An efficient synthesis of a new series of acyclonucleosides starting from β-amino alcohols

Article abstract of DOI:10.1021/jo000812d

A series of new acyclonucleosides analogues 3 has been synthesized very efficiently in three steps starting from β-amino alcohols 1. The key step of this process is a nucleophilic substitution with various nucleophiles on 2,2'-anhydronucleosides 2. The chemo- and stereoselectivities of this reaction are discussed. AM1 calculations sustained the observed chemoselectivity.

Full text of DOI:10.1021/jo000812d

6666
J . Org. Chem. 2000, 65, 6666-6669
An Efficien t Syn th esis of a New Ser ies of Acyclon u cleosid es
Sta r tin g fr om â-Am in o Alcoh ols
Claude Agami, Luc Dechoux,* Louis Hamon, and Mohand Melaimi
Laboratoire de Synthe`se Asyme´trique (UMR CNRS 7611), Case courrier 47, Universite´ P. et M. Curie,
4 place J ussieu, 75005 Paris, France
dechoux@ccr.jussieu.fr
Received May 26, 2000
A series of new acyclonucleosides analogues 3 has been synthesized very efficiently in three steps
starting from â-amino alcohols 1. The key step of this process is a nucleophilic substitution with
various nucleophiles on 2,2′-anhydronucleosides 2. The chemo- and stereoselectivities of this reaction
are discussed. AM1 calculations sustained the observed chemoselectivity.
Sch em e 1
Sch em e 2
Sch em e 3
In tr od u ction
Considerable interest in the synthesis of nucleoside
analogues stems from their antiviral and antitumoral
activities.1 Sugar-modified nucleosides have assumed a
major role since the development of AZT in HIV chemo-
therapy. Removal of the furanose moiety leading to a
simplification of the structures led to new therapeutic
antiviral agents. Thus, the emergence of Acyclovir2 as a
successful agent has stimulated the synthesis of acyclic
nucleosides,3 and much effort has been devoted to broaden
our knowledge of this new class of nucleosides. Majority
of reactions concerning the synthesis of such acyclo-
nucleosides had been made by regioselective N-alkyla-
tions of the purine ring system.4 We have developed a
more convergent method starting from â-amino alcohols5
(Scheme 1) that allows the efficient synthesis of a great
variety of nucleosides 3.
Pyrimidinones 2 could be used as synthons to produce
new classes of acyclonucleosides by reaction with the
appropriate nucleophiles. Moreover, this synthesis allows
the introduction of a substituent on C-6 of the uracil ring.
An analogous method, involving an intermediate similar
to 2, had already been reported in the ribonucleoside
series.6
Herein we report full details about the preparation of
pyrimidinones 2 and about their reactions with various
nucleophiles and the stereo- and chemoselective trans-
formations into pyrimidines 3.
* Corresponding author. Fax: (33) 01 44 27 26 20.
(1) Nucleosides and Nucleotides as Antitumor and Antiviral Agents;
Chu, C. K., Baker, D. C., Eds., Plenum Press: New York, 1993.
(2) Shaeffer, H. J .; Beauchamp, L.; De Miranda, P.; Elion, G. B.;
Bauer, D. J .; Collins, P. Nature 1978, 272, 583. For a review on the
synthesis of acyclovir and related compounds, see: Gao, H.; Mitra, A.
K. Synthesis 2000, 329.
(3) (a) Campos, J .; Pineda, M. J .; Gomez, J . A.; Entrena, A.; Trujillo,
M. A.; Gallo, M. A.; Espinosa, A. Tetrahedron 1996, 52, 8907. (b)
Gomez, J . A.; Campos, J .; Marchal, J . A.; Trujillo, M. A.; Melguizo, C.;
Prados, J .; Gallo, M. A.; Aranega, A.; Espinosa, A. Tetrahedron 1997,
53, 7319. (c) Chu, C. K.; Cutler, S. J . Heterocycl. Chem. 1986, 23, 289.
(d) Hossain, N.; Rozenski, J .; De Clercq, E.; Herdewijn, P. Tetrahedron
1996, 52, 13655.
(4) For recent examples, see: (a) Cadet, G.; Chan, C. S.; Daniel, R.
Y.; Davis, C. P.; Guiadeen, D.; Rodriguez, G.; Thomas, T.; Walcott, S.;
Scheiner, P. J . Org. Chem. 1998, 63, 4574. (b) Inagaki, J .; Sakamoto,
H.; Nakajima, M.; Nakamura, S.; Hashimoto, S. Synlett 1999, 1274.
(c) Guan, H. P. G.; Ksebati, M. B.; Cheng, Y. C.; Drach, J . C.; Kern, E.
R.; Zemlicka, J . J . Org. Chem. 2000, 65, 1280.
Resu lts
Syn th esis of P yr im id in on es 2. Pyrimidinones 2
were synthesized by the following two-step sequence: (i)
reaction between â-amino alcohols 1 and cyanogen bro-
mide7 affording compounds 4 in quantitative yields, (ii)
condensation of these heterocycles with ethyl propiolate
or ethyl butynoate to form bicyclic compounds 2 (Scheme
2).
Nu cleop h ilic Op en in g of P yr im id in on es 2. We
have already reported that synthons 2a react stereo-
selectively at the C-6 site of the uracil ring with different
organocuprate reagents (Scheme 3), leading to alkylated
compounds 5. These heterocycles eventually were trans-
formed into pure â-amino acids.8
(5) Preliminary communication: Agami, C.; Dechoux, L.; Melaimi,
M. Org. Lett. 2000, 2, 633.
(6) (a) Holy, A. Coll. Czech. Chem. Commun. 1973, 38, 3912. (b) Holy,
A. Coll. Czech. Chem. Commun. 1974, 39, 3177. (c) Pragnacharyulu,
P. V. P.; Vargeese, C.; McGregor, M.; Abushanab, E. J . Org. Chem.
1995, 60, 3096
(7) Kampe, K. D.; Liebigs Ann. Chem. 1974, 593.
(8) (a) Agami, C.; Cheramy, S.; Dechoux, L.; Kadouri-Puchot, C.
Synlett 1999, 727. (b) Agami, C.; Cheramy, S.; Dechoux, L. Synlett
1999, 1838.
10.1021/jo000812d CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

A New Series of Acyclonucleosides
J . Org. Chem., Vol. 65, No. 20, 2000 6667
Ta ble 1
entry
substrate
R1
R2
R3
conditions
product
yield (%)
Nu
Cl
OMe
OH
N3
/
Cl
Cl
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2b
2c
2c
2c
2d
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
H
H
H
H
H
H
Ph
Ph
Ph
Me
H
H
H
H
H
Me
H
H
H
H
TMSCl/THF
3a
3b
3c
3d
/
3e
3f
3g
3h
3i
80
87
91
95
/
78
79
78
95
85
MeOH/PTSA
H2O/THF/PTSA
TMSN3/TBAF
TMSCN/TBAF
TMSCl/THF
TMSCl/THF
H2O/THF/PTSA
MeOH/PTSA
TMSCl/THF
OH
OMe
Cl
10
Sch em e 4
Sch em e 5
Perusal of the literature showed that 2,2′-anhydro-
nucleosides, whose heterocyclic core corresponds to py-
rimidinones 2, can be substituted with nucleophiles such
as azide9 and halide ions.10 To obtain functionalized
pyrimidines 3, we investigated the reactivity of com-
pounds 2 with such nucleophiles. To this aim, H2O,
MeOH, and trimethylsilyl chloride, azide, and cyanide
were reacted with pyrimidinones 2 (Table 1).
All nucleophiles, except cyanide ion from TMSCN,
react in acidic conditions to afford functionalized pyrim-
idines 3 in good yields. These nucleophilic substitutions
are chemo- and diastereoselective as well. Substrate 2c,
which possesses a stereocenter at the reaction site (C-
2′), reacts with three different nucleophiles (entries 7-9)
in a completely stereoselective way: each product was
obtained as a unique diastereomer. The reactions with
trimethylsilyl derivatives were completed in 2 h at room
temperature (entries 1, 4, 6, 7, 10) but needed 12 h at
reflux under solvolytic conditions (entries 2, 3, 8, 9).
When trimethylsilyl cyanide was used as a nucleophile
(entry 5), the substitution took place but the resulting
product 6 was unstable and underwent a â-elimination
to afford cinnamonitrile 7 (Scheme 4).
To further scrutinize the regiochemical outcome of
these hydrolytic reactions, we performed similar nucleo-
philic substitutions in basic media. The chemoselectivity
was inverted: in water (NaOH/H2O) as well as in
methanol (MeONa/MeOH) the same hydroxylic com-
pound 3j was obtained. This compound results from an
addition of the nucleophile on the C-2 center followed by
hydrolysis. Such addition-elimination reactions at C-2
of 2,2′-anhydronucleosides by a variety of basic nucleo-
philes (-OH, NH2, -SH, dithiane anions) are well-
known.13 Structures of compounds 3g and 3j were
ascertained because they afford ethers 3h and 3k when
they are methylated in THF by using sodium hydride as
the base and methyl iodide as the methylating agent
(Scheme 6). Compound 3h was also obtained directly via
an acidic methanolysis of 2c.
It is noteworthing that when trimethylsilyl cyanide and
azide were used without addition of tetrabutylammonium
fluoride (TBAF), no reaction occurs.11
Structures of compound 3h and 3k and thereby 3g and
3j shows clearly that the stereochemical outcome of the
reaction in acidic mediums involves an inversion of
configuration at C-2′. It seems likely that the same
stereochemistry should be observed in the reaction with
trimethylsilyl derivatives as nucleophiles.
Str u ctu r e of P yr im id in es 3. The chemoselectivity
of the reaction in acidic solvolysis was surprising. Hy-
drolysis and methanolysis of compound 2c afforded,
respectively, optically pure derivatives 3g and 3h , i.e.,
the nucleophile attack occurred exclusively at the C-2′
site (Scheme 6). In the ribonucleoside series, many
authors reported that 2,2′anhydronucleosides 9 were
cleaved with an inverse chemoselectivity (i.e., attack on
C-2 leading to products 10) (Scheme 5).12
Summing up our results in acidic conditions, the
conversion of pyrimidinones 2 into pyrimidines 3 can be
(12) (a) Skaric, V.; Matulic-Adamic J . J . Chem. Soc., Perkin Trans.
1 1985, 779. (b) Tong, W.; Xi, Z.; Gioeli, C.; Chattopadhyaya, J .
Tetrahedron 1991, 47, 3431. (c)Yoshimura, Y.; Ueda, T.; Matsuda, A.
Tetrahedron Lett. 1991, 35, 4549. (d) Katalenic, D.; Skaric, V. J . Chem.
Soc., Perkin Trans. 1 1992, 1065. (e) Tatsuoka, T.; Imao, K.; Suzuki,
K. Heterocycles 1986, 24, 2133. (f) Itoh, Y.; Haraguchi, K.; Tanaka,
H.; Gen, E.; Miyasaka, T. J . Org. Chem. 1995, 60, 656.
(9) Costa, A. M.; Faja, M.; Farras, J .; Vilarrasa, J . Tetrahedron Lett.
1998, 39, 1835.
(10) (a) Mercer, J . R.; Knaus, E. E.; Wiebe, L. I. J . Med. Chem. 1987,
30, 670. (b) Kumar, A.; Walker, R. T. Tetrahedron 1990, 46, 3101.
(11) When TBAF was added prior to trimethylsilylcyanide or azide,
substrate 2a led quickly to a compound which resulted from
â-elimination.
a
(13) (a) Rosenthal, A.; Dodd, R. H. Carbohydr. Res. 1980, 78, 33.
(b) Bera, S.; Langley, G. J .; Pathak, T. J . Org. Chem. 1998, 63, 1754.

6668 J . Org. Chem., Vol. 65, No. 20, 2000
Agami et al.
Sch em e 6
minimizing the energy with respect to all internal coordinates.
Approximative transition states were obtained from the energy
profiles in a reaction path (the reaction coordinates being the
distance between the carbon atom of C2′-0 or C2-O and the
reactive oxygen of MeO- and MeOH; then the transition states
were optimized by minimizing the energy gradient (NLLSQ
procedure).
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr im id i-
n on es 2. To a stirred solution of â-amino alcohol 1 (13.2 mmol)
in EtOH (50 mL) was added, over a period of 5 min, cyanogen
bromide (2.8 g, 21.7 mmol). After 6 h at reflux, EtOH was
removed under reduced pressure, replaced with a aqueous
solution of NaOH (50 mL, 1 M), and extracted twice with CH2-
Cl2 (50 mL). The organic layer was washed with water, dried
over MgSO4, and evaporated under reduced pressure. To a
stirred solution of the obtained intermediate 4 in EtOH (50
mL) was added ethyl propiolate or ethyl butynoate (14.5
mmol). After 12 h at reflux, the reaction mixture was concen-
trated under reduced pressure, and CH2Cl2 was added and
washed with water, dried over MgSO4, and removed under
reduced pressure. The solid obtained was washed with 20 mL
of hot EtOAc and filtered of to afford pyrimidinones 2 as white
solids.
3-P h en yl-2,3-dih ydr ooxazolo[3,2-a ]pyr im idin -7-on e (2a):
70.5% yield, 1H NMR (CDCl3) δ 4.49 (dd, J ) 7.8, 9.2 Hz, 1H),
5.01 (t, J ) 9.2 Hz, 1H), 5.53 (dd, J ) 7.8, 9.2 Hz, 1H), 5.95 (d,
J ) 7.5 Hz, 1H), 6.90 (d, J ) 7.5 Hz, 1H), 7.27 (m, 5H). 13C
NMR (CDCl3) δ 61.8, 73.9, 109.8, 127.0, 129.7, 130.0, 135.0,
135.8, 160.9, 175.0. HRMS calcd for C12H10O2N2 + H+ m/z
215.0821, obs m/z 215.0816.
F igu r e 1.
interpreted as an N-3 protonation followed by a selective
C-2′sO rather than C-2sO bond cleavage. This mecha-
nism is sustained by AM1 calculations indicating that
cation 11 (Figure 1) showing that N-3 protonation is
favored over N-1, O-7, or O-3′ protonation since it leads
to the more-stabilized cation. This cation could react with
a nucleophile either at C-2 or C-2′. Calculations show that
the former attack is the preferred one. Addition on C-2
would lead to a highly energetic intermediate (133 kcal
mol-1) whereas nucleophilic substitution at C-2′ affording
intermediate 12 (Figure 1) needs an activation energy
equal to only 26.2 kcal mol-1. This transition state shows
parameters that are characteristic of an SN2 process
(bond orders for MesOsC-2′, for Cs2′sOC-2 and for Cs
2′OsC-2 equal to 0.377, 0.212, 1.521, respectively).
On the other hand, the reaction of methoxy anion on
substrate 2a shows that, in basic medium, addition on
C-2 is preferred to substitution on C-2′. AM1 calculations
show that the addition-elimination process involves a
transition state whose energy is lower compared to the
9-Meth yl-3-ph en yl-2,3-dih ydr ooxazolo[3,2-a ]pyr im idin -
7-on e (2b): 72% yield, 1H NMR (CDCl3) δ 1.85 (s, 3H), 4.40
(dd, J ) 4.0, 8.9 Hz, 1H), 5.06 (t, J ) 8.9 Hz, 1H), 5.62 (dd, J
) 4.0, 8.9 Hz, 1H), 5.70 (s, 1H), 7.27 (m, 5H). 13C NMR (CDCl3)
δ 17.8, 60.5, 73.8, 108.2, 125.8, 128.9, 129.6, 137.5,147.6, 161.5,
172.7.
substitution pathway ∆(Ea) ) 2.2 kcal mol-1
.
In summary, a concise and practical synthesis of
pyrimidines 3 has been developed starting from â-amino-
alcohols. This procedure has a wide scope and should
allow for the synthesis of a large variety of acyclonucleo-
sides.
From a mechanistic point of view, AM1 calculations
are consistent with the observed results indicating that,
in acidic conditions, SN2 is operating on C-2′ and that,
in basic medium, addition on C-2 is observed.
(3S)-Meth yl-(2R)-p h en yl-2,3-d ih yd r ooxa zolo[3,2-a ]p y-
1
r im id in -7-on e (2c): 76.% yield, H NMR (CDCl3) δ 1.01 (d, J
) 6.5 Hz, 3H), 4.76 (m,1H), 6.04 (d, J ) 8.2 Hz, 1H), 6.11 (d,
J ) 7.2 Hz, 1H), 7.22 (d, J ) 8.2 Hz, 1H), 7.30 (m, 5H). 13C
NMR (CDCl3) δ 16.5, 58.0, 83.4, 110.5, 126.5, 129.3, 129.4,
133.0, 136.1, 162.0, 173.0. [R]25D: -305 (c 0.85, CHCl3). HRMS
calcd for C13H12O2N2 + H+ m/z, 229.0977obs m/z 229.0979.
2-Meth yl-2,3-dih ydr ooxazolo[3,2-a ]pyr im idin -7-on e (2d):
1
38.% yield, H NMR (CDCl3) δ 1.54 (d, J ) 8.5 Hz, 3H), 3.74
(dd, J ) 7.7, 9.5 Hz, 1H), 4.28 (dd, J ) 8.5, 9.5 Hz, 1H,), 5.05
(m,1H), 5.95 (d, J ) 7.5 Hz, 1H), 7.17 (d, J ) 7.5 Hz, 1H). 13C
NMR (CDCl3) δ 20.4, 53.1, 76.2, 110.3, 136.4, 171.1, 175.2.
HRMS calcd for C7H8O2N2 + H+ m/z 153.0664, obs m/z
153.0664.
Gen er a l P r oced u r e for th e Acid ic Hyd r olysis: P r ep a -
r a tion of P yr im id in e 3c a n d 3g. To a stirred solution of
pyrimidinones 2a or 2c (0.438 mmol) in a 1:1 mixture of THF
and H2O (4 mL) was added p-toluenesulfonic acid (100 mg,
0.581 mmol). After 12h at reflux, CH2Cl2 was added, and the
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR and 13C NMR spectra (CDCl3
solutions unless otherwise stated) were carried out at 250 and
62.9 MHz. Column chromatography was performed on silica
gel 230-400 mesh with various mixtures of ethyl acetate
(AcOEt) and methanol (MeOH). Tetrahydrofuran was distilled
from benzophenone ketyl.
The geometries of the initial states were optimized by using
the Davidson-Fletcher-Powell algorithm (FLEPO procedure),

A New Series of Acyclonucleosides
J . Org. Chem., Vol. 65, No. 20, 2000 6669
organic layer was washed with an aqueous saturated solution
of NaHCO3, dried over MgSO4, and evaporated under reduced
pressure. Flash chromatography (MeOH/ethyl acetate 1/99) of
the residue afforded pyrimidines 3c and 3g as white solids.
1-(2-H yd r oxy-1-p h e n yle t h yl)-1H -p yr im id in e -2,4-d i-
on e (3c): 91% yield, 1H NMR (CDCl3) δ 4.21 (m, 2H), 5.54 (d,
J ) 8 Hz, 1H), 5.85 (m, 1H), 7.15 (d, J ) 8 Hz, 1H), 7.30 (m,
5H). 13C NMR (CDCl3) δ 59.5, 62.0, 102.1, 128.0, 128.7, 129.2,
135.7, 142.9, 152.0, 163.7. HRMS calcd for C12H12O3N2 + H+
m/z 233.0926, obs m/z 233.0920.
pressure. Flash chromatography (MeOH/ethyl acetate 1/99) of
the residue afforded pyrimidines 3k (71 mg, 66% yield) as a
1
white solid. H NMR (CDCl3) δ 1.27 (d, J ) 6.2 Hz, 3H), 3.29
(s,3H), 4.41 (d, 1H), 4.79 (m, 1H), 5.70 (d, J ) 8.2 Hz, 1H),
7.32 (m, 5H), 7.48 (d, J ) 8 Hz, 1H), 9.2 (brs, 1H). 13C NMR
(CDCl3) δ 16.3, 57.7, 60.8, 85.2, 101.9, 127.3, 128.8, 129.0,
137.8, 143.1, 151.4, 163.8. [R]25D: -31 (c 0.32, MeOH).
Gen er a l P r oced u r e for th e Rea ction of P yr im id in on es
2 w ith TMSCl. To a stirred solution of pyrimidinones 2 (0.703
mmol) in THF (8 mL) was added TMSCl (0.178 mL, 1.408
mmol). After 2 h at room temperature, CH2Cl2 was added, and
the organic layer was washed with an aqueous saturated
solution of NaHCO3, dried over MgSO4, and evaporated under
reduced pressure. Flash chromatography (MeOH/ethyl acetate
1/99) of the residue afforded pyrimidines 3a , 3e, 3f, 3i as white
solids
1-((2S)-H yd r oxy-(1S)-m et h yl-2-p h en ylet h yl)-1H -p yr i-
1
m id in e-2,4-d ion e (3g): 78% yield, H NMR (CDCl3) δ 0.9 (d,
J ) 7.2 Hz, 3H), 2.74 (brs,1H), 4.86 (m, 2H), 5.02 (m, 1H),
5.66 (d, J ) 5.0 Hz,1H), 7.33 (m,6H), 8.75 (brs, 1H). 13C NMR
(CDCl3) δ 15.8, 60.9, 78.3, 104.9, 130.0, 131.7, 132.4, 145.7,
147.8, 155.0, 168.0. [R]25D: +13 (c 0.3, MeOH). HRMS calcd
for C13H14O3N2 + H+ m/z 247.1083, obs m/z 247.1078.
1-(2-Ch lor o-1-p h en ylet h yl)-1H -p yr im id in e-2,4-d ion e
Gen er a l P r oced u r e for th e Ba sic Hyd r olysis: P r ep a r a -
tion of P yr im id in e 3j. To a stirred solution of pyrimidinones
2c (100 mg, 0.438 mmol) in a 1:1 mixture of THF and H2O (4
mL) was added NaOH as solid (26 mg, 0.650 mmol). After 1 h
at room temperature, CH2Cl2 was added, and the organic layer
was washed with an aqueous saturated solution of NH4Cl,
dried over MgSO4, and evaporated under reduced pressure.
Flash chromatography (MeOH/ethyl acetate 1/99) of the
residue afforded pyrimidines 3j as white solids (105 mg).
1-((2R)-Hyd r oxy-(1S)-m eth yl-2-p h en yleth yl)-1H-p yr i-
1
(3a ): 80% yield, H NMR (CDCl3) δ 4.10 (m, 2H), 5.63 (d, J )
8.2 Hz,1H), 5.93 (t, J ) 7.2 Hz, 1H), 7.03 (d, J ) 8.2 Hz, 1H),
7.30 (m, 5H). 13C NMR (CDCl3) δ 43.2, 59.1, 102.5, 127.5, 129.2,
129.4, 134.7, 141.7, 151.2, 163.1. Anal. Calcd for C12H11ClO2N2
C, 57.49; H, 4.42; N, 11.17. Found C, 57.20; H, 4.71; N, 10.43.
1-(2-Ch lor o-1-p h en ylet h yl)-6-m et h yl-1H -p yr im id in e-
2,4-d ion e (3e): 78% yield, 1H NMR (CDCl3) δ 2.31 (s, 3H),
4.18 (dd, J ) 5,0, 11.2 Hz, 1H), 4.75 (dd, J ) 8.9, 11.2 Hz,
1H), 5.30 (brs, 1H), 5.55 (s, 1H), 7.29 (m, 5H), 8.8 (brs, 1H).
13C NMR (CDCl3) δ 20.7, 43.0, 61.1, 102.3, 126.0, 127.9, 128.2,
135.3, 150.1, 153.6, 161.9.
1
m id in e-2,4-d ion e (3j): 97% yield, H NMR (CDCl3) δ 0.9 (d,
J ) 7.2 Hz, 3H), 2.74 (brs,1H), 4.86 (m, 2H), 5.66 (d, J ) 5
Hz,1H), 7.33 (m,5H), 8.75 (brs, 1H). 13C NMR (CDCl3) δ 15.8,
60.9, 78.3, 104.9, 130.0, 131.7, 132.4, 145.7, 147.8, 155.0, 168.0.
[R]25D: -25 (c 0.7, CHCl3).
1-((2R)-Ch lor o-(1S)-m eth yl-2-p h en yleth yl)-1H-p yr im i-
1
d in e-2,4-d ion e (3f): 79% yield, H NMR (CDCl3) δ 1.20 (d, J
) 8 Hz, 3H), 5.10 (brs, 1H), 5.20 (m, 1H), 5.65 (d, J ) 7.5 Hz,
1H), 7.07 (d, J ) 7.5 Hz, 1H), 7.28 (m, 5H), 9.0 (brs, 1H). 13C
NMR (CDCl3). δ 16.8, 53.5, 64.6, 102.7, 128.1, 129.4, 129.7,
137.3, 163.4, 166.6. [R]25D: +432 (c 0.48, MeOH). HRMS calcd
for C13H13ClO2N2 + H+ m/z 265.0744, obs m/z 265.0753.
Gen er a l P r oced u r e for th e Acid ic Meth a n olysis: P r ep a -
r a tion of P yr im id in e 3b a n d 3h . To a stirred solution of
pyrimidinones 2a and 2c (0.438 mmol) in MeOH (4 mL) was
added p-toluenesulfonic acid (100 mg, 0.581 mmol). After 12
h at reflux, MeOH was evaporated under reduced pressure,
CH2Cl2 was added, and the organic layer was washed with an
aqueous saturated solution of NaHCO3, dried over MgSO4, and
evaporated under reduced pressure. Flash chromatography
(MeOH/ethyl acetate 1/99) of the residue afforded pyrimidines
3b and 3h as white solids.
1-(2-Me t h oxy-1-p h e n yle t h yl)-1H -p yr im id in e -2,4-d i-
on e (3b): 87.% yield, 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.85 (dd,
J ) 5.2, 10.7 Hz, 1H), 3.96 (dd, J ) 5.2, 10.7 Hz, 1H), 5.56 (d,
J ) 8.1 Hz, 1H), 5.88 (t, J ) 5.2 Hz, 1H), 7.16 (d, J ) 8.1 Hz,
1H), 7.28 (m, 5H), 8.9 (brs, 1H).13C NMR (CDCl3) δ 57.0, 59.2,
71.7 101.7, 127.9, 128.6, 129.1, 136.5, 142.9, 150.5, 163.5.
1-((2S)-Met h oxy-(1S)-m et h yl-2-p h en ylet h yl)-1H -p yr i-
m id in e-2,4-d ion e (3h ): 95% yield, 1H NMR (CDCl3) δ 1.18
(d, J ) 5.0 Hz, 3H), 3.21 (s, 3H), 4.33 (d, J ) 2.5 Hz,1H), 4.72
(m,1H,), 5.62 (d, J ) 7.5 Hz,1H), 7.25 (m, 5H), 7.40 (d, J ) 7.5
Hz,1H), 9.2 (brs, 1H). 13C NMR (CDCl3) δ 12.2, 56.3, 57.9, 84.9,
101.7, 126.9, 128.5, 129.0, 138.1, 142.9, 151.5, 163.8. Anal.
Calcd for C14H16O3N2 C, 64.60; H, 6.20; N, 10.76. Found C,
64.70; H, 6.20; N, 10.59.
1-(2-Ch lor op r op yl)-1H-p yr im id in e-2,4-d ion e (3i): 85%
1
yield, H NMR (CDCl3) δ 1.52 (d, J ) 6.8 Hz, 3H), 3.44 (dd, J
) 9.2, 14.2 Hz, 1H), 4.21 (dd, J ) 3.2, 14.2 Hz, 1H), 4.32 (m,
1H), 5.64 (d, J ) 7.5 Hz, 1H), 7.20 (d, J ) 7.5 Hz, 1H). 13C
NMR (CDCl3) δ 22.7, 55.7, 56.9, 102.2, 145.9, 151.4, 164.2.
1-(2-Azid o-1-p h en yleth yl)-9-m eth yl-1H-p yr im id in e-2,4-
d ion e (3d ). To a stirred solution of pyrimidinones 2a (0.703
mmol) in THF (4 mL) was added TMSN3 (0.123 mL, 0.934
mmol) and TBAF (0.70 mL of a 1 M solution in THF, 0.700
mmol). After 24 h at room temperature, CH2Cl2 was added,
and the organic layer was washed with an aqueous saturated
solution of NaHCO3, dried over MgSO4, and evaporated under
reduced pressure. Flash chromatography (MeOH/ethyl acetate
1/99) of the residue afforded pyrimidines 3d (103 mg, 95%
yield) as white solids: 1H NMR (CDCl3) δ 4.05 (m, 2H), 5.70
(d, J ) 7.5 Hz, 1H), 5.92 (t, J ) 5.0 Hz, 1H), 7.07 (d, J ) 7.5
Hz, 1H), 7.35 (m, 5H), 9.18 (brs, 1H). 13C NMR (CDCl3) δ 52.0,
57.5, 103.1, 128.2, 129.6, 129.8, 135.2, 142.1, 151.5, 163.3.
HRMS calc. For C12H11O2N5 + H+ m/z 258.0991, obs m/z
258.0987.
1-((2R)-Meth oxy-(1S)-m eth yl-2-p h en yleth yl)-1H-p yr i-
m id in e-2,4-d ion e (3k ). To a stirred solution of pyrimidinones
3j (100 mg, 0.438 mmol) in THF (4 mL) were added NaH (32
mg, 0.880 mmol) and methyl iodide (0.038 mL, 0.600 mmol).
After 12 h at room temperature, CH2Cl2 was added, and the
organic layer was washed with an aqueous saturated solution
of NH4Cl, dried over MgSO4, and evaporated under reduced
Su p p or tin g In for m a tion Ava ila ble: Spectrometric in-
formation (1H NMR) for compounds 2a ,b, 3a -d , 3e-k and
13C NMR for compounds 2a -d , 3c-e, 3g-k . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O000812D