Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium cyclization and O-N Smiles rearrangement

Article abstract of DOI:10.1016/j.tet.2008.07.002

The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O-N Smiles rearrangement. The present cascade exhibited a different profile compared to the previously reported ones, which consisted of N-N Smiles rearrangement. Lewis acid (TiCl₄) under carefully controlled conditions was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives with potential biological activities.

Full text of DOI:10.1016/j.tet.2008.07.002

Tetrahedron 64 (2008) 9101–9107
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium
cyclization and O–N Smiles rearrangement
*
*
Jinbao Xiang, Lianyou Zheng, Hongxiang Xie, Xiaowei Hu, Qun Dang , Xu Bai
The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai Street, Changchun, Jilin 130012, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded
hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O–N Smiles re-
arrangement. The present cascade exhibited a different profile compared to the previously reported ones,
which consisted of N–N Smiles rearrangement. Lewis acid (TiCl4) under carefully controlled conditions
was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A
plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This
methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives
with potential biological activities.
Received 11 April 2008
Received in revised form 27 June 2008
Accepted 1 July 2008
Available online 3 July 2008
Keywords:
TiCl4
Pteridine
Iminium cyclization
Smiles rearrangement
Cascade reactions
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
nitrogen ring systems. As an attractive strategy, both endo-cycli-
zations and exo-cyclizations have been reported.6 Another impor-
Pyrimidine moiety, as a structural component of several key bio-
molecules, has been widely explored in designing privileged
structures in medicinal chemistry and has attracted much great
attention of organic and medicinal chemists.1 Its fused bicyclic
analogs, pteridines, have been reported to exhibit a variety of bio-
logical activities and constitute the backbones of several marketed
drugs. For example, methotrexate (MTX) is used as an anti-tumor
agent and triamterene as diuretics. In addition, some pteridine
derivatives are reported to have potent inhibitory activity against
biological targets.2 Despite interesting biological activities exhibi-
ted by pteridines, few methodologies are available for the synthesis
of pyrrolo[1,2-f]pteridines.3 Therefore, efficient synthetic methods
to access pyrrolo[1,2-f]pteridines are desired.
tant reaction often reported in the synthesis of condensed
heterocyclic systems is the Smiles rearrangement.7 We have suc-
cessfully combined the iminium cyclization reaction with a N–N
Smiles rearrangement reaction and developed an unique cascade
reaction to efficiently access pyrrolo[1,2-f]pteridines (Scheme 1).3c
As a result of our investigation on the scope of this new cascade
reaction, we have demonstrated that this strategy can be extended
to a similar pyridine system with an O–N Smiles rearrangement.8 To
further explore the scope of these types of cascade reactions, it is
logical to investigate the potential of combining iminium cycliza-
tion reactions with an O–N Smiles rearrangement within a pyrim-
idine system as outlined in Scheme 2. Herein, the results from such
investigations are reported.
Tandem reactions are often developed as efficient strategies in
the synthesis of complex organic molecules, since they enable
multiple transformations via a series of cascade reactions.4 For
example, tandem reactions have been applied to the synthesis of
a number of important nitrogen-containing natural products.4b,5
The success of tandem reactions provides the impetus to new
synthetic strategies that combine existing reactions into new sin-
gle-operation tandem reactions. Iminium cyclization reactions
have been widely used for C–C bond formation to build various
Cl
Cl
N
R2
NH
N
N
R2NH2
N
O
TFA/CH2Cl2
N
N
N
N
R1
R1
A
B
Cl
N
N
N
NHR1
N
R2
C
* Corresponding authors. Tel.: þ86 431 85188955; fax: þ86 431 85188900.
E-mail addresses: qdang@jlu.edu.cn (Q. Dang), xbai@jlu.edu.cn (X. Bai).
Scheme 1. Tandem iminium cyclization and N–N Smiles rearrangement.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.002

9102
J. Xiang et al. / Tetrahedron 64 (2008) 9101–9107
Cl
Cl
Cl
N
Cl
N
N
O
N
O
Cl
N
N
R2NH2
NHR2
R1
N
HN
O
N
O
p-Cl-PhNH2
TFA/CH2Cl2
R1
N
2
3.14a
+
1
1a
N
H
(trace)
N
O
N
Cl
N
N
N
R1
a, R1 = H
Cl
OH
N
N
b, R1 = Me
R2
6 (89%)
3
Scheme 4. Tandem reaction with p-chloroaniline promoted by TFA.
Scheme 2. Tandem iminium cyclization and O–N Smiles rearrangement.
formation of 1,2,3,4-tetrahydroquinoline from aliphatic aldehydes
and arylamines has been precedented in the literature.10
2. Results and discussion
The starting aldehyde 1a and ketone 1b were prepared from
Cl
4,6-dichloro-5-pyrrolylpyrimidine
4 according to a procedure
analogous to its nitrogen analogue (Scheme 3).3c Nucleophilic
substitution of dichloropyrimidine 4 by ethyleneglycol in the
presence of K2CO3 in DMF afforded 5 in 80% yield. Alcohol 5 was
oxidized by Parikh–Doering oxidation9 to its corresponding alde-
hyde 1a in 67% yield. Aldehyde 1a was surprisingly stable to silica
gel column chromatography purification. In contrast, the corre-
sponding amino aldehyde (compound A in Scheme 1) readily
cyclized to form a diazepine on a silica gel column. Starting ketone
1b was synthesized through nucleophilic substitution of dichloro-
pyrimidine 4 by hydroxyacetone in 77% yield.
Cl
N
N
N
2 p-ClPhNH2
N
O
1a
+
1a
6
TFA/CH2Cl2
NH
N
O
N
N
Cl
Cl
7
Scheme 5. Proposed path to structure 6.
Cl
N
Cl
The above results prompted us to search for milder reaction
conditions. Thus, various acids and solvents were screened for the
reactions of aldehyde 1a and p-chloroaniline to accommodate
electron-rich anilines, and the results are summarized in Table 1.
Since Smiles rearrangement was reported to occur in the pres-
ence of protic acids,11 other protic acids, such as AcOH and TsOH
N
O
N
a
N
N
OH
N
Cl
5
4
c
b
Cl
N
Cl
N
Table 1
N
O
N
O
N
N
Optimization results in conversion of 1a to 3.14a
O
O
Entry
Solvent
Temp (ꢀC)
Time (h)
Acid (equiv)
3.14a/6a
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Dioxane
THF
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
0
0.25
3.0
3.0
0.25
0.25
0.25
0.25
0.25
1.5
0.6
0.25
0.6
0.6
0.6
TFA (0.6)
5:95
2:98
1:99
5:95
2:98
1a
1b
AcOH (0.6)
TsOH (0.04)
BF3$Et2O (0.7)
BF3$Et2O (0.7)
BF3$Et2O (0.7)
BF3$Et2O (0.7)
BF3$Et2O (0.7)
TFA (0.6)
ZnCl2 (0.05)
SnCl4 (0.8)
FeCl3 (0.04)
TMSCl (0.4)
TfOTMS (0.3)
TiCl4 (1.0)
Scheme 3. Synthesis of starting materials 1. Reagents and conditions: (a) HO(CH2)2OH,
K2CO3, MgSO4, DMF, room temperature, 12 h, 80%; (b) Pyr$SO3, DMSO/CH2Cl2 (1:1),
room temperature, 35 min, 67%; (c) HOCH2COCH3, K2CO3, MgSO4, DMF, room tem-
perature, 7 h, 77%.
1:99
1:99
22:78b
6:94
Initially, pyrimidine aldehyde 1a was treated with p-chloro-
aniline under our previously reported TFA reaction condition.3c
Unfortunately, only trace amount of the desired 6-hydroxy-
methylpyrrolo[1,2-f]pteridine 3.14a was observed by LC–MS, but
instead a product with higher molecular weight (MþNaþ¼715.0)
was obtained. Extensive characterization by MS, NMR, and HRMS
confirmed the by-product as the diastereoisomeric mixture of
compound 6, a 1,2,3,4-tetrahydroquinoline derivative (Scheme 4).
The formation of compound 6 could be attributed to iminium
cyclization of intermediate 7 derived from aldol condensation of
two molecules of 1a followed by Michael addition and formation of
imine with aniline under the strong acidic condition of TFA
(Scheme 5). This rationalization was supported by the fact that the
employment of p-nitroaniline completely suppressed the forma-
tion of corresponding by-product to give the desired product 3.17a
in 86% yield since the strong electron-withdrawing nitro group
deactivated the phenyl ring of aniline as an acceptor of the iminium
ion, which also indicated that the last step was irreversible. The
9
10
11
12
13
14
15
16
17
18
19
20
N.R.c
6:94
5:95
14:86
13:87
43:56
51:49
72:28
45:55
45:55
100:0e
1.0
0.6
1.5
0.25
1.5
TiCl4 (1.0)
TiCl4 (1.0)
ꢁ15 to 24
50
TiCl4 (1.0)
ꢁ15 to 24
ꢁ15 to 24
TiCl4 (1.0)d
TiCl4 (2.4)
4.0
a
Ratio of products was estimated based on the peak areas of LC–ELSD. This ratio is
only a reflection of conversions, but not the conversion ratio since the molecular
weights of the two compounds are different and the peak areas of LC–ELSD may not
be linear to the weights.
b
The desired product 3.14a was isolated in 26% yield.
The reaction was heated to reflux for 2 h after stirring for 0.6 h at 24 ꢀC and
c
LC–ELSD showed the ratio of 3.14a/6 to be 2:98.
d
MgSO4 was added to trap moisture.
The desired product 3.14a was isolated in 70% yield.
e

J. Xiang et al. / Tetrahedron 64 (2008) 9101–9107
9103
were also investigated. However, these Bro¨nsted acids did not lead
to any improvement over the TFA condition (entries 1–3, Table 1).
Lewis acids are generally viewed as milder alternatives to protic
acids such as TFA, and they have been shown to promote iminium
cyclization reactions such as Pictet–Spengler reactions.12 To test the
effectiveness of Lewis acids, the combination of BF3$Et2O with
various solvents was studied (entry 4–8, Table 1). We were en-
couraged by the combination of BF3$Et2O as the catalyst and ace-
tonitrile as the solvent, in which more desired product 3.14a was
generated compared to the ones with other solvents (entry 8 vs
entries 4–7, Table 1) or the one of TFA and acetonitrile (entry 8 vs
entry 9). More importantly, 26% yield of desired product 3.14a was
isolated. These results prompted us to screen other Lewis acids
using acetonitrile as the solvent. Thus, a number of Lewis acids
(ZnCl2, SnCl4, FeCl3, TMSCl, TfOTMS, and TiCl4) were investigated
(entries 10–15). Among them, TiCl4 (1.0 equiv) promoted the cas-
cade reaction more effectively than BF3$Et2O (entry 15 vs entry 8,
Table 1). Finally, the TiCl4-promoted cascade reaction in CH3CN was
further optimized at various reaction temperatures and with the
stoichiometry of TiCl4 (entries 16–20, Table 1). The by-product 6
was completely suppressed by using 2.4 equiv TiCl4 at ꢁ15 ꢀC
(entry 20, Table 1), and the desired rearrangement product 3.14a
was isolated in 70% yield. It is also noted that no intermediate
oxazepine 2.14a was observed (Scheme 2), which indicated that
O–N Smiles rearrangement was indeed faster than the N–N version
as expected.
substituted aniline did generate the desired product 3.9a (entry 9)
compared to ortho-Cl substitution that failed to produce 3.8a (entry
8), which indicated that this tandem reaction is sensitive to elec-
tronic effects at the ortho position. In addition, ketone 1b gave only
18% of the desired product 3.7b under reflux conditions and no pre-
Smiles rearrangement intermediate 2.7b was obtained. This result
is consistent with an iminium cyclization as the rate determining
step since a ketone is less reactive than an aldehyde in the imine
formation.13
A plausible mechanism involving Lewis acid promoted iminium
cyclization and Smiles rearrangement for the above tandem pro-
cess is outlined in Scheme 6. Pyrimidine aldehyde 1a could react
with an amine in presence of TiCl4 to give an imine 8, which could
be coordinated by Ti4þ to form iminium ion-intermediate 9. Elec-
trophilic substitution of intermediate 9 at the electron-rich C-2 of
the pyrrole ring could produce oxazepine 2a.14 Subsequently,
intramolecular attack of the C-6 by the resulting secondary amine,
which could be activated by the coordination of Ti4þ to N1 of the
pyrimidine ring, forming a bridged ring intermediate 11. Finally,
intermediate 11 could undergo an intramolecular rearrangement
with loss of Ti4þ to yield pyrrolo[1,2-f]pteridine 3a. This mechanism
is consistent with the facts that Smiles rearrangement could be
effected under various conditions (such as in the presence of
a protic acid or a base or under thermal conditions)11a and iminium
cyclization could be promoted by a Lewis acid.12
To explore the scope of this cascade reaction, a number of
amines were studied under the above optimized reaction conditions
using TiCl4 as the promoter. The results are summarized in Table 2.
As disclosed in Table 2, various amines ranging from ammonia to
aliphatic and aromatic amines are compatible to this reaction
conditions to produce the expected pyrrolo[1,2-f]pteridines 3 in
moderate to good yields when R1¼H (Scheme 2). Higher product
yields were obtained when aromatic amines with an electron-
withdrawing group were employed. Higher yields were obtained
with benzylamine and n-butylamine compared to cyclohexylamine
and isopropylamine. The presence of an ortho substituent of the
aromatic amine led to lower yields of the final products 3 compared
to the corresponding meta- and para-substituted analogs. These
results indicate that the steric effect of substrate amine is important
in this cascade of reactions. However, the reaction of ortho-MeO
Cl
Cl
N
O
N
O
R
N
N
NH
N
Cl3Ti
N+
N
TiCl3
H
R
10
TiCl4
11
+
-TiCl3
Cl
N
Iminium
Smiles
N
cyclization
R
NH
rearrangement
N
1a
3a
O
2a
NH2
-H2O
+
-TiCl3
R
Cl
N
Cl
Table 2
N
N
R
N
R
N
N
The TiCl4-promoted cascade reactions (Scheme 2)
TiCl4
N
R1
R2
Time (h)
Yielda (%)
TiCl3
Entry
Compd
O
N
O
1
2
3
4
5
6
7
8
3.1a
3.2a
3.3a
3.4a
3.5a
3.6a
3.7a
3.8a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Bn
12
12
5.0
7.5
10
60
32
48
40
22
12
55
Trace
25
23d
53
50
38
70
71
9
8
Hb
Mec
Scheme 6. Proposed mechanism for the iminium cyclization and O–N Smiles
n-Bu
Cyclohexyl
i-Pr
rearrangement.
12
The 4-Cl group in compound 3 was added by design to provide
an entry to introduce an additional diversity point. For this purpose,
compound 3.14a was selected as representative example to ex-
amine their reactivity toward various nucleophiles as shown in
Table 3. As expected, compounds 12 were obtained in good to ex-
cellent yields.
Ph
4.0
4.0
4.0
4.0
4.0
4.0
4.0
12
4.0
4.0
4.0
5.0e
o-ClPh
o-MeOPh
o-MePh
m-MePh
p-MePh
p-MeOPh
p-ClPh
p-BrPh
p-FPh
p-NO2Ph
Ph
9
3.9a
10
11
12
13
14
15
16
17
18
3.10a
3.11a
3.12a
3.13a
3.14a
3.15a
3.16a
3.17a
3.7b
Nuc
Cl
N
N
N
N
52
73
18
N
N
OH
OH
N
N
a
All reactions were performed on 0.5 mmol scale using 2.4 equiv TiCl4 in aceto-
nitrile at ꢁ15 to 24 ꢀC.
b
Ammonia/methanol was used.
c
Cl
Methylamine alcohol solution (27–32%) was used.
Cl
d
About 23% of atropisomer was observed by 1H NMR conclusion.
12
3.14a
e
Refluxed.

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J. Xiang et al. / Tetrahedron 64 (2008) 9101–9107
Table 3
2H, J¼2.1), 6.37 (t, 2H, J¼2.1), 4.54 (t, 2H, J¼4.5), 3.88 (d, 2H, J¼3.0),
2.25 (s, 2H); 13C NMR:
d
¼165.5,157.2, 155.4,122.0,109.9,109.7, 69.9,
Substitution with various nucleophiles
60.8; MS (ESI): m/z 240.0 [MþHþ].
Entry
Compd
Nucleophile
Time (h)
Yield (%)
1
2
3
12.1
12.2
12.3
Pyrrolidin-1-yla
PhSa
10
4.0
20
98
85
59
3.1.3. 2-(4-Chloro-5-(1H-pyrrol-1-yl)pyrimidin-6-yloxy)
acetaldehyde 1a
4-Chloro-6-hydroxylethoxyl-5-pyrrol-1-yl-pyrimidine 5 (3.0 g,
12.55 mmol) in 50 mL of DMSO/DCM (1:1) was treated with TEA
n-BuOb
a
Reaction was conducted in the presence of K2CO3 in DMF.
Reaction was conducted in butan-1-ol with NaH as the base.
b
(17.6 mL, 125.52 mmol).
A solution of SO3-pyridine (12.05 g,
75.31 mmol) in 60 mL DMSO was added and the mixture was
stirred for 35 min at ambient temperature. The reaction solution
was then diluted with 10% citric acid (250 mL) and extracted with
DCM (4ꢂ150 mL). The combined organic layers were washed with
10% citric acid (100 mL), water (3ꢂ80 mL) followed by drying
(MgSO4), and concentrated in vacuo. The residue was purified by
flash column chromatography twice (petroleum ether/EtOAc 4:1,
v/v and DCM) to afford 2.0 g (67%) of 1a as a white solid. Mp: 48–
In summary, the tandem iminium cyclization and O–N Smiles
rearrangement of pyrrolopyrimidinyloxyacetaldehyde or methyl
ketone and amines have been thoroughly investigated. The present
cascade with O–N Smiles rearrangement exhibits a different re-
action profile compared to the one with N–N Smiles rearrange-
ment. While the previously reported TFA promoted conditions
might lead to the formation of imine dimers, TiCl4 under carefully
controlled conditions can completely suppress the dimer formation
to give the desired pyrrolo[1,2-f]pteridine 3 in high yield. A plau-
sible mechanism involving iminium cyclization and Smiles rear-
rangement promoted by TiCl4 is proposed. In this cascade process,
a Lewis acid (TiCl4) promotes both an electrophilic substitution
to an aromatic ring (iminium cyclization) and a nucleophilic
replacement (Smiles rearrangement). The utility of this reaction
sequence is demonstrated via the preparation of novel 6-hydroxy-
methylpyrrolo[1,2-f]pteridine derivatives, which may have
potential biological activities.
50 ꢀC; 1H NMR:
d
¼9.67 (s, 1H), 8.49 (s, 1H), 6.84 (t, 2H, J¼1.8), 6.40
(t, 2H, J¼1.8), 5.06 (s, 2H); 13C NMR:
¼194.5, 164.4, 157.7, 155.1,
d
122.0, 110.1, 109.7, 71.3.
3.1.4. (4-Chloro-5-(1H-pyrrol-1-yl)pyrimidin-6-yloxy) acetone 1b
To a stirred solution of 4,6-dichloro-5-pyrrol-1-yl-pyrimidine
(213 mg, 1.0 mmol) and hydroxyacetone (0.114 mL, 1.5 mmol) in
DMF (2 mL) was added MgSO4 (48 mg, 0.4 mmol) followed by
K2CO3 (207 mg,1.5 mmol). The resulting solution was stirred for 7 h
at ambient temperature. Water (10 mL) was added and extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were washed
with water (3ꢂ8 mL), dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash column chromatography (petro-
leum ether/EtOAc 2:1, v/v) to afford 192 mg (77%) of 1b as a white
3. Experimental
3.1. General considerations
solid. Mp: 60–61 ꢀC; 1H NMR:
d
¼8.46 (s, 1H), 6.85 (t, 2H, J¼2.4),
Acetonitrile (CH3CN) was dried with CaH2 and distilled.
Dichloromethane (DCM) was dried with P2O5 and distilled. All
other commercial reagents were used as received without purifi-
cation. Melting points were uncorrected. Mass spectra and HPLC
data were recorded on a LC/MS system with ELSD. The 1H and 13C
NMR data were obtained on a 300 MHz NMR spectrometer with
TMS as the internal standard and CDCl3 as the solvent unless oth-
erwise stated. Multiplicities are indicated as the following: s, sin-
glet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doubled
doublet; br, broad. Coupling constants (J values) are quoted in hertz.
6.39 (t, 2H, J¼2.4), 5.03 (s, 2H), 2.19 (s, 3H); 13C NMR:
¼200.6,
d
164.5, 157.4, 155.1, 122.0, 121.1, 109.9, 70.9, 25.9; MS (ESI): m/z 252.0
[MþHþ].
3.1.5. 2-((6-Chloro-5-(1H-pyrrol-1-yl)pyrimidin-4-yloxy)methyl)-
6-chloro-3-((6-chloro-5-(1H-pyrrol-1-yl)pyrimidin-4-yl)methyl)-
N-(4-chlorophenyl)-1,2,3,4-tetrahydroquinolin-4-amine 6
To
a stirred solution of 2-(4-chloro-5-(1H-pyrrol-1-yl)pyr-
imidin-6-yloxy)acetaldehyde 1a (300 mg, 1.27 mmol) in DCM
(40 mL) was added p-chloroaniline (177 mg, 1.39 mmol) and TFA
(136 mL), and the mixture was stirred for 15 min at ambient tem-
3.1.1. 4,6-Dichloro-5-pyrrol-1-yl-pyrimidine 4
perature. The reaction solution was washed with saturated aqueous
NaHCO3, dried over MgSO4, and concentrated in vacuo. Purification
of the residue by flash chromatography (petroleum ether/
EtOAc¼4:1, v/v) afforded 384 mg (89%) of 6. MS (ESI): m/z 715.0
[MþNaþ]. 1H NMR indicated the ratio of two isomers of 6 to be 2:1
(6.1/6.2). Compound 6 was further purified by column chroma-
tography (DCM) to afford 80 mg of 6.1 as a white solid (mp: 104–
106 ꢀC) and 295 mg of mixture (6.1, 6.2). Compound 6.1: 1H NMR:
To a stirred solution of 4,6-dichloro-5-aminopyrimidine (15.0 g,
92.02 mmol) in acetic acid (150 mL), 2,5-dimethoxy tetrahydrofu-
ran (11.9 mL, 92.02 mmol) was added. The resulting solution was
stirred for 1 h at reflux. Then acetic acid was evaporated and the
residue was diluted with DCM and washed with water. The organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography (pe-
troleum ether/EtOAc 20:1, v/v) afforded 15.3 g (78%) of 4 as a white
d
¼8.64 (s, 1H), 8.46 (s, 1H), 7.21 (d, 2H, J¼8.7), 7.13–7.07 (m, 2H),
solid. Mp: 120–122 ꢀC; 1H NMR:
d
¼8.80 (s, 1H), 6.74 (t, 2H, J¼2.4),
6.89 (d, 2H, J¼8.7), 6.65 (t, 2H, J¼2.1), 6.50 (d, 1H, J¼8.4), 6.37 (t, 2H,
J¼2.1), 6.33 (t, 2H, J¼2.1), 6.16 (t, 2H, J¼2.1), 5.51 (s, 1H), 4.59 (t, 1H,
J¼4.5), 4.53–4.48 (m, 1H), 4.30–4.24 (m, 1H), 4.06–4.02 (m, 2H),
6.45 (t, 2H, J¼2.1); MS (ESI): m/z 214.0 [MþHþ].
3.1.2. 4-Chloro-6-hydroxylethoxyl-5-pyrrol-1-yl-pyrimidine 5
To a stirred solution of 4,6-dichloro-5-pyrrol-1-yl-pyrimidine
(4.0 g, 18.78 mmol) and ethyleneglycol (11.5 mL, 205.68 mmol) in
DMF (150 mL) was added MgSO4 (0.75 g, 6.25 mmol) followed by
K2CO3 (3.89 g, 28.19 mmol). The resulting solution was stirred for
12 h at ambient temperature, water (200 mL) was added, and
extracted with EtOAc (4ꢂ100 mL). The combined organic layers
were washed with water (3ꢂ80 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (petroleum ether/EtOAc 4:1, v/v) to afford 3.59 g (80%)
3.71 (d, 1H, J¼5.4); 13C NMR:
¼164.8, 164.1, 157.3, 157.1, 155.4,
d
154.9, 144.2, 140.8, 130.2, 129.5, 129.3, 123.2, 122.5, 121.8, 121.75,
121.70, 121.2, 118.7, 115.9, 114.1, 110.2, 109.7, 70.5, 67.5, 52.0, 48.5;
HRMS (ESI-Q-TOF): calcd for C32H24Cl4N8O2: 393.0854 [MþHþ],
found: 693.0848.
3.2. General procedure for the synthesis of 6-
hydroxymethylpyrrolo[1,2-f]pteridine 3
To a stirred solution of 2-(4-chloro-5-(1H-pyrrol-1-yl)pyri-
midin-6-yloxy)acetaldehyde 1a (119 mg, 0.5 mmol) in CH3CN
of 5 as a white solid. Mp: 46–47 ꢀC; 1H NMR:
d
¼8.53 (s, 1H), 6.77 (t,

J. Xiang et al. / Tetrahedron 64 (2008) 9101–9107
9105
(18 mL) was added the appropriate amine (0.55 mmol), then cooled
3.2.7. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-phenyl
pyrrolo[1,2-f]pteridine 3.7a
to ꢁ15 ꢀC, and TiCl4 (132
mL, 1.2 mmol) was added dropwise. The
reaction was held at this temperature for 1 h and then allowed to
warm slowly to 24 ꢀC. After complete consumption of the starting
material 1a by TLC, the solvent was removed in vacuo and the
residue was diluted with DCM (40 mL), which was washed with
saturated aqueous NH4Cl, dried over MgSO4, and concentrated in
vacuo. Purification of the crude product by flash chromatography
(DCM/EtOAc¼10:1 or 5:1, v/v) afforded the desired products.
Yield 55%, mp: 185–187 ꢀC. 1H NMR:
d
¼8.10 (s, 1H), 8.03 (d, 1H,
J¼1.8), 7.51–7.34 (m, 5H), 6.47 (t, 1H, J¼3.3), 6.18 (d, 1H, J¼2.4), 5.05
(t, 1H, J¼4.8), 3.88–3.73 (m, 2H), 1.78 (t, 1H, J¼6.6); 13C NMR:
d
¼153.9, 152.0, 143.2, 141.4, 129.6, 127.6, 127.2, 125.5, 120.1, 116.5,
111.8, 106.5, 64.0, 60.2; MS (ESI): m/z 313.0 [MþHþ].
3.2.8. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(2-methoxyl
phenyl)pyrrolo[1,2-f]pteridine 3.9a
3.2.1. 5-Benzyl-1-chloro-5,6-dihydro-6-hydroxylmethyl
pyrrolo[1,2-f]pteridine 3.1a
Yield 25%, mp: 159–161 ꢀC. 1H NMR:
d
¼8.07 (dd, 1H, J1¼3.3,
J2¼1.8), 8.03 (s, 1H), 7.42 (t, 1H, J¼8.1), 7.28 (br, 1H), 7.11 (t, 2H,
Yield 60%, mp: 162–163 ꢀC. 1H NMR:
d
¼8.19 (s, 1H), 7.97 (dd, 1H,
J¼7.8), 6.46 (t, 1H, J¼3.3), 6.16 (d, 1H, J¼3.0), 5.01 (t, 1H, J¼3.9), 3.86
J1¼3.0, J2¼1.5), 7.36–7.28 (m, 5H), 6.39 (t, 1H, J¼3.3), 6.07 (dd, 1H,
(s, 3H), 3.73 (s, 2H), 3.00 (br, 1H); 13C NMR:
d
¼151.9, 142.5, 129.9,
J1¼3.3, J2¼1.5), 5.61 (d, 1H, J¼15.3), 4.70 (t, 1H, J¼5.1), 4.54 (d, 1H, J¼
126.1, 122.0, 121.9, 119.9, 116.0, 112.8, 111.7, 110.1, 109.8, 106.1, 64.9,
15.6), 3.71–3.67 (m, 2H), 1.69 (t, 1H, J¼6.6) (D2O exchangeable); 13
C
60.6, 56.1; MS (ESI): m/z 343.0 [MþHþ].
NMR:
d
¼154.1, 152.1, 142.3, 136.2, 128.8, 127.8, 125.4, 119.9, 116.1,
111.5, 109.8, 106.2, 64.2, 56.1, 50.5; MS (ESI): m/z 327.0 [MþHþ].
Anal. Calcd for C17H15ClN4O: C, 62.48; H, 4.63; N, 17.15. Found: C,
62.49; H, 4.54; N, 17.11.
3.2.9. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(2-methyl
phenyl)pyrrolo[1,2-f]pteridine 3.10a
Yield 23%. 1H NMR:
d
¼8.13 (dd, 0.38H, J1¼3.3, J2¼1.5), 8.06 (s,
1H), 8.06 (d, 1H, J¼1.8), 7.35–7.31 (m, 4.57H), 7.22–7.19 (m, 0.43H),
6.50–6.46 (m, 1.21H), 6.20 (d, 1.24H, J¼3.6), 5.16 (d, 0.36H, J¼3.3),
4.77 (t, 0.83H, J¼4.8), 3.86–3.81 (m, 2.14H), 3.74–3.70 (m, 0.41H),
2.26 (s, 1.21H), 2.14 (s, 2.62H), 1.70–1.62 (m, 1.28H); MS (ESI): m/z
327.0 [MþHþ].
3.2.2. 1-Chloro-5,6-dihydro-6-hydroxylmethylpyrrolo-
[1,2-f]pteridine 3.2a
Yield 32%, mp: 214–216 ꢀC. 1H NMR (DMSO-d6):
d
¼8.36 (br, 1H),
8.02 (s, 1H), 7.85 (dd, 1H, J1¼3.3, J2¼1.5), 6.36 (t, 1H, J¼3.3), 6.16 (dd,
1H, J1¼3.9, J2¼1.2), 5.04 (br, 1H), 4.69 (dd, 1H, J1¼7.2, J2¼4.5), 3.63–
3.53 (m, 2H); 13C NMR (DMSO-d6):
d
¼155.5, 152.2, 140.6, 127.2,
3.2.10. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(3-methyl
phenyl)pyrrolo[1,2-f]pteridine 3.11a
118.4, 114.4, 111.2, 105.8, 65.6, 51.4; MS (ESI): m/z 237.0 [MþHþ].
Yield 53%, mp: 160–161 ꢀC. 1H NMR:
d
¼8.09 (s, 1H), 8.01 (dd, 1H,
3.2.3. 1-Chloro-5,6-dihydro-5-methyl-6-hydroxylmethyl
pyrrolo[1,2-f]pteridine 3.3a
J1¼3.3, J2¼1.5), 7.36 (t, 1H, J¼8.1), 7.18–7.16 (m, 3H), 6.45 (t, 1H,
J¼3.9), 6.17 (dd, 1H, J1¼2.7, J2¼0.9), 5.02 (t, 1H, J¼5.1), 3.82–3.75 (m,
Yield 48%, mp: 175–176 ꢀC. 1H NMR:
d
¼8.17 (s, 1H), 7.97 (dd, 1H,
2H), 2.39 (s, 3H), 1.84 (s, 1H); 13C NMR:
d¼153.9, 152.0, 142.9, 141.3,
J1¼3.0, J2¼1.2), 6.41 (t, 1H, J¼3.3), 6.16 (d, 1H, J¼2.7), 4.72 (t, 1H,
139.7, 129.3, 128.5, 127.7, 125.6, 124.3, 120.0, 116.4, 111.7, 106.4, 64.0,
J¼5.1), 3.82–3.76 (m, 2H), 3.31 (s, 3H), 1.72 (t, 1H, J¼6.6); 13C NMR
60.2, 21.4; MS (ESI): m/z 327.0 [MþHþ]. Anal. Calcd for
(DMSO-d6):
d
¼154.6, 151.8, 140.1, 127.5, 118.4, 115.9, 111.3, 105.3,
C17H15ClN4O: C, 62.48; H, 4.63; N, 17.15. Found: C, 62.45; H, 4.56; N,
63.4, 58.6, 35.4; MS (ESI): m/z 251.0 [MþHþ]. Anal. Calcd for
16.99.
C
11H11ClN4O: C, 52.70; H, 4.42; N, 22.35. Found: C, 52.75; H, 4.37; N,
22.19.
3.2.11. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-methyl
phenyl)pyrrolo[1,2-f]pteridine 3.12a
3.2.4. 5-(n-Butyl)-1-chloro-5,6-dihydro-6-hydroxylmethyl
pyrrolo[1,2-f]pteridine 3.4a
Yield 50%, mp: 136–138 ꢀC. 1H NMR:
d
¼8.08 (s, 1H), 8.02 (dd, 1H,
J1¼3.0, J2¼1.5), 7.31–7.23 (m, 4H), 6.46 (t, 1H, J¼3.3), 6.18 (dd, 1H,
Yield 40%, mp: 89–90 ꢀC. 1H NMR:
d
¼8.13 (s, 1H), 7.94 (dd, 1H,
J1¼3.9, J2¼0.9), 5.01 (t, 1H, J¼5.1), 3.83–3.76 (m, 2H), 2.40 (s, 3H),
J1¼3.3, J2¼1.2), 6.40 (t, 1H, J¼3.3), 6.15–6.14 (m, 1H), 4.74–4.71 (m,
1.78 (t,1H, J¼6.6); 13C NMR:
¼154.1,152.0,142.9,138.6,137.7,130.3,
d
1H), 4.36–4.27 (m, 1H), 3.78–3.63 (m, 2H), 3.26–3.16 (m, 1H), 1.83
127.2, 125.5, 120.0, 116.2, 111.7, 106.4, 64.0, 60.2, 21.1; MS (ESI): m/z
327.0 [MþHþ].
(br, 1H), 1.71–1.60 (m, 2H), 1.39–1.32 (m, 2H), 0.94 (t, 3H, J¼7.5); 13
C
NMR:
d
¼153.7,152.1,141.9,125.3,119.9,115.9,111.4,106.2, 64.3, 57.2,
47.7, 29.6, 20.0, 13.8; MS (ESI): m/z 293.1 [MþHþ].
3.2.12. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-methoxyl
phenyl)pyrrolo[1,2-f]pteridine 3.13a
3.2.5. 1-Chloro-5-cyclohexyl-5,6-dihydro-6-hydroxylmethyl
pyrrolo[1,2-f]pteridine 3.5a
Yield 38%, mp: 141–142 ꢀC. 1H NMR:
d¼8.08 (s, 1H), 8.03 (dd, 1H,
J1¼3.3, J2¼1.5), 7.30–7.26 (m, 2H), 7.02–6.99 (m, 2H), 6.46 (t, 1H,
J¼3.0), 6.18 (dd, 1H, J1¼3.6, J2¼1.5), 4.98 (dd, 1H, J1¼5.1, J2¼3.6), 3.85
Yield 22%, mp: 151–153 ꢀC. 1H NMR:
d
¼8.18 (s, 1H), 7.89 (d, 1H,
J¼1.8), 6.40 (t, 1H, J¼3.3), 6.13 (d, 1H, J¼2.4), 4.80 (dd, 1H, J1¼8.4,
J2¼4.5), 4.60–4.54 (m, 1H), 3.67–3.62 (m, 1H), 3.47–3.41 (m, 1H),
2.08 (d, 1H, J¼9.3), 1.92–1.84 (m, 2H), 1.75–1.43 (m, 7H), 1.26–1.16
(s, 3H), 3.82 (br, 2H), 1.77 (s, 1H); 13C NMR:
d¼158.8, 154.3, 151.9,
142.6, 133.8, 128.9, 125.6, 119.9, 116.1, 114.8, 111.6, 106.3, 64.0, 60.5,
55.4; MS (ESI): m/z 343.0 [MþHþ].
(m, 1H); 13C NMR:
105.9, 64.7, 57.2, 52.1, 31.8, 30.7, 25.9, 25.8, 25.4; MS (ESI): m/z 319.0
[MþHþ].
d
¼153.9, 152.0, 142.6, 126.1, 119.9, 116.1, 111.5,
3.2.13. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-chloro
phenyl)pyrrolo[1,2-f]pteridine 3.14a
Yield 70%, mp: 158–159 ꢀC. 1H NMR:
d
¼8.10 (s, 1H), 8.01 (d, 1H,
J¼1.8), 7.44 (d, 2H, J¼8.7), 7.34 (d, 1H, J¼8.7), 6.46 (t, 1H, J¼3.3), 6.18
3.2.6. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(iso-
propyl)pyrrolo[1,2-f]pteridine 3.6a
(d,1H, J¼2.7), 5.02 (t,1H, J¼4.8), 3.85–3.73 (m, 2H),1.90 (br,1H); 13
C
NMR:
d
¼153.8, 151.7, 143.0, 139.9, 133.1, 129.7, 128.6, 125.5, 120.0,
Yield 12%, mp: 139–141 ꢀC. 1H NMR:
d
¼8.18 (s, 1H), 7.90 (dd, 1H,
116.7, 111.8, 106.5, 64.0, 60.2; MS (ESI): m/z 346.9 [MþHþ].
J1¼3.0, J2¼1.2), 6.41 (t, 1H, J¼3.3), 6.15 (d, 1H, J¼2.4), 4.92–4.85 (m,
1H), 4.83–4.78 (m, 1H), 3.72–3.65 (m, 1H), 3.51–3.43 (m, 1H), 1.69–
1.64 (m, 1H), 1.41 (d, 3H, J¼6.9), 1.33 (d, 3H, J¼6.6); 13C NMR:
3.2.14. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-bromo
phenyl)pyrrolo[1,2-f]pteridine 3.15a
Yield 71%, mp: 102–103 ꢀC. 1H NMR:
d
¼8.12 (s, 1H), 8.02 (dd, 1H,
d
¼153.9,152.0,142.5,126.1, 119.9, 116.6,111.5,106.0, 64.9, 52.0, 49.3,
21.4, 20.3; MS (ESI): m/z 279.0 [MþHþ].
J1¼3.0, J2¼1.5), 7.62–7.57 (m, 2H), 7.32–7.28 (m, 2H), 6.47 (t, 1H,

9106
J. Xiang et al. / Tetrahedron 64 (2008) 9101–9107
J¼3.3), 6.19 (dd, 1H, J1¼3.6, J2¼1.5), 5.03 (t, 1H, J¼4.8), 3.83–3.74 (m,
5.00 (t, 1H, J¼6.9), 3.93–3.72 (m, 4H), 3.17 (br, 2H), 2.62 (br, 1H),
2.02–1.84 (m, 4H); MS (ESI): m/z 382.1 [MþHþ].
2H), 1.76 (t, 1H, J¼6.6); 13C NMR:
¼153.6, 151.7, 143.2, 140.5, 132.6,
d
128.8, 125.6, 121.0, 119.9, 116.8, 111.8, 106.5, 64.0, 60.1; MS (ESI): m/z
390.9 [MþHþ].
3.2.19. 5,6-Dihydro-6-hydroxylmethyl-5-(4-chlorophenyl)-
1-(phenylthio)pyrrolo[1,2-f]pteridine 12.2
3.2.15. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-fluoro
phenyl)pyrrolo[1,2-f]pteridine 3.16a
To
methyl-5-(4-chlorophenyl)pyrrolo[1,2-f]pteridine 3.14a (52 mg,
0.15 mmol) and thiophenol (46 L, 0.45 mmol) in DMF (1 mL) was
added K2CO3 (31 mg, 0.225 mmol). The resulting solution was
stirred for 6 h at ambient temperature, water (20 mL) was added,
and extracted with EtOAc (3ꢂ10 mL). The combined organic layers
were washed with water (3ꢂ8 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (petroleum ether/EtOAc 4:1, v/v) to afford 54 mg (85%)
of 12.2 as a yellow solid. Mp: 186–188 ꢀC. 1H NMR (DMSO-d6):
a stirred solution of 1-chloro-5,6-dihydro-6-hydroxyl-
Yield 52%, mp: 229–230 ꢀC. 1H NMR (DMSO-d6):
d¼8.04 (s, 1H),
m
7.89 (dd, 1H, J1¼3.0, J2¼1.5), 7.53–7.49 (m, 2H), 7.34–7.28 (m, 2H),
6.44 (t, 1H, J¼3.0), 6.18 (dd, 1H, J1¼3.3, J2¼1.5), 5.23 (t, 1H, J¼5.1),
5.10 (t, 1H, J¼3.3), 3.67–3.64 (m, 1H), 3.57–3.52 (m, 1H); 13C NMR
(DMSO-d6):
d
¼162.2, 158.9, 154.2, 151.3, 141.5, 137.7, 129.9, 129.8,
127.6, 118.6, 116.3, 116.0, 115.7, 111.5, 105.6, 63.4, 59.9; MS (ESI): m/z
331.0 [MþHþ].
3.2.16. 1-Chloro-5,6-dihydro-6-hydroxylmethyl-5-(4-nitro
phenyl)pyrrolo[1,2-f]pteridine 3.17a
(a) Procedure 1. To a stirred solution of 2-(4-chloro-5-(1H-pyr-
rol-1-yl)pyrimidin-6-yloxy)acetaldehyde 1a (119 mg, 0.5 mmol) in
DCM (18 mL) was added p-nitroaniline (76 mg, 0.55 mmol) and TFA
d
¼8.00 (s, 1H), 7.82 (t, 1H, J¼1.5), 7.57–7.44 (m, 9H), 6.43 (t, 1H,
J¼3.3), 6.16 (d,1H, J¼3.6), 5.27 (t,1H, J¼5.1), 5.12 (t,1H, J¼4.2), 3.62–
3.53 (m, 2H); 13C NMR (DMSO-d6):
d
¼151.7, 151.6, 150.4, 141.2,
135.0,130.1, 129.3,129.2,128.8,128.5,128.3,127.8,118.4,116.8,111.2,
105.5, 63.2, 59.3; MS (ESI): m/z 421.2 [MþHþ].
(68 mL). The mixture was stirred for 15 min, then washed with
saturated aqueous NaHCO3, dried over MgSO4, and concentrated in
vacuo. Purification of the residue by flash chromatography (DCM/
EtOAc¼10:1, v/v) to afford 154 mg (86%) of the desired products
3.17a as a yellow solid.
(b) Procedure 2. General procedure for the synthesis of 6-
hydroxymethylpyrrolo[1,2-f]pteridine 3. Yield 73%, mp: 173–174 ꢀC.
3.2.20. 1-Butoxy-5,6-dihydro-6-hydroxylmethyl-5-(4-chloro
phenyl)pyrrolo[1,2-f]pteridine 12.3
To
a stirred solution of 1-chloro-5,6-dihydro-6-hydroxyl-
methyl-5-(4-chlorophenyl)pyrrolo[1,2-f]pteridine 3.14a (52 mg,
0.15 mmol) in n-BuOH (1 mL) was added NaH (18 mg, 0.45 mmol).
The resulting solution was stirred for 24 h at ambient temperature,
the solvent was evaporated in vacuo, water (20 mL) was added, and
extracted with EtOAc (2ꢂ10 mL). The combined organic layers were
washed with water (2ꢂ8 mL) followed by drying (MgSO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography (DCM/Et2O 40:1, v/v) to afford 34 mg (59%) of 12.3
1H NMR:
d
¼8.30 (d, 1H, J¼7.2), 8.27 (s, 1H), 7.98 (dd, 1H, J1¼3.3,
J2¼1.5), 7.64 (d, 1H, J¼6.9), 6.47 (t, 1H, J¼3.3), 6.22 (dd, 1H, J1¼3.3,
J2¼0.9), 5.23 (t, 1H, J¼5.4), 3.88–3.81 (m, 2H), 1.82 (t, 1H, J¼6.3); 13
C
NMR (DMSO-d6):
d
¼153.1, 151.7, 148.2, 143.7, 143.6, 127.6, 124.9,
124.3, 119.0, 118.5, 111.6, 106.2, 63.7, 58.6; MS (ESI): m/z 358.0
[MþHþ].
as a white solid. Mp: 126–127 ꢀC. 1H NMR:
d
¼8.08 (s, 1H), 7.78 (s,
1H), 7.40–7.26 (m, 4H), 6.37 (t, 1H, J¼2.7), 6.12 (s, 1H), 5.50 (t, 1H,
J¼5.1), 4.57–4.46 (m, 2H), 3.82–3.64 (m, 2H), 1.91–1.84 (m, 2H),
1.59–1.52 (m, 2H), 1.02 (t, 1H, J¼6.9); MS (ESI): m/z 385.1 [MþHþ].
3.2.17. 1-Chloro-5,6-dihydro-6-methyl-6-hydroxylmethyl-5-phenyl
pyrrolo[1,2-f]pteridine 3.7b
To
imidin-6-yloxy)acetone 1b (126 mg, 0.5 mmol) in CH3CN (18 mL)
was added aniline (53 L, 0.55 mmol) at ambient temperature,
then TiCl4 (132 L, 1.2 mmol) was added dropwise. The resulting
a stirred solution of 2-(4-chloro-5-(1H-pyrrol-1-yl)pyr-
Acknowledgements
m
m
This work was supported by grants (nos. 20572032, 20232020)
from the National Natural Science Foundation of China and
Changchun Discovery Sciences, Ltd.
solution was stirred for 9 h at reflux. The solvent was removed
in vacuo and the residue was diluted with DCM (40 mL), washed
with saturated aqueous NH4Cl, dried over MgSO4, and concen-
trated in vacuo. Purification of the residue by flash chromato-
graphy (petroleum ether/EtOAc¼4:1, v/v) afforded the desired
products to afford 30 mg (18%) of 3.7b as a coffee solid. Mp:
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.002.
198–200 ꢀC. 1H NMR:
d
¼8.06 (dd, 1H, J1¼3.0, J2¼1.5), 8.04 (s,
1H), 7.53–7.46 (m, 3H), 7.35 (d, 1H, J¼7.8), 7.15 (d, 1H, J¼7.5),
6.47 (t, 1H, J¼3.3), 6.19 (dd, 1H, J1¼3.6, J2¼1.2), 3.74 (t, 1H,
References and notes
J¼5.7), 1.77 (t, 1H, J¼6.6), 1.44 (s, 3H); 13C NMR:
¼151.8, 142.1,
d
1. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (b)
Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X. J. Comb. Chem. 2005, 7, 474; (c)
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138.0, 130.9, 130.7, 130.4, 129.5, 129.4, 128.5, 119.9, 111.4, 105.5,
68.9, 61.2, 22.7; MS (ESI): m/z 327.0 [MþHþ].
3.2.18. 5,6-Dihydro-6-hydroxylmethyl-5-(4-chlorophenyl)-
1-(pyrrolidin-1-yl)pyrrolo[1,2-f]pteridine 12.1
To
methyl-5-(4-chlorophenyl)pyrrolo[1,2-f]pteridine 3.14a (52 mg,
0.15 mmol) and pyrrolidine (37 L, 0.45 mmol) in DMF (1 mL) was
a stirred solution of 1-chloro-5,6-dihydro-6-hydroxyl-
m
added K2CO3 (31 mg, 0.225 mmol). The resulting solution was
stirred for 6 h at ambient temperature, water (20 mL) was added,
and extracted with DCM (3ꢂ10 mL). The combined organic layers
were washed with water (3ꢂ8 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (DCM/Et2O 40:1, v/v) to afford 56 mg (98%) of 12.1 as
a yellow solid. Mp: 170–171 ꢀC. 1H NMR:
(m, 4H), 7.11 (d, 1H, J¼1.5), 6.34 (t, 1H, J¼3.0), 6.00 (dd, 1H, J¼3.0),
d¼8.03 (s, 1H), 7.37–7.30
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