A facile reduction of 2-aminopyrimidines with triethylsilane and trifluoroacetic acid

Article abstract of DOI:10.1016/j.tetlet.2004.01.056

2-Aminopyrimidines were facilely reduced to 2-amino-dihydro- or 2-amino-tetrahydropyrimidines with triethylsilane and trifluroacetic acid in high yields. By controlling the equivalents of reducing reagents and temperature, selective reduction could also be achieved for some substrates.

Full text of DOI:10.1016/j.tetlet.2004.01.056

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2107–2111
A facile reduction of 2-aminopyrimidines with triethylsilane and
trifluoroacetic acid
Subramanian Baskaran, Emily Hanan, Daniel Byun and Wang Shen*
Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA
Received 12 September 2003; revised 9 January 2004; accepted 14 January 2004
Abstract—2-Aminopyrimidines were facilely reduced to 2-amino-dihydro- or 2-amino-tetrahydropyrimidines with triethylsilane and
trifluroacetic acid in high yields. By controlling the equivalents of reducing reagents and temperature, selective reduction could also
be achieved for some substrates.
ꢀ 2004 Elsevier Ltd. All rights reserved.
2-Amino-3,4,5,6-tetrahydro- and 2-amino-3,4-dihydro-
pyrimidines have been used extensively in biologically
important molecules against a variety of targets.1;2 2-
Aminotetrahydropyrimidines are usually synthesized by
displacing the methylmercapto- group from tetrahydro-
2-methylmercaptopyrimidines1 or hydrogenation of 2-
aminopyrimidines.3 While these methods provide an
efficient synthesis of the target molecules, they suffer
during the concurrent removal of protecting groups 2,4-
dimethoxybenzyl and tert-butylcarboxylate (Boc) of
compound 16 with trifluoroacetic acid (TFA) in the
presence of triethylsilane, 2-aminodihydropyrimidine 2
was obtained exclusively in quantitative yield (Eq. 1).7
Although triethylsilane in TFA has been used extensively
as a reducing reagent,8 to our knowledge this is the first
application of reagents to the pyrimidine ring reduction.
O
O
S S
Et3SiH
N
N
H
S
ð1Þ
TFA
S
N
N
NH
Boc
Cl
Cl H2N
MeO
OMe
H2N
N
H2N
N
H
1
2
from multi-step preparation of the reagents or potential
chemical selectivity problems. Only one method has
been reported for the preparation of 2-aminodihydro-
pyrimidines.4 During the development of TetheringSM;5
we needed to generate disulfide (S–S) linked 2-amino-
pyrimidines, as well as 2-amino-dihydro- and tetrahy-
dropyrimidines. We encountered difficulties in the
syntheses of these classes of compounds, due primarily to
the presence of the disulfide bond. To our surprise,
With the serendipitous discovery, the reaction condi-
tions were examined as shown in Table 1. It was found
that the reduction of 3 to corresponding 2-aminodihy-
dropyrimidine 4 could be carried out at lower temper-
ature with equal efficiency (entry 1). Further reduction
of 4 to 2-aminotetrahydropyrimidine 5 was not observed
after 10 h (entry 2). However, when the reaction was run
in refluxing TFA, 4 was slowly converted to 5. Heating
the reaction in a pressure vessel at 90 ꢁC for 24 h gave 5
as the major product (entries 3and 4). It was discovered
that the reduction of 3 to 4 could be carried out in
dichloromethane with as few as 2.5 equiv of triethyl-
silane and 5 equiv of TFA at room temperature (entry
5). However, the amounts of triethylsilane and TFA
Keywords: Reduction; Pyrimidine; Triethylsilane; Guanidine.
* Corresponding author. Tel.: +1-650-266-3682; fax: +1-650-266-3501;
e-mail: wshen@sunesis.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.056

2108
S. Baskaran et al. / Tetrahedron Letters 45 (2004) 2107–2111
Table 1. Survey of reaction conditionsa
4
4
3
5
Ph
Ph
5
Et3SiH
HN
HN
3
+
N
6
4
CF3CO2H
H2N
N
1
H2N
N
5
3
H2N
N
1
6
Entry
Et3SiH (eq)
Solvent
T (ꢁC)
Time
Resultb
1
10
10
TFA
TFA
75
)20
25
10 min
10 h
4 (100%)
4 (100%)
2
310
4
TFA
10 · 2d
2.5e
48 h
4:5 (1:1)c
TFA
DCM
90
25
24 h
2 h
4:5 (15:85, 91%)c
5 (100%)
5
a The reactions were run with 86 mg (0.50 mmol) 3 in the given solvent (2 mL).
b Isolated yield given in parentheses.
c The products 4 and 5 are not separable, ratios are based on NMR and LC-MS.
d Et3SiH (10 equiv) was added at the beginning and after 12 h.
e TFA (5 equiv) was used.
could not be further reduced even though the reaction
theoretically requires only 1 equiv of triethylsilane.
Reduction
of
4,6-disubstituted-2-aminopyrimidine
(entries 10 and 11) is much slower, and only about
50% conversions to the corresponding tetrahydro-
pyrimidines are achieved after the reactions were
refluxed for 24 h in TFA. The intermediate dihydro-
pyrimidines were not obtained in these cases. The
sluggish reduction could be rationalized by the increased
difficulty in hydride delivery from triethylsilane because
of the steric hindrance (see first step in Scheme 1). It
was also found that the reduction failed when 2-amino-
pyrimidine rings were further substituted with amine,
hydroxy, or alkoxy functionality at the C4 position
(entries 12–14).
This facile reduction is widely applicable, as shown in
Table 2. Substitutions on the amino nitrogen do not
impact the reduction (entries 1–6), which proceeds rap-
idly even when the amine is substituted by an aryl or
sulphonyl group. However, reduction of unsubstituted
2-aminopyrimidines yields 2-aminotetrahydropyrim-
idines (entries 3–5). In these cases, attempts to stop the
reduction at the dihydropyrimidine stage failed,9 possi-
bly due to the lack of conjugative stabilization of the
corresponding 2-aminodihydropyrimidine as seen in 2
and 4. Interestingly, 2-amino-5-bromopyrimidine is
reduced cleanly to the corresponding dihydropyrimidine
(entry 6).
Conversion of 4-aminopyrimidine 12 to product 13 was
observed when it was subjected to similar reduction
conditions, but the reaction is much slower than the
reduction of 2-aminopyrimidines (Eq. 2). 2-Aminopyr-
idine 14 remained unchanged even after refluxing in
TFA for 3days (Eq. 3). Interestingly, the reduction
of pyrimidine 15 to dihydropyrimidine 16 is facile (Eq.
4), and the scope and limitation of this and other related
reactions are under investigation and will be reported in
the future.
When 4-arylvinyl-2-aminopyrimidine is reduced by tri-
ethylsilane in TFA (entry 7A), 4-arylethyl-2-aminotet-
rahydropyrimidine is obtained. However, when the
reaction is subjected to milder conditions (entry 7B), the
product from an apparent reduction of the olefin moiety
was obtained cleanly. The structure of this product was
unequivocally established by proton NMR and mass
spectra. Reduction of 4-aryl-2-aminopyrimidine to 4-
aryl-2-aminotetrahydropyrimidine occurred readily
(entry 8). However, attempts to obtain corresponding
2-aminodihydropyrimidines from C4-substituted 2-am-
inopyrimidines were not successful.
Cl
Cl
10 eq. TES
HN
N
ð2Þ
ð3Þ
Reduction of the pyrimidine ring can be more facile than
reduction of the ketone functionality, as evidenced by
the formation of 2-amino-dihydropyrimidine 7 from
5-acetyl-4-methyl-2-aminopyrimidine 6 (Table 2, entry
9B; also see Scheme 1). The fully reduced product 11 is
obtained after 6 is subjected to the reduction conditions
for 24 h. LC-MS monitoring of the reaction did not
reveal the presence of potential intermediates 8, 9 and/or
10 over the course of the reaction. The mechanism of
this particular reduction is proposed in Scheme 1, and
the observed results could be explained by different
reaction rates for each step.
TFA, reflux, 24 h
50% conversion
N
NH2
N
NH2
12
13 (yield: 35%)
HN
10 eq. TES
TFA reflux
O
No Reaction
S
S
N
NH2
NH2
14

S. Baskaran et al. / Tetrahedron Letters 45 (2004) 2107–2111
Table 2. Reduction of 2-aminopyrimidines
2109
Entry
SM (structure)
Conditionsa
Product
Yieldb
DMB
N
HN
O
S
NH
O
N
1c
2c
A, 25 ꢁC, 4 h
A, 25 ꢁC, 4 h
61% (R1 ¼ H, R2 ¼ Me)
68% (R1 ¼ R2 ¼ Me)
R1
S
S
R1
S
N
N
N
N
NH2
R2
NHBoc
R2
N
NH
3
4
A, 25 ꢁC, 5 h
A, 25 ꢁC, 5 h
58%
78%
Ph
Ph
N
N
N
H
N
N
N
H
N
N
NH
N
N
CO2H
N
CO2H
O2
S
O2
S
N
H
N
H
5
A, 25 ꢁC, 0.5 h
25% (R ¼ H) 50%
(R ¼ COCF3)
NH
R
N
N
H
NH2
Br
Br
N
NH
6
A, 25 ꢁC, 10 min
90%
81%
N
NH2
N
NH2
Cl
Cl
NH2
N
NH2
N
7A
A, 25 ꢁC, 0.5 h
N
HN
Cl
Cl
Cl
NH2
N
7B
B, 25 ꢁC, 2 h
67%
73%
N
Cl
N
NH
Br
Br
8
A, 25 ꢁC, 2 h
N
NH2
N
NH2
O
NH
N
9A
9B
A, 25 ꢁC, 24 h
A, 0 ꢁC, 30 min
65%
N
NH2
N
NH2
11
6
O
81%d
NH
NH2
N
7
50%e
N
NH
NH2
10
A, 75 ꢁC, 24 h
N
NH2
N
(continued on next page)

2110
S. Baskaran et al. / Tetrahedron Letters 45 (2004) 2107–2111
Table 2 (continued)
Entry
SM (structure)
Conditionsa
Product
Yieldb
30%f
CF3
N
CF3
NH
NH2
11
A, 75 ꢁC, 24 h
t-Bu
N
NH2
t-Bu
N
O
N
12
A, 75 ꢁC, 24 h
NR
N
NH2
N
N
13
14
A, 75 ꢁC, 24 h
A, 75 ꢁC, 24 h
NR
NR
N
HO
Ph
Me2N
N
N
NH2
a Conditions A: 2-Aminopyrimidine (0.5 mmol), Et3SiH (5 mmol) in TFA (2 mL); B: 2-aminopyrimidine (0.5 mmol), Et3SiH (1.5 mmol) and TFA
(2.5 mmol) in DCM.
b Isolated yield (as a TFA salt).
c DMB is 2,6-dimethoxybenzyl.
d Inseparable mixture with compound 11 (ratio of 7:11, 15:1).
e Recovered starting material 30%.
f Recovered starting material 50%.
1. General procedures
H SiEt3
O
O
OH
k2
slow
H
(1) To a solution of a 2-aminopyrimidine (1 mmol) in
TFA (3mL) was added Et 3SiH (10 mmol). Upon com-
pletion, the reaction was concentrated in vacuum and
the residue was rinsed with ether and dried to give the
desired product in quantitative yield as a TFA salt.
Alternatively, the residue after ether rinse was loaded on
a reversed phase (C18) silica gel column, and eluted with
0–50% acetonitrile in water to give the desired product
as a TFA salt. (2) Mild reduction condition: same as (1)
except the reaction is run with Et3SiH (2.5–3mmol) and
TFA (5 mmol) in dichloromethane (3mL).
k1
N
NH
NH2
NH
NH2
fast
N
NH2
N
N
N
6
7
8
k3
fast
OH
NH
NH
NH2
k4
NH and/or
NH2
fast
N
11
NH2
N
10
9
Scheme 1.
Br
Br
10 eq. TES
TFA
N
N
Acknowledgements
ð4Þ
N
H
N
15
16 (yield: 81%)
The authors thank Mr. Stuart Lam, Thomas Webb and
Alex Shi for their expertise in the analysis and purifi-
cation of complex reaction mixtures. The authors also
thank Dr. Matthew Williams for helpful discussions.
In conclusion, we have demonstrated the facile reduc-
tion of 2-aminopyrimidines to yield partially or fully
reduced cyclic guanidines. With the easy access of
2-aminopyrimidines via commercial sources or synthe-
sis, this methodology provides an efficient entry to
2-amino-3,4-dihydro- or 2-amino-3,4,5,6-tetrahydro-
pyrimidines. This reaction could find many useful
applications considering the importance of guanidine
derivatives in modern medicinal chemistry.
References and notes
1. Recent biological applications of 2-amino-3,4,5,6-tetrahy-
dropyrimidines: (a) Perron-Sierra, F.; Saint Dizier, D.;
Bertrand, M.; Genton, A.; Tucker, G. C.; Casara, P.
Bioorg. Med. Chem. Lett. 2002, 12, 3291; (b) Reiner, J. E.;

S. Baskaran et al. / Tetrahedron Letters 45 (2004) 2107–2111
2111
Siev, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J.; Reddy, K. M.;
Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K.;
Gibson, T. S.; Anderson, S. M.; Bradbury, A. E.; Nolan, T.
G.; Semple, J. E. Bioorg. Med. Chem. Lett. 2002, 12, 1203;
(c) Batt, D. G.; Petraitis, J. J.; Houghton, G. C.; Modi, D.
P.; Cain, G. A.; Corjay, M. H.; Mousa, S. A.; Bouchard, P.
J.; Forsynthe, M. S.; Harlow, P. P.; Barbera, F. A.; Spitz, S.
M.; Wexler, R. R.; Jadhav, P. K. J. Med. Chem. 2000, 43,
41.
J. Heterocycl. Chem. 1989, 26, 251; (b) Vargo, L.; Nagy, T.;
Kovesdi, I.; Benet-Buchholz, J.; Dorman, G.; Uerge, L.;
Darvas, F. Tetrahedron 2003, 59, 655.
5. TetheringSM is a service mark of Sunesis Pharmaceuticals
Inc. for its fragment-based drug discovery.
6. Pyrimidines 1, 3 starting pyrimidines in Table 2 (entries 1
and 2) are synthesized by Suzuki coupling from the
corresponding 2-amino-5-bromo(or chloro)pyrimidines.
Pyridine 14 was synthesized in a similar manner.
2. Biological application of 2-amino-5,6-dihydropyrimidines:
Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu,
M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka,
K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.;
Funahashi, K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med.
Chem. 1989, 32, 2399.
3. Duggan, M. E.; Duong, L. T.; Fisher, J. E.; Hamill, T. G.;
Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.-T.; Nagy,
R. M.; Perkins, J. T.; Rodan, S. B.; Wesolowski, G.;
Whitman, D. B.; Zartman, A. E.; Rodan, G. A.; Hartman,
G. D. J. Med. Chem. 2000, 43, 3736.
7. The intended 2-amino-pyrimidine derivative was obtained
at 40–60% yield if anisole is used instead of triethylsilane in
TFA, or by using 4.0 M HCl in dioxane.
8. Triethylsilane as reducing reagent, (a) a review: Fry, J. L. In
Handbook of Reagents for Organic Synthesis: Oxidizing and
Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.;
Wiley-VCH: Chichester, 1999; p 479; (b) Aurelio, L.; Box,
J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, M. M. J.
Org. Chem. 2003, 68, 2652; (c) Olivo, H. F.; Colby, D. A.;
Hemenway, M. S. J. Org. Chem. 1999, 64, 4966.
9. Monitoring the reactions with LC-MS revealed that
2-aminodihydropyrimidines always appeared concurrently
with significant amounts of starting material and further
reduced 2-aminotetrahydropyrimidines.
4. 2-Amino-3,4-dihydropyrimidines are prepared by Michael
addition of guanidine and subsequent condensation, see
Reference 2 and (a) Kahsima, C.; Shimizu, M.; Omote, Y.