiv) within a few hours (2–
14 h) to afford the 8-arylated purines of type 5 in 48–97%
yields. For example, purine 1c was readily metalated by
using TMPZnCl·LiCl within 30 minutes at 25 °C. The or-
ganometallic intermediate reacted with either ethyl 4-io-
dobenzoate or 4-iodoanisole at 25 °C to provide the
purine derivatives 5a and 5b in 97% and 61% yield, re-
SYNTHESIS 2013, 45, 3029–3037
Advanced online publication: 02.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338524; Art ID: SS-2013-T0427-OP
© Georg Thieme Verlag Stuttgart · New York

3030
F. Crestey et al.
PAPER
spectively (Table 2, entries 1, 2). Similarly, compound 1a
furnished the 8-arylated 6-chloropurines 5c and 5d in 91%
and 95% yield, respectively (entries 3, 4). Noticeably, de-
rivative 5e was only detected in traces due to the deprot-
ection of the THP group during the cross-coupling
reaction. The unprotected arylated product was isolated
instead in 75% yield (entry 5). Remarkably, functional
groups like thioether and TMS are tolerated in position 2
during both the deprotonation and the Negishi cross-cou-
pling reaction (entries 9–12). In the case of purine 1e, the
cross-coupling reaction was performed at 45 °C for 14
hours leading to the trisubstituted purine 5l in 91% (entry
12). The same reaction was performed on 20 and 30 mmol
scales furnishing the expected product 5l in 70% and 85%
yield, respectively. Unfortunately attempts with aryl bro-
mides or heteroaryl halides as electrophiles for the
Negishi cross-coupling reaction failed.
Table 1 Synthesis and Yields of Purine Derivatives of Type 3
Entry
1
SMa
Electrophile
Productb
Cl
N
N
I
1a
I2
N
N
MOM
3a (98)c
N
N
N
I
N
2
3
4
5
1i
I2
Bn
3b (80)c (84)d
Cl
N
N
I
1k
1i
I2
N
N
THP
Table 2 Synthesis and Yields of Purine Derivatives of Type 5
3c (60)c
N
N
Br
Entry
1
SMa
ArI
Productb
N
N
(CCl2Br)2
(CCl2Br)2
Bn
N
CO2Et
N
3d (82)e
CO2Et
N
Cl
N
1c
MOM
N
N
N
Br
5a (97)c
I
1j
N
OMe
N
N
Bn
N
N
OMe
3e (75)e
2
3
1c
1a
MOM
Cl
5b (61)c
N
N
I
N
Br
Cl
6
7
8
1f
1i
1f
(CCl2Br)2
I
N
CO2Et
N
N
MOM
N
N
CO2Et
3f (87)e
MOM
N
N
N
I
SPh
5c (91)c
N
PhSO2SPh
Cl
Bn
OMe
N
N
3g (60)e
N
N
OMe
4
1a
Cl
MOM
N
N
I
5d (95)c
Br
N
I
N
Cl
MOM
CO2Et
N
N
3h (84)f
N
N
CO2Et
5
6
7
1k
1b
1d
a Starting material.
THP
b Yield (%) of isolated analytically pure product is given in parenthe-
ses.
I
5e (traces)d
c 1) TMPZnCl·LiCl (1.1 equiv), 25 °C, 30 min; 2) I2 (1.2 equiv),
25 °C, 1 h.
CO2Et
N
N
N
CO2Et
d 1) TMPMgCl·LiCl (1.1 equiv), –60 °C, 15 min; 2) I2 (1.2 equiv),
–60 °C, 2.5 h.
Cl
N
MOM
e 1) Electrophile (1 equiv), 0 °C, 5 min; 2) TMP2Zn·2MgCl2·2LiCl
(1.2 equiv), 0 °C to 25 °C, 15 min.
5f (58)c
I
f 1) ZnCl2 (1 equiv), 25 °C, 5 min; 2) TMPMgCl·LiCl (1.13 equiv),
–65 °C, 30 min; 3) CuCN·2LiCl (0.1 equiv), 3-bromocyclohexene
(1.4 equiv), –65 °C to 25 °C, 2 h.
Cl
CO2Et
N
N
N
CO2Et
Cl
N
MOM
I
5g (62)c
Synthesis 2013, 45, 3029–3037
© Georg Thieme Verlag Stuttgart · New York

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Regioselective Functionalization of Purine Derivatives
3031
Table 2 Synthesis and Yields of Purine Derivatives of Type 5
(continued)
coupling reactions of compound 5a and 5b with iodoben-
zene and ethyl 4-iodobenzoate in the presence of Pd(dba)2
(2 mol%) and (o-furyl)3P (4 mol%) gave the 6,8-bisarylated
products 7c and 7d in 55% and 63% yield, respectively
(entries 3, 4). Particularly, starting from derivative 5i and
using the same conditions described above a trisubstituted
purine 7e was obtained in 53% yield.
Entry
SMa
ArI
Productb
Cl
N
OMe
N
N
OMe
8
1d
Cl
N
MOM
Table 3 Synthesis and Yields of Purine Derivatives of Type 7
I
5h (71)c
Entry
SMa
Electrophile
Productb
N
N
N
F3C
I
TMS
N
9
1g
1h
CF3
MOM
N
N
I
CO2Et
5i (48)c
1
5a
I2
N
N
N
MOM
N
OMe
OMe
N
S
N
7a (70)
MOM
I
10
N
N
N
N
OMe
I
2
3
5b
5a
I2
OMe
MOM
5j (85)c
N
7b (60)
N
CO2Et
CO2Et
N
TMS
N
11
12
1g
1e
MOM
N
N
5k (52)c
I
N
N
CO2Et
Cl
I
CO2Et
MOM
N
N
CO2Et
7c (63)c
N
TMS
N
MOM
CO2Et
I
5l (91)e
CO2Et
a Starting material.
b Yield (%) of isolated analytically pure product is given in parenthe-
ses.
N
N
4
5b
N
N
OMe
c Obtained by palladium-catalyzed cross-coupling reaction using
Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) at 25 °C for 2–14 h.
d The deprotected product was obtained instead in 75% yield.
e Obtained by palladium-catalyzed cross-coupling reaction using
Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) at 45 °C for 14 h.
I
MOM
7d (55)c
CO2Et
CO2Et
CF3
R
N
R
N
R
N
N
5
5i
N
N
N
N
N
i
ii
N
N
N
N
N
ZnCl
Ar
TMS
N
I
R'
R'
R'
N
MOM
PG
PG
PG
1
4
5
7e (53)c
Scheme 2 General reaction scheme for the selective zincation of pu-
rine derivatives of type 1 at position 8 and subsequent Negishi cross-
coupling reaction with an aryl iodide. Reagents and conditions: (i)
TMPZnCl·LiCl (1.1 equiv), anhyd THF, 30 min, 25 °C; (ii) ArI (1.2
equiv), 48–97%. LiCl in 4 is omitted for clarity. See Table 2 for more
details.
a Starting material.
b Yield (%) of isolated analytically pure product is given in parenthe-
ses.
c Transmetalation with ZnCl2 (1.3 equiv) then palladium-catalyzed
cross-coupling reaction using Pd(dba)2 (2 mol%) and (o-furyl)3P (4
mol%) at 25 °C for 3–14 h.
The deprotonation at position 6 of the purine scaffold was
achieved with TMPMgCl·LiCl within 60 minutes at
–20 °C leading to organomagnesium intermediates of
type 6 as illustrated in Scheme 3. Thus, after subsequent
iodolysis purine derivatives 5a and 5b furnished the cor-
responding 6-iodopurines 7a and 7b in 70% and 60%
yield, respectively (Table 3, entries 1, 2). Negishi cross-
In conclusion, a regioselective functionalization of a
broad range of protected purine derivatives has been
achieved successfully at positions 8 and 6 via zinc and
magnesium intermediates providing a large variety of
polysubstituted purines after subsequent trapping with
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3029–3037

3032
F. Crestey et al.
PAPER
flux conditions for 3 h, then t-BuONO (0.50 mL, 4 mmol, 2 equiv)
was added again, and the mixture stirred for further 3 h. After cool-
ing to 25 °C, the solvents were removed in vacuo, and the crude ma-
terial was purified by column chromatography using a gradient
elution (CH2Cl2–MeOH, 100:0, then 100:1 to 30:1) to provide pu-
rine 1c; yield: 0.23 g (70%); pale yellow solid; mp 87–88 °C.
MgCl
N
R
N
N
N
N
i
ii
N
N
N
N
N
R
R
R
N
R'
N
R'
R'
MOM
MOM
MOM
5
6
7
Scheme 3 General reaction scheme for the selective magnesiation of
purine derivatives of type 5 at position 6 and subsequent reaction with
an electrophile. Reagents and conditions: (i) TMPMgCl·LiCl (1.2
equiv), anhyd THF, 1 h, –20 °C; (ii) electrophile, 53–70%. LiCl in 6
is omitted for clarity. See Table 3 for more details.
1H NMR (CDCl3): δ = 9.17 (s, 1 H), 9.01 (s, 1 H), 8.24 (s, 1 H), 5.64
(s, 2 H), 3.38 (s, 3 H).
13C NMR (CDCl3): δ = 153.1, 148.8, 145.2, 133.8, 73.9, 57.3.
MS (70 eV): m/z (%) = 164 (8), 135 (11), 134 (100), 133 (38), 78
(5), 45 (86).
various electrophiles. This study completes our previous
work9 by extending the scope of the purine scaffold and
allows access now to a wide library of highly substituted
compounds. Further studies concerning construction of
new substituted derivatives are currently in progress.
HRMS: m/z calcd for C7H8N4O: 164.0698; found: 164.0697.
2,6-Dichloro-9-(methoxymethyl)-9H-purine (1d)23
A solution of MOMCl (7.50 mL, 2 M in toluene, 15 mmol, 1.5
equiv) was added dropwise to a solution of 2,6-dichloro-9H-purine
(1.89 g, 10 mmol, 1.0 equiv) and K2CO3 (6.20 g, 45 mmol, 4.5
equiv) in DMF (20 mL) at 25 °C. The mixture was stirred at this
temperature for 3 h, and then quenched with H2O (20 mL). The
aqueous layer was extracted with EtOAc (2 × 40 mL), then the com-
bined organic layers were washed with H2O (60 mL) and brine (60
mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude
material was purified by column chromatography using a gradient
elution (CH2Cl2–EtOH, 100:0 then 500:1 to 100:1) to provide pu-
rine 1d; yield: 0.86 g (37%); white solid; mp 126–127 °C.
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes, which were used to transfer anhydrous
solvents or reagents, were purged with argon prior to use. THF was
continuously refluxed and freshly distilled from sodium benzophe-
none ketyl under N2. 2,2,6,6-Tetramethylpiperidine (TMPH) was
distilled prior to use. Yields refer to isolated compounds estimated
to be >95% pure as determined by 1H NMR spectroscopy (25 °C)
and capillary GC. NMR spectra were recorded on Bruker ARX-200,
AC-300, or WH-400 using CDCl3 as solvent. Standard abbrevia-
tions are used to indicate spin multiplicities. GC analyses were per-
formed with instruments of type Hewlett-Packard 6890 or 5890
series II using a column of type HP 5. Column chromatography was
performed using SiO2 (0.040–0.063 mm, 230–400 mesh ASTM)
from Merck. Melting points were measured using a Büchi B-540
apparatus and are uncorrected. Mass spectra and high-resolution
mass spectra (HRMS) were recorded on Finnigan MAT 95Q or
Finnigan MAT 90 instrument using electron impact (EI); where oth-
erwise noted electrospray ionization (ESI) was used.
TMPZnCl·LiCl,11 TMPMgCl·LiCl,12 TMP2Zn·2MgCl2·2LiCl,14
CuCN·2LiCl,17 ZnCl2,17 MOMCl solution in toluene18 as well as
purines 1a,19 1e,9 1i,20 1j,21 and 1k22 were prepared according to lit-
erature procedures. The freshly prepared TMP-amide bases were
titrated prior to use at 25 °C with benzoic acid using 4-(phenyl-
azo)diphenylamine as indicator.
1H NMR (CDCl3): δ = 8.27 (s, 1 H), 5.61 (s, 2 H), 3.41 (s, 3 H).
13C NMR (CDCl3): δ = 153.6, 152.1, 145.7, 130.6, 74.7, 57.6.
MS (70 eV): m/z (%) = 232 (9), 212 (9), 211 (12), 204 (40), 203
(20), 202 (62), 201 (21), 196 (12), 45 (100).
HRMS: m/z calcd for C7H6Cl2N4O: 231.9919; found: 231.9919.
6-Chloro-2-iodo-9-(methoxymethyl)-9H-purine (1f)
A solution of I2 (0.95 g, 3.75 mmol, 1.5 equiv) in anhydrous THF (4
mL) was added dropwise to a solution of 6-chloro-9-(methoxy-
methyl)-2-(tributylstannyl)-9H-purine (1.22 g, 2.5 mmol, 1.0
equiv) in anhydrous THF (12 mL) at 25 °C. The mixture was stirred
for 1 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aque-
ous layer was extracted with EtOAc (2 × 20 mL), then the combined
organic layers were washed with H2O (40 mL) and brine (60 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude ma-
terial was purified by column chromatography using pentane as el-
uent to furnish purine 1f; yield: 0.73 g (90%); pale yellow solid; mp
128–130 °C.
2-Chloro-9-(methoxymethyl)-9H-purine (1b)
A solution of MOMCl (30.0 mL, 2 M in toluene, 60 mmol, 2.3
equiv) was added dropwise to a solution of 2-chloro-9H-purine (4.0
g, 26 mmol, 1.0 equiv) and Et3N (7.2 mL, 52 mmol, 2 equiv) in
DME (300 mL) at 25 °C. The mixture was stirred at this tempera-
ture for 3 h, and then quenched with K2CO3 (ca. 10 g) and H2O (200
mL). The aqueous layer was extracted with EtOAc (2 × 150 mL),
then the combined organic layers were washed with H2O (200 mL)
and brine (300 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The crude material was purified by column chromatography
using CH2Cl2–EtOH (20:1) as eluent to lead to purine 1b; yield: 3.0
g (58%); white solid; mp 113–115 °C.
1H NMR (CDCl3): δ = 8.17 (s, 1 H), 5.60 (s, 2 H), 3.42 (s, 3 H).
13C NMR (CDCl3): δ = 152.9, 150.8, 145.0, 131.5, 117.2, 74.8, 57.7.
MS (70 eV): m/z (%) = 325 (9), 324 (28), 296 (33), 294 (100), 197
(7), 45 (16).
HRMS: m/z calcd for C7H6ClIN4O: 323.9275; found: 323.9252.
9-(Methoxymethyl)-2-(trimethylsilyl)-9H-purine (1g)
Pd/C (0.25 g, 40 wt%) and ammonium formate (1.25 g, 19.8 mmol,
7.9 equiv) were successively added to a solution of purine 1e (0.68
g, 2.5 mmol, 1.0 equiv) in MeOH (5 mL) at 45 °C. When the reac-
tion started proceeding (intensive bubbling), the mixture was stirred
for further 30 min until the starting material was completely con-
verted as monitored on TLC (EtOAc). The solution was filtered
through a pad of Celite. The pad was washed several times with
EtOH and the combined filtrates were concentrated in vacuo. The
crude material was dissolved in CH2Cl2 (100 mL) and the remaining
ammonium formate was filtered off. The solvent was removed in
vacuo and the resulting crude material was purified by column chro-
matography using EtOAc as eluent to afford purine 1g; yield: 0.55
g (90%); pale yellow oil.
1H NMR (CDCl3): δ = 9.01 (s, 1 H), 8.24 (s, 1 H), 5.61 (s, 2 H), 3.41
(s, 3 H).
13C NMR (CDCl3): δ = 155.0, 153.5, 150.4, 145.9, 132.9, 74.1, 57.5.
MS (70 eV): m/z (%) = 200 (7), 198 (20), 170 (24), 169 (15), 168
(84), 167 (36), 52 (5), 45 (100).
HRMS: m/z calcd for C7H7ClN4O: 198.0308; found: 198.0309.
9-(Methoxymethyl)-9H-purine (1c)
t-BuONO (0.50 mL, 4 mmol, 2 equiv) was added to a solution of
9-(methoxymethyl)-9H-purin-6-amine (0.56 g, 2 mmol, 1 equiv) in
anhydrous THF (10 mL) at 25 °C. The mixture was heated under re-
1H NMR (CDCl3): δ = 9.12 (s, 1 H), 8.14 (s, 1 H), 5.58 (s, 2 H), 3.32
(s, 3 H), 0.30 (s, 9 H).
Synthesis 2013, 45, 3029–3037
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Functionalization of Purine Derivatives
3033
13C NMR (CDCl3): δ = 174.6, 150.9, 147.1, 144.7, 132.3, 73.6, 57.5,
–1.9.
1H NMR (CDCl3): δ = 9.08 (s, 1 H), 8.95 (s, 1 H), 7.35–7.31 (m, 5
H), 5.48 (s, 2 H).
HRMS (ESI): m/z calcd for C10H16N4OSi + H+: 237.1166; found:
237.1166.
13C NMR (CDCl3): δ = 152.8, 147.1, 136.4, 134.7, 128.9, 128.5,
127.9, 108.3, 49.0.
MS (70 eV): m/z (%) = 337 (5), 336 (41), 335 (18), 210 (16), 209
(100), 208 (9), 104 (6), 92 (7), 91 (84), 65 (16).
9-(Methoxymethyl)-2-[(4-methoxyphenyl)thio]-9H-purine (1h)
4-Methoxythiophenol (168 mg, 1.2 mmol, 1.2 equiv) was added to
a solution of t-BuOK (224 mg, 2.0 mmol, 2 equiv) in NMP (2 mL)
at 25 °C. The mixture was stirred for 5 min at 110 °C, then purine
1b (193 mg, 1.0 mmol, 1.0 equiv) was added, and the resulting mix-
ture was heated for 1 h at this temperature. After cooling to 25 °C,
EtOAc (30 mL) was added and the organic layer was washed with
H2O (3 × 15 mL) and brine (15 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated in vacuo. The crude material
was purified by column chromatography using pentane–EtOAc
(1:2) as eluent to afford purine 1h; yield: 160 mg (53%); yellow oil.
1H NMR (CDCl3): δ = 8.87 (s, 1 H), 8.03 (s, 1 H), 7.55–7.50 (m, 2
H), 6.95–6.90 (m, 2 H), 5.37 (s, 2 H), 3.82 (s, 3 H), 3.23 (s, 3 H).
13C NMR (CDCl3): δ = 167.2, 160.6, 152.8, 149.1, 144.2, 137.2,
131.1, 120.7, 114.6, 73.7, 57.7, 55.4.
HRMS: m/z calcd for C12H9IN4: 335.9872; found: 335.9859.
6-Chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine
(3c)25
Freshly prepared TMPZnCl·LiCl (1.0 mL, 1.1 M in THF, 1.1 mmol,
1.1 equiv) was added dropwise within 2 min to a solution of purine
1k (239 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1.5 mL) at
25 °C. The mixture was stirred for 30 min, then a solution of I2 (305
mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (2 mL) was added
dropwise. The mixture was stirred for 1 h, and then quenched with
sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), then the combined organic layers were washed
with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography using CH2Cl2 as eluent to afford purine 3c; yield:
220 mg (60%); white solid; mp 143–145 °C.
MS (70 eV): m/z (%) = 304 (5), 303 (17), 302 (100), 301 (88), 272
(6), 271 (19), 259 (7), 257 (23), 139 (7), 45 (27).
1H NMR (CDCl3): δ = 8.68 (s, 1 H), 5.67 (dd, J = 11.4, 2.4 Hz, 1 H),
4.25–4.19 (m, 1 H), 3.79–3.71 (m, 1 H), 3.20–3.07 (m, 1 H), 2.20–
2.13 (m, 1 H), 1.94–3.63 (m, 4 H).
13C NMR (CDCl3): δ = 152.5, 151.6, 149.5, 134.3, 106.6, 87.4, 69.3,
28.8, 24.6, 23.3.
HRMS: m/z calcd for C14H14N4O2S: 302.0837; found: 302.0829.
6-Chloro-8-iodo-9-(methoxymethyl)-9H-purine (3a)
Freshly prepared TMPZnCl·LiCl (0.92 mL, 1.2 M in THF, 1.1
mmol, 1.1 equiv) was added dropwise within 2 min to a solution of
purine 1a (199 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1.5
mL) at 25 °C. The mixture was stirred for 30 min, then a solution of
I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (4 mL) was
added dropwise. The mixture was stirred for 1 h, and then quenched
with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with
Et2O (2 × 30 mL), then the combined organic layers were washed
with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The crude material was purified by column
chromatography using pentane–EtOAc (1:2) as eluent to furnish pu-
rine 3a; yield: 317 mg (98%); beige solid; mp 125–127 °C.
MS (70 eV): m/z (%) = 282 (27), 281 (6), 280 (100), 245 (27), 127
(6), 118 (7), 99 (7), 91 (6), 85 (6).
HRMS: m/z calcd for C10H10ClIN4O: 363.9588; found: 363.9580.
Metalation at Position 8 of Purines Using
TMP2Zn·2MgCl2·2LiCl as Base and Subsequent Quench with
Electrophile; General Procedure 1 (GP1)
Freshly prepared TMP2Zn·2MgCl2·2LiCl (1.2 equiv) was added
dropwise within 2 min to a solution of the desired purine (1.0 equiv)
and the desired electrophile (1.0 equiv) in anhydrous THF (c = ca.
0.5 M) at 0 °C. The mixture was allowed to warm up to 25 °C over
15 min, and then quenched with sat. aq NH4Cl (10 mL). The aque-
ous layer was extracted with Et2O (3 × 20 mL), then the combined
organic layers were washed with H2O (30 mL) and brine (30 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude ma-
terial was purified by column chromatography.
1H NMR (CDCl3): δ = 8.71 (s, 1 H), 5.61 (s, 2 H), 3.42 (s, 3 H).
13C NMR (CDCl3): δ = 153.5, 152.3, 149.6, 133.7, 107.4, 76.0, 57.6.
MS (70 eV): m/z (%) = 323 (20), 296 (28), 295 (9), 294 (94), 292
(8), 197 (7), 169 (29), 168 (9), 167 (100), 77 (7), 45 (66).
HRMS: m/z calcd for C7H6ClIN4O: 323.9275; found: 323.9266.
9-Benzyl-8-bromo-9H-purine (3d)26
9-Benzyl-8-iodo-9H-purine (3b)24
Starting from purine 1i (210 mg, 1.0 mmol), following GP1 and us-
ing 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the de-
sired purine 3d was obtained after purification by column
chromatography using a gradient elution (CH2Cl2–MeOH, 200:0,
then 200:1 to 100:1); yield: 238 mg (82%); white solid; mp 130–
131 °C.
1H NMR (CDCl3): δ = 9.05 (s, 1 H), 8.99 (s, 1 H), 7.37–7.31 (m, 5
H), 5.49 (s, 2 H).
13C NMR (CDCl3): δ = 152.9, 152.5, 147.2, 134.5, 134.3, 134.2,
129.0, 128.5, 127.9, 47.6.
Method A: Freshly prepared TMPZnCl·LiCl (0.92 mL, 1.2 M in
THF, 1.1 mmol, 1.1 equiv) was added dropwise within 2 min to a
solution of purine 1i (210 mg, 1.0 mmol, 1.0 equiv) in anhydrous
THF (1.5 mL) at 25 °C. The mixture was stirred for 30 min, then a
solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (4
mL) was added dropwise. The mixture was stirred for 1 h, and then
quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 30 mL), then the combined organic layers
were washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. The crude material was purified
by column chromatography using pentane–Et2O (1:9) as eluent to
furnish purine 3b; yield: 270 mg (80%); white solid; mp 211–
213 °C.
MS (70 eV): m/z (%) = 290 (36), 289 (20), 288 (37), 287 (16), 209
(100), 92 (13), 91 (87), 65 (28).
Method B: Freshly prepared TMPMgCl·LiCl (0.92 mL, 1.2 M in
THF, 1.1 mmol, 1.1 equiv) was slowly added dropwise within 5 min
to a solution of purine 1i (210 mg, 1.0 mmol, 1.0 equiv) in anhy-
drous THF (4 mL) at –60 °C. The mixture was stirred for 15 min,
then a solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous
THF (3 mL) was added dropwise. The mixture was stirred for 2.5 h,
and then quenched with sat. aq Na2S2O3 (10 mL). After workup and
purification as described above, purine 3b was obtained as a white
solid; yield: 284 mg (84%).
HRMS: m/z calcd for C12H9BrN4: 288.0011; found: 287.9994.
9-Benzyl-8-bromo-6-chloro-9H-purine (3e)27
Starting from purine 1j (245 mg, 1.0 mmol), following GP1 and us-
ing 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the de-
sired purine 3e was obtained after purification by column
chromatography using a gradient elution (CH2Cl2–pentane, 5:1 to
7:1); yield: 240 mg (75%); white solid; mp 87–88 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3029–3037

3034
F. Crestey et al.
PAPER
1H NMR (CDCl3): δ = 8.75 (s, 1 H), 7.36–7.31 (m, 5 H), 5.49 (s, 2
H).
13C NMR (CDCl3): δ = 152.2, 152.1, 149.5, 134.5, 134.1, 134.0,
129.0, 128.7, 128.0, 48.3.
tive (1 equiv) in anhydrous THF (c = ca. 0.7 M) at 25 °C. The reac-
tion mixture was stirred for 30 min prior to adding successively
Pd(dba)2 (2 mol%), (o-furyl)3P (4 mol%), and the desired aryl io-
dide (1.2 equiv). After the completion of the reaction (checked by
GC-analysis of reaction aliquots quenched with sat. aq NH4Cl, 2–14
h), the reaction mixture was quenched with sat. aq. NH4Cl (10 mL)
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the
combined organic layers were washed with H2O (30 mL) and brine
(30 mL), dried (Na2SO4), and concentrated in vacuo. The crude ma-
terial was purified by column chromatography.
MS (70 eV): m/z (%) = 324 (15), 323 (7), 322 (11), 245 (14), 244
(6), 243 (45), 92 (6), 91 (100), 65 (9).
HRMS: m/z calcd for C12H8BrClN4: 321.9621; found: 321.9617.
8-Bromo-6-chloro-2-iodo-9-(methoxymethyl)-9H-purine (3f)
Starting from purine 1f (325 mg, 1.0 mmol), following GP1 and us-
ing 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the de-
sired purine 3f was obtained after purification by column
chromatography using a gradient elution (EtOAc–pentane, 1:3 to
1:2); yield: 348 mg (87%); white solid; mp 144–146 °C.
1H NMR (CDCl3): δ = 5.60 (s, 2 H), 3.44 (s, 3 H).
13C NMR (CDCl3): δ = 153.8, 149.0, 134.3, 131.6, 117.1, 74.9, 57.8.
Negishi Cross-Coupling Reactions; General Procedure 3 (GP3)
The reaction was carried out as described above in GP2 except that
the cross-coupling reaction was performed at 45 °C for 14 h.
Ethyl 4-[9-(Methoxymethyl)-9H-purin-8-yl]benzoate (5a)
Starting from purine 1c (0.82 g, 5.0 mmol), following GP2 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 5a was
obtained after purification by column chromatography using EtOAc
as eluent; yield: 1.51 g (97%); white solid; mp 117–119 °C.
1H NMR (CDCl3): δ = 9.34 (s, 1 H), 9.18 (s, 1 H), 8.24–8.19 (m, 4
H), 5.66 (s, 2 H), 4.43 (q, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 1.43 (t,
J = 7.2 Hz, 3 H).
MS (70 eV): m/z (%) = 404 (16), 402 (13), 376 (12), 374 (48), 372
(35), 323 (15), 295 (13), 293 (40), 45 (100).
HRMS: m/z calcd for C7H5BrClIN4: 401.8380; found: 401.8376.
9-Benzyl-8-(phenylthio)-9H-purine (3g)
Starting from purine 1i (420 mg, 2.0 mmol), following GP1 (the
base was added dropwise within 1.5 h) and using PhSO2SPh as elec-
trophile, the desired purine 3g was obtained after purification by
column chromatography using a gradient elution (CH2Cl2–MeOH,
400:1 to 100:1); yield: 380 mg (60%); white solid; mp 134–135 °C.
13C NMR (CDCl3): δ = 165.7, 156.8, 154.4, 152.8, 147.7, 133.3,
133.1, 132.0, 130.1, 129.8, 73.5, 61.5, 57.9, 14.3.
MS (70 eV): m/z (%) = 312 (18), 283 (13), 282 (64), 281 (77), 267
(17), 253 (13), 209 (17), 133 (11), 45 (100).
HRMS: m/z calcd for C16H16N4O3: 312.1222; found: 312.1216.
1H NMR (CDCl3): δ = 8.94 (s, 1 H), 8.93 (s, 1 H), 7.61–7.57 (m, 2
H), 7.46–7.41 (m, 3 H), 7.40–7.31 (m, 5 H), 5.50 (s, 2 H).
13C NMR (CDCl3): δ = 155.6, 153.5, 151.7, 145.7, 134.9, 134.3,
134.2, 129.9, 129.8, 129.0, 128.4, 128.0, 127.2, 46.5.
9-(Methoxymethyl)-8-(4-methoxyphenyl)-9H-purine (5b)
Starting from purine 1c (164 mg, 1.0 mmol), following GP2 and us-
ing 4-iodoanisole as aryl iodide, the desired purine 5b was obtained
after purification by column chromatography using Et2O as eluent;
yield: 165 mg (61%); white solid; mp 164–166 °C.
1H NMR (CDCl3): δ = 9.10 (s, 1 H), 8.97 (s, 1 H), 8.09–8.04 (m, 2
H), 7.09–7.04 (m, 2 H), 5.62 (s, 2 H), 3.89 (s, 3 H), 3.59 (s, 3 H).
MS (70 eV): m/z (%) = 319 (17), 318 (83), 317 (54), 227 (7), 209
(30), 167 (39), 92 (7), 91 (100), 65 (12).
HRMS: m/z calcd for C18H14N4S: 318.0939; found: 318.0935.
13C NMR (CDCl3): δ = 162.1, 156.8, 154.1, 152.3, 147.2, 133.6,
131.4, 120.9, 114.5, 73.2, 57.6, 55.5.
6-Chloro-8-(cyclohex-2-en-1-yl)-2-iodo-9-(methoxymethyl)-
9H-purine (3h)
A solution of ZnCl2 (1.0 mL, 1 M in THF, 1.0 mmol, 1.0 equiv) was
added to a solution of purine 1f (325 mg, 1.0 mmol, 1.0 equiv) in
anhydrous THF (1 mL) at 25 °C. The mixture was stirred for 5 min,
then cooled to –65 °C prior to add freshly prepared TMPMgCl·LiCl
(1.0 mL, 1.13 M in THF, 1.13 mmol, 1.13 equiv) dropwise within 2
min. The mixture was stirred for 30 min, then a solution of
CuCN·2LiCl (0.1 mL, 1 M in THF, 0.1 mmol, 0.1 equiv) and 3-bro-
mocyclohexene (225 mg, 1.4 mmol, 1.4 equiv) were successively
added. The mixture was allowed to warm up to 25 °C over 2 h, and
then quenched with sat. aq NH4Cl (10 mL). The aqueous layer was
extracted with Et2O (3 × 20 mL), then the combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. The crude material was purified
by column chromatography using pentane–Et2O (3:1) as eluent to
furnish purine 3h; yield: 340 mg (84%); white solid; 102–104 °C.
MS (70 eV): m/z (%) = 270 (100), 240 (61), 239 (94), 227 (18), 226
(11), 225 (25), 209 (10), 134 (11), 133 (12), 45 (81).
HRMS: m/z calcd for C14H14N4O2: 270.1117; found: 270.1109.
Ethyl 4-[6-Chloro-9-(methoxymethyl)-9H-purin-8-yl]benzoate
(5c)
Starting from purine 1a (199 mg, 1.0 mmol), following GP2 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 5c was
obtained after purification by column chromatography using pen-
tane–EtOAc (5:1) as eluent; yield: 317 mg (91%); white solid; mp
142–144 °C.
1H NMR (CDCl3): δ = 8.77 (s, 1 H), 8.21–8.18 (m, 4 H), 5.63 (s, 2
H), 4.42 (q, J = 7.3 Hz, 2 H), 3.58 (s, 3 H), 1.42 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3): δ = 165.7, 155.7, 154.2, 152.2, 150.6, 132.9,
1H NMR (CDCl3): δ = 6.06–5.99 (m, 1 H), 5.79–5.73 (m, 1 H), 5.60
(s, 2 H), 3.97–3.88 (m, 1 H), 3.40 (s, 3 H), 2.24–2.10 (m, 3 H), 2.08–
1.94 (m, 2 H), 1.79–1.64 (m, 1 H).
13C NMR (CDCl3): δ = 161.8, 154.5, 149.0, 130.8, 130.8, 124.3,
115.7, 73.2, 57.4, 35.5, 28.1, 24.5, 21.2.
132.0, 131.1, 130.0, 129.8, 73.9, 61.5, 57.8, 14.3.
MS (70 eV): m/z (%) = 348 (15), 346 (39), 317 (34), 316 (50), 315
(92), 314 (97), 300 (20), 286 (10), 271 (12), 243 (14), 45 (100).
HRMS: m/z calcd for C16H15ClN4O3: 346.0833; found 346.0823.
6-Chloro-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-purine
(5d)
MS (70 eV): m/z (%) = 406 (13), 404 (39), 375 (13), 374 (28), 373
(19), 361 (28), 359 (23), 345 (14), 308 (15), 81 (14), 79 (14), 45
(100).
Starting from purine 1a (1.19 g, 6.0 mmol), following GP2 and us-
ing 4-iodoanisole as aryl iodide, the desired purine 5d was obtained
after purification by column chromatography using a gradient elu-
tion (EtOAc–pentane, 1:1 to 2:1); yield: 1.74 g (95%); white solid;
mp 157–159 °C.
HRMS: m/z calcd for C13H14ClIN4O: 403.9901; found: 403.9892.
Negishi Cross-Coupling Reactions; General Procedure 2 (GP2)
Freshly prepared TMPZnCl·LiCl (1.1 M in THF, 1.1 equiv) was
added dropwise within 2 min to a solution of desired purine deriva-
1H NMR (CDCl3): δ = 8.74 (s, 1 H), 8.10 (d, J = 8.6 Hz, 2 H), 7.07
(d, J = 9.1 Hz, 2 H), 5.63 (s, 2 H), 3.91 (s, 3 H), 3.59 (s, 3 H).
Synthesis 2013, 45, 3029–3037
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Functionalization of Purine Derivatives
3035
13C NMR (CDCl3): δ = 162.3, 157.0, 154.4, 151.5, 149.6, 131.6,
131.1, 120.3, 114.5, 73.9, 57.7, 55.5.
HRMS (ESI): m/z calcd for C17H19F3N4OSi + H+: 381.1353; found:
381.1350.
MS (70 eV): m/z (%) = 306 (29), 305 (16), 304 (100), 276 (11), 275
(16), 274 (35), 273 (39), 261 (13), 259 (12), 45 (65).
9-(Methoxymethyl)-8-(4-methoxyphenyl)-2-[(4-methoxyphe-
nyl)thio]-9H-purine (5j)
Starting from purine 1h (302 mg, 1.0 mmol), following GP2 and us-
ing 4-iodoanisole as aryl iodide, the desired purine 5j was obtained
after purification by column chromatography using a gradient elu-
tion (EtOAc–pentane, 1:1 to 8:1); yield: 345 mg (85%); orange sol-
id; mp 150–152 °C.
1H NMR (CDCl3): δ = 8.86 (s, 1 H), 7.99 (d, J = 8.6 Hz, 2 H), 7.57
(d, J = 8.6 Hz, 2 H), 7.02 (d, J = 9.1 Hz, 2 H), 6.96 (d, J = 8.6 Hz, 2
H), 5.35 (s, 2 H), 3.86–3.85 (m, 6 H), 3.35 (s, 3 H).
HRMS: m/z calcd for C14H13ClN4O2: 304.0727; found: 304.0721.
Ethyl 4-[2-Chloro-9-(methoxymethyl)-9H-purin-8-yl]benzoate
(5f)
Starting from purine 1b (199 mg, 1.0 mmol), following GP2 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 5f was
obtained after purification by column chromatography using pen-
tane–EtOAc (4:1) as eluent; yield: 200 mg (58%); white solid; mp
142–143 °C.
13C NMR (CDCl3): δ = 166.0, 161.8, 160.4, 155.5, 154.9, 147.5,
137.2, 131.1, 130.7, 121.0, 120.8, 114.5, 114.4, 73.2, 57.7, 55.3,
55.3.
1H NMR (CDCl3): δ = 9.02 (s, 1 H), 8.25–8.23 (m, 2 H), 8.20–8.18
(m, 2 H), 5.62 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.61 (s, 3 H), 1.44
(t, J = 7.2 Hz, 3 H).
MS (70 eV): m/z (%) = 409 (40), 408 (100), 407 (79), 363 (39), 69
(36), 57 (52), 55 (47), 44 (48), 43 (35), 41 (44).
13C NMR (CDCl3): δ = 165.7, 156.4, 155.6, 154.7, 149.8, 133.1,
132.4, 132.0, 130.2, 129.7, 73.4, 61.5, 57.8, 14.3.
HRMS: m/z calcd for C21H20N4O3S: 408.1256; found: 408.1252.
MS (70 eV): m/z (%) = 348 (17), 346 (48), 318 (24), 317 (41), 316
(59), 315 (79), 301 (16), 287 (13), 271 (14), 243 (21), 45 (100).
Ethyl 4-[9-(Methoxymethyl)-2-(trimethylsilyl)-9H-purin-8-
yl]benzoate (5k)9
HRMS: m/z calcd for C16H15ClN4O3: 346.0833; found: 346.0824.
Starting from purine 1g (236 mg, 1.0 mmol), following GP2 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 5k was
obtained after purification by column chromatography using pen-
tane–EtOAc (9:1) as eluent; yield: 200 mg (52%); white solid; mp
179–180 °C.
1H NMR (CDCl3): δ = 9.24 (s, 1 H), 8.20 (s, 4 H), 5.67 (s, 2 H), 4.40
(q, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H), 0.41 (s,
9 H).
Ethyl 4-[2,6-Dichloro-9-(methoxymethyl)-9H-purin-8-yl]ben-
zoate (5g)
Starting from purine 1d (1.4 g, 6.0 mmol), following GP2 and using
ethyl 4-iodobenzoate as aryl iodide, the desired purine 5g was ob-
tained after purification by column chromatography using pentane–
EtOAc (2:1) as eluent; yield: 1.4 g (62%); beige solid; mp 149–151 °C.
1H NMR (CDCl3): δ = 8.25–8.18 (m, 4 H), 5.61 (s, 2 H), 4.44 (q,
J = 7.2 Hz, 2 H), 3.61 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3): δ = 165.7, 156.4, 155.5, 153.1, 151.4, 133.3,
13C NMR (CDCl3): δ = 174.7, 165.8, 154.8, 153.0, 146.8, 132.9,
132.6, 132.2, 130.0, 129.6, 73.1, 61.4, 57.9, 14.3, –1.8.
131.6, 130.3, 130.1, 129.9, 74.0, 61.5, 58.0, 14.3.
MS (70 eV): m/z (%) = 384 (79), 383 (25), 369 (61), 351 (30), 350
(30), 338 (25), 337 (100), 89 (36), 73 (24), 45 (31).
MS (70 eV): m/z (%) = 382 (13), 380 (19), 352 (13), 351 (20), 350
(21), 349 (26), 335 (6), 274 (5), 45 (100).
HRMS: m/z calcd for C19H24N4O3Si: 384.1618; found: 384.1620.
HRMS: m/z calcd for C16H14Cl2N4O3: 380.0443; found: 380.0437.
Ethyl 4-[6-Chloro-9-(methoxymethyl)-2-(trimethylsilyl)-9H-
purin-8-yl]benzoate (5l)9
2,6-Dichloro-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-pu-
rine (5h)23
Starting from purine 1d (2.33 g, 10.0 mmol), following GP2 and us-
ing 4-iodoanisole as aryl iodide, the desired purine 5h was obtained
after purification by column chromatography using CH2Cl2 as elu-
ent; yield: 2.40 g (71%); white solid; mp 179–181 °C.
Starting from purine 1e (271 mg, 1.0 mmol), following GP3 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 5l was
obtained after purification by column chromatography using hex-
ane–EtOAc (10:1) as eluent; yield: 380 mg (91%); white solid; mp
121–122 °C. The reaction was performed also on 20 and 30 mmol
scales furnishing the desired purine 5l in 70% and 85% yield, re-
spectively.
1H NMR (CDCl3): δ = 8.08–8.03 (m, 2 H), 7.06–7.02 (m, 2 H), 5.57
(s, 2 H), 3.89 (s, 3 H), 3.59 (s, 3 H).
1H NMR (CDCl3): δ = 8.20 (s, 4 H), 5.65 (s, 2 H), 4.41 (q, J = 7.2
Hz, 2 H), 3.60 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H), 0.40 (s, 9 H).
13C NMR (CDCl3): δ = 175.3, 165.8, 154.9, 153.5, 149.5, 132.8,
13C NMR (CDCl3): δ = 162.4, 157.6, 155.7, 152.2, 150.1, 131.6,
130.3, 120.0, 114.6, 74.0, 57.8, 55.5.
MS (70 eV): m/z (%) = 340 (22), 338 (34), 310 (11), 309 (10), 308
(17), 307 (12), 295 (6), 293 (6), 133 (11), 45 (100).
132.3, 130.0, 129.9, 129.8, 73.8, 61.4, 58.0, 14.3, –1.9.
MS (70 eV): m/z (%) = 418 (55), 404 (100), 389 (64), 388 (51), 384
(100), 374 (72), 93 (57), 57 (46), 45 (83), 43 (56).
HRMS: m/z calcd for C14H12Cl2N4O2: 338.0337; found: 338.0327.
9-(Methoxymethyl)-8-[3-(trifluoromethyl)phenyl]-2-(trimeth-
ylsilyl)-9H-purine (5i)
HRMS: m/z calcd for C19H23ClN4O3Si: 418.1228; found: 418.1225.
Starting from purine 1g (1.90 g, 8.0 mmol), following GP2 and us-
ing 1-iodo-3-(trifluoromethyl)benzene as aryl iodide, the desired
purine 5i was obtained after purification by column chromatogra-
phy using pentane–EtOAc (3:1) as eluent; yield: 1.45 g (48%);
white solid; mp 135–136 °C.
1H NMR (CDCl3): δ = 9.27 (s, 1 H), 8.46 (br s, 1 H), 8.36–8.34 (m,
1 H), 7.85–7.83 (m, 1 H), 7.73–7.69 (m, 1 H), 5.69 (s, 2 H), 3.64 (s,
3 H), 0.44 (s, 9 H).
13C NMR (CDCl3): δ = 174.7, 154.4, 153.0, 146.7, 132.8 (q,
3JC,F = 1 Hz), 132.1, 131.7 (q, 2JC,F = 33 Hz), 129.7, 129.6, 127.7 (q,
3JC,F = 4 Hz), 126.7 (q, 3JC,F = 4 Hz), 123.7 (q, 1JC,F = 272 Hz), 73.1,
57.9, –1.8.
Ethyl 4-[6-Iodo-9-(methoxymethyl)-9H-purin-8-yl]benzoate
(7a)
A solution of purine 5a (312 mg, 1.0 mmol, 1.0 equiv) in anhydrous
THF (10 mL) was added dropwise within 3 min to freshly prepared
TMPMgCl·LiCl (1.3 mL, 0.94 M in THF, 1.2 mmol, 1.2 equiv) at
–20 °C. The reaction mixture was stirred for 1 h prior to add a solu-
tion of I2 (1.00 g, 3.9 mmol, 3.9 equiv) in anhydrous THF (2 mL).
The resulting mixture was allowed to warm up to 0 °C over 3 h, and
then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer
was extracted with EtOAc (2 × 20 mL), then the combined organic
layers were washed with H2O (30 mL) and brine (30 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude material
was purified by column chromatography using pentane–EtOAc
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3029–3037

3036
F. Crestey et al.
PAPER
(1:1) as eluent to furnish purine 7a; yield: 306 mg (70%); beige sol-
id; mp 152–154 °C.
Ethyl 4-[9-(Methoxymethyl)-8-(4-methoxyphenyl)-9H-purin-6-
yl]benzoate (7d)
Starting from purine 5b (270 mg, 1.0 mmol), following GP4 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 7d was
obtained after purification by column chromatography using pen-
tane–EtOAc (3:1) as eluent; yield: 230 mg (55%); beige solid; mp
158–159 °C.
1H NMR (CDCl3): δ = 8.68 (s, 1 H), 8.24–8.20 (m, 4 H), 5.61 (s, 2
H), 4.44 (q, J = 7.3 Hz, 2 H), 3.59 (s, 3 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3): δ = 165.7, 155.1, 152.2, 150.5, 138.1, 133.0,
132.1, 130.1, 129.9, 121.6, 73.8, 61.5, 57.8, 14.3.
MS (70 eV): m/z (%) = 439 (14), 438 (62), 409 (17), 408 (100), 407
(88), 393 (17), 239 (11), 238 (14), 221 (11), 207 (16), 45 (70).
1H NMR (CDCl3): δ = 9.05–9.01 (m, 3 H), 8.24–8.22 (m, 2 H),
8.18–8.14 (m, 2 H), 7.12–7.08 (m, 2 H), 5.68 (s, 2 H), 4.43 (q,
J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 3.62 (s, 3 H), 1.44 (t, J = 7.1 Hz, 3
H).
HRMS: m/z calcd for C16H15IN4O3: 438.0189; found: 438.0182.
13C NMR (CDCl3): δ = 166.3, 162.1, 156.4, 155.6, 151.7, 151.7,
139.5, 132.1, 131.5, 131.1, 129.8, 129.7, 121.0, 114.5, 73.4, 61.1,
57.5, 55.5, 14.3.
6-Iodo-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-purine
(7b)
A solution of purine 5b (270 mg, 1.0 mmol, 1.0 equiv) in anhydrous
THF (10 mL) was added dropwise within 3 min to freshly prepared
TMPMgCl·LiCl (1.3 mL, 0.94 M in THF, 1.2 mmol, 1.2 equiv) at
–20 °C. The reaction mixture was stirred for 1 h prior to add a solu-
tion of I2 (1.00 g, 3.9 mmol, 3.9 equiv) in anhydrous THF (2 mL).
The resulting mixture was allowed to warm up to 0 °C over 3 h. and
then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer
was extracted with EtOAc (2 × 20 mL), then the combined organic
layers were washed with H2O (30 mL) and brine (30 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude material
was purified by column chromatography using pentane–Et2O (1:1)
as eluent to furnish purine 7b; yield: 238 mg (60%); beige solid; mp
156–158 °C.
MS (70 eV): m/z (%) = 419 (21), 418 (86), 389 (9), 388 (43), 387
(100), 373 (17), 359 (15), 315 (9), 300 (9), 159 (8), 45 (28).
HRMS: m/z calcd for C23H22N4O4: 418.1641; found 418.1640.
Ethyl 4-{9-(Methoxymethyl)-8-[3-(trifluoromethyl)phenyl]}-2-
(trimethylsilyl)-9H-purin-6-yl)benzoate (7e)
Starting from purine 5i (380 mg, 1.0 mmol), following GP4 and us-
ing ethyl 4-iodobenzoate as aryl iodide, the desired purine 7e was
obtained after purification by column chromatography using pen-
tane–CH2Cl2 (5:4) as eluent; yield: 280 mg (55%); beige solid; mp
148–149 °C.
1H NMR (CDCl3): δ = 9.10–9.06 (m, 2 H), 8.52 (br s, 1 H), 8.45–
8.42 (m, 1 H), 8.27–8.23 (m, 2 H), 7.87–7.84 (m, 1 H), 7.76–7.71
(m, 1 H), 5.72 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.66 (s, 3 H), 1.45
(t, J = 7.2 Hz, 3 H), 0.49 (s, 9 H).
13C NMR (CDCl3): δ = 174.0, 166.5, 154.6, 153.9, 150.8, 140.4,
133.0 (q, 4JC,F = 1 Hz), 131.9, 131.7 (q, 2JC,F = 33 Hz), 130.0, 129.8,
129.7, 129.7, 129.6, 127.5 (q, 3JC,F = 4 Hz), 126.8 (q, 3JC,F = 4 Hz),
123.8 (q, 1JC,F = 272 Hz), 73.2, 61.1, 57.8, 14.3, –1.7.
1H NMR (CDCl3): δ = 8.63 (s, 1 H), 8.10–8.08 (m, 2 H), 7.08–7.06
(m, 2 H), 5.59 (s, 2 H), 3.90 (s, 3 H), 3.58 (s, 3 H).
13C NMR (CDCl3): δ = 162.3, 156.3, 151.6, 150.6, 138.1, 131.7,
120.3, 120.2, 114.5, 73.9, 57.7, 55.5.
MS (70 eV): m/z (%) = 397 (15), 396 (100), 366 (21), 365 (23), 269
(12), 239 (11), 238 (9), 197 (7), 133 (12), 45 (30).
HRMS: m/z calcd for C14H13IN4O2: 396.0083; found: 396.0074.
HRMS (ESI): m/z calcd for C26H27F3N4O3Si + H+: 529.1877; found:
529.1872.
Negishi Cross-Coupling Reactions; General Procedure 4 (GP4)
A solution of the desired purine derivative in anhydrous THF (c =
ca. 0.1 M) was added dropwise within 3 min to freshly prepared
TMPMgCl·LiCl (0.94 M in THF, 1.2 equiv) at –20 °C. The reaction
mixture was stirred for 1 h prior to add a solution of ZnCl2 (1 M in
THF, 1.3 equiv). The resulting reaction mixture was allowed to
warm up to 25 °C over 30 min, then Pd(dba)2 (2 mol%), (o-furyl)3P
(4 mol%), and the desired aryl iodide (1.3 equiv) were successively
added. After the completion of the reaction (checked by GC-analy-
sis of reaction aliquots quenched with sat. aq NH4Cl, 3–14 h), the
reaction mixture was quenched with sat. aq NH4Cl (10 mL). The
aqueous layer was extracted with EtOAc (3 × 20 mL) and the com-
bined organic layers were washed with H2O (30 mL) and brine (30
mL), dried (Na2SO4), and concentrated in vacuo. The crude material
was purified by column chromatography.
Acknowledgment
We thank the European Research Council (ERC-227763) for finan-
cial support as well as Rockwood Lithium GmbH (Frankfurt), Evo-
nik AG (Hanau), W. C. Heraeus GmbH (Hanau), and BASF AG
(Ludwigshafen) for the generous gift of chemicals. We also
acknowledge Dr. Vladimir Malakhov and Christelle Pecceu for
their helpful supports.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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itmnatr
Ethyl 4-[9-(Methoxymethyl)-6-phenyl-9H-purin-8-yl]benzoate
(7c)
Starting from purine 5a (312 mg, 1.0 mmol), following GP4 and us-
ing 4-iodobenzene as aryl iodide, the desired purine 7c was obtained
after purification by column chromatography using pentane–EtOAc
(5:1) as eluent; yield: 245 mg (63%); beige solid; mp 156–157 °C.
1H NMR (CDCl3): δ = 9.07 (s, 1 H), 8.94–8.92 (m, 2 H), 8.28–8.23
(m, 4 H), 7.61–7.43 (m, 3 H), 5.68 (s, 2 H), 4.45 (q, J = 7.0 Hz, 2
H), 3.62 (s, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3): δ = 165.8, 155.1, 154.7, 154.2, 152.4, 135.2,
132.8, 132.6, 131.2, 130.5, 130.0, 129.9, 129.8, 128.7, 73.4, 61.4,
57.6, 14.3.
References
(1) Current address: Medicinal Chemistry Research, H.
Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
(2) (a) Rosemeyer, H. Chem. Biodiversity 2004, 1, 361.
(b) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem.
2006, 14, 3987. (c) Brændvang, M.; Gundersen, L.-L.
Bioorg. Med. Chem. 2007, 15, 7144. (d) Legraverend, M.
Tetrahedron 2008, 64, 8585.
(3) Čerňa, I.; Pohl, R.; Klepetářová, B.; Hocek, M. J. Org.
Chem. 2010, 75, 2302; and references cited therein.
(4) (a) He, R.; Ching, S. M.; Lam, Y. J. Comb. Chem. 2006, 8,
923. (b) Lin, X.; Robins, M. J. Collect. Czech. Chem.
Commun. 2006, 71, 1029. (c) Kalla, R. V.; Elzein, E.; Perry,
T.; Li, X.; Gimbel, A.; Yang, M.; Zeng, D.; Zablocki, J.
Bioorg. Med. Chem. Lett. 2008, 18, 1397.
MS (70 eV): m/z (%) = 388 (26), 359 (9), 358 (46), 357 (100), 343
(10), 329 (13), 285 (6), 209 (9), 45 (23).
HRMS: m/z calcd for C22H20N4O3: 388.1535; found: 388.1529.
Synthesis 2013, 45, 3029–3037
© Georg Thieme Verlag Stuttgart · New York

PAPER
(5) (a) Hocek, M.; Hocková, D.; Dvořáková, H. Synthesis 2004,
Regioselective Functionalization of Purine Derivatives
3037
(14) (a) Wunderlich, S.; Knochel, P. Angew. Chem. Int. Ed. 2007,
46, 7685. (b) Wunderlich, S.; Knochel, P. Org. Lett. 2008,
10, 4705. (c) Rohbogner, C.; Wunderlich, S.; Clososki, G.;
Knochel, P. Eur. J. Org. Chem. 2009, 1781.
(15) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
(16) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi,
E.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, Chap.
15. (c) Casares, J. A.; Espinet, P.; Fuentes, B.; Salas, G. J.
Am. Chem. Soc. 2007, 129, 3508.
(17) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun.
2008, 5824.
(18) Berliner, M.; Belecki, K. Org. Synth. 2007, 84, 102.
(19) Maurer, H. K. Ph. D. Dissertation; Universität Heidelberg:
Germany, 1963.
889. (b) Hocek, M.; Pohl, R. Synthesis 2004, 2869.
(c) Čerňa, I.; Pohl, R.; Klepetářová, B.; Hocek, M. J. Org.
Chem. 2008, 73, 9048.
(6) (a) Tobrman, T.; Dvořák, D. Org. Lett. 2003, 5, 4289.
(b) Tobrman, T.; Dvořák, D. Org. Lett. 2006, 8, 1291.
(7) (a) Stevenson, T. M.; Prasad, A. S. B.; Citineni, J. R.;
Knochel, P. Tetrahedron Lett. 1996, 37, 8375. (b) Prasad, A.
S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.; Knochel,
P. Tetrahedron 1997, 53, 7237.
(8) (a) Leonard, N. J.; Bryant, D. J. J. Org. Chem. 1979, 44,
4612. (b) Tanaka, H.; Uchida, Y.; Shinozaki, M.; Hayakawa,
H.; Matsuda, A.; Miyasaka, T. Chem. Pharm. Bull. 1983, 31,
787. (c) Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto,
H.; Shindoh, S.; Shuto, S.; Miyasaka, T. J. Org. Chem. 1997,
62, 6833. (d) Ghosh, A. K.; Lagisetty, P.; Zajc, B. J. Org.
Chem. 2007, 72, 8222.
(9) Zimdars, S.; Mollat du Jourdin, X.; Crestey, F.; Carell, T.;
Knochel, P. Org Lett. 2011, 13, 792.
(20) Graham, T. H.; Liu, W.; Shen, D.-M. Org. Lett. 2011, 13,
6232.
(10) For a recent review on hindered metal amide bases, see:
Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P.
Angew. Chem. Int. Ed. 2011, 50, 9794.
(11) (a) Mosrin, M.; Bresser, T.; Knochel, P. Org Lett. 2009, 11,
3406. (b) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P.
Chem. Commun. 2009, 5615. (c) Mosrin, M.; Knochel, P.
Org. Lett. 2009, 11, 1837. (d) Crestey, F.; Knochel, P.
Synthesis 2010, 1097. (e) Bresser, T.; Mosrin, M.; Monzon,
G.; Knochel, P. J. Org. Chem. 2010, 75, 4686.
(21) Tromp, R. A.; Spanjersberg, R. F.; von Frijtag Drabbe
Künzel, J.; IJzerman, A. P. J. Med. Chem. 2005, 48, 321.
(22) Kode, N. R.; Phadtare, S. Molecules 2011, 16, 5840.
(23) Stathakis, C. I.; Bernhardt, S.; Quint, V.; Knochel, P. Angew.
Chem. Int. Ed. 2012, 51, 9428.
(24) Guthmann, H.; Könemann, M.; Bach, T. Eur. J. Org. Chem.
2007, 632.
(25) Ibrahim, N.; Chevot, F.; Legraverend, M. Tetrahedron Lett.
2011, 52, 305.
(12) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.;
Knochel, P. Org. Lett. 2006, 8, 5673.
(26) Nair, V.; Chi, G.; Uchil, V. R. Patent WO 2007106450,
2007; Chem. Abstr. 2007, 147, 385768
(27) Gamadeku, T.; Gundersen, L.-L. Synth. Commun. 2010, 40,
2723.
(13) Blomberg, C.; Hartog, F. A. Synthesis 1977, 18.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3029–3037