An efficient entry to furo[2,3-d]pyrimidines via inverse electron demand Diels-Alder reactions of 2-aminofurans with 1,3,5-triazines

Article abstract of DOI:10.1016/j.tetlet.2009.09.087

Furo[2,3-d]pyrimidines were readily prepared via an inverse electron demand Diels-Alder (IDA) reaction between 2-aminofurans and 1,3,5-triazines. 2-Aminofurans proved to be productive dienophiles leading to the IDA product in moderate to good yields. This

Full text of DOI:10.1016/j.tetlet.2009.09.087

Tetrahedron Letters 50 (2009) 6758–6760
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An efficient entry to furo[2,3-d]pyrimidines via inverse electron demand
Diels–Alder reactions of 2-aminofurans with 1,3,5-triazines
*
Qun Dang , Yan Liu
Department of Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Furo[2,3-d]pyrimidines were readily prepared via an inverse electron demand Diels–Alder (IDA) reaction
between 2-aminofurans and 1,3,5-triazines. 2-Aminofurans proved to be productive dienophiles leading
to the IDA product in moderate to good yields. This study further expanded the scope of 1,3,5-triazine IDA
reactions with five-membered aromatic heterocycles as dienophiles.
Received 6 August 2009
Revised 16 September 2009
Accepted 16 September 2009
Available online 20 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Furo[2,3-d]pyrimidines are an interesting class of heterocycles
with various biological activities. For example, furo[2,3-d]pyrimi-
dines were reported to be potent and selective glycogen synthase
kinase-3 inhibitors1 and antifolate agents.2 Furo[2,3-d]pyrimidines
are often prepared via stepwise cyclization reactions.3,4 A potential
alternative method to prepare furo[2,3-d]pyrimidines was envi-
sioned to entail cascade reactions involving an inverse electron de-
mand Diels–Alder (IDA) reaction, followed by the elimination of
ammonia, and a final retro Diels–Alder reaction, depicted in
Scheme 1.
refluxing toluene (110 °C), 24 h led to mostly starting furan 7 being
recovered. Conversely, the Lewis acid BF3–OEt2 promoted Boc re-
R2
R2
X
N
X
N
R1
R1
H2N
O
O
X
N
3 - 5
N
N
1a - c
Furans are often reported as dienes for Diels–Alder reactions,5–9
but less frequently as dienophiles.10–12 For example, the Padwa
group demonstrated 2-aminofurans as productive dienes for
Diels–Alder reactions and developed these reactions into elegant
methods to prepare substituted anilines efficiently.13 To date,
1,3,5-triazine IDA reactions involving furans have not been re-
ported. Herein the investigation of 2-aminofurans as dienophiles
in IDA reactions of 1,3,5-triazines and the development of this
method for the efficient preparation of furo[2,3-d]pyrimidines is
X
X
IDA
2a - e
- NC-X
X
R2
O
N
X
R2
N
X
-NH3
X
R1
R1
N
N
N
N
O
X
NH2
X
reported. Such
a method should produce highly substituted
Scheme 1. IDA reactions of 2-aminofurans with triazines.
furo[2,3-d]pyrimidines and complement existing methods to
access this interesting class of heterocycles.
The 2-N-Boc-amino-furan 7 was readily prepared from 2-furoic
acid 6 via a Curtius rearrangement14 as shown in Scheme 2.
Treatment of 2-furoic acid 6 with diphenyl phosphorylazide
(DPPA) and triethylamine (TEA) in refluxing tert-butanol gave the
Boc-protected 2-aminofuran 7 in 65% yield. Removal of the Boc
group proved to be more complicated since several conventional
methods did not produce the desired 2-aminofuran 1b. Thus, treat-
ment of furan 7 with TFA (10 equiv) in anhydrous CH2Cl2 at 25 °C
for 18 h led to mostly decomposition, while milder conditions such
as TMSCl (5 equiv) in EtOH, 25 °C, 24 h, and pTsOH (0.1 equiv) in
O
O
DPPA
HO2C
P(OEt)2
BocHN
P(OEt)2
O
6
TEA
t-BuOH
65%
O
7
BF3-OEt2
AcOH-CHCl3
57%
O
H2N
P(OEt)2
O
1b
* Corresponding author at present address: Merck Research Laboratories,
Rahway, NJ 07065, USA. Tel.: +1 732 594 2018; fax: +1 732 594 7444.
E-mail address: qun_dang@merck.com (Q. Dang).
Scheme 2. Syntheses of 2-aminofurans 7 and 1b.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.087

Q. Dang, Y. Liu / Tetrahedron Letters 50 (2009) 6758–6760
6759
moval method developed by Hiskey et al.15 generated the desired
2-aminofuran 1b in 57% yield (unoptimized).
The IDA reactions with 1,3,5-triazines (2a–e) were investigated
using furans 7, 1a (methyl 2-amino-5-furancarboxylate), 1b and 1c
(2-methoxy-furan); results are summarized in Table 1.16
was run with a lower amount or no BF3–OEt2: 2 equiv of BF3–OEt2
led to a lower yield (Table 1, entry 8), while eliminating BF3–OEt2
did not produce any desired product (Table 1, entries 9 and 10).
These observations suggest that BF3–OEt2 is essential for this
one-pot procedure, while the AcOH–CHCl3 solvent system alone
is not enough to promote the one-pot procedure. Alternatively,
an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate)
was found to be suitable for the one-pot Boc removal IDA reaction
and with the same efficiency in generating the IDA product 4a (Ta-
ble 1, entry 11). Next, furan 7 was reacted with triazines 2b–e un-
der the newly developed Lewis acid-promoted IDA reaction
conditions. Triazines 2a and 2b (with electron-withdrawing groups
such as ethoxycarbonyl and CF3) gave higher yields of the desired
IDA products (entries 7 and 12) compared to the unsubstituted tri-
azine 2c (entry 13). Omitting acetic acid from the reaction of tri-
azine 2c and furan 1b gave comparable yield of the IDA product
4c (entry 14), while conducting the reaction in neat BF3–OEt2 sig-
nificantly increased the yield of 4c from 30% to 57% (entry 15). It is
noteworthy that even though the IDA reaction of furan 1b with tri-
ethyl triazine 2d only gave 4d in moderate yield (entry 16), this is
the first example of triazine 2d participating in an IDA reaction.
The more electron-rich triazine 2e was not reactive enough for
the current IDA reaction (entry 17). To check if the Lewis acid reac-
tion conditions are compatible with other 2-aminofurans, furan 1a
was reacted with triazine 2b in the presence of BF3–OEt2, but much
lower yield of 3b was obtained (entry 18) compared to the conven-
tional thermal conditions (entry 3). Another furan derivative
shown to participate in IDA reactions is 2-methoxyfuran (1c); Liao
et al. reported reactions of furan 1c with electron-deficient pyrones
under thermal conditions.12 Treatment of triazine 2a with furan 1c
under either thermal conditions (starting materials remained, en-
try 19) or Lewis acid conditions (decompositions observed, entry
20) did not produce any desired IDA products. Thus, furan 1c is
not reactive enough for an IDA reaction with triazine 2a, which is
Although 2-aminofurans were reported as the 4
p diene in
Diels–Alder reactions by Padwa and co-workers, no example of
2-aminofurans as dienophiles was uncovered. Initially, IDA reac-
tions were investigated using 2-aminofuran 1a and 2 equiv of tri-
azine 2b (which was chosen based on better solubility compared
to triazine 2a). After 24 h at room temperature, most of 1a were
consumed but several products were detected by TLC, which are
likely products associated with the various stages of this cascade
reaction (Scheme 1). Heating of the reaction solution at 80 °C for
12 h generated a single product, which was isolated and identified
as the desired IDA product 3b in 75% yield, Table 1, entry 1. Con-
ducting the reaction at 80 °C for 18 h gave a slightly lower yield
of 64% (Table 1, entry 2), while heating at 100 °C for 12 h gave com-
pound 3b in 75% yield (Table 1, entry 3). Furan 1b also proved to be
a productive dienophile in the IDA reaction with triazines 2b and
2a under thermal conditions, leading to 4b and 4a in 63% and
52% yields, respectively (Table 1, entries 4 and 5). Encouraged by
these results, the Boc-protected 2-aminofuran 7 was also investi-
gated as a potential dienophile. However, after prolonged heating
of furan 7 and triazine 2b at 100 °C for 24 h, no IDA product 4b
was detected; only starting materials remained. The significantly
decreased reactivity of furan 7 compared to furan 1b in the current
IDA reactions is likely due to the electron-withdrawing ability of
the Boc group. Thus, various conditions were explored to combine
the Boc removal and IDA reaction into a one-pot procedure. Furan
7 was treated with triazine 2a under the Hiskey Boc deprotection
conditions (4 equiv BF3–OEt2, AcOH–CHCl3, 25 °C, 15 h) and indeed
the desired IDA product 4a was isolated in 50% yield (Table 1, entry
7). To test the importance of the Lewis acid BF3–OEt2, the reaction
Table 1
IDA reactions of furans with various 1,3,5-triazines leading to furo[2,3-d]pyrimidinesa
X
X
N
N
N
R2
R5
R5
+
O
O
X
N
X
X
N
1b - c, 7
2a - e
3b, 4a - e, 5a
Entry
R2
R5
Furans
X
Triazines
Conditions
Pdt
Yield (%)
1
2
3
4
5
6
7
8
H2N
H2N
H2N
H2N
CO2Me
CO2Me
CO2Me
1a
1a
1a
1b
1b
7
7
7
7
7
7
7
7
7
7
7
7
CF3
CF3
CF3
CF3
CO2Et
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CF3
H
H
H
Et
2b
2b
2b
2b
2a
2b
2a
2a
2a
2a
2a
2b
2c
2c
2c
2d
2e
2b
2a
2a
DMSO, 25 °C, 24 h; 80 °C, 12 h
DMSO, 80 °C, 18 h
DMSO, 100 °C, 18 h
DMF, 100 °C, 18 h
DMSO–DMF (1:1), 100 °C, 18 h
DMSO, 100 °C, 24 h
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
BF3–OEt2 (2 equiv), AcOH–CHCl3, 25 °C, 15 h
AcOH–CHCl3, 25 °C, 24 h
3b
3b
3b
4b
4a
4a
4a
4a
4a
4a
4a
4b
4c
4c
4c
4d
4e
3b
5a
5a
75
64
75
63
52
0b
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
CO2Me
H2N
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
H2N
50c
36
0b
9
10
11
12
13
14
15
16
17
18
19
20
AcOH–DMF, 100 °C, 48 h
0b
BF3–OEt2 (4 equiv), ionic liquid,d 25 °C, 15 h
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
BF3–OEt2 (4 equiv), CHCl3, 25 °C, 15 h
BF3–OEt2 (35 equiv), 25 °C, 15 h
BF3–OEt2 (35 equiv), 25 °C, 15 h
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
DMSO, 100 °C, 24 h
52c
68c
33c
30c
57c
28c
0c
OMe
CF3
CO2Et
CO2Et
1a
1c
1c
27
MeO
MeO
H
H
0b
BF3–OEt2 (4 equiv), AcOH–CHCl3, 25 °C, 15 h
0
a
b
c
All reactions were conducted under nitrogen and yields are based on isolated products.
Starting materials remained.
Furan 7 was consumed.
d
1-Butyl-3-methylimidazolium tetrafluoroborate.

6760
Q. Dang, Y. Liu / Tetrahedron Letters 50 (2009) 6758–6760
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In summary, 2-amino-furans 1a and 1b were introduced as pro-
ductive dienophiles in IDA reactions with various 1,3,5-triazines
(2a–e), leading to furo[2,3-d]pyrimidines in moderate to good
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16. Representative procedures for the IDA reactions:
A mixture of 2b (312 mg,
1.10 mmol) and 1b (120 mg, 0.55 mmol) in anhydrous DMSO (2 mL) was
heated to 80 °C under nitrogen. After 18 h, the cooled reaction solution was
evaporated to dryness and the residue was partitioned between EtOAc (50 mL)
and saturated sodium bicarbonate (25 mL). The layers were separated and the
organic layer was washed (brine, 25 mL), dried (MgSO4), filtered, and
evaporated. The residue was purified by flash chromatography (SiO2,
2 Â 15 cm,
30%
EtOAc–hexane)
to
give
6-diethylphosphono-2,4-
References and notes
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A mixture of 2b (114 mg,
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was treated with BF3–OEt2 (0.8 mmol) at 25 °C under nitrogen. After 15 h, the
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(53 mg, 68%).1H NMR (DMSO-d6): d 7.17 (m, 1H), 4.31 (m, 4H), 1.31 (m, 6H).
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