A tandem decarboxylation and inverse electron-demand Diels-Alder reaction of amino-thiophenecarboxylic acids with 1,3,5-triazines

Article abstract of DOI:10.1016/j.tetlet.2009.03.180

The scope of 1,3,5-triazine inverse electron-demand Diels-Alder (IDA) reactions was expanded to include aminothiophenecarboxylic acids as latent dienophiles. A series of 2-amino-3-thiophenecarboxylic acids (1a-d) and a 3-amino-2-thiophenecarboxylic acid (

Full text of DOI:10.1016/j.tetlet.2009.03.180

Tetrahedron Letters 50 (2009) 2874–2876
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A tandem decarboxylation and inverse electron-demand Diels–Alder
reaction of amino-thiophenecarboxylic acids with 1,3,5-triazines
*
Qun Dang , Edmund Carruli, Feng Tian, Francis W. Dang, Tony Gibson, Wenyu Li, Huachen Bai,
Michael Chung, Scott J. Hecker
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:
The scope of 1,3,5-triazine inverse electron-demand Diels–Alder (IDA) reactions was expanded to include
aminothiophenecarboxylic acids as latent dienophiles. A series of 2-amino-3-thiophenecarboxylic acids
(1a–d) and a 3-amino-2-thiophenecarboxylic acid (5) were introduced as productive dienophiles in
IDA reactions with various 1,3,5-triazines (2a–e). This method is useful for the one-step synthesis of both
thieno[2,3-d]pyrimidines and thieno[3,2-d]pyrimidines, which should complement existing methods.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 26 February 2009
Revised 24 March 2009
Accepted 25 March 2009
Available online 28 March 2009
R2
X
R2
Inverse electron-demand Diels–Alder (IDA) reactions have been
developed as a powerful method to construct various heterocycles
efficiently.1 In particular, the IDA reactions with 1,3,5-triazines as
azadienes have been applied to the efficient synthesis of pyrimi-
dine derivatives.2–4 Recently, five-membered heterocycles were
introduced as electron-rich dienophiles, and their IDA reactions
with 1,3,5-triazines were reported as a one-step synthesis of vari-
ous pyrimidine-fused heterocycles.5–8 One common property of
electron-rich five-membered heterocycles (e.g., with an amino
group as a substituent) is poor thermal stability, which often ren-
ders these compounds (such as 5-aminoimidazoles and 2-amino-
pyrroles) too unstable for isolation. One way to circumvent this
issue is to generate these electron-rich dienophiles in situ. In fact,
such tandem decarboxylation-IDA reactions using 5-amino-4-imi-
dazolecarboxylic acids and 5-amino-4-pyrazolecarboxylic acids as
latent dienophiles6,8 have been reported. A logical extension of the
tandem decarboxylation IDA reaction is to explore the readily
available 2-amino-3-thiophenecarboxylic acids, which have been
reported to undergo decarboxylation.9,10 Such new IDA reactions
(Scheme 1) could provide an efficient method for the synthesis of
thienopyrimidines, which would be complementary to existing
methods for rapid synthesis of this class of biologically interesting
heterocycles.11–13
HO2C
H2N
N
R1
R1
S
X
N
S
1a - d
3a - d, 4b-d
X
N
Decarboxylation
N
N
X
R2
S
N
R2
X
X
X
H
R1
2a - e
N
N
R1
IDA
H2N
S
X
NH2
Scheme 1. IDA reactions of 2-aminothiophenes (1a–d).
Table 1
IDA reactions of thiophene 1a with triazines 2a–ea
Entry
Dienes
X
Conditions
Pdt
Yieldb (%)
1
2
3
4
5
6
2a
2a
2b
2c
2d
2e
CO2Et
CO2Et
CF3
CF2Cl
H
90 °C, 18 hc
80 °C, 18 h
80 °C, 18 h
80 °C, 18 h
80 °C, 18 h
80 °C, 18 h
3a
3a
3b
3c
3d
3e
20
76
76
51
33
0
Various 2-amino-3-thiophenecarboxylic acids were prepared
from their corresponding esters via saponification. Initially, 2-ami-
no-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid (1a)
was tested with 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine (2a) un-
der mild thermal conditions, and indeed the desired thieno[2,3-
d]pyrimidine 3a was obtained in moderate yield (Table 1, entry
1). The regiochemistry of 3a was assigned based on 1D Roesy
Ph
a
All reactions were conducted under nitrogen in DMF–AcOH unless otherwise
noted.
b
c
Yields were based on isolated pure products.
DMSO was used as the solvent.
experiments: there is a strong NOE interaction between the –
CH2– at the 3-position of the thiophene moiety and one of the ethyl
ester groups. Conversely, if the IDA product is the other regio-iso-
mer thieno[3,2-d]pyrimidine (e.g., compound 6, Eq. 3) then there
* Corresponding author. Tel.: +1 858 755 0284.
E-mail address: dang3qun2@yahoo.com (Q. Dang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.180

Q. Dang et al. / Tetrahedron Letters 50 (2009) 2874–2876
2875
Further modification of the IDA products obtained from 1,3,5-tri-
azine 2a is anticipated to provide access to a wide variety of substi-
tuted thienopyrimidines. The activating ester groups may be
removed by hydrolysis and decarboxylation to afford compound
3d (Eq. 4, 55% yield). Alternatively, the two ester groups could be
selectively functionalized as Boger et al. reported in their bleomycin
work17 or they could be converted to carboxamides via the corre-
sponding carboxylic acids.
In summary, a series of 2-amino-3-thiophenecarboxylic acids
(1a–d) and a 3-amino-2-thiophenecarboxylic acid (5) were intro-
duced as productive dienophiles in IDA reactions with various
1,3,5-triazines (2a–e). This method is useful for the one-step syn-
thesis of both thieno[2,3-d]pyrimidines and thieno[3,2-d]pyrimi-
dines, which should complement existing methods.
should not be any NOE interaction between the –CH2– at the 3-po-
sition of the thiophene moiety and one of the ethyl ester groups on
the pyrimidine side.
Screening of reaction conditions such as solvent and reaction
temperature led to the identification of DMF–AcOH as an optimum
solvent system, producing compound 3a in good yield (76%; entry
2, Table 1). The scope of this tandem decarboxylation IDA reaction
was explored using various 1,3,5-triazines (2a–e) as the azadienes
and thiophene 1a as the latent dienophile (Eq. 1); results are sum-
marized in Table 1.18
X
X
HO2C
H2N
N
N
N
+
ð1Þ
S
X
N
X
S
X
N
2a - d
1a
3a - d
References and notes
1. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in Organic Synthesis;
Academic Press: New York, 1987.
2. Boger, D. L.; Schumacher, J.; Panek, J. S.; Mullican, M. D.; Patel, M. J. Org. Chem.
1982, 47, 2673–2675.
Consistent with past observations, 1,3,5-triazines with electron-
withdrawing groups such as ethoxycarbonyl and CF3 gave a higher
yield of the desired IDA product (entries 2 and 3) compared to the
unsubstituted 1,3,5-triazine (2d, entry 5). The 2,4,6-triphenyl-1,3,5-
triazine (2e) was not reactive enough to participate in the IDA reac-
tion despite prolonged heating (entry 6).
To explore the scope of this IDA reaction with regard to 2-amino-3-
thiophenecarboxylic acids, three other thiophenes (1b–d) were
tested under the current reaction conditions (Eq. 2) and results are
summarized in Table 2.
3. Boger, D. L.; Dang, Q. Tetrahedron 1988, 44, 3379–3390.
4. Boger, D. L.; Kochanny, M. J. J. Org. Chem. 1994, 59, 4950–4955.
5. Dang, Q.; Brown, B. S.; Erion, M. D. J. Org. Chem. 1996, 61, 5204.
6. Dang, Q.; Liu, Y.; Erion, M. D. J. Am. Chem. Soc. 1999, 121, 5833.
7. Dang, Q.; Gomez-Galeno, J. E. J. Org. Chem. 2002, 67, 8703–8705.
8. Dang, Q.; Liu, Y.; Sun, Z. Tetrahedron Lett. 2001, 42, 8419–8422.
9. Gewald, K. Z. Chem. 1967, 7, 186–187.
10. Noravyan, A. S.; Mkrtchyan, A. P.; Dzhagatspanyan, I. A.; Nazaryan, I. M.;
Akopyan, N. E.; Vartanyan, S. A. Khim.-Far. Zh. 1977, 11, 20–24.
11. Gangjee, A.; Qiu, Y.; Li, W.; Kisliuk, R. L. J. Med. Chem. 2008, 51, 5789–5797.
12. Hafez, H. N.; El-Gazzar, A. B. A. Bioorg. Med. Chem. Lett. 2008, 18, 5222–5227.
13. Horiuchi, T.; Chiba, J.; Uoto, K.; Soga, T. Bioorg. Med. Chem. Lett. 2009, 19, 305–
308.
14. Krebs, H. Aust. J. Chem. 1989, 42, 1291–1306.
15. Barker, J. M.; Huddleston, P. R.; Wood, M. L. Synth. Commun. 1995, 25, 3729–
3734.
16. Yu, Z. Ph. D. Thesis, Hong Kong University of Science and Technology,
2001.
17. Boger, D. L.; Honda, T.; Dang, Q. J. Am. Chem. Soc. 1994, 116, 5619–5630.
R2
CO2Et
R2
HO2C
N
R1
2a
+
ð2Þ
R1
H2N
S
S
EtO2C
N
1b - d
4b - d
All three 2-amino-3-thiophenecarboxylic acids (1b–d) pro-
duced the desired IDA products (4b–d) in good yields. Both methyl
and phenyl substituents are tolerated at the 4- and 5-positions.
Certain 3-amino-2-thiophenecarboxylic acids have been re-
ported to undergo decarboxylation reactions to generate 3-amino-
thiophenes.14,15 Theoretical studies16 suggested that 3-
aminothiophenes could also function as dienophiles and would
produce the corresponding regioisomer.
18. Representative procedure for the tandem decarboxylation IDA reactions:
A
mixture of 1a (133 mg, 0.672 mmol) and 2a (100 mg, 0.336 mmol) in
anhydrous DMF (3 mL) and acetic acid (0.4 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 ꢀ 15 cm, 20% EtOAc–hexane) to
give 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-2,4-dicarboxylate
diethyl ester (3a) as a light brown solid (85 mg, 76%). mp 52–54 °C. 1H NMR
(DMSO-d6): d 4.50 (q, J = 7 Hz, 2H), 4.41 (q, J = 7 Hz, 2H), 2.99 (t, J = 6 Hz, 2H),
2.66 (t, J = 6 Hz, 2H), 1.89–1.83 (m, 4H), 1.38 (t, J = 7 Hz, 3H), 1.37 (t, J = 7 Hz,
3H). MS calcd for C16H18N2O4S + H+: 335.4, found 335.4. Anal. Calcd for
C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38. Found: C, 57.52; H, 5.30; N, 8.47.
2,4-Bis(trifluoromethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (3b)
(87 mg, 76%). 1H NMR (CDCl3): d 3.12-2.82 (m, 4H), 2.06–1.86 (m, 4H). MS
calcd for C12H8F6N2S+H+: 327.3, found 327.4. Anal. Calcd for C12H8F6N2S: C,
44.18; H, 2.47; N, 8.59. Found: C, 44.23; H, 2.48; N, 8.34.
2,4-Bis(chlorodifluoromethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyri
midine (3c) (220 mg, 51.2%). 1H NMR (CDCl3): d 3.02 (appar. d, J = 6.3 Hz, 4H),
1.95 (appar. dd, J = 2.7, 1.2 Hz, 4H). MS calcd for C12H8ClF4N2S+H+: 359.0,
found 359.1. Anal. Calcd for C12H8ClF4N2S + 0.5 H2O: C, 39.15; H, 2.46; N, 7.61.
Found: C, 39.11; H, 2.19; N, 7.27.
5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (3d) (153 mg, 91% pure
@254 nM, 32.6%). 1H NMR (CDCl3): d 7.58 (s, J = 1H), 6.13 (s, 1H), 2.62 (t,
J = 5.7 Hz, 2H), 2.48 (t, J = 5.7 Hz, 2H), 1.85–1.81 (m, 4H). MS calcd for
C10H10N2S+H+: 191.27, found 191.4.
CF3
Ph
H2N
S
49%
N
2b
+
CF3
ð3Þ
CF3
HO2C
S
F3C
N
Ph
5
6
Thus, thiophene 5 was reacted with 1,3,5-triazine 2b under the pre-
ferred reaction conditions and the desired IDA product 6 was ob-
tained in good yield (Eq. 3).
CO2Et
H
1. NaOH
N
N
ð4Þ
2. Ac2O/AcOH
55%
S
S
EtO2C
N
H
N
3a
3d
5,6-Dimethyl-thieno[2,3-d]pyrimidine-2,4-dicarboxylate diethyl ester (4b) as
a foam (419 mg, 47%). 1H NMR (CDCl3): d 4.57 (q, J = 7.2 Hz, 2H), 4.55 (q,
J = 6.9 Hz, 2H), 2.60 (s, 3H), 2.32 (s, 3H), 1.51–1.44 (m, 6H). MS calcd for
C14H16N2O4S + H+: 309.36, found 309.4. Anal. Calcd for C14H16N2O4S: C, 54.53;
H, 5.23; N, 9.08. Found: C, 54.19; H, 5.11; N, 9.00.
Table 2
IDA reactions of 2a with thiophenes (1b-d)a
Entry
Thiophenes
R1
R2
Pdt
Yieldb (%)
6-Phenyl-thieno[2,3-d]pyrimidine-2,4-dicarboxylate
diethyl
ester
(4c)
(370 mg, 46%). mp 108–110 °C. 1H NMR (CDCl3): d 8.33 (s, 1H), 7.84–7.81 (m,
2H), 7.53–7.50 (m, 3H), 4.61 (q, J = 7.2 Hz, 4H), 1.55 (t, J = 6.9 Hz, 3H), 1.52
(t, J = 7.2 Hz, 3H). MS calcd for C18H16N2O4S + H+: 357.4, found 357.4. Anal.
Calcd for C18H16N2O4S: C, 60.66; H, 4.52; N, 7.86. Found: C, 60.89; H, 4.75; N,
7.71.
1
2
3
1b
1c
1d
Me
Ph
Me
Me
H
H
4b
4c
4d
47
46
55
a
All reactions were conducted under nitrogen in DMF–AcOH unless otherwise
6-Methyl-thieno[2,3-d]pyrimidine-2,4-dicarboxylate diethyl ester (4d)
(519 mg, 55%). mp 95–97 °C. 1H NMR (CDCl3): d 7.78 (s, 1H), 4.61–4.53 (m,
4H), 2.74 (s, 3H), 1.53–1.47 (m, 6H). MS calcd for C13H14N2O4S + H+: 295.3,
noted.
b
Yields were based on isolated pure products.

2876
Q. Dang et al. / Tetrahedron Letters 50 (2009) 2874–2876
found 295.1. Anal. Calcd for C13H14N2O4S + 0.2 H2O: C, 52.41; H, 4.87; N, 9.40.
Found: C, 52.07; H, 4.98; N, 9.60.
7-Phenyl-2,4,6-tris-trifluoromethyl-thieno[3,2-d]pyrimidine (6) (71 mg, 49%).
1H NMR (DMSO-d6): d 7.62–7.61 (m, 3H), 4.41 (q, J = 7 Hz, 2H). MS calcd for
C15H5N2S + H+: 417.27, found 417.4. Anal. Calcd for C15H5N2F9S + 0.2 C6H14: C,
44.88; H, 1.81; N, 6.46. Found: C, 44.76; H, 1.66; N, 6.43.