Efficient synthesis of 2-ureaguanines via the in situ reactions of 2-isocyanatopurines with amines

Article abstract of DOI:10.1055/s-0033-1338482

The synthesis of 2-ureaguanines is reported. The preparation involves a suitably protected intermediate, formation of a 2-isocyanatopurine and in situ trapping with a diverse range of amines followed by double deprotection. This is the first application of 2-isocyanatopurines for the synthesis of 2-ureaguanines. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338482

PAPER
▌1983
Paper
Efficient Synthesis of 2-Ureaguanines via the in situ Reactions of
2-Isocyanatopurines with Amines
Efficient Synthesis of 2-Ureaguanines
Antoine Le Roux, Eric Marsault*
Laboratoire de Chimie Médicinale, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12e avenue Nord, Sherbrooke, QC,
J1H 5N4, Canada
Fax +1(819)5645400; E-mail: eric.marsault@usherbrooke.ca
Received: 13.03.2013; Accepted after revision: 24.04.2013
reaction with isocyanates and related compounds
Abstract: The synthesis of 2-ureaguanines is reported. The prepa-
emerged as the most straightforward toward this end, the
ration involves a suitably protected intermediate, formation of a 2-
low reactivity of the amino group of 2-aminopurines im-
isocyanatopurine and in situ trapping with a diverse range of amines
followed by double deprotection. This is the first application of 2-
posed the use of stronger electrophiles.3 This lack of reac-
isocyanatopurines for the synthesis of 2-ureaguanines.
tivity was confirmed in the reactions of guanine (1) or 2-
amino-6-chloropurine (2) with several electrophiles under
a variety of conditions (Scheme 1).11 This is not surprising
since the 2-amino group donates its electron density to the
purine system. Additionally, the imidazole nitrogen can
also react under these conditions. In order to achieve in-
sertion of diverse ureas at position 2 of purines, we turned
our attention toward a more efficient method to generate
2-isocyanatopurines, which were expected to be more re-
active and selective. Such compounds have already been
used as intermediates for the insertion of carbamates at
position 2,12 and their preparation involved the use of tri-
phosgene as the reagent, but they have not been used with
amines. This appeared as a promising alternative to gen-
erate ureas from a diverse range of amines.
Key words: guanine, purines, heterocycles, isocyanates, ureas, tri-
phosgene
Purines, and especially guanine derivatives, are of partic-
ular importance in the field of heterocyclic chemistry.1 As
constituents of oligonucleotides, purines have been wide-
ly studied in medicinal chemistry2 and in supramolecular
chemistry,3 owing to their ability to form Watson–Crick4
and Hoogsteen5 base pairs. Although the synthesis of gua-
nines modified at positions 2 and 6 has been studied ex-
tensively,1 there are only a few examples of the
preparation of 2-ureaguanines6 and 2-ureapurines.7,8 Iso-
cyanates such as phenyl isocyanate7 and n-butyl
isocyanate8 have been used, but the reaction appeared to
be very dependent on the isocyanate, and sometimes forc-
ing conditions were required. The use of phenyl chloro-
formate has also been described to introduce
cyclohexylamine derivatives9 or ammonia.10 To the best
of our knowledge, however, there is no general method
for the preparation of this class of compounds.
Initial results indicated that the imidazole moiety inter-
fered with electrophiles such as triphosgene, thus this
moiety was protected with a 2-tetrahydropyran (THP)
group.13 Although this group is not often used for purine
protection, it can be easily cleaved under mild acidic con-
ditions and suited our needs perfectly. It was inserted us-
ing standard Vorbrüggen conditions by employing 2-
acetoxytetrahydropyran (3) as an electrophile (Scheme 2).
This method gave superior results in terms of purity com-
pared to the direct reaction of 1 or 2 with 2,3-dihydropy-
In the course of our research to access 2-ureaguanines and
related compounds, we investigated several methods to
functionalize the 2-amino group of purines. Although the
X
X
6
electrophile
N
5
4
N
N
Y
1N
2
7
8
R2
9
3
N
H
N
pyridine, reflux, overnight
or NaH in DMF, r.t. to 120 °C, overnight
N
N
N
R1
N
NH2
H
H
1 X = OH (guanine)
2 X = Cl
S
O
electrophiles: Bz-NCS, MeNCS,
NBoc
,
Cl
NMe2 Cl
NMe2
O
/HgCl2,
MeS
NHBoc
Cl
OPh
Scheme 1
SYNTHESIS 2013, 45, 1983–1990
Advanced online publication: 06.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338482; Art ID: SS-2013-M0206-OP
© Georg Thieme Verlag Stuttgart · New York

1984
A. Le Roux, E. Marsault
PAPER
ran in the presence of a catalytic amount of p-
toluenesulfonic acid (PTSA). The silylation of 1 with
N,O-bis(trimethylsilyl)acetamide (BSA) in refluxing ace-
tonitrile, followed by addition of 3 and trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) allowed the isolation
of a 1.7:1 mixture of N9 (4) and N7 (5) protected guanines,
respectively, in a moderate 58% combined yield. Under
the same conditions, protection of 2 occurred in 73% yield
and regioisomer 6 was recovered as the major compound,
the N7 regioisomer 7 being only observed as traces
(Scheme 2).14 The mixture of isomers 4 and 5 was then re-
acted with triphosgene in the presence of N,N-diisopro-
pylethylamine (DIPEA) in tetrahydrofuran for one hour,
followed by the addition of a methanolic solution of am-
monia. After 16 hours at room temperature, only starting
materials were recovered (Scheme 3). The same was ob-
served with aqueous methylamine.
O
N
O
N
i
N
N
NH
O
NH
R
N
THP
THP
N
H
N
H
N
NH2
H
H
4/5
R = H, Me
Scheme 3 Reagents and conditions: (i) triphosgene, DIPEA, THF,
0 °C to r.t., 1 h, then NH3/MeOH or aq MeNH2.
in 61% yield (Scheme 4), however, when the intermediate
isocyanate 8 was quenched with ethanolic methylamine,
compound 10 was not observed. Instead, urea 11 was iso-
lated in a good yield (70%), but only after reaction for five
minutes at 0 °C. The same reaction performed with one
equivalent of morpholine delivered only the double addi-
tion product after five minutes of reaction at 0 °C, as was
observed by LC–MS.
X
Accordingly, protection of position 6 appeared to be nec-
essary. As 6-O-alkyl groups can be cleaved under the
same conditions as the tetrahydropyran moiety, the ethoxy
(12) and benzyloxy (13) groups were selected (Scheme 5).
Compounds 12 and 13 were obtained in 81% and 93%
yields, respectively, by reacting purine 6 with the corre-
sponding alkoxide for four hours at room temperature. It
is noteworthy that this reaction on an N9-protected 2-ami-
no-6-chloropurine proceeded under mild conditions,
whereas the 6-chloro substitution of unprotected 2-amino-
6-chloropurine usually requires forcing conditions.15
X
N
N
X
O
i
N
N
+
N
N
NH2
N
N
N
N
H
O
N
NH2
N
NH2
1 X = OH
2 X = Cl
4 X = OH
6 X = Cl
5 X = OH
7 X = Cl
O
O
X = OH: 58%, 4/5 = 1.7:1
X = Cl: 73%, 6 only
O
3
With 6,9-diprotected guanines 12 and 13 in hand, the pre-
vious procedure was repeated with a wide range of amines
(Table 1). The use of ammonia, and primary and second-
ary amines gave moderate to good yields (53–81%) of
products 14a–k. Piperidine gave a very satisfactory 81%
yield of isolated 14k. Complete chemoselectivity was ob-
served when 2-aminoethanol was used, to yield 53% of
Scheme 2 Reagents and conditions: (i) BSA, MeCN, reflux, 3 h,
then 3, TMSOTf, 0 °C to r.t., overnight.
In contrast, when compound 6 was reacted with triphos-
gene and N,N-diisopropylethylamine, followed by
quenching with methanolic ammonia, urea 9 was isolated
Cl
N
Cl
N
Cl
N
N
N
N
N
N
O
N
N
O
i
ii
C
N
N
N
NH2
NH2
N
H
O
O
O
6
9, 61%
8
iii
Me
Cl
NH
N
N
N
N
N
N
O
O
Me
Me
N
N
N
N
N
N
H
H
H
H
O
O
11, 70%
10
not observed
Scheme 4 Reagents and conditions: (i) triphosgene, DIPEA, 0 °C to r.t., 1 h; (ii) NH3/MeOH, 0 °C to r.t., 1 h; (iii) MeNH2/EtOH, 0 °C to r.t., 1 h.
Synthesis 2013, 45, 1983–1990
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of 2-Ureaguanines
1985
gave a complex mixture, and compound 14m was not ob-
served by LC–MS.
Cl
N
OR
N
N
N
N
N
N
i or ii
With the protected 2-ureaguanines 14 in hand, we next
turned our attention to the simultaneous deprotection of
the 2-tetrahydropyranyl and 6-O-alkyl groups. Com-
pounds 14a–l were dissolved in 1,4-dioxane, then a 10%
aqueous solution of hydrochloric acid was added (Table
2). After one hour at room temperature, LC–MS analyses
showed that in all cases the tetrahydropyran moiety had
been cleaved. With compounds 14a–d (R = Et), only in-
termediates 15a–d were observed, and continuous stirring
did not lead to complete cleavage of the ethoxy group.
Heating to reflux temperature appeared necessary to ef-
fect complete conversion of intermediates 15a–d, but was
N
NH2
NH2
O
O
6
12: R = Et, 81%
13: R = Bn, 93%
Scheme 5 Reagents and conditions: (i) Na, EtOH, r.t., 4 h; (ii)
BnOH, NaH, THF, r.t., 4 h.
product 14i. In this case, no trace of the corresponding
carbamate was evident by LC–MS. The use of tyramine
led to urea 14l in 40% yield; whilst the use of hydrazine
Table 1 Formation of Ureas 14a
OR1
OR1
OR1
i
ii
N
N
N
N
N
N
O
N
N
O
R3
C
N
N
N
N
N
N
N
NH2
H
THP
R2
THP
THP
12: R1 = Et
13: R1 = Bn
14a–m
Product
R1
R2R3NH
Yieldb
c
14a
14b
14c
Et
Et
Et
NH3
56%
58%
65%
d
MeNH2
n-BuNH2
HN
O
14d
Et
72%
b
14e
14f
Bn
Bn
NH3
71%
78%
c
MeNH2
HN
O
14g
14h
Bn
Bn
54%
54%
H2N
N
O
H2N
HN
14i
14j
Bn
Bn
53%
66%
OH
HN
14k
Bn
81%
OH
14l
Bn
Bn
40%
0%
H2N
14m
N2H4
a Reaction conditions: (i) triphosgene, DIPEA, THF, 0 °C to r.t., 1 h; (ii) R1R2NH, 0 °C to r.t., 1 h.
b Yield of isolated product.
c Used as a 7 M solution in MeOH, 20 equivalents.
d Used as a 33% solution in EtOH, 20 equivalents.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1983–1990

1986
A. Le Roux, E. Marsault
PAPER
Table 2 Double Deprotection by Acidolysisa
OR1
OR1
O
N
N
N
N
N
i
N
O
N
O
NH
O
R3
R3
R3
N
H
N
H
N
N
N
R2
N
N
N
R2
N
N
R2
H
H
H
THP
14a–l
15a–l
16a–i
Product
R1
R2R3N-
Yield
16a
16b
16c
Et
Et
Et
-NH2
45%
31%
44%
-NHMe
-NHn-Bu
N
16d
Et
0%
O
16a
16b
Bn
Bn
-NH2
-NHMe
N
56%
53%
16d
16e
Bn
Bn
37%
76%
O
H
N
N
O
H
N
16f
Bn
Bn
56%
40%
OH
N
N
16g
16h
16i
Bn
Bn
71%
82%
OH
N
H
a Reaction conditions: (i) HCl (10%), 1,4-dioxane, r.t., overnight.
accompanied by some degradation of the final compound. ward recovery of the 2-ureaguanines by simple trituration.
Compounds 16a–c were recovered in moderate yields This procedure was also applicable to the preparation of
whereas compound 16d was completely degraded. With 6-O-alkyl-2-ureaguanines.
substrates 14e–l (R = Bn), LC–MS after one hour at room
temperature indicated complete cleavage of the tetrahy-
All reactions were carried out under an Ar atmosphere. THF was
dropyran group as well as partial cleavage of the benzyl
ether. Further stirring overnight at room temperature led
to complete conversion into ureas 16e–i without any trace
of degradation. The products were isolated by trituration
in water, and in some cases, subsequent purification of the
filtrate by preparative HPLC increased the yield above
70% (16e, 16h and 16i).
distilled over Na with benzophenone. Thin-layer chromatography
(TLC) was conducted with Merck KGA silica gel 60 F254 pre-coat-
ed plates and samples were made visual by exposure to UV light
(254 nm). Flash chromatography was performed using normal
phase silica (230–400 mesh, Merck KGA). Melting points were re-
corded on a Buchi apparatus and are uncorrected. 1H NMR spectra
were recorded on a Bruker spectrometer at 300 MHz and are report-
ed relative to the deuterated solvent signals. 1H NMR spectroscopic
data are reported as follows: chemical shift (δ ppm), multiplicity (s:
singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, quin:
quintet, sext: sextet), integration and coupling constant (Hz). 13C
NMR spectra were recorded on a Bruker spectrometer at 75 MHz.
13C NMR spectroscopic data are reported in terms of chemical shift
(δ ppm). LC–MS spectra were recorded on a Waters Alliance 2695
HPLC apparatus using H2O + 0.1% TFA and MeCN + 0.1% TFA
In summary, we have reported a general methodology to
prepare 2-ureaguanines. The simultaneous use of the 9-
tetrahydropyranyl and 6-benzyloxy protective groups ap-
peared to be the most suitable combination. Subsequent
acidolysis of both protecting groups allowed straightfor-
Synthesis 2013, 45, 1983–1990
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of 2-Ureaguanines
1987
as eluents, with detection at 254 nm; MS were recorded on a Waters
Micromass ZQ2000 (electrospray) instrument. The purities of the
final compounds were determined using a Dionex HPLC with a
HILIC column (Inertsil Amide, purchased from GL Sciences), with
a gradient made with MeCN and 10 mM ammonium formate buffer.
Preparative HPLC was performed using Waters equipment (Autos-
ampler 2707, Quaternary gradient module 2535, UV detector 2489,
fraction collector WFCIII) using H2O + 0.1% TFA and MeCN as el-
uents. Exact mass measurements (HRMS) were recorded on an
electrospray quadrupole time-of-flight Maxis 3G from Bruker using
positive mode.
1H NMR (300 MHz, DMSO-d6): δ = 8.33 (s, 1 H), 6.99 (br s, 2 H),
5.48 (dd, J = 11.0 Hz, J = 2.2 Hz, 1 H), 4.02–3.98 (m, 1 H), 3.66–
3.57 (m, 1 H), 2.29–2.15 (m, 1 H), 1.97–1.89 (m, 2 H), 1.73–1.52
(m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.9, 153.5, 149.6, 140.9,
123.2, 80.8, 67.7, 29.7, 24.5, 22.5.
MS (ES): m/z = 253.7 (100%) [35Cl, M + H]+, 255.7 (37%) [37Cl, M
+ H]+.
6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-amine (12)
Na (291 mg, 12.7 mmol, 2.2 equiv) was dissolved in abs EtOH (100
mL), and 6 (1.46 g, 5.8 mmol, 1 equiv) was added in portions. The
mixture was stirred at r.t. until completion of the reaction. The mix-
ture was quenched by the addition of sat. aq NH4Cl soln and then
extracted with EtOAc (3 × 50 mL). The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo, and the crude
residue was purified by silica gel chromatography (CH2Cl2–MeOH,
100:0 to 95:5) to yield 1.23 g of 12 as a beige solid (4.7 mmol,
81%).
Tetrahydro-2H-pyran-2-yl Acetate (3)
To a mixture of AcOH (5.6 mL, 97 mmol, 0.9 equiv) and PPTS (1
g) in CH2Cl2 (100 mL) at 0 °C was added dropwise 2,3-dihydrofu-
ran (10 mL, 110 mmol, 1 equiv), and the mixture was stirred over-
night from 0 °C to r.t. The mixture was then washed with sat. aq
NaHCO3 soln (3 × 50 mL) and brine (3 × 50 mL), dried over Na2SO4
and concentrated in vacuo to yield 13.3 g of 3 (92 mmol, 95%) as a
yellowish colored liquid.
1H NMR (300 MHz, DMSO-d6): δ = 8.04 (s, 1 H), 6.44 (br s, 2 H),
5.45 (dd, J = 11.0 Hz, J = 2.2 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H),
4.01–3.97 (m, 1 H), 3.64–3.56 (m, 1 H), 2.24–2.11 (m, 1 H), 1.99–
1.85 (m, 2 H), 1.75–1.52 (m, 3 H), 1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.3, 159.9, 153.6, 137.3,
113.6, 80.4, 67.7, 61.5, 30.0, 24.5, 22.6, 14.5.
1H NMR (300 MHz, CDCl3): δ = 5.94 (m, 1 H), 3.94–3.86 (m, 1 H),
3.71–3.64 (m, 1 H), 2.09 (s, 3 H), 1.87–1.75 (m, 2 H), 1.68–1.60 (m,
4 H).
13C NMR (75 MHz, CDCl3): δ = 165.1, 87.9, 58.6, 24.4, 20.1, 16.4,
13.9.
2-Amino-9-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-6H-purin-
6-one (4) and 2-Amino-7-(tetrahydro-2H-pyran-2-yl)-1,7-di-
hydro-6H-purin-6-one (5)
MS (ES): m/z = 263.8 [M + H]+.
6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
amine (13)
To a suspension of guanine (2 g, 13.2 mmol, 1 equiv) in MeCN (200
mL) was added BSA (16.2 mL, 66 mmol, 5 equiv) and the mixture
was heated at reflux temperature for 4 h under Ar. After cooling to
r.t. and then to 0 °C, compound 3 (2.5 g, 17.2 mmol, 1.5 equiv) was
added, followed by the dropwise addition of TMSOTf (3.6 mL, 19.8
mmol, 1.2 equiv), and the mixture was stirred overnight from 0 °C
to r.t. The mixture was quenched by the addition of aq Na2CO3 soln
(1 M) and then extracted with EtOAc (3 × 100 mL). The combined
organic phases were dried over Na2SO4 and concentrated in vacuo.
Concentration of the aqueous phase followed by recrystallization of
the solid residue from H2O allowed recovery of another fraction of
a mixture of 4 and 5. The combined fractions yielded 1.8 g (7.6
mmol, 58%) of a 1.7:1 mixture of 4 and 5 as a white solid.
1H NMR (300 MHz, DMSO-d6): δ (major isomer) = 8.16 (s, 1 H),
6.18 (br s, 2 H), 5.75 (dd, J = 10.4 Hz, J = 2.5 Hz, 1 H), 4.01–3.97
(m, 1 H), 3.63–3.55 (m, 1 H), 2.12–1.87 (m, 3 H), 1.69–1.50 (m, 3
H).
1H NMR (300 MHz, DMSO-d6): δ (minor isomer) = 7.87 (s, 1 H),
6.52 (br s, 2 H), 5.35 (dd, J = 11.3 Hz, J = 2.5 Hz, 1 H), 4.01–3.97
(m, 1 H), 3.63–3.55 (m, 1 H), 2.12–1.87 (m, 3 H), 1.69–1.50 (m, 3
H).
NaH (60% in oil, 790 mg, 19.7 mmol, 2.5 equiv) was added to a soln
of benzyl alcohol (1.71 mL, 16.5 mmol, 2.1 equiv) in THF (50 mL),
and the mixture was stirred at r.t. for 1 h. Compound 6 (2 g, 7.9
mmol, 1 equiv) was then added, and the mixture stirred at r.t. until
completion of the reaction. The mixture was quenched with sat. aq
NH4Cl soln and extracted with EtOAc (3 × 25 mL). The combined
organic extracts were then dried over Na2SO4 and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(CH2Cl2–MeOH, 100:0 to 95:5) to yield 2.40 g of 13 as a beige solid
(7.4 mmol, 93%).
1H NMR (300 MHz, DMSO-d6): δ = 8.06 (s, 1 H), 7.51–7.48 (m, 2
H), 7.43–7.34 (m, 3 H), 6.54 (br s, 2 H), 5.49 (s, 2 H), 5.45 (dd, J =
11.0 Hz, J = 1.9 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.65–3.60 (m, 1 H),
2.25–2.12 (m, 1 H), 1.98–1.85 (m, 2 H), 1.76–1.52 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.1, 159.8, 153.9, 137.6,
136.6, 128.5, 128.4, 128.1, 113.5, 80.5, 67.7, 66.9, 30.0, 24.5, 22.6.
MS (ES): m/z = 325.8 [M + H]+.
2-Ureapurines; General Procedure
To a soln of the 2-aminopurine (1 equiv) in THF (0.5 M) at 0 °C was
added triphosgene (0.36 equiv) and DIPEA (3.5 equiv). The mix-
ture was stirred for 30 min at 0 °C, then the ice bath was removed
and the mixture was stirred for another 30 min, before again cooling
to 0 °C. The amine (2 equiv) was then added, and the mixture was
stirred for 1 h at 0 °C and at r.t. until completion of the reaction.
EtOAc was added and the mixture was washed with brine (three
times), dried Na2SO4 and concentrated in vacuo. The crude residue
was purified by silica gel chromatography (CH2Cl2–MeOH, 100:0
to 95:5).
13C NMR (75 MHz, CDCl3): δ (major isomer) = 159.8, 154.3,
152.9, 140.8, 107.3, 83.1, 67.7, 30.6, 24.5, 22.5.
MS (ES): m/z = 235.8 [M + H]+.
6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-amine (6)
To a suspension of 2-amino-6-chloropurine (5 g, 29.5 mmol, 1
equiv) in MeCN (500 mL) was added BSA (21 mL, 85.9 mmol, 2.9
equiv) and the mixture was heated at reflux temperature for 4 h. Af-
ter cooling to r.t. and then to 0 °C, compound 3 (6.3 g, 44.2 mmol,
1.3 equiv) was added, followed by the dropwise addition of
TMSOTf (8 mL, 44.2 mmol, 1.5 equiv), and the mixture was stirred
overnight from 0 °C to r.t. The mixture was quenched by the addi-
tion of aq Na2CO3 soln (1 M) and extracted with EtOAc (3 × 200
mL). The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (CH2Cl2–MeOH, 100:0 to 95:5) to yield 5.5 g of 6
as a beige solid (21.7 mmol, 73%).
1-[6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea
(9)
Prepared according to the general procedure starting from 200 mg
of 6, yielding 143 mg of 9 as a white solid (61%).
1H NMR (300 MHz, DMSO-d6): δ = 9.89 (br s, 1 H), 8.63 (s, 1 H),
8.06 (br s, 1 H), 7.27–7.12 (m, 1 H), 5.72 (dd, J = 10.7 Hz, J = 2.2
Hz, 1 H), 4.03–3.99 (m, 1 H), 3.71–3.63 (m, 1 H), 2.26–2.16 (m, 1
H), 2.01–1.96 (m, 2 H), 1.80–1.57 (m, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1983–1990

1988
A. Le Roux, E. Marsault
PAPER
13C NMR (75 MHz, DMSO-d6): δ = 154.1, 153.4, 151.7, 149.7,
143.7, 126.0, 81.4, 67.6, 29.6, 24.5, 22.2.
13C NMR (75 MHz, DMSO-d6): δ = 160.0, 154.4, 154.1, 152.6,
139.9, 116.3, 80.8, 67.8, 66.1, 62.4, 46.8, 44.6, 29.9, 24.5, 22.5,
14.4.
MS (ES): m/z = 296.8 (100%) [35Cl, M + H]+, 298.8 (37%) [37Cl, M
+ H]+.
MS (ES): m/z = 376.9 [M + H]+.
1-Methyl-3-[6-(methylamino)-9-(tetrahydro-2H-pyran-2-yl)-
9H-purin-2-yl]urea (11)
Prepared according to the general procedure starting from 200 mg
of 6, yielding 170 mg of 11 as a white solid (70%).
1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]urea (14e)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 200 mg of 14e as a white solid (71%).
1H NMR (300 MHz, DMSO-d6): δ = 9.26 (q, J = 4.7 Hz, 1 H), 8.93
(br s, 1 H), 8.13 (s, 1 H), 7.92–7.91 (m, 1 H), 5.50 (d, J = 9.6 Hz, 1
H), 4.02–3.98 (m, 1 H), 3.67–3.59 (m, 1 H), 2.92 (d, J = 4.1 Hz, 3
H), 2.79 (d, J = 4.7 Hz, 3 H), 2.26–2.14 (m, 1 H), 1.98–1.90 (m, 2
H), 1.77–1.56 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 155.1, 154.7, 154.1, 137.2,
80.8, 67.6, 29.9, 27.0, 26.1, 24.6, 22.5.
1H NMR (300 MHz, CD3OD): δ = 8.19 (s, 1 H), 7.49–7.19 (m, 5 H),
5.61 (dd, J = 10.7 Hz, J = 2.5 Hz, 1 H), 5.51 (s, 2 H), 4.08–4.03 (m,
1 H), 3.75–3.68 (m, 1 H), 2.13–1.97 (m, 3 H), 1.76–1.55 (m, 3 H).
13C NMR (75 MHz, CD3OD): δ = 161.7, 158.0, 154.8, 152.9, 141.2,
137.2, 129.5, 129.3, 117.5, 83.5, 70.0, 69.5, 31.7, 26.0, 23.7.
1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]-3-methylurea (14f)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 230 mg of 14f as a white solid (78%).
1H NMR (300 MHz, DMSO-d6): δ = 9.65 (br s, 1 H), 8.70 (q, J =
4.7 Hz, 1 H), 8.34 (s, 1 H), 7.57–7.54 (m, 2 H), 7.43–7.35 (m, 3 H),
5.64 (dd, J = 10.7 Hz, J = 1.9 Hz, 1 H), 5.58 (s, 2 H), 4.03–3.99 (m,
1 H), 3.72–3.64 (m, 1 H), 2.81 (d, J = 4.7 Hz, 3 H), 2.28–2.16 (m, 1
H), 1.98–1.94 (m, 2 H), 1.80–1.58 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.9, 154.5, 153.3, 151.8,
140.2, 136.1, 128.8, 128.5, 128.3, 116.0, 81.2, 67.9, 67.6, 29.7,
26.3, 24.6, 22.3.
MS (ES): m/z = 305.8 [M + H]+.
1-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea
(14a)
Prepared according to the general procedure starting from 200 mg
of 12, yielding 130 mg of 14a as a white solid (56%).
1H NMR (300 MHz, DMSO-d6): δ = 9.34 (br s, 1 H), 8.34 (s, 1 H),
8.29 (br s, 1 H), 7.04 (br s, 1 H), 5.61 (dd, J = 10.7 Hz, J = 1.9 Hz,
1 H), 4.54 (q, J = 7.1 Hz, 2 H), 4.02–3.98 (m, 1 H), 3.69–3.60 (m, 1
H), 2.28–2.16 (m, 1 H), 1.97–1.93 (m, 2 H), 1.78–1.56 (m, 3 H),
1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.2, 154.7, 153.5, 151.8,
MS (ES): m/z = 382.7 [M + H]+.
140.1, 116.0, 81.1, 67.6, 62.8, 29.8, 24.5, 22.4, 14.4.
N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]morpholine-4-carboxamide (14g)
Prepared according to the general procedure starting from 240 mg
of 13, yielding 176 mg of 14g as a white solid (54%).
1H NMR (300 MHz, DMSO-d6): δ = 9.41 (br s, 1 H), 8.36 (s, 1 H),
7.56–7.53 (m, 2 H), 7.43–7.31 (m, 3 H), 5.61–5.54 (m, 3 H), 4.03–
3.99 (m, 1 H), 3.67–3.59 (m + t, J = 4.9 Hz, 5 H), 3.44 (t, J = 4.9 Hz,
4 H), 2.31–2.19 (m, 1 H), 1.99–1.90 (m, 2 H), 1.78–1.57 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.8, 154.3, 154.0, 152.9,
140.1, 136.3, 128.8, 128.5, 128.2, 116.2, 80.9, 67.8, 67.6, 66.1,
44.7, 29.9, 24.5, 22.5.
1-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-
methylurea (14b)
Prepared according to the general procedure starting from 142 mg
of 12, yielding 100 mg of 14b as a white solid (58%).
1H NMR (300 MHz, CD3OD): δ = 9.07 (q, J = 4.4 Hz, 1 H), 8.19 (s,
1 H), 5.64 (dd, J = 10.4 Hz, J = 2.2 Hz, 1 H), 4.54 (q, J = 7.1 Hz, 3
H), 4.12–4.08 (m, 1 H), 3.81–3.73 (m, 1 H), 2.95 (d, J = 4.4 Hz, 3
H), 2.08–1.66 (m, 6 H), 1.46 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CD3OD): δ = 161.9, 157.5, 154.9, 152.6, 141.0,
117.4, 83.6, 69.5, 64.6, 31.7, 26.7, 26.1, 23.7, 14.7.
MS (ES): m/z = 320.8 [M + H]+.
MS (ES): m/z = 438.8 [M + H]+.
1-Butyl-3-[6-ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl)urea (14c)
Prepared according to the general procedure starting from 200 mg
of 12, yielding 180 mg of 14c as a white solid (65%).
1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]-3-(2-morpholinoethyl)urea (14h)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 200 mg of 14h as a white solid (54%).
1H NMR (300 MHz, CD3OD): δ = 9.11 (t, J = 5.2 Hz, 1 H), 8.19 (s,
1 H), 5.59 (dd, J = 10.2 Hz, J = 2.5 Hz, 1 H), 4.53 (q, J = 7.1 Hz, 2
H), 4.12–4.08 (m, 1 H), 3.79–3.70 (m, 1 H), 3.37 (q, J = 6.6 Hz, 2
H), 2.18–2.04 (m, 4 H), 1.80–1.56 (m, 6 H), 1.46 (t, J = 7.1 Hz, 3
H), 0.98 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 160.2, 153.8, 153.5, 151.6,
140.0, 116.0, 81.4, 67.7, 62.8, 31.6, 24.5, 22.4, 19.7, 14.3, 13.7.
1H NMR (300 MHz, DMSO-d6): δ = 9.66 (br s, 1 H), 8.81 (t, J = 5.2
Hz, 1 H), 8.36 (s, 1 H), 7.58–7.55 (m, 2 H), 7.43–7.36 (m, 3 H),
5.62–5.57 (m, 3 H), 4.04–4.00 (m, 1 H), 3.69–3.61 (m, 1 H), 3.51 (t,
J = 4.4 Hz, 4 H), 3.37 (q, J = 6.3 Hz, 2 H), 2.47 (t, J = 6.3 Hz, 2 H),
2.38 (t, J = 4.4 Hz, 4 H), 2.29–2.17 (m, 1 H), 1.98–1.95 (m, 2 H),
1.74–1.58 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.9, 153.9, 153.3, 151.9,
140.3, 135.9, 128.9, 128.5, 128.4, 116.0, 81.2, 68.1, 67.7, 66.1,
57.9, 53.4, 36.5, 29.7, 24.5, 22.4.
MS (ES): m/z = 362.9 [M + H]+.
N-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl)morpholine-4-carboxamide (14d)
Prepared according to the general procedure starting from 200 mg
of 12, yielding 207 mg of 14d as a white solid (72%).
1H NMR (300 MHz, CD3OD): δ = 8.24 (s, 1 H), 5.77 (dd, J = 10.7
Hz, J = 2.2 Hz, 1 H), 4.59 (q, J = 6.9 Hz, 3 H), 4.11–4.07 (m, 1 H),
3.81–3.76 (m, 1 H), 3.73 (t, J = 4.9 Hz, 4 H), 3.57 (t, J = 4.9 Hz, 4
H), 2.15–2.02 (m, 3 H), 1.85–1.59 (m, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).
1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]-3-(2-hydroxyethyl)urea (14i)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 167 mg of 14i as a white solid (53%).
1H NMR (300 MHz, DMSO-d6): δ = 9.67 (br s, 1 H), 9.27 (t, J = 5.2
Hz, 1 H), 8.36 (s, 1 H), 7.58–7.55 (m, 2 H), 7.44–7.36 (m, 3 H), 5.66
(dd, J = 10.7 Hz, J = 1.9 Hz, 1 H), 5.58 (s, 2 H), 4.97 (t, J = 4.9 Hz,
1 H), 4.01–3.97 (m, 1 H), 3.75–3.66 (m, 1 H), 3.57 (q, J = 5.2 Hz, 2
H), 3.36–3.31 (m, 2 H), 2.33–2.11 (m, 1 H), 1.97–1.91 (m, 2 H),
1.79–1.56 (m, 3 H).
Synthesis 2013, 45, 1983–1990
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of 2-Ureaguanines
1989
13C NMR (75 MHz, DMSO-d6): δ = 160.1, 154.0, 153.4, 151.6,
140.0, 136.0, 129.0, 128.5, 128.3, 115.8, 80.9, 68.0, 67.7, 60.1,
42.1, 30.0, 24.5, 22.4.
1-Methyl-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16b)
Prepared according to the general procedure starting from 100 mg
of 14b or 230 mg of 14f, yielding 20 mg (R = Et, 31%) or 66 mg
(R = Bn, 53%) of 16b as a white solid (97% purity).
N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]pyrrolidine-1-carboxamide (14j)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 170 mg of 14j as a white solid (66%).
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.39 (br s, 1 H), 10.55 (br s,
1 H), 8.87 (s, 1 H), 7.36 (q, J = 4.7 Hz, 1 H), 2.72 (d, J = 4.7 Hz, 3
1H NMR (300 MHz, DMSO-d6): δ = 9.04 (br s, 1 H), 8.35 (s, 1 H),
7.57–7.54 (m, 2 H), 7.43–7.35 (m, 3 H), 5.60–5.54 (m, 3 H), 4.02–
3.99 (m, 1 H), 3.67–3.58 (m, 1 H), 3.43–3.39 (m, 4 H), 2.31–2.16
(m, 1 H), 1.95–1.90 (m, 2 H), 1.86–1.81 (m, 4 H), 1.75–1.57 (m, 3
H).
13C NMR (75 MHz, DMSO-d6): δ = 159.7, 154.0, 152.9, 152.7,
140.1, 136.4, 128.8, 128.5, 128.2, 116.1, 80.8, 67.8, 67.5, 46.0,
30.0, 25.1, 25.0, 24.5, 22.5.
H).
HRMS (ES): m/z [M + Na]+ calcd for C7H8N6O2Na: 231.0601;
found: 231.0601
1-Butyl-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16c)
Prepared according to the general procedure starting from 180 mg
of 14c, yielding 55 mg (44%) of 16c as a brown solid.
Mp >250 °C.
1H NMR (300 MHz, 10% NaOD–D2O): δ = 7.27 (s, 1 H), 2.81 (t,
J = 6.9 Hz, 2 H), 1.10 (quin, J = 6.9 Hz, 2 H), 0.91 (sext, J = 7.1 Hz,
2 H), 0.44 (t, J = 7.1 Hz, 3 H).
N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]piperidine-1-carboxamide (14k)
Prepared according to the general procedure starting from 250 mg
of 13, yielding 273 mg of 14k as a white solid (81%).
HRMS (ES): m/z [M + Na]+ calcd for C10H14N6O2Na: 273.1070;
found: 273.1075.
1H NMR (300 MHz, DMSO-d6): δ = 9.25 (br s, 1 H), 8.33 (s, 1 H),
7.56–7.53 (m, 2 H), 7.42–7.35 (m, 3 H), 5.57–5.53 (m, 3 H), 4.03–
3.99 (m, 1 H), 3.67–3.58 (m, 1 H), 3.42–3.39 (m, 4 H), 2.32–2.16
(m, 1 H), 1.98–1.90 (m, 2 H), 1.76–1.43 (m, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.7, 154.7, 153.8, 152.9,
139.9, 136.4, 128.8, 128.5, 128.2, 116.0, 80.8, 67.8, 67.5, 45.2,
29.9, 25.5, 24.5, 24.1, 22.5.
N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)morpholine-4-carbox-
amide (16d)
Prepared according to the general procedure starting from 176 mg
of 14g, yielding 39 mg (37%) of 16d as a white solid (98% purity).
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.62 (br s, 1 H), 10.59 (br s,
1 H), 8.93 (s, 1 H), 3.62–3.59 (m, 4 H), 3.53–3.50 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): δ = 154.8, 152.7, 150.5, 150.1,
138.5, 112.1, 65.8, 44.4.
HRMS (ES): m/z [M + Na]+ calcd for C10H12N6O3Na: 287.0863;
1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-
yl]-3-(4-hydroxyphenethyl)urea (14l)
Prepared according to the general procedure (using 5.4 equiv of
DIPEA) starting from 250 mg of 13, yielding 152 mg of 14l as a
white solid (40%).
1H NMR (300 MHz, DMSO-d6): δ = 9.67 (br s, 1 H), 9.18 (br s, 1
H), 8.90 (t, J = 5.8 Hz, 1 H), 8.33 (s, 1 H), 7.55–7.48 (m, 2 H), 7.43–
7.36 (m, 3 H), 7.00 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.5 Hz, 2 H),
5.47 (s, 2 H), 5.43 (dd, J = 11.0 Hz, J = 1.9 Hz, 1 H), 3.99–3.95 (m,
1 H), 3.60–3.37 (m, 3 H), 2.72–2.67 (m, 2 H), 2.27–2.11 (m, 1 H),
1.93–1.90 (m, 2 H), 1.73–1.48 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 159.9, 155.7, 153.9, 153.3,
151.7, 140.2, 136.0, 129.6, 129.5, 128.9, 128.5, 128.4, 116.0, 115.2,
81.4, 67.9, 67.6, 41.4, 34.9, 29.6, 24.5, 22.3.
found: 287.0871.
1-(2-Morpholinoethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-
yl)urea (16e)
Prepared according to the general procedure starting from 200 mg
of 14h, yielding 96 mg (76%) of 16e as a white solid (97% purity).
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.81 (br s, 1 H), 10.48 (br s,
1 H), 10.22 (br s, 1 H), 7.98 (s, 1 H), 7.77 (br s, 1 H), 3.95 (br s, 2
H), 3.76 (br s, 2 H), 3.59–3.49 (m, 4 H), 3.25–3.11 (m, 4 H).
MS (ES): m/z = 488.8 [M + H]+.
HRMS (ES): m/z [M + H]+ calcd for C12H18N7O3Na: 308.1466;
found: 308.1466.
Double Deprotection; General Procedure
To a soln of the protected urea 14a–l (1 equiv) in 1,4-dioxane (1 M)
was added an aq soln of HCl (10%, 1 M), and the mixture was
stirred at r.t. (R = Bn) or at reflux temperature (R = Et) until LC–MS
showed that the double deprotection was complete. The mixture
was concentrated in vacuo, and the solid residue triturated with
H2O. When required, purification by preparative HPLC on a C-18
column was performed.
1-(2-Hydroxyethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea
(16f)
Prepared according to the general procedure starting from 167 mg
of 14i, yielding 53 mg (56%) of 16f as a white solid (99% purity).
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.84 (br s, 1 H), 9.72 (br s, 1
H), 7.97 (s, 1 H), 7.26 (br s, 1 H), 4.86 (br s, 1 H), 3.47 (t, J = 5.5
Hz, 2 H), 3.22 (q, J = 5.5 Hz, 2 H).
HRMS (ES): m/z [M + Na]+ calcd for C8H10N6O3Na: 261.0707;
found: 261.0706.
1-(6-Oxo-6,9-dihydro-1H-purin-2-yl)urea (16a)
Prepared according to the general procedure starting from 130 mg
of 14a or 200 mg of 14e, yielding 37 mg (R = Et, 45%) or 59 mg
(R = Bn, 56%) of 16a as a white solid (100% purity).
Mp >250 °C.
N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)pyrrolidine-1-carbox-
amide (16g)
Prepared according to the general procedure starting from 172 mg
of 14j, yielding 40 mg (40%) of 16g as a white solid (99% purity).
1H NMR (300 MHz, DMSO-d6): δ = 12.47 (br s, 1 H), 10.43 (br s,
1 H), 8.86 (s, 1 H), 7.34 (br s, 1 H), 6.92 (br s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 156.3, 152.6, 150.3, 149.9,
138.1, 111.7.
HRMS (ES): m/z [M + Na]+ calcd for C6H6N6O2Na: 217.0444;
found: 217.0444.
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.97 (br s, 1 H), 10.36 (br s,
1 H), 8.97 (s, 1 H), 3.46–3.38 (m, 4 H), 1.85 (br s, 4 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1983–1990

1990
A. Le Roux, E. Marsault
PAPER
(2) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
HRMS (ES): m/z [M + Na]+ calcd for C10H12N6O2Na: 271.0914;
found: 271.0917.
(b) Babu, P. A.; Narasu, M. L.; Srinivas, K. ARKIVOC 2007,
(ii), 247.
N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)piperidine-1-carbox-
amide (16h)
Prepared according to the general procedure starting from 273 mg
of 14k, yielding 115 mg (71%) of 16h as a white solid.
(3) (a) Lena, S.; Masiero, S.; Pieraccini, S.; Spada, G. P. Mini
Rev. Org. Chem. 2008, 5, 262. (b) Lena, S.; Masiero, S.;
Pieraccini, S.; Spada, G. P. Chem. Eur. J. 2009, 15, 7792.
(c) Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128,
14236.
(4) Watson, J. D.; Crick, F. H. Nature 1953, 171, 737.
(5) Hoogsteen, K. Acta Crystallogr. 1963, 16, 907.
(6) Jones, A. S.; Warren, J. H. Tetrahedron 1970, 26, 791.
(7) Martin, A. M.; Butler, R. S.; Ghivirigia, I.; Giessert, R. E.;
Abboud, K. A.; Castellano, R. K. Chem. Commun. 2006,
4413.
(8) Park, T.; Todd, E. M.; Nakashima, S.; Zimmerman, S. C.
J. Am. Chem. Soc. 2005, 127, 18133.
(9) Seio, K.; Kurohagi, S.; Kodama, E.; Masaki, Y.; Tsunoda,
H.; Ohkubo, A.; Sekine, M. Org. Biomol. Chem. 2012, 10,
994.
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.78 (br s, 1 H), 10.51 (br s,
1 H), 8.93 (s, 1 H), 3.50–3.47 (m, 4 H), 1.59–1.50 (m, 6 H).
HRMS (ES): m/z [M + Na]+ calcd for C11H14N6O2Na: 285.1070;
found: 285.1077.
1-(4-Hydroxyphenethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-
yl)urea (16i)
Prepared according to the general procedure starting from 152 mg
of 14l, yielding 80 mg (82%) of 16i as a white solid (95% purity).
Mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.09 (br s, 1 H), 10.08 (br s,
1 H), 9.22 (br s, 1 H), 8.41 (s, 1 H), 7.26 (t, J = 5.5 Hz, 1 H), 7.04
(d, J = 8.5 Hz, 2 H), 6.70 (d, J = 8.5 Hz, 2 H), 3.34 (q, J = 6.9 Hz, 2
H), 2.66 (t, J = 6.9 Hz, 2 H).
HRMS (ES): m/z [M + Na]+ calcd for C14H14N6O3Na: 337.1020;
found: 337.1022.
(10) Sasami, T.; Odawara, Y.; Ohkubo, A.; Sekine, M.; Seio, K.
Tetrahedron Lett. 2007, 48, 5325.
(11) NB: In schemes 1 and 2, compounds 1, 4 and 5 are depicted
as the enol form for convenience; however, it should be kept
in mind that this form is in equilibrium with the keto form.
(12) (a) Adebambo, K. F.; Zanoli, S.; Thomas, M. G.; Cancio, R.;
Howarth, N. M.; Maga, G. ChemMedChem 2007, 2, 1405.
(b) Debaene, F.; Winssinger, N. Org. Lett. 2003, 5, 4445.
(13) Robins, R. K.; Godefroi, E. F.; Taylor, E. C.; Lewis, L. R.;
Jackson, A. J. Am. Chem. Soc. 1961, 83, 2574.
(14) The correct structure of 6 was assumed based on NOESY
experiments with 14, which showed no correlation between
the protons of the THP ring and those of the benzyl group
(see Supporting Information).
Acknowledgment
This work was supported financially by the ministère du Dévelop-
pement Économique, de l’innovation et des Exportations du
Québec. Financial support from the MITACS program in the form
of a scholarship to A.L.R. is gratefully acknowledged.
(15) (a) Huang, L.-K.; Cherng, Y.-C.; Cheng, Y.-R.; Jang, J.-P.;
Chao, Y.-L.; Cherng, Y.-J. Tetrahedron 2007, 63, 5323.
(b) Qu, G.-R.; Wu, J.; Wu, Y.-Y.; Zhang, F.; Guo, H.-M.
Green Chem. 2009, 11, 760. (c) Guo, H.-M.; Xin, P.-Y.; Niu,
H.-Y.; Wang, D.-C.; Jiang, Y.; Qu, G.-R. Green Chem.
2010, 12, 2131.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
References
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.;
Wiley: Oxford, 2010, 515–538 and 629–644.
Synthesis 2013, 45, 1983–1990
© Georg Thieme Verlag Stuttgart · New York