Synthesis of 2-Amino-4-pyrimidinones from Resin-Bound Guanidines Prepared Using Bis(allyloxycarbonyl)-Protected Triflylguanidine

Article abstract of DOI:10.1021/jo035201a

We have synthesized novel heterocyclic compounds from resin-bound guanidines. For this purpose, an amine immobilized on a solid support was acylated with protected amino acids. Following the deprotection, the liberated amines were guanidinylated utilizing a new member of the family of diurethane-protected triflyl guanidine reagents, N,N′ -bis(allyloxycarbonyl)-N′-triflylguanidine. The deprotected guanidines were subsequently regioselectively cyclized with β-keto esters yielding novel compounds containing heterocyclic structures in high purities.

Full text of DOI:10.1021/jo035201a

Syn th esis of 2-Am in o-4-p yr im id in on es fr om Resin -Bou n d
Gu a n id in es P r ep a r ed Usin g Bis(a llyloxyca r bon yl)-P r otected
Tr iflylgu a n id in e
Christoph W. Zapf and Murray Goodman*
Department of Chemistry and Biochemistry, University of California San Diego,
La J olla, California, 92093-0343
mgoodman@ucsd.edu
Received August 15, 2003
We have synthesized novel heterocyclic compounds from resin-bound guanidines. For this purpose,
an amine immobilized on a solid support was acylated with protected amino acids. Following the
deprotection, the liberated amines were guanidinylated utilizing a new member of the family of
diurethane-protected triflyl guanidine reagents, N,N′-bis(allyloxycarbonyl)-N′′-triflylguanidine. The
deprotected guanidines were subsequently regioselectively cyclized with â-keto esters yielding novel
compounds containing heterocyclic structures in high purities.
In tr od u ction
Modern drug design cannot be imagined without the
chemistry of heterocycles. These molecules offer unique
advantages over linear or carbocyclic structures, a fact
which has been recognized by medicinal chemists for
decades. Heterocycles are commonly regarded as inter-
esting scaffolds which can be synthesized readily and
which are able to incorporate substituents. The cyclic
nature of heterocycles provides an inherent constraint
arraying the substituents in the desired orientation. For
these and other reasons, many pharmaceuticals contain
heterocyclic groups.1
F IGURE 1. Isocytosine 1 and 2-aminoquinazolinones 2.
,2
Resu lts a n d Discu ssion
A substantial body of work has been reported on the
synthesis of 2-aminopyrimidinones 1 and bicyclic ana-
logues such as 2-aminoquinazolinones 2 shown in Figure
1
.
F IGUR E 2. Biologically interesting 2-aminopyrimidine-
derived compounds.
Compounds derived from the parent structures 1 and
have provided a basis for different medicinal applica-
2
tions (Figure 2). Cyano-substituted aminopyrimidine 3
has been shown to act as a potential antimycotic, while
6
properties, while compound 7 acts as a reverse-tran-
3
7,8
scriptase inhibitor and pyrrolopyrimidinone 8 has been
the piperazine-substituted pyrimidine structure 4 shows
shown to possess antiherpetic activities.9
4
remarkable selectivity for the R2-adrenoceptors whereas
The structural nature of this class of pyrimidines lends
itself to condensation chemistry. Cyclizations have been
a dominant approach for the synthesis of pyrimidines
with modifications determined by the specific structures
of the target molecules.10 For this purpose, a 1,3-dicar-
bonyl compound 10 can be allowed to react with guani-
piperidine-substituted aminopyrrolopyrimidine 5 serves
5
as a Y5 receptor antagonist. Bromo-substituted 2-amino-
4
-pyrimidinone structure 6 displays anti-inflammatory
(
1) Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.;
Academic Press: New York, 2001; Vol. 36.
2) Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.;
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3) Kreutzberger, A.; Sellheim, M. J . Heterocycl.. Chem. 1985, 22,
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(
7
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4
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1
0.1021/jo035201a CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003
1
0092
J . Org. Chem. 2003, 68, 10092-10097

Synthesis of 2-Amino-4-pyrimidinones from Resin-Bound Guanidines
SCHEME 1. Solid -P h a se Syn th esis of
Hyd r oxybu tyl Regioisom er s 17 a n d 18
The utility of reactions on solid support was initially
demonstrated in peptide chemistry. Chemical transfor-
F IGURE 3. 2-Aminopyrimidines can be synthesized through
different approaches.
29
mations on solid supports have now been extended to
many important organic reactions.3
0-32
Substantial
dine, a substituted guanidine 11, or a precursor thereof
progress has been achieved toward the synthesis of
heterocycles on a solid-support. The methods employed
and the structures prepared in this manner are varied.
Recent reviews describe the syntheses of heterocyclic
structures utilizing solid-phase chemistry.3
(route a, Figure 3). During the reaction, the heterocycle
is formed as well as a byproduct such as a molecule of
water or alcohol. The 1,3-dicarbonyl compounds generally
utilized are substituted malonic esters, 1,3-diketones, and
3,34
â-keto esters.9,11-23
There have been several reports on the solid-phase
Furthermore, route b in Figure 3 illustrates how
substituted propiolates 12 can be utilized in a manner
similar to â-keto esters to cyclize a substituted guanidine
synthesis of heterocycles related to the 2-aminopyrimi-
dinones noted above.3
5,36
Scheme 1 illustrates a very
interesting approach to prepare 2-aminopyrimidines via
resin-bound guanidines which was reported by Botta and
co-workers.7 For this purpose, immobilized acid chloride
14, which was derived from a Merrifield resin, was
allowed to react with N,N′-bis(tert-butoxycarbonyl)-N′′-
1
1 yielding 2-aminopyrimidinones 9. Propiolates 12 can
be regarded as dehydrated analogues of â-keto esters and
,8
therefore have been utilized as well in the design and
synthesis of heterocyclic compounds.2
4-27
Other methods to synthesize heterocyclic structures 9
have been reported in the literature. For instance, the
aminopyrimidine system can also be obtained by in-
4
-hydroxybutyl guanidine 15 to immobilize the guanidine
on the solid support via an ester linkage. Subsequent
removal of the protecting groups with methanesulfonic
acid generated the resin-bound guanidine 16. Exposure
of the terminal guanidine to ethyl acetoacetate and ethyl-
tramolecular reaction of an amine functionality with a
substituted aromatic carbodiimide (route c).28
3
-oxo-4-phenylbutanoate in refluxing methanol in the
(
10) Kenner, G. W.; Todd, A. In Heterocyclic Compounds; Elderfield,
R. C., Ed.; J ohn Wiley and Sons: New York, 1957; Vol. 6, pp 234-323
and references therein.
presence of sodium methoxide resulted in the formation
and simultaneous removal of the heterocycle from the
solid support. As indicated in Scheme 1, the â-keto ester
did not react regiospecifically but led to the formation of
two regioisomers 17 and 18 in a ratio of about 3:1.
The encouraging results from Botta et al. to prepare
heterocyclic structures from resin-bound guanidines
prompted us to design novel target structures based on
(
11) Legraverend, M.; Nia Ngongo-Tekam, R.-M.; Bisagni, E.; Zerial,
A. J . Med. Chem. 1985, 28, 1477-1480.
12) Miller, D. J .; Ravikumar, K.; Shen, H.; Suh, J .-K.; Kervin, S.
M.; Robertus, J . D. J . Med. Chem. 2002, 45, 90-98.
13) Alberola, A.; Antol ´ı n, L. F.; Gonz a´ ez, A. M.; Laguna, M. A.;
Pulido, F. J . Heterocycles 1987, 25, 393-397.
14) Gangjee, A.; Yu, J .; McGuire, J . J .; Cody, V.; Galitsky, N.;
Kisliuk, R. L.; Queener, S. F. J . Med. Chem. 2000, 43, 3837-3851.
15) Cho, H.; Shima, K.; Hayashimatsu, M.; Ohnaka, Y.; Mizuno,
A.; Takeuchi, Y. J . Org. Chem. 1985, 50, 4227-4230.
16) Nugent, R. A.; Murphy, M. J . Heterocycl. Chem. 1986, 23, 245-
47.
17) Alker, D.; Campbell, S. F.; Cross, P. E.; Burges, R. A.; Carter,
A. J .; Gardiner, D. G. J . Med. Chem. 1989, 32, 2381-2388.
18) Troxler, F.; Weber, H. P. Helv. Chim. Acta 1974, 57, 2356-
364.
(
(
(
(
3
7-40
our experience with guanidinylation chemistry
and
(
2
(
(28) Okawa, T.; Kawase, M.; Eguchi, S.; Kakehi, A.; Shiro, M. J .
Chem. Soc., Perkin Trans. 1 1998, 2277-2285.
(29) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
(30) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron
1996, 52, 4537-4554.
(31) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron
1997, 53, 5643-5678.
(32) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D.
Tetrahedron 1998, 54, 15385-15443.
(33) Franz e´ n, R. G. J . Comb. Chem. 2000, 2, 195-214.
(34) Krchn a´ k, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61-91.
(35) Hamper, B. C.; Gan, K. Z.; Owen, T. J . Tetrahedron Lett. 1999,
40, 4973-4976.
(36) Yu, Y.; Ostresh, J . M.; Houghten, R. A. J . Org. Chem. 2002,
67, 5831-5834.
(37) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J . Org.
Chem. 1998, 63, 3804-3805.
(
2
1
2
1
(
19) Wade, J . J .; Hegel, R. F.; Toso, C. B. J . Org. Chem. 1979, 44,
811-1816.
(20) Nair, M. D.; Sudarsanam, V.; Desaj, J . A. Indian J . Chem. 1982,
1B, 1030-1032.
21) Miyamoto, Y.; Yamazaki, C. J . Heterocycl. Chem. 1994, 31,
445-1448.
22) Vasudevan, A.; Mavandadi, F.; Chen, L.; Gangjee, A. J . Org.
Chem. 1999, 64, 634-638.
23) J ones, T. R.; Betteridge, R. F.; Newell, D. R.; J ackman, A. L. J .
Heterocycl. Chem. 1989, 26, 1501-1507.
24) H a¨ rter, H. P.; Lichti, H.; Stauss, U.; Schindler, O. Helv. Chim.
Acta 1976, 59, 1203-1212.
25) Al-J allo, H. N.; Muniem, M. A. J . Heterocycl. Chem. 1978, 15,
(
(
(
(
(
8
49-853.
(
981, 2, 415-422.
(
(38) Feichtinger, K.; Sings, H. L.; Baker, T. J .; Matthews, K.;
Goodman, M. J . Org. Chem. 1998, 63, 8432-8439.
(39) Baker, T. J .; Goodman, M. Synthesis 1999, No SI, 1423-1426.
(40) Baker, T. J .; Luedtke, N. W.; Tor, Y.; Goodman, M. J . Org.
Chem. 2000, 65, 9054-9058.
26) Acheson, R. M.; Wallis, J . D. J . Chem. Soc., Perkin Trans. 1
1
27) Campbell, M. M.; Campbell, A. C.; Peace, A.; Pick, J .; Woods,
G. F. J . Chem. Soc., Chem. Commun. 1985, 1164-1165.
J . Org. Chem, Vol. 68, No. 26, 2003 10093

Zapf and Goodman
SCHEME 4. Syn th esis of Resin -Bou n d Ben zyl
SCHEME 2. Am id es, Ur ea s, a n d Su lfon a m id es 20
Ca n Be Lin k ed to a Resin via th e Nitr ogen Atom
Utilizin g Ald eh yd e Resin 19 a n d Su bsequ en tly
Clea ved in a Tr a celess F a sh ion
Am id es 25 a n d 26 Utilizin g Ald eh yd e r esin 19
SCHEME 3. Syn th esis of Ald eh yd e Resin 22
diversity into the target molecule (Scheme 4). Synthesis
of the secondary amine 24 was accomplished by allowing
aldehyde resin 19 to react with benzylamine and sodium
triacetoxyborohydride, in the presence of acetic acid in
DMF. To ascertain the homogeneity of the resin-bound
structure, an aliquot of the secondary amine resin 24 was
treated with benzoyl chloride in the presence of triethyl-
amine, producing the corresponding benzoylamide which
was cleaved with neat TFA. Analysis of this sample by
RP-HPLC and 1H NMR indicated high purity of the
target compound.
The secondary amine 24 is ready for the introduction
of a second element of diversity by acylation with amine-
protected amino acids. A comparison of different coupling
reagents revealed that diisopropylcarbodiimide (DIC) and
1-hydroxybenzotriazole (HOBt) represent a highly effec-
tive reagent combination for the coupling of amino acids
to the resin-bound secondary amine 24. On the basis of
these findings, Fmoc-Gly-OH and Fmoc-Ile-OH were
coupled to resin-bound secondary amine 24 utilizing DIC
and HOBt as shown in Scheme 4 yielding the Fmoc-
protected benzyl amides after their removal from the
solid support with TFA.
To confirm the completion of the amide bond formation,
analytical samples of resin 25 and 26 were treated with
20% piperidine in DMF followed by benzoyl chloride in
the presence of triethylamine. Subsequent cleavage with
TFA yielded the corresponding diamides. The absence of
benzoyl benzamides in the RP-HPLC chromatogram
indicated complete amide bond formation and Fmoc
deprotection.
The primary amine liberated by the removal of the
Fmoc protecting group represents an excellent substrate
for resin-bound guanidinylation. As noted above, the
linkage to the solid support is acid sensitive. Therefore,
the utilization of N,N′-bis(tert-butoxycarbonyl)-N′′-(tri-
fluoromethylsulfonyl)guanidine to convert the resin-
bound amine into the corresponding guanidine could not
be employed since the removal of the Boc groups requires
acidic conditions. The corresponding N,N′-bis(benzyloxy-
carbonyl) derivative of this reagent was also not consid-
ered since removal of these protecting groups requires
strongly acidic conditions or heterogeneous hydrogenoly-
sis. We therefore sought an alternative protecting group
strategy and decided to synthesize N,N′-bis(allyloxycar-
bonyl)-N′′-(trifluoromethylsulfonyl)guanidine 29 (Scheme
in the context of solid-phase chemistry.41,42 We also
envisioned possibilities of incorporating amino acids into
the design of novel heterocyclic compounds.43
Syn th esis of Resin -Bou n d Gu a n id in es on Solid
Su p p or t To P r ep a r e Novel Heter ocycles. Over the
last several years, methoxy-substituted benzaldehyde
linkers 19 (Scheme 2) have become popular because of
their robust nature toward a large variety of reagents
and chemical transformations.4
4,45
After reductive ami-
nation and subsequent activation, the amine can be
converted into an immobilized acyl-, urea or sulfonyl
derivative 20. It is possible to cleave these structures
from the electron-rich benzylic position by treatment with
strong acid such as TFA. The “traceless” nature of this
resin is a useful feature, as the linkage to the solid
support is converted to a proton as seen in substrate 21.
We chose to employ the trimethoxybenzyl group as a
suitable linkage to the solid support. Structural diversity
can be derived from structure 21 since a wide variety of
primary amines is readily available for the reductive
amination of resin 19, as well as reactions with carboxylic
acids, isocyanates, and sulfonic acids. Employing these
reagents in a combinatorial manner can lead to the
generation of amides, ureas, or sulfonamides 21 with a
large degree of structural diversity. At the outset of the
project, we sought a synthetic route to obtain heterocyclic
compounds which would incorporate as much structural
diversity as possible and would not limit the possible
chemical reactions.
To prepare linker 19, we utilized a tentagel-grafted
polystyrene resin which terminated in a bromoalkyl
group 22. The bromide was displaced successfully by
readily available 2,6-dimethoxy-4-hydroxybenzaldehyde
2
3 in the presence of cesium carbonate at elevated
temperature as shown is Scheme 3.
Resin 19 was prepared on a multigram scale. A portion
was treated with a primary amine under reductive
amination conditions to introduce the first point of
(
41) Zapf, C. W.; Creighton, C. J .; Tomioka, M.; Goodman, M. Org.
Lett. 2001, 3, 1133-1136.
42) Goodman, M.; Zapf, C. W.; Rew, Y. Biopolymers 2001, 60, 229-
45.
(
2
(
(
43) Zapf, C. W. Ph.D. Thesis, University of California, 2003.
44) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J . A.
5
).
As with the previously reported reagents,37,38,41 the
synthesis of this new analogue commenced from guani-
J . Org. Chem. 1997, 62, 1240-1256.
45) J ensen, K. J .; Alsina, J .; Songster, M. F.; Vagner, J .; Albericio,
F.; Barany, G. J . Am. Chem. Soc. 1998, 120, 5441-5452.
(
1
0094 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 2-Amino-4-pyrimidinones from Resin-Bound Guanidines
SCHEME 5. Syn th esis of
N,N′-Bis(a llyloxyca r bon yl)-
TABLE 1. Resu lts of Solven t Stu d y To Op tim ize th e
Cycliza tion of Resin -Bou n d Gu a n id in e 31
N′′-tr iflu or om eth ylsu lfon yl Gu a n id in e 29
purity of 2-amino-
solvent
pyrimidinone 33 (%)
1
,4-dioxane
80
80
90
92
N,N-dimethylformamide/methanol 1:1
tetrahydrofuran: methanol 1:1
methanol
TABLE 2. Resu lts of Stu d y of Requ ir ed Ad d itives To
Op tim ize Cycliza tion of Resin -Bou n d Gu a n id in e 31
purity of 2-amino-
additive
pyrimidinone 33 (%)
dine hydrochloride 27, which was allowed to react with
allyl chloroformate under strongly basic conditions in a
two-phase system to produce N,N′-bis(allyloxycarbonyl)-
guanidine 28 in 66% yield. Subsequent conversion of the
no additive
acetic acid
trimethyl orthoformate (TMOF)
triethylamine
sodium methoxide
0
0
0
22
93
2
remaining NH group into the sulfonamide utilizing triflic
anhydride yielded reagent 29 in 74% yield. The N,N′-
bis(allyloxycarbonyl)-N′′-(trifluoromethylsulfonyl)guani-
dine 29 was characterized by H and C NMR spectros-
copy and was synthesized on a multigram scale.
With this new guanidinylating reagent available and
after establishing amide bond formation conditions for
coupling protected amino acids, we carried out the
synthesis of resin-bound guanidines as outlined in Scheme
The solvent study for the cyclization was conducted in
the presence of trimethyl orthoformate (TMOF) and
sodium methoxide. A further investigation of the addi-
tives required for the cyclization of resin-bound guanidine
31 revealed that sodium methoxide is the sole additive
necessary for the formation of 2-aminopyrimidinone 33
(Table 2). A strong base is required for the cyclization
reaction, presumably giving rise to the guanidine moiety
in its deprotonated state. The target structure 33 was
obtained under these conditions in high purity after its
removal from the solid support (Scheme 7).
Having established a viable protocol for the formation
of a desired heterocycle, we investigated the generality
of the cyclization reaction utilizing different â-keto esters
(Scheme 8). For this purpose, resin-bound guanidines 31
and 32 were treated with three â-keto esters in the
presence of methoxide base to form 2-amino pyrimidino-
nes 33-36 after removal from the resin. As illustrated
below, the final molecules were obtained with high
purities which indicate essentially quantitative conver-
sions for all chemical reactions.
1
13
6
. Removal of the Fmoc group under standard conditions
was followed by conversion of the resin-bound primary
amine into the corresponding bis-Alloc-protected guani-
dine 30 utilizing reagent 29. Subsequently, the protecting
groups were removed under palladium-catalyzed condi-
tions. It is presumed that the cleavage occurs via a
π-allylpalladium(II) intermediate, which can act as an
4
6
alkylating agent. Therefore, the allyl cation must be
scavenged by nucleophiles, thus preventing undesired
alkylations and simultaneously regenerating the pal-
ladium(0) catalyst. Phenylsilane has recently been shown
to be an effective scavenger of the π-allyl palladium
complexes in solution47 and on solid support.
48
Cleavage of small resin quantities of the protected
guanidine 30 and the deprotected guanidines 31 and 32
indicated complete conversions and high purities, respec-
tively. Further analysis of compounds 30-32 by mass
Mass spectrometry, RP-HPLC, and NMR spectroscopy
were employed to determine the structure and purity of
the desired heterocycles. The results of these studies
provide a high level of confidence for the chemistry we
employed to prepare the target heterocyclic compounds.
1
spectrometry and H NMR spectroscopy facilitated the
identification of the desired compounds.
Con ver sion of R esin -Bou n d Gu a n id in es in t o
2
-Am in o-4-p yr im id in on es. Previously reported litera-
Su m m a r y a n d Ou tlook
ture by Botta and co-workers indicated reactivity of resin-
bound guanidines with â-keto esters.7,8 With these find-
We have successfully synthesized novel heterocyclic
compounds from resin-bound guanidines. For this pur-
pose, a secondary amine 24 immobilized on a solid
support was acylated with different Fmoc-protected
amino acids utilizing diisopropylcarbodiimide (DIC). Fol-
lowing the removal of the protecting group, the liberated
primary amines were guanidinylated utilizing N,N′-bis-
ings, attempts were undertaken to synthesize heterocycles
from resin-bound guanidines 31 and 32 using â-keto
esters as substrates to accomplish this transformation.
After preparation of the free guanidine 31, we subse-
quently investigated different solvent conditions to obtain
optimal purity for the synthesis of 2-amino-pyrimidino-
nes. We were able to demonstrate that methanol was the
best solvent (Table 1) for the clean conversion of the
resin-bound guanidine 31 into the corresponding hetero-
cycle utilizing â-keto esters.
(allyloxycarbonyl)-N′′-triflylguanidine 29, a new version
of our diurethane-protected triflyl guanidines. We have
synthesized this reagent in multigram quantities from
readily available guanidine hydrochloride in two steps
in good overall yield. The deprotected guanidines were
subsequently cyclized with â-keto esters producing het-
erocycles 33-36 in high purity.
The design of our novel heterocycles offers several
points of diversity. As demonstrated, different amino
acids can be incorporated as well as different â-keto
(
46) Merzouk, A.; Guib e´ , F.; Loffet, A. Tetrahedron Lett. 1992, 33,
77-480.
47) Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guib e´ , F.; Loffet,
A. Tetrahedron Lett. 1995, 36, 5741-5744.
48) Thieriet, N.; Alsina, J .; Giralt, E.; Guib e´ , F.; Albericio, F.
Tetrahedron Lett. 1997, 38, 7275-7278.
4
(
(
J . Org. Chem, Vol. 68, No. 26, 2003 10095

Zapf and Goodman
SCHEME 6. Solid -P h a se Syn th esis of Resin -Bou n d Gu a n id in es 31 a n d 32 by Gu a n id in yla tion of
Im m obilized Am in o Acid s Utilizin g N,N′-Bis(a llyloxyca r bon yl)-N′′-tr iflu or om eth ylsu lfon yl Gu a n id in e 29
SCHEME 7. Con ver sion of Resin -Bou n d
Gu a n id in e 31 in to N-Ben zyl-2-(4-m eth yl-6-
oxo-1,6-d ih yd r op yr im id in -2yla m in o)a ceta m id e 33
structures which could serve as a promising route for
drug discovery.
Exp er im en ta l Section
Reactions in solution were monitored by thin-layer chro-
matography (TLC) carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as the visualization agent. The
N-H-containing compounds were visualized by exposing the
TLC plates to chlorine gas (freshly generated by concentrated
hydrochloric acid and potassium permanganate) for approxi-
mately 30-60 s. Subsequently, the TLC plates were dipped
into a solution prepared by combining an aqueous KI (500 mg
SCHEME 8. Syn th esis of Ta r get Heter ocycles
3
3-36 Utilizin g Differ en t â-Keto Ester s
of KI in 50 mL of H
2
O) and an aqueous o-tolidine (500 mg of
O and 8 mL of acetic acid) solution.
o-tolidine in 45 mL of H
2
Alternatively, TLC plates were visualized utilizing a 2%
ninhydrin solution in ethanol.
The NMR spectra were obtained on a 400 MHz spectrom-
eter. Chemical shifts (δ) are reported in parts per million (ppm)
relative to residual undeuterated solvent as an internal
standard. The following abbreviations were used to explain
the multiplicities: s ) singlet, d ) doublet, t ) triplet, q )
quartet, dd ) doublet of doublets, dt ) doublet of triplets, m
)
multiplet.
Mass spectra were obtained using electrospray and MALDI-
FTMS techniques.
For analytical RP-HPLC, the flow rate was set to 1.0 mL/
min, using a analytical C18 column (25 × 0.46 cm, 5 µm, 300
2
Å). Solvents used were as follows: solvent A, 0.1% TFA/H O;
3
solvent B, 0.1% TFA/CH CN. Analysis of compounds by RP-
HPLC was carried out utilizing a gradient condition (solvent
A 90-10% over 30 min).
N,N′-Di-Alloc-gu a n id in e 28. In a 250 mL round-bottom
flask, guanidine hydrochloride 27 (2.87 g, 30 mmol) and
benzyltriethylammonium chloride (137 mg, 0.6 mmol, 0.02
equiv) were dissolved in aqueous NaOH (20 mL, 6 N) and
methylene chloride (60 mL). The solution was cooled to 0 °C
in an ice bath for 15 min. Allyl chloroformate (12.73 mL, 120
mmol, 4 equiv) was added quickly with vigorous stirring.
The reaction was allowed to proceed for 6 h during which
the initially clear two-phase system became a white suspen-
sion. A white solid was removed by filtration which was
identified as N-(allyloxycarbonyl) guanidine. The filtrate was
diluted with 50 mL of water and 50 mL of DCM. The organic
phase was collected and the aqueous extracted two additional
times with 50 mL of DCM. The combined organic phases were
esters. In addition, the primary amine utilized for the
reductive amination of aldehyde resin 19 must be re-
garded as a third point of diversity which lends itself to
further structural diversity. Primary amines are abun-
dant, and a wide variety is commercially available.
Taking the three points of diversity into account, large
libraries of heterocycles can be constructed. Amines,
natural and unnatural amino acids, as well as â-keto
esters are popular building blocks for combinatorial
chemistry which are either commercially available or can
be readily synthesized. In utilizing these building blocks,
many compounds can be synthesized in a parallel fashion
and subsequently evaluated in a high-throughput screen-
ing process for biological activity. In this paper, we have
shown the way to synthesize these novel heterocyclic
dried with MgSO
pressure and the oily residue purified by column chromatog-
raphy. A solvent mixture of 5% Et O in DCM was chosen as
the initial solvent condition to elute tri-Alloc guanidine (R
.59, 10% Et O in DCM). To elute the desired product from
4
. The solvent was removed under reduced
2
f
)
0
2
the column, the solvent mixture was changed to 50% MeOH
in DCM. The compound was isolated as a white solid (4.50 g,
1
0096 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 2-Amino-4-pyrimidinones from Resin-Bound Guanidines
1
6
5.9%): R
f
) 0.27 (10% Et
2
O in DCM); H NMR (CDCl
3
, 400
NaOMe (58 µL, 0.35 mmol, 10 equiv) and ethyl acetoacetate
(44 µL, 0.35 mmol, 10 equiv). The reaction vessel was shaken
for 22 h followed by thorough washing of the resin, alternating
methanol and methylene chloride. The resin was dried in a
desiccator and cleaved with 2 mL of neat TFA for 2 h. After
the cleavage solution was collected, the resin was rinsed with
methanol and the combined solutions were taken to dryness.
On the basis of the initial loading the heterocycle was obtained
MHz, δ): 5.91 (2H, ddt, J ) 5.8, 10.4, 17.2 Hz), 5.32 (2H, dd,
J ) 2, 17.2 Hz), 5.24 (2H, dd, J ) 1, 10.6 Hz), 4.60 (4H, d, J
1
3
)
6
2
3
5.6 Hz); C NMR (CDCl , 100 MHz, δ) 159.0, 131.8, 118.1,
+
+
-
6.3; MS (ESI) 228 [M + H] , 250 [M + Na] , 226 [M - H] ,
-
62 [M + Cl] .
N,N′-Di-Alloc-N′′-tr iflylgu a n id in e 29. Thoroughly dried
N,N’-di-Alloc-guanidine 28 (4.50 g, 19.78 mmol) was flushed
extensively with argon and dissolved in freshly distilled
methylene chloride (70 mL). The solution was cooled to -78
in quantitative yield: 1H NMR (DMSO-d
, 400 MHz, δ) 8.56
6
(t, 1H, J ) 5.8 Hz), 7.34-7.21 (m, 6H), 4.31 (d, 2H, J ) 6.0
Hz), 3.98 (d, 2H, J ) 4.4 Hz), 2.07 (s, 3H); MS (ESI) 273 [M +
°
C in a 2-propanol/dry ice bath. After the mixture was cooled
+
+
+
for 10 min, freshly distilled triethylamine (4.14 mL, 29.67
mmol, 1.5 equiv) was added dropwise via syringe and cooled
for another 10 min. Triflic anhydride (4.99 mL, 29.67 mmol,
H] , 295 [M + Na] ; HRMS (m/z) [M + H] calcd for
C
14
H
17
N
4
O
2
273.1346, found 273.1342; analytical RP-HPLC t
R
) 18.05 min.
1
.5 equiv) was added dropwise over 15 min via a syringe, and
N-Ben zyl-2-(4,5-d im eth yl-6-oxo-1,6-d ih yd r op yr im id in -
2-yla m in o)a ceta m id e 34. To resin-bound guanidine 31 (67
mg, 26 µmol) suspended in MeOH (2 mL) were added 6 N
NaOMe (44 µL, 0.26 mmol, 10 equiv) and ethyl 2-methylac-
etoacetate (37 µL, 0.26 mmol, 10 equiv). The reaction vessel
was shaken for 21 h followed by thorough washing of the resin,
alternating methanol and methylene chloride. The resin was
dried in a desiccator and cleaved with 2 mL of neat TFA for 2
h. After the cleavage solution was collected, the resin was
rinsed with methanol and the combined solutions were taken
the reaction was allowed to warm to rt. The cooling bath
reached rt after approximately 5 h, and the reaction was
allowed to proceed for an additional 1 h. The reaction mixture
was transferred into a separatory funnel, diluted with 70 mL
of DCM, and extracted four times with 25 mL of 1 N HCl. The
organic phase was dried over MgSO and the solvent removed
4
under reduced pressure. The brown, oily residue was purified
by column chromatography utilizing DCM as eluent. The
product was obtained as a clear oil (5.22 g, 73.5%): R
f
) 0.29
, 400 MHz, δ) 5.91 (2H, ddt, J ) 6.0,
0.8, 17.0 Hz), 5.40 (2H, dd, J ) 1.2, 17.2 Hz), 5.34 (2H, dd, J
1.2, 10.8 Hz), 4.72 (4H, d, J ) 6 Hz); 13C NMR (CDCl
, 100
MHz, δ) 150.7, 149.8, 129.9, 120.5, 119.0 (q, J ) 317 Hz), 68.5;
1
to dryness: 1H NMR (DMSO-d
(DCM); H NMR (CDCl
3
6
, 400 MHz, δ) 8.63 (t, 1H, J )
1
)
5.6 Hz), 7.35-7.22 (m, 5H), 4.31 (d, 2H, J ) 5.6 Hz), 4.06 (d,
+
J ) 5.2 Hz), 2.19 (s), 1.82 (s); MS (ESI) 287 [M + H] , 309 [M
3
+
-
-
+
+ Na] , 285 [M - H] , 321 [M + Cl] ; HRMS (m/z) [M + H]
+
+
+
MS (ESI) 360 [M + H] , 382 [M + Na] , 398 [M + K] , 358 [M
calcd for C15
19 4 2
H N O 287.1502, found 287.1501; analytical RP-
-
+
-
H] ; HRMS (m/z) [M + H] calcd for C10
found 360.0478.
-(N′,N′′-Bis(a llyloxyca r bon yl)-N-gu a n id in o)a cylben -
zyla m id e 30. After deprotection of resin 25 and 26 utilizing
0% piperidine in DMF, the benzyl amide resin was allowed
to react with N,N′-di-Alloc-N′′-triflyl uanidine 29 (5 equiv) for
2 h followed by thorough washing of the resin alternating
methylene chloride and methanol. An analytical resin sample
H
13
N
3
O
6
S 360.0472,
HPLC t ) 14.08 min.
R
N-Ben zyl-2-(4-eth yl-6-oxo-1,6-dih ydr opyr im idin -2-ylam i-
n o)a ceta m id e 35: To resin-bound guanidine 31 (97 mg, 38
µmol) suspended in MeOH (2 mL) were added 6 N NaOMe
2
(
63 µL, 0.38 mmol, 10 equiv) and ethyl propionyl acetate (48
µL, 0.38 mmol, 10 equiv). The reaction vessel was agitated for
1 h followed by thorough washing of the resin, alternating
2
2
2
methanol and methylene chloride. The resin was dried in a
desiccator and cleaved with 2 mL of neat TFA for 2 h. After
the cleavage solution was collected, the resin was rinsed with
1
3
(R ) H) was cleaved with neat TFA for 2 h: H NMR (CDCl ,
4
5
2
00 MHz, δ) 7.34-7.25 (m, 5H), 6.59 (t, 1H, 4.8 Hz), 5.95-
methanol and the combined solutions were taken to dryness:
.84 (m, 2H), 5.38-5.19 (m, 4H), 4.66 (d, 2H, 6.0 Hz), 4.56 (d,
1
H NMR (DMSO-d , 400 MHz, δ) 8.58 (t, 1H, 5.8 Hz), 7.43-
6
H, 6.0 Hz), 4.45 (d, 2H, 5.6 Hz), 4.13 (s, 2H); MS (ESI) 375
+
+
+
7.20 (m, 6H), 4.30 (d, 2H, 5.6 Hz), 3.99 (s, 2H), 2.35 (s, 2H),
1
2
for C15
t
[
t
M + H] , 397 [M + Na] , 413 [M + K] ; analytical RP-HPLC
) 22.28 min.
-Gu a n id in oa cetylben zyla m id e 31. To remove the Alloc
+
+
.10 (t, 3H, 7.2 Hz); MS (ESI) 287 [M + H] , 309 [M + Na] ,
- - +
R
85 [M - H] , 399 [M + TFA] ; HRMS (m/z) [M + H] calcd
287.1502, found 287.1505; analytical RP-HPLC
) 12.97 min.
S)-2-(4-Eth yl-6-oxo-1,6-d ih yd r op yr im id in -2yla m in o)-
S)-3-m eth ylp en ta n oic Acid Ben zyla m id e 36. To resin-
2
19 4 2
H N O
protecting groups, resin 30 (R ) H) (2 g, 0.82 mmol) was
prewashed with freshly distilled DCM. Subsequently, the resin
was suspended in 20 mL of freshly distilled DCM to which
phenylsilane (2 mL, 16.4 mmol, 20 equiv) and tetrakis-
R
(
(
bound guanidine 32 (130 mg, 52 µmol) suspended in MeOH
(
triphenylphosphine)palladium(0) (95 mg, 82 µmol, 0.1 equiv)
(2 mL) were added 6 N NaOMe (87 µL, 0.52 mmol, 10 equiv)
were added. After 3 h, the resin was washed with DCM,
methanol, and aqueous NaCN until the resin beads became
colorless. Excess cyanide was removed by washing the resin
twice with water, followed by two washings with THF to
remove residual water. The resin was further rinsed several
times alternating methanol and DCM. An analytical resin
and ethyl propionyl acetate (65 µL, 0.52 mmol, 10 equiv). The
reaction vessel was shaken for 24 h followed by thorough
washing of the resin, alternating methanol and methylene
chloride. The resin was dried in a desiccator and cleaved with
2
mL of neat TFA for 2 h. After the cleavage solution was
1
collected, the resin was rinsed with methanol and the com-
bined solutions were taken to dryness: H NMR (DMSO-d
sample was cleaved with neat TFA for 2 h: H NMR (DMSO-
d
Hz), 7.34-7.22 (m, 9H), 4.31 (d, 2H, J ) 6.0 Hz), 3.88 (d, 2H,
J ) 5.6 Hz); MS (ESI) 207 [M + H] ; HRMS (m/z) [M + H]
calcd for C10 O 207.1246, found 207.1242. analytical RP-
HPLC t ) 14.74 min.
2S,3S)-2-Gu a n id in o-3-m eth ylp en ta n oic Acid Ben zy-
1
6
,
6
, 400 MHz, δ) 8.62 (t, 1H, J ) 5.8 Hz), 7.55 (t, 1H, J ) 5.8
4
00 MHz, δ) 8.66 (t, 1H, 5.6 Hz), 7.32-7.19 (m, 6H), 4.43 (m,
+
+
1H), 4.30 (t, 2H, J ) 6.2 Hz), 2.30 (m, 2H), 1.83 (m, 1H), 1.44
+
(
3
m, 1H), 1.09 (m, 4H), 0.87 (m, 6H); MS (ESI) 343 [M + H] ,
15 4
H N
+
-
-
65 [M + Na] , 341 [M - H] , 377 [M + Cl] ; analytical RP-
) 26.54 min.
R
HPLC t
R
(
la m id e 32. This compound was prepared in an analogous
fashion as carried out for 2-guanidino-acetyl benzyl amide 31.
Ack n ow led gm en t. We thank Dr. Chris Holmes for
his comments and suggestions and the Affymax Re-
search Institute for support of this project. We also
thank Dr. Christopher Creighton for insightful discus-
sions at the outset of this project.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and full characterization data for com-
pounds 22, 25, 26, and 28-36. This material is available free
of charge via the Internet at http://pubs.acs.org.
An analytical resin sample was cleaved with neat TFA for 2
1
h: H NMR (DMSO-d
7
(
1
6
, 400 MHz, δ) 8.63 (t, 1H, J ) 5.8 Hz),
.68 (d, 1H, J ) 9.6 Hz), 7.60-6.90 (m, 9H), 4.31 (m, 2H), 4.00
dd, 1H, J ) 6.8, 9.6 Hz), 1.85 (m, 1H), 1.41-1.35 (m, 1H),
+
.11-1.03 (m, 1H), 0.87-0.80 (m, 6H); MS (ESI) 263 [M + H] ;
analytical RP-HPLC t ) 22.94 min.
R
N -Be n zyl-2-(4-m e t h yl-6-oxo-1,6-d ih yd r op yr im id in -
yla m in o)a ceta m id e 33. To resin-bound guanidine 31 (91
2
mg, 35 µmol) suspended in MeOH (2 mL) were added 6 N
J O035201A
J . Org. Chem, Vol. 68, No. 26, 2003 10097