A Convenient Synthesis of N2-Alkylated Guanines

Article abstract of DOI:10.1134/S1070428019060198

An improved three-step synthesis of N²-alkylated guanines has been developed starting from N²-Boc-protected 2-amino-6-chloropurine which was treated with Boc₂O, and the resulting doubly N²,9-protected derivative was subjected to N²-alkylation with alkyl halides, followed by hydrolysis. The advantages of this procedure include short reaction steps, simple operations, and good yields.

Full text of DOI:10.1134/S1070428019060198

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 6, pp. 874–878. © Pleiades Publishing, Ltd., 2019.
2
A Convenient Synthesis of N -Alkylated Guanines
a
a
a
a
H. T. Zhu , L. Y. Qin , T. Liu , and Y. Luo *
a
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,
School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
е-mail: yluo@chem.ecnu.edu.cn
*
Received December 20, 2018; revised December 25, 2018; accepted December 29, 2018
2
Abstract—An improved three-step synthesis of N -alkylated guanines has been developed starting from
2
2
N -Boc-protected 2-amino-6-chloropurine which was treated with Boc
2
O, and the resulting doubly N ,9-pro-
2
tected derivative was subjected to N -alkylation with alkyl halides, followed by hydrolysis. The advantages of
this procedure include short reaction steps, simple operations, and good yields.
2
Keywords: guanine, N -alkylation, Boc protection.
DOI: 10.1134/S1070428019060198
Guanine is one of the four main nucleobases
found in the nucleic acids DNA and RNA playing the
key role in living cells [1]. Many guanine derivatives
have been used as anticancer and antiviral agents for
decades [2–7]. Among numerous guanine derivatives,
peratures [14]. However, many 2-halopurines are
costly and not easily available. Other approaches in-
clude the reductive amination of 2-aminopurines with
aldehydes and classical N-alkylation of the corre-
sponding amide followed by diacylation [15, 16].
Recently, Fletcher and coworkers reported a concise
2
some N -substituted guanines exhibit interesting bio-
2
logical activities such as thymidine kinase inhibitory
activity, antimicrobial activity, and cyclin-dependent
kinase inhibitory activity [8–11]. In addition, some
access to a series of N -alkylated guanines from
2-amino-6-chloropurine (Scheme 1) [17]. The key
9
strategy involved trityl protection at the N position
2
N -substituted guanines serve as synthetic interme-
and the Mitsunobu reaction at the exocylic 2-amino
group. However, we feel that the trityl protection is not
good enough, since triphenylmethanol is produced as
by-product, which has to be removed by silica gel flash
column chromatography. Due to the poor solubility
and the high polarity of these guanines, this work-up
process is not welcomed.
diates for the preparation of nucleobase-containing
drugs, molecular biological tools, diagnostic agents,
etc. [12, 13]. Thus, facile and efficient synthetic proto-
cols would be of great benefit.
So far, several synthetic approaches have been
2
reported for the synthesis of N -substituted guanines.
The most frequently used method is the reaction of
To develop a more efficient and practical synthetic
protocol, we improved Fletcher’s method. Herein, we
2
-halopurines with primary amines at elevated tem-
Scheme 1.
Cl
Cl
Cl
N
N
N
N
N
N
N
N
N
Boc
N
H N
2
N
H N
2
N
N
H
H
Tr
Tr
2
-Amino-6-chloropurine
Cl
N
OH
N
N
N
N
N
+
[Ph COH]
3
Boc
N
R
N
N
H
N
H
Tr
R
8
74

2
A CONVENIENT SYNTHESIS OF N -ALKYLATED GUANINES
875
Scheme 2.
Cl
N
Cl
Cl
N
N
N
N
N
N
Boc2O, DMAP, DMF
95%
N
RX, K2CO3, DMF
82–91%
N
Boc
Boc
Boc
N
H
N
N
N
N
N
R
H
H
Boc
Boc
1
2
3a–3g
OH
N
OH
HCOOH/H O or
2
N
N
TFA/H O
N
N
2
or
>
80%
R
N
H
N
N
H
N
N
H
4
a–4f
4g
3
, 4, R = Me (a), Et (b), Bu (c), CH
2
=CHCH
2
2 2 2 4
(d), MeC≡CCH (e), PhCH (f); 3g, R = Br(CH ) .
1
report the detailed investigations about the synthesis of
these N -alkylated guanines.
rected. H NMR spectra were recorded on a Bruker
DRX-400 (400 MHz) spectrometer or a Bruker DRX-
5
2
1
3
00 (500 MHz) spectrometer. C NMR spectra were
Our synthesis of 4 is shown in Scheme 2.
Purine 1 protected at the 2-amino group was prepared
in two steps from 2-amino-6-chloropurine and used as
starting material [18]. Purine 1 was first subjected to
obtained on a JNM-EX400 (100 MHz) spectrometer.
High resolution mass spectra (ESI) were determined
on a Bruker MicroTof II mass spectrometer. Low
resolution mass spectra (EI) were determined with
an Agilent 5975C mass-selective detector. IR spectra
were obtained using KBr disks on a Bruker Tensor 27
FTIR instrument.
9
Boc protection at N position in near-quantitative
yield, and compound 2 was treated with alkyl halides
2
under basic conditions to afford a series of N -al-
kylated guanines. As shown in Table 1, purines 3a–3g
were synthesized in very good yields using a broad
range of halides, including benzyl, allyl, butynyl, and
other primary aliphatic halides. However, the reactions
with secondary aliphatic halides failed to give the
desired compound (Table 1, entry no. 8). Finally, the
hydrolytic dechlorination and Boc removal were ac-
complished in very good yields in one pot by treatment
with a mixture of acid/water for 2 h at 75°C to afford
tert-Butyl 2-[(tert-butoxycarbonyl)amino]-6-
chloro-9H-purine-9-carboxylate (2). 4-Dimethyl-
aminopyridine (0.23 g, 1.8 mmol), was added to
a suspension of purine 1 (10.0 g, 37.1 mmol) and
Boc O (8.1 g, 37.1 mmol) in DMF (50 mL). The
2
mixture was stirred at room temperature for 1 h, the
solvent was removed under reduced pressure, and the
residuewas extracted with ethyl acetate (100 mL). The
organic layer was washed with 1 M HCl (70 mL) and
brine (70 mL), dried over anhydrous Na SO , and
2
the target compounds. These N -alkylated guanines
were purified by simple trituration in a mixture of
petroleum ether and ethyl acetate. Thus, column chro-
matography was spared, making the purification proc-
ess more convenient.
2
4
concentrated in vacuo to give the crude product, which
Table 1. Alkylation of compound 2 at the 2-amino group
In conclusion, we have developed a convenient
three-step synthetic approach to N -alkylated guanines
a–4g in good overall yields from easily available
N -Boc purine 1. This procedure has a potential for
Entry no.
Alkylating agent
Product
Yield, %
2
4
1
2
3
4
5
6
7
8
Iodomethane
3a
3b
3c
3d
3e
3f
91
2
Iodoethane
90
scale-up productions.
1-Iodobutane
85
Allyl bromide
1-Bromobut-2-yne
Benzyl bromide
1,4-Dibromobutane
2-Iodopropane
85
EXPERIMENTAL
87
89
Commercial reagents were used without further
purification. The boiling range of petroleum ether is
0–90°C. Melting points were measured on a SGW
3g
–
82
6
No reaction
X-4 (INESA) temperature apparatus and are uncor-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

8
76
ZHU et al.
–
1
was triturated with a 5:1 mixture of petroleum ether
and ethyl acetate. Yield 13.0 g (95%), white solid,
(85%), white solid, mp 53–55°C. IR spectrum, ν, cm :
1
2957, 1760, 1559, 1357, 1129. H NMR spectrum
(500 MHz, CDCl ), δ, ppm: 8.39 s (1H, Harom), 3.88–
3.94 m (2H, CH N), 1.58–1.66 m [11H, CH ,
–
1
mp 126–127°C. IR spectrum, ν, cm : 3221, 2984,
3
1
1
744, 1138. H NMR spectrum (500 MHz, CDCl ), δ,
3
2
2
ppm: 8.40 s (1H, Harom), 7.76 s (1H, NH), 1.72 s [9H,
C(CH ) ], 1.46 s [9H, C(CH ) ], 1.25–1.30 m (2H,
CH ), 0.85 t (3H, CH , J = 7.4 Hz). C NMR spectrum
2 3
3 3 3 3
1
3
13
C(CH ) ], 1.54 s [9H, C(CH ) ]. C NMR spectrum
3
3
3 3
(
126 MHz, CDCl ), δ , ppm: 154.0, 152.4, 152.1,
(126 MHz, CDCl ), δ , ppm: 156.9, 153.5, 151.4,
3
C
3 C
1
49.8, 145.6, 142.5, 128.4, 87.8, 81.9, 28.2, 27.9.
151.2, 146.0, 143.1, 128.6, 87.3, 81.7, 77.2, 48.0, 30.9,
28.1, 27.9, 20.1, 13.8. Found: m/z 448.1731 [M + Na] .
+
+
Found: m/z 392.1106 [M + Na] . C H ClN NaO .
1
5
20
5
4
Calculated: M + Na 392.1102.
C H ClN NaO . Calculated: M + Na 448.1728.
1
9
28
5
4
General procedure for the synthesis of 3a–3g. All
substitution reactions were run on the same scale,
using the following general procedure.
tert-Butyl 2-[(tert-butoxycarbonyl)(prop-2-en-1-
yl)amino]-6-chloro-9H-purine-9-carboxylate (3d).
The product was purified by column chromatography
on silica gel (petroleum ether–ethyl acetate, 5:1).
Yield 0.94 g (85%), yellow solid, mp 90–92°C. IR
tert-Butyl 2-[(tert-butoxycarbonyl)(methyl)-
amino]-6-chloro-9H-purine-9-carboxylate (3a).
Methyl iodide (0.58 g, 4.1 mmol) was added to a mix-
ture of purine 2 (1.00 g, 2.7 mmol) and potassium
carbonate (0.75 g, 5.4 mmol) in DMF (4 mL). The
mixture was stirred at room temperature until the reac-
tion was complete and extracted with ethyl acetate
–
1
1
spectrum, ν, cm : 2993, 1740, 1612, 1129. H NMR
spectrum (500 MHz, CDCl ), δ, ppm: 8.33 s (1H,
3
Harom), 5.80–5.89 m (1H, CH), 5.12 d.d (1H, CH , J =
2
1
4
1
7.2, 1.3 Hz), 4.99 d.d (1H, CH , J = 10.3, 1.1 Hz),
2
.48 d (2H, CH N, J = 5.5 Hz), 1.57 s [9H, C(CH ) ],
2
3 3
1
3
.40 s [9H, C(CH ) ]. C NMR spectrum (126 MHz,
(
1
2×15 mL). The extract was washed with water (2×
2 mL), dried over Na SO , and concentrated in vacuo
3 3
CDCl ), δ , ppm: 156.5, 153.1, 151.4, 151.2, 146.0,
3
C
2
4
1
2
43.1, 133.7, 128.7, 116.83, 87.3, 82.1, 50.3, 28.1,
to give brown oil, which was purified by column
chromatography on silica gel (petroleum ether–ethyl
acetate, 5:1). Yield 0.98 g (91%), pale solid, mp 107–
+
8. 0. Found: m/z 432. 1404 [M + Na] .
C H ClN NaO . Calculated: M + Na 432.1415.
18 24
5
4
–
1
1
1
8
09°C. IR spectrum, ν, cm : 2984, 1712, 1364, 1137,
tert-Butyl 2-[(tert-butoxycarbonyl)(but-2-yn-1-
yl)amino]-6-chloro-9H-purine-9-carboxylate (3e).
The product was purified by column chromatography
on silica gel (petroleum ether–ethyl acetate, 5:1).
Yield 0.99 g (87%), white solid, mp 68.5–70.4°C. IR
1
014. H NMR spectrum (500 MHz, CDCl ), δ, ppm:
.46 s (1H, Harom), 3.49 s (3H, CH ), 1.70 s [9H,
C(CH ) ], 1.54 s [9H, C(CH ) ]. C NMR spectrum
3
3
1
3
3
3
3 3
(
126 MHz, CDCl ), δ , ppm: 157.1, 153.5, 151.4,
3 C
–
1
1
51.2, 145.9, 143.0, 128.5, 87.3, 82.0, 35.3, 28.1, 27.9.
spectrum, ν, cm : 3109, 2990, 1710, 1241, 1152.
+
1
Found: m/z 406.1269 [M + Na] . C H ClN NaO .
1
6
22
5
4
H NMR spectrum (500 MHz, CDCl ), δ, ppm: 8.51 s
3
Calculated: M + Na 406.1258.
(
1H, Harom), 4.77 d (2H, CH N, J = 2.2 Hz), 1.78 t
2
tert-Butyl 2-[(tert-butoxycarbonyl)(ethyl)amino]-
-chloro-9H-purine-9-carboxylate (3b). The product
(3H, J = 2.1 Hz), 1.75 s [9H, C(CH
3
)
3
], 1.58 s [9H,
1
3
6
C(CH
3
)
3
]. C NMR spectrum (126 MHz, CDCl ), δ
3
,
C
was purified by column chromatography on silica gel
ppm: 155.9, 152.6, 151.3, 146.0, 143.1, 128.8, 87.4,
(
(
petroleum ether–ethyl acetate, 8:1). Yield 0.97 g
82.5, 78.5, 77.3, 74.9, 38.0, 28.1, 27.9, 3.6. Found:
+
90%), white solid, mp 68.6–71°C. IR spectrum, ν,
m/z 444.1434 [M + Na] . C19
ed: M + Na 444.1415.
H24ClN NaO . Calculat-
5 4
–
1
1
cm : 2990, 1743, 1570, 1154. H NMR spectrum
(
(
[
500 MHz, CDCl ), δ, ppm: 8.46 s (1H, Harom), 4.05 q
3
tert-Butyl 2-[benzyl(tert-butoxycarbonyl)amino]-
-chloro-9H-purine-9-carboxylate (3f). The product
was purified by column chromatography on silica gel
2H, CH , J = 7.0 Hz), 1.70 s [9H, C(CH ) ], 1.54 s
2
3 3
6
1
3
9H, C(CH ) ], 1.29 t (3H, CH , J = 7.0 Hz). C NMR
3
3
3
spectrum (126 MHz, CDCl ), δ , ppm: 156.7, 153.2,
1
2
3
C
(
(
petroleum ether–ethyl acetate, 5 :1). Yield 1.1 g
51.4, 151.2, 146.0, 143.0, 128.5, 87.3, 81.8, 43.3,
89%), white solid, mp 104–105°C. IR spectrum, ν,
+
8.1, 28.0, 14.0. Found: m/z 420.1417 [M + Na] .
–1
1
cm : 3094, 2981, 1748, 1146, 945. H NMR spectrum
500 MHz, CDCl ), δ, ppm: 8.84 s (1H, Harom), 7.23–
C H ClN NaO . Calculated: M + Na 420.1415.
1
7
24
5
4
(
3
tert-Butyl 2-[(tert-butoxycarbonyl)(butyl)amino]-
-chloro-9H-purine-9-carboxylate (3c). The product
was purified by column chromatography on silica gel
petroleum ether–ethyl acetate, 8 :1). Yield 0.98 g
7.36 m (5H, Harom), 5.11 s (2H, CH N), 1.56 s [9H,
C(CH ) ], 1.40 s [9H, C(CH ) ]. C NMR spectrum
3 3 3 3
2
1
3
6
(126 MHz, CDCl ), δ , ppm: 156.7, 153.3, 151.4,
3
C
(
151.3, 146.0, 143.1, 138.3, 128.7, 128.2, 127.5, 127.1,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

2
A CONVENIENT SYNTHESIS OF N -ALKYLATED GUANINES
877
1
8
7.3, 82.2, 51.2, 28.0, 27.9. Found: m/z 482.1585
0.45 g (83%), white solid, mp 287–288°C [8]. H NMR
+
[
M + Na] . C H ClN NaO . Calculated: M + Na
spectrum (500 MHz, DMSO-d ), δ, ppm:11.69 s (1H,
2
2
26
5
4
6
4
82.1571.
tert-Butyl 2-[(4-bromobutyl)(tert-butoxycar-
bonyl)amino]-6-chloro-9H-purine-9-carboxylate
3g). The product was purified by column chromatog-
raphy on silica gel (petroleum ether–ethyl acetate,
OH), 8.95 s (1H, Harom), 7.65 s (1H, NH), 3.27 d.d (2H,
CH , J = 12.4, 6.7 Hz), 1.46–1.55 m (2H, CH ), 1.30–
2
2
1
.39 m (2H, CH ), 0.89 t (3H, CH , J = 7.3 Hz).
2 3
+
Found: m/z 208.1177 [M + H] . C H N O. Calculated:
9
13
5
(
M + H 208.1198.
1
7
1
8
3
0:1). Yield 1.12 g (82%), white solid, mp 76.4–
2-(Prop-2-en-1-ylamino)-9H-purin-6-ol (4d). The
crude product was triturated with acetone (2 mL).
Yield 0.43 g (87%), white solid, mp 230–231°C. IR
–
1
8.7°C. IR spectrum, ν, cm : 3115, 2984, 1753, 1700,
1
147. H NMR spectrum (500 MHz, CDCl ), δ, ppm:
3
–
1
1
.40 s (1H, Harom), 3.97 t (2H, CH N, J = 7.0 Hz),
spectrum, ν, cm : 3265, 2737, 1683, 1603. H NMR
spectrum (500 MHz, DMSO-d ), δ, ppm: 11.82 s (1H,
OH), 8.93 s (1H, Harom), 7.70 s (1H, NH), 5.87–5.95 m
(1H, CH), 5.25 d (1H, CH , J = 17.3 Hz), 5.13 d (1H,
CH , J = 10.4 Hz), 3.94 s (2H, CH
trum (126 MHz, DMSO-d ), δ , ppm: 154.6, 154.0,
2
.38 t (2H, CH Br, J = 6.6 Hz), 1.83–1.88 m (2H,
6
2
CH ), 1.74–1.81 m (2H, CH ), 1.64 s [9H, C(CH ) ],
1
CDCl ), δ , ppm: 156.6, 153.5, 151.5, 151.3, 145.8,
1
2
2
2
3 3
1
3
.47 s [9H, C(CH ) ]. C NMR spectrum (126 MHz,
2
3
3
1
3
N). C NMR spec-
2
3
C
2
43.2, 128.7, 87.4, 82.1, 47.0, 33.3, 30.0, 28.1,
6
C
1
50.8, 136.7, 134.8, 116.1, 108.9, 43.1. Found:
8.0, 27.4. Found: m/z 526.0847/528.0828
+
+
m/z 192.0878 [M + H] . C H N O. Calculated: M + H
[M + Na] . C H BrClNaN O . Calculated: M + Na
8
9
5
1
9
27
5
4
1
92.0885.
5
26.0833/528.0812.
2
-(But-2-yn-1-ylamino)-9H-purin-6-ol (4e). The
General procedure for the synthesis of 4a–4g.
product was prepared according to the general proce-
dure, but trifluoroacetic acid was used in place of
formic acid. The crude product was triturated with
MeOH (2 mL). Yield 0.46 g (87%), gray solid decom-
The hydrolytic dechlorination and Boc removal for all
compounds 4a–4g were run on the same scale, using
the following general procedure.
2
-(Methylamino)-9H-purin-6-ol (4a). Purine 3a
–1
posing at 272°C. IR spectrum, ν, cm : 3212, 3052,
(
1 g, 2.6 mmol) was added to a 4:1 mixture of formic
1
2
616, 1602, 1469. H NMR spectrum (500 MHz,
acid and water, and the mixture was stirred at 75°C
overnight and evaporated to dryness to give the crude
product, which was triturated with MeOH (2 mL).
Yield 0.36 g (85%), yellow solid, mp > 300°C. IR
DMSO-d ), δ, ppm: 12.69 s (1H, OH), 10.59 (1H,
6
Harom), 7.74 s (1H, NH), 6.48 s (1H), 4.02 s (2H, CH ),
2
13
1
.78 s (3H, CH ). C NMR spectrum (126 MHz,
3
DMSO-d ), δ , ppm: 156.5, 152.1, 137.6, 100.0, 79.7,
6
C
–
1
1
spectrum, ν, cm : 3302, 2661, 1700, 1613. H NMR
+
7
8.7, 77.0, 30.9, 3.5. Found: m/z: 204.0883 [M + H] .
spectrum (500 MHz, DMSO-d ), δ, ppm: 11.87 s (1H,
6
C H N O. Calculated: M + H 204.0885.
9
9
5
OH), 9.07 s (1H, Harom), 7.50 s (1H, NH), 2.84 s (3H,
1
3
2-(Benzylamino)-9H-purin-6-ol (4f). The crude
CH3). C NMR spectrum (126 MHz, DMSO-d ), δ ,
6
C
product was triturated with acetone (2 mL). Yield
0.50 g (80%), yellow solid, mp 230–231°C; published
ppm: 155.4, 153.7, 150.5, 136.7, 108.0, 28.1. Found:
+
m/z 166.0725 [M + H] . C H N O. Calculated: M + H
6
7
5
1
data [8]: mp 225–228°C. H NMR spectrum
1
66.0651.
-(Ethylamino)-9H-purin-6-ol (4b). The crude
product was triturated with acetone (2 mL). Yield
.40 g (86%), white solid, mp 246–247°C. IR spec-
(
500 MHz, DMSO-d ), δ, ppm: 12.06 br.s (1H, OH),
6
2
9
.17 s (1H, Harom), 8.23 s (1H, NH), 7.44 d (5H, Harom
,
J = 41.0 Hz), 4.68 s (2H, CH ). Found: m/z 242.1042
2
+
0
[
M + H] . C H N O. Calculated: M + H 242.1042.
12 11 5
–
1
1
trum, ν, cm : 3350, 2720, 1700, 1612, 1463. H NMR
2
-(Pyrrolidin-1-yl)-9H-purin-6-ol (4g). The crude
product was triturated with acetone (2 mL). Yield
.43 g (81%), white solid decomposing at 251°C. IR
spectrum (500 MHz, DMSO-d ), δ, ppm: 11.53 s (1H,
6
OH), 8.79 s (1H, Harom), 7.39 s (1H, NH), 3.30 d.d (2H,
0
CH , J = 7.1, 5.4 Hz), 1.14 t (3H, CH , J = 7.2 Hz).
–1
1
2
3
spectrum, ν, cm : 3371, 2737, 1692, 1138. H NMR
1
3
C NMR spectrum (126 MHz, DMSO-d ), δ , ppm:
6
C
spectrum (500 MHz, DMSO-d ), δ, ppm: 11.43 s (1H,
6
1
54.3, 151.2, 136.7, 109.3, 35.9, 14.8. Found:
OH), 9.11 s (1H, H
), 3.47–3.49 m (4H, CH2),
+
arom
13
m/z 180.0883 [M + H] . C H N O. Calculated: M + H
7
9
5
1
.93 br.s (4H, CH2). C NMR spectrum (126 MHz,
1
80.0885.
-(Butylamino)-9H-purin-6-ol (4c). The crude
product was triturated with acetone (2 mL). Yield
DMSO-d ), δ , ppm: 154.6, 152.4, 150.5, 137.1, 107.1,
6
C
+
2
47.9, 25.2. Found: m/z 206.1027 [M + H] . C H N O.
9 11 5
Calculated: M + H 206.1042.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

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78
ZHU et al.
9. Sharma, P., Kumar, A., and Sharma, S., Indian J. Chem.,
ACKNOWLEDGMENTS
The authors thank the Laboratory of Organic Func-
Sect. B, 2004, vol. 43, p. 385.
1
0. Malumbres, M. and Barbacid, M., Nat. Rev. Cancer,
tional Molecules, the Sino–French Institute of ECNU,
for supports.
2009, vol. 9, p. 153.
1
1. Coxon, C.R., Anscombe, E., Harnor, S.J., Martin, M.P.,
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CONFLICT OF INTERESTS
The authors declare no conflict of interests.
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