Synthesis of 1-[2-(hydroxymethyl)cyclohexyl]pyrimidine analogues of nucleosides: A comparative study

Article abstract of DOI:10.1055/s-2004-831224

The synthesis of a new series of 1,2-disubstituted carbonucleosides analogues of pyrimidine (cyclohexane derivatives) is reported. For the synthesis of the uridine analogue 5a, either construction of the base on the amino group of the amino alcohol 3 or o

Full text of DOI:10.1055/s-2004-831224

PAPER
2517
Synthesis of 1-[2-(Hydroxymethyl)cyclohexyl]pyrimidine Analogues of
Nucleosides: A Comparative Study
S
ynthesis of 1-[2-(
o
H
ydroxymet
l
hyl)cyc
o
lohexyl]pyr
r
A
e
nalogues
of
N
ucleosides Viña,*a Lourdes Santana,a Eugenio Uriarte,a Elías Quezada,a Laura Valenciab
a
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qovina@usc.es
b
Departamento de Química Inorgánica, Facultad de Química, Universidad de Santiago de Compostela, Spain
Received 5 May 2004; revised 21 June 2004
have been examining a group of such 2¢,3¢-dideoxy-cyclo-
pentyl analogues which have the hydroxymethyl group
and the heterocyclic base attached to contiguous positions
of the carbocycle2 (1,2-disubstituted carbonucleosides or
Abstract: The synthesis of a new series of 1,2-disubstituted carbo-
nucleosides analogues of pyrimidine (cyclohexane derivatives) is
reported. For the synthesis of the uridine analogue 5a, either con-
struction of the base on the amino group of the amino alcohol 3 or
on the amido group of the predecessor b-lactam 1 was more effi- OTCs) and yet retain stereochemistry similar to natural
cient than condensation of the base with a protected diol. The cis-
configuration of 5a was confirmed by X-ray crystallography. Com-
pound 5a was halogenated with Cl, Br and I at uracil position 5.
nucleosides and certain pharmacologically interesting nu-
cleoside analogues. In this work, we extend this research
to cyclohexyl OTCs,3 reporting the synthesis of a repre-
Key words: amino alcohols, cyclizations, heterocycles, Mitsunobu
reaction, nucleosides
sentative pyrimidinyl compound, cis-1-[(2-hydroxymeth-
yl)cyclohexyl]uridine, and their 5-haloderivatives.
Despite the fact that carbocyclic nucleosides have been
extensively studied, little effort has been directed toward
the synthesis of six-membered carbocyclic analogues.4
However, recent publications have described the potent
antiviral activity of such compounds.5 On the other hand,
5-halopyrimidines are not only of interest due to their po-
tential chemotherapeutic properties6 but also as synthetic
Carbocyclic analogues of nucleosides, in which a methyl-
ene group replaces the furan oxygen of nucleosides, are
generally more stable to hydrolysis than the correspond-
ing furanyl compounds and in some cases have potent an-
tiviral and/or anticancer activities.1 For some years, we
HO
BzO
O
OH
OH
a
h
NH
8
1
7
b
f
i
COOH
Bz
N
O
NH2
BzO
O
O
H
N
N
OEt
N
O
O
2
6
5b
g
j
c
H
N
H
N
HO
HO
O
O
HO
O
O
NH2
N
NH
e
d
OR
5a
3
4a, R = Me
4b, R = Et
Scheme 1 Reagents and conditions: a) CSI, –78 °C, 43%; b) HCl 12 M, r.t., 99%; c) LiAlH4, THF, reflux, 72 h, 55%; d)
O=C=NCOCH=CHOCH3–C6H6, DMF, r.t., 4a: 53%; e) 2 M H2SO4, reflux, from 4a: 86%, from 4b: 90%; f) O=C=NCOCH=CHOCH2CH3–
C6H6, DMF, r.t., 37%; g) NaBH4–MeOH, r.t., 4b: 76%; h) C6H5COCl–Et3N–CH2Cl2, 32%; i) N3-benzoyluracil–Ph3P–N2(CO2Et)2–THF, r.t.,
18%; j) MeONa–MeOH, r.t., 60%
SYNTHESIS 2004, No. 15, pp 2517–2522
x
x.
x
x
.
2
0
0
4
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831224; Art ID: T04904SS
© Georg Thieme Verlag Stuttgart · New York

2518
D. Viña et al.
PAPER
intermediates in the formation of new carbon-carbon or pendent molecules of the compound. Both of them have
carbon-heteroatom bonds.7
the same cis configuration. The molecules are connected
by a strong intermolecular hydrogen bond between the
N2….O4 and N4….O1. The planarity of the uracil ring is
maintained due to sp2 character of the atoms of the ring
(rms = 0.0077 Å and 0.0071 Å). Table 1 shows the bonds
lengths (Å) and angles (°) for 5a.
In this paper, we investigated the efficiency with which it
was possible to prepare the cis uridine analogue 5a as a ra-
cemic mixture, using the two routes that have been most
widely employed in this field. These two routes are (i)
construction of the heterocyclic base on the primary am-
ino group of an appropriate amino alcohol by reaction
with a b-alkoxyacryloyl isocyanate followed by acid-cat-
alyzed cyclization according to published procedures8,9
and (ii) direct condensation between the heterocyclic base
and an appropriately functionalized carbocyclic moiety;
in this case Mitsunobu condensation of N3-benzoyluracil
with the corresponding protected diol10 (Scheme 1).
Following route (i) amino alcohol 3 was obtained by a
[2+2]-cycloaddition between cyclohexene and chlorosul-
phonyl isocyanate (CSI)11 followed by hydrolysis of the
resulting lactam 1. Amino acid 2 was either converted into
the corresponding amino ester12 and subsequently reduced
with NaBH4 or directly reduced with LiAlH4 to afford 3 in
a similar yield of 20% from cyclohexene. Treatment of 3
with 3-methoxyacryloyl isocyanate13 in anhydrous ben-
zene afforded the corresponding acyclic ureide 4a, which
by acidic cyclization turned out to afford 5a in 46% yield
from amino alcohol 3.
Figure 1 ORTEP plot of the molecular structure of compound 5a in
the crystal (crystallographic numbering does not correspond to the
systematic numbering).
Table 1 Bonds Lengths (Å) and Angles (°) of 5a
O(1)-C(1)
O(2)-C(2)
O(3)-C(11)
N(1)-C(4)
N(1)-C(1)
N(1)-C(5)
N(2)-C(1)
N(2)-C(2)
C(2)-C(3)
C(3)-C(4)
C(5)-C(6)
C(5)-C(10)
C(6)-C(11)
C(6)-C(7)
C(7)-C(8)
C(8)-C(9)
C(9)-C(10)
O(4)-C(12)
O(5)-C(13)
O(6)-C(22)
N(3)-C(15)
N(3)-C(12)
N(3)-C(16)
1.216 (7)
1.225 (7)
1.505 (7)
1.352 (7)
1.371 (7)
1.520 (8)
1.366 (7)
1.381 (7)
1.430 (9)
1.316 (7)
1.435 (8)
1.549 (8)
1.525 (9)
1.631 (9)
1.442 (9)
N(2)-C(1)-N(1)
O(2)-C(2)-N(2)
O(2)-C(2)-C(3)
N(2)-C(2)-C(3)
C(4)-C(3)-C(2)
C(3)-C(4)-N(1)
C(6)-C(5)-N(1)
C(6)-C(5)-C(10)
N(1)-C(5)-C(10)
C(5)-C(6)-C(11)
C(5)-C(6)-C(7)
C(11)-C(6)-C(7)
C(8)-C(7)-C(6)
C(7)-C(8)-C(9)
C(10)-C(9)-C(8)
114.0 (6)
120.5 (7)
127.6 (7)
111.9 (6)
121.5 (6)
122.3 (6)
106.6 (6)
115.6 (6)
113.5 (5)
115.2 (6)
105.7 (6)
110.0 (6)
113.5 (6)
106.3 (7)
111.2 (7)
108.3 (6)
109.4 (6)
120.1 (6)
122.3 (5)
117.6 (5)
129.0 (6)
123.6 (6)
122.0 (6)
Additionally, we have introduced a modification on route
(i), which has been described previously with other car-
bocyclic analogues of nucleosides.14 It involved initial re-
action of the b-lactam 1 with a 3-ethoxyacryloyl
isocyanate2b,15 in anhydrous benzene affording the corre-
sponding carbamoyl derivative 6. Reduction of compound
6 with an excess of NaBH4 in MeOH gave the correspond-
ing acyclic ureide 4b with cis stereochemistry and subse-
quent acidic ring closure afforded the desired uracil
derivative 5a in 25% yield from the b-lactam 1. This alter-
native procedure is a more direct way and also avoids the
preparation of amino alcohol 3,16 which is an unstable
compound that is difficult to isolate and purify.
Alternatively, compound 5a was obtained from alcohol 8
in two steps following the route (ii): direct condensation
of N3-benzoyluracil and ( )-trans-(2-hydroxy)cyclohex-
ylmethyl benzoate (8) in the presence of triphenylphos-
phine and diethyl azodicarboxylate17 gave the cis
compound 5b in 18% yield, which was deprotected by hy-
drolysis with MeONa–MeOH to give 5a in 60% yield. Al-
cohol 8 was prepared in 23% overall yield by reduction of
ethyl 2-oxocyclohexanecarboxylate with NaBH4 to give a
mixture of ( )-cis/trans diols 7.18 Subsequent benzoyla-
tion of the primary hydroxyl group using benzoyl chloride
gave a mixture of ( )-cis/trans-(2-hydroxy)cyclohexyl-
methyl benzoate, which could be separated by silica gel
column chromatography (1.2:1 ratio of compounds trans
and cis, respectively).
1.638 (10) C(9)-C(10)-C(5)
1.474 (9)
1.216 (7)
1.215 (7)
1.453 (6)
1.361 (8)
1.380 (7)
1.495 (7)
O(3)-C(11)-C(6)
C(15)-N(3)-C(12)
C(15)-N(3)-C(16)
C(12)-N(3)-C(16)
C(12)-N(4)-C(13)
O(4)-C(12)-N(4)
O(4)-C(12)-N(3)
The cis configuration of 5a could be confirmed by X-ray
structure determination of a crystal19 obtained from
CHCl3 using Mo-Ka radiation as the X-ray source
(Figure 1). The asymmetric unit cell contains two inde-
Synthesis 2004, No. 15, 2517–2522 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-[2-(Hydroxymethyl)cyclohexyl]pyrimidine Analogues of Nucleosides
2519
Table 1 Bonds Lengths (Å) and Angles (°) of 5a (continued)
logue 5a starting from the lactam 1 via amino alcohol
leads to a longer synthetic strategy. Therefore intermedi-
ate amino alcohol 3 is difficult to manipulate and purify.
Treatment of b-lactam 1 with a 3-ethoxyacryloyl isocyan-
ate is a more direct procedure and also avoids the prepara-
tion of amino alcohol 3.
N(4)-C(12)
1.354 (7)
1.396 (7)
1.417 (8)
1.335 (8)
1.522 (8)
1.531 (7)
1.485 (7)
1.557 (8)
1.508 (8)
N(4)-C(12)-N(3)
O(5)-C(13)-N(4)
O(5)-C(13)-C(14)
N(4)-C(13)-C(14)
C(15)-C(14)-C(13)
C(14)-C(15)-N(3)
N(3)-C(16)-C(17)
N(3)-C(16)-C(21)
C(17)-C(16)-C(21)
114.4 (6)
120.5 (7)
127.1 (7)
112.4 (6)
120.2 (7)
123.9 (6)
110.4 (5)
113.0 (5)
112.3 (5)
114.4 (5)
112.3 (5)
109.6 (5)
110.7 (6)
110.0 (6)
111.6 (6)
108.1 (5)
112.4 (5)
N(4)-C(13)
C(13)-C(14)
C(14)-C(15)
C(16)-C(17)
C(16)-C(21)
C(17)-C(22)
C(17)-C(18)
C(18)-C(19)
C(19)-C(20)
C(20)-C(21)
C(4)-N(1)-C(1)
C(4)-N(1)-C(5)
C(1)-N(1)-C(5)
C(1)-N(2)-C(2)
O(1)-C(1)-N(2)
O(1)-C(1)-N(1)
Mitsunobu reaction between the protected diol 8 and
uracil involves the same number of the steps than the last
alternative and although the uridine analogue derivative
5a is afforded in a lower yield, synthesis of b-alkoxyacryl-
oyl isocyanate could be avoided. The cis-configuration of
5a was confirmed by X-ray crystallography. Selective ha-
logenation at uracil position 5 of 5a was achieved in an ef-
ficient way.
1.533 (10) C(22)-C(17)-C(16)
1.532 (8) C(22)-C(17)-C(18)
Melting points were determined using a Stuart Scientific melting
point apparatus and are uncorrected. IR spectra were recorded on a
Perkin-Elmer 1640 FT spectrophotometer. 1H and 13C NMR spectra
were recorded on Bruker DPX (250 MHz) and Bruker AMX (500
MHz) spectrometers, using TMS as internal standard (chemical
shifts as d in ppm, J in Hz). Mass spectra and HRMS (EI) were ob-
tained using a Hewlett Packard 5988A spectrometer and Micromass
Autospec spectrometer, respectively. Silica gel (Merck 60, 230–400
mesh) was used for flash chromatography (FC). Analytical TLC
was performed on plates precoated with silica gel (Merck 60 F254,
0.25 mm). Crystal data were collected on a Bruker Smart CCD-
1000 area detector diffractometer using Mo-Ka radiation and the
absorption effects were corrected using the SADABS program. Fig-
ures were obtained using the programs ORTEP III and PLATON.
121.7 (5) C(16)-C(17)-C(18)
121.9 (5) C(19)-C(18)-C(17)
116.2 (5) C(18)-C(19)-C(20)
128.5 (6) C(19)-C(20)-C(21)
123.8 (6) C(20)-C(21)-C(16)
122.2 (6) O(6)-C(22)-C(17)
Finally, we proceeded to investigate the halogenation of
uracil position 5 (Scheme 2). Bromination and chlorina-
tion reactions, were carried out with the corresponding N-
( )-7-Azabicyclo[4.2.0]octan-8-one (1); Typical Procedure
CSI (3.25 g, 2 mL, 22.98 mmol) was added dropwise to cyclohex-
ene (2.03 g, 2.5 mL, 24.68 mmol) under Ar at –78 °C. The temper-
halosuccinimide in HOAc20 at 80 °C; these reactions gave ature was maintained at 0 °C for 8 h, then overnight at 25 °C. After
this period the reaction mixture was poured into a solution of 25%
sodium bisulfite and treated with KOH (10%) to pH 8. The resulting
solution was extracted with EtOAc, the organic phase was evaporat-
ed under vacuum and the residue was chromatographed on silica gel
yields of 45% and 51%, respectively. However, as one
would expect, iodination of 5a under the same conditions
was not possible and yielded a complex mixture of com-
pounds. Then it was carried out with iodine
(hexane–EtOAc, 6:4) to give 1; yield: 1.3 g (43%); mp 52–54 °C.
monochloride21 in MeOH at 50 ºC to afford 11 in 20%
IR (KBr): 3200, 2934, 2866, 1734, 1447.9, 1303, 1218, 715 cm–1.
yield.
1H NMR (CDCl3): d = 1.20–1.65 [m, 8 H, (CH2)4], 2.92–3.05 (m, 1
H, CHCO), 3.55–3.66 (m, 1 H, CHN), 6.85 (br s, 1 H, NH).
13C NMR (CDCl3): d = 17.1, 19.2, 20.0, 25.6, 46.9, 47.5, 173.2.
H
HO
O
N
O
X
a, b or c
MS: m/z (%) = 127 (63) [M + 2]+, 125 (100) [M+], 96 (37) [M+ –
N
5a
HCO], 81 (100) [M+ – CONH].
HRMS (EI): m/z [M+] calcd for C7H11NO: 125.0841; found:
125.0840.
9, X = Br
10, X = Cl
11, X = I
( )-cis-2-Aminocyclohexanecarboxylic Acid (2); Typical Proce-
dure
Scheme 2 Reagents and conditions: a) NBS–HOAc, 80 °C, 45%; b)
NCS–HOAc, 80 °C, 51%; c) ClI–MeOH, 50 °C, 20%
To compound 1 (3.73 g, 29.84 mmol) was slowly added, under ice-
cooling and stirring, 12 M HCl (75 mL). The reaction mixture was
stirred for 30 min at r.t. and then evaporated to dryness to give the
crude hydrochloride of 2, which was submitted to ion exchange
chromatography on Dowex 50X8-100 resin. Elution with aq
NH4OH (1 M) afforded 2; yield: 4.22 g (99%); mp 216–218 °C.
Conclusion
IR (KBr): 3502, 2952, 1654, 1584, 1154 cm–1.
1H NMR (DMSO-d6): d = 1.30–1.85 [m, 8 H, (CH2)4], 2.30 (dt, J =
4.1, 6.4 Hz, 1 H, CHCO), 3.17 (dt, J = 4.1, 8.1 Hz, 1 H, CHN).
13C NMR (DMSO-d6): d = 22.0, 22.7, 26.4, 27.4, 42.9 (1), 49.9 (2),
178.5.
For the synthesis of the uridine analogue 5a, either con-
struction of the base on the amino group of the amino al-
cohol 3 or on the amido group of the predecessor b-lactam
1 was more efficient than condensation of the base with
the corresponding diol 8. The synthesis of uridine ana-
Synthesis 2004, No. 15, 2517–2522 © Thieme Stuttgart · New York

2520
D. Viña et al.
PAPER
MS: m/z (%) = 144 (56) [M + 1]+, 143 (58) [M+], 126 (15) [M+ –
13C NMR (CDCl3): d = 14.7, 16.9, 19.0, 19.7, 23.3, 27.6, 51.1, 67.6,
98.5, 147.2, 164.9, 166.9, 171.4.
OH], 100 (86) [(M + 1)+ – CO2].
HRMS (EI): m/z [M+] calcd for C7H13NO: 143.0946; found:
MS: m/z (%) = 266 (2) [M+], 237 (10) [M+ – C2H5], 221 (26) [M+ –
143.0946.
C2H5O], 109 (29), 99 (C5H7O2, 100), 71 (64).
HRMS (EI): m/z [M+] calcd for C13H18N2O4: 266.1267; found:
266.1274.
( )-cis-2-Amino-3-cyclohexanemethanol (3); Typical Procedure
LiAlH4 (719 mg, 18.92 mmol) was added portion wise to a cooled
(0 °C) solution of 2 (770 mg, 5.38 mmol) in anhyd THF (100 mL)
with stirring under Ar. The mixture was heated under reflux for 72
h, cooled to 0 °C and quenched by slow addition of H2O–ice mix-
ture. After a further 30 min stirring at r.t., the resulting solid was fil-
tered off, organic phase was washed with H2O, dried with Na2SO4
and the filtrate was concentrated in vacuo to give 3 as a colourless
oil, which was used in the next step without further purification;
yield: 1.5 g (55%).
( )-cis-N-[2-(Hydroxymethyl)cyclohexylcarbamoyl]-3-ethoxy-
2-propenamide (4b); Typical Procedure
To a stirred solution of 3 (130 mg, 0.49 mmol) in anhyd MeOH (4
mL) at 0 °C was added NaBH4 (64 mg, 1.69 mmol) portion wise.
The mixture was stirred for 1 h at r.t. and the excess reducing re-
agent was destroyed by the addition of HOAc–MeOH (1:10). The
solvent was evaporated under reduced pressure and the residue was
purified by FC (EtOAc) to afford 4b; yield: 100 mg (76%); mp 137–
138 °C.
IR (KBr): 3286, 2924, 2841, 1574, 1455, 1040 cm–1.
1H NMR (CDCl3): d = 1.25–1.80 [m, 9 H, (CH2)4 + CHCO], 3.29
(br s, 1 H, OH), 3.60–4.10 (m, 5 H, CHN + CH2O + NH2)
IR (KBr): 3430, 3224, 3119, 2925, 2856, 1674, 1606, 1564, 1164
cm–1.
13C NMR (CDCl3): d = 21.8, 24.4, 25.1, 32.6, 41.2, 51.4, 66.2.
MS: m/z (%) = 129 (30) [M+], 112 (12) [M+ – OH], 86 (60), 56
1H NMR (CDCl3): d = 0.96–1.39 [m, 4 H, (CH2)2], 1.39 (t, J = 7.0
Hz, 3 H, CH3), 1.57–1.89 (m, 5 H, (CH2)2 + CHCO], 3.16–3.41 (m,
2 H, CH2OH), 3.99 (q, J = 7.0 Hz, 2 H, OCH2), 4.15 (dd, J = 4.2, 6.4
Hz, 1 H, CHN), 4.28–4.32 (m, 1 H, OH), 5.23 (d, J = 12.2 Hz, 1 H,
=CH), 7.67 (d, J = 12.2 Hz, 1 H, =CH), 9.17 (br s, 1 H, NH), 9.21
(br s, 1 H, NH).
(100).
HRMS (EI): m/z [M+] calcd for C7H15NO: 129.1154; found:
129.1173.
13C NMR (CDCl3): d = 14.9, 21.6, 23.6, 25.5, 30.9, 43.7, 45.4, 64.2,
( )-cis-N-[2-(Hydroxymethyl)cyclohexylcarbamoyl]-3-meth-
oxy-2-propenamide (4a); Typical Procedure
68.0, 97.7, 125.5, 156.6, 163.9.
A solution of 3-methoxyacryloyl isocyanate in benzene (1.08 g, 25
mL, 8.56 mmol) was added very slowly to a solution of amino alco-
hol 3 (1.10 g, 8.56 mmol) in DMF (32 mL) at –20 °C under Ar. This
mixture was stirred overnight arriving slowly to r.t. The solvent was
evaporated under vacuum below 40 °C (by forming an azeotropic
mixture with EtOH–toluene), and the resulting residue was purified
by FC (CH2Cl2–MeOH, 98:2) to give 4a; yield: 600 mg (53%); mp
167–169 °C.
MS: m/z (%) = 270 (0.5) [M+], 240 (6) [(M + 1)+ – CH3O], 159 (62),
128 (26) [M+ – C6H8O3N], 99 (100) [C5O2H7].
HRMS (EI): m/z [M+] calcd for C13H22N2O4: 270.1580; found:
270.1586.
( )-cis/trans-(2-Hydroxy)cyclohexylmethanol (7); Typical Pro-
cedure
Anhydrous EtOH (75 mL) was cooled to –30 °C and treated with
NaBH4 (6.05 g, 160 mmol). To this solution was added dropwise a
solution of ethyl cyclohexanone-2-carboxylate (5.46 g, 5.1 mL,
32.09 mmol) in EtOH (15 mL) so that the temperature did not rise
to more than –20 °C. After stirring for 1 h at temperature between
–20 °C and –30 °C the cooling bath was removed and stirring was
continued at r.t. for another 20 h. Thereafter the reaction mixture
was treated dropwise with glacial HOAc (25 mL). The resulting so-
lution was concentrated under reduced pressure. The residue was
treated with brine (100 mL) and extracted with EtOAc (3 × 100
mL). The combined organic extracts were dried with Na2SO4 and
the solvent was removed under reduced pressure. The residue was
purified by FC using hexane–EtOAc (20:80) to give 7; yield: 2.98 g
(71%).
IR (KBr): 3432, 3228, 3101, 2928, 1672, 1613, 1566, 1152, 810
cm–1.
1H NMR (CDCl3): d = 1.15–1.47 [m, 9 H, (CH2)4 + CHCO], 3.16–
3.24 (m, 1 H, HCHO), 3.32–3.47 (m, 1 H, HCHO), 3.70 (s, 3 H,
OCH3), 4.10–4.21 (m, 1 H, OH), 4.29–4.31 (m, 1 H, CHN), 5.21 (d,
J = 12.2 Hz, 1 H, =CHO), 7.75 (d, J = 12.2 Hz, 1 H, =CHCO), 9.08
(s, 1 H, NH imide), 9.16 (d, 1 H, NH amide, J = 8.8 Hz).
MS: m/z (%) = 256 (3) [M+], 226 (12) [M+ – CH2O], 183 (8), 145
(83) [M+ – C7H11O], 128 (26), 65 (100).
HRMS (EI): m/z [M+] calcd for C12H20N2O4: 256.1423; found:
256.1433.
N-(3-Ethoxy-2-propenoyl)-8-oxo-7-azabicyclo[4.2.0]octan-7-
carboxamide (6); Typical Procedure
( )-trans-(2-Hydroxy)cyclohexylmethyl Benzoate (8); Typical
Procedure
According to the procedure described for the preparation of 4a, a so-
lution of 3-ethoxyacryloyl isocyanate (846 mg, 6.00 mmol) in an-
hyd benzene (20 mL) was treated with a solution of 1 (500 mg, 4.00
mmol) in anhyd benzene (5 mL). The solid residue was purified by
FC (hexane–EtOAc, 9:1) to give 3 as a colorless oil which later be-
came solid; yield: 393 mg (37%); mp 74 °C.
Benzoyl chloride (605 mg, 0.5 mL, 4.31 mmol) was added to a so-
lution of diol 7 (500 mg, 3.84 mmol) and Et3N (1.8 mL) in anhyd
CH2Cl2 (10 mL) under Ar. The mixture was stirred at r.t. for 3 h.
The organic layer was washed with NaHCO3, dried (Na2SO4) and
the solvent was evaporated under vacuum. The residue was purified
by FC using hexane–EtOAc (85:15) to give first compound cis-822
and then compound trans-8; yield of 8: 290 mg (32%).
IR (KBr): 3305, 3121, 2973, 2871, 1766, 1732, 1683, 1607, 1397
cm–1.
IR (KBr): 3434, 2921, 2846, 1713, 1446, 1275, 1114, 708 cm–1.
1H NMR (CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H, CH3), 1.52–1.63 [m,
4 H, (CH2)2], 1.80–2.22 (m, 4 H, (CH2)2], 3.37–3.46 (m, 1 H,
CHC=O), 4.00 (q, J = 7.1 Hz, 2 H, CH2O), 4.27–4.33 (m, 1 H,
CHN), 6.32 (d, J = 12.3 Hz, 1 H, =CH), 7.77 (d, J = 12.3 Hz, 1 H,
=CH), 8.90 (br s, 1 H, NH).
1H NMR (CDCl3): d = 1.28–1.35 (m, 2 H, CH2), 1.58–1.90 [m, 5 H,
(CH2)2 + HCH], 2.01–2.06 (m, 1 H, HCH), 2.64–2.66 (m, 1 H,
CHCH2OBz), 3.32–3.44 (m, 1 H, CHOH), 4.27 (dd, J = 11.2, 4.3
Hz, 1 H, HCHOBz), 4.70 (dd, J = 11.2, 4.7 Hz, 1 H, HCHOBz),
7.42–7.46 (m, 2 H, ArH), 7.54–7.61 (m, 1 H, ArH), 8.03–8.07 (m,
2 H, ArH).
Synthesis 2004, No. 15, 2517–2522 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-[2-(Hydroxymethyl)cyclohexyl]pyrimidine Analogues of Nucleosides
2521
13C NMR (CDCl3): d = 25.2, 25.7, 28.7, 35.3, 45.9, 67.1, 71.5,
128.8, 130.0, 130.4, 133.5, 166.8.
Dr = 0.413 eÅ–3, S = 0.946. Hydrogen atoms were included using a
riding model or rigid methyl groups.
MS: m/z (%) = 235 (100) [M + 1]+, 217 (92) [(M + 1)+ – H2O], 123
(45), 105 (86), 95 (64) [C7H5O].
HRMS (EI): m/z [M+] calcd for C14H18O3: 234.1256; found:
234.1256.
( )-cis-1-[2-(Hydroxymethyl)cyclohexyl]-5-bromouracil (9);
Typical Procedure
NBS (55 mg, 0.31 mmol) in HOAc (3.5 mL) was added to a solution
of the uracil derivative 5a (63 mg, 0.28 mmol) in HOAc (2.5 mL) at
r.t. The mixture was heated at 80 °C for 1 h, the solvent was evapo-
rated (azeotropic mixture with EtOH–toluene), and the residue was
re-dissolved in 0.5 M NaOH and neutralized with 0.5 M HCl. The
solvent was evaporated under vacuum (azeotropic mixture with
EtOH–toluene) and the residue was chromatographed on silica gel
[hexane–i-PrOH, 90:10] to give 9; yield: 38 mg (45%); mp 174 °C.
( )-cis-1-[2-(Benzoyloxymethyl)cyclohexyl]-N3-benzoyluracil
(5b); Typical Procedure
N3-Benzoyluracil (1.14 g, 5.30 mmol) was added to a solution of
Ph3P (1.39 g, 5.30 mmol) and diethyl azodicarboxylate (885 mg, 0.8
mL, 5.30 mmol) in anhyd THF (40 mL) at 0 °C, and the mixture was
stirred for 10 min. Alcohol 8 (999 mg, 4.27 mmol) in anhyd THF (4
mL) was added dropwise, and the mixture was stirred overnight at
r.t. The solvent was evaporated under vacuum and the residue puri-
fied by FC (hexane–EtOAc, 8:2) to give 5b; yield: 320 mg (18%);
mp 84–86 °C.
IR (KBr): 3500, 3283, 3109, 2957, 1658, 1614 cm–1.
1H NMR (DMSO-d6): d = 1.29–1.87 [m, 7 H, (CH2)3 + HCH], 2.05–
2.20 (m, 2 H, HCH + CHCO), 3.40–3.60 (m, 2 H, CH2O), 4.29–4.39
(m, 1 H, OH), 4.44–4.46 (m, 1 H, CHN), 7.98 (s, 1 H, H-6), 11.75
(br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.3, 25.3, 26.1, 27.5, 38.9 (2¢), 57.9 (1¢),
58.6 (7¢), 94.5 (5), 143.2 (6), 150.7 (2), 159.5 (4).
MS: m/z (%) = 304 (2) [M + 2]+, 302 (6) [M+], 193 (32) [(M + 2)+ –
C7H11O], 192 (32) [(M + 2)+ – C7H12O], 191 (31) [M+ – C7H11O],
190 (31) [M+ – C7H12O], 158 (19), 95 (61), 58 (100).
IR (KBr): 3079, 2927, 2851, 1747, 1704, 1660, 1443, 1270, 1107,
711 cm–1.
1H NMR (CDCl3): d = 1.30–2.01 [m, 8 H, (CH2)4], 2.70–2.90 (m, 1
H, CHCH2), 4.35–4.41 (m, 1 H, HCHO), 4.49–4.53 (m, 1 H,
HCHO), 4.61–4.66 (m, 1 H, CHN), 5.65 (d, J = 8.1 Hz, 1 H, H-5),
7.29–8.00 (m, 11 H, 10 ArH + H-6).
HRMS (EI): m/z [M+] calcd for C25H24N2O5: 432.1685; found:
HRMS (EI): m/z [M+] calcd for C11H15BrN2O3: 302.0266; found:
432.1672.
302.0269.
( )-cis-1-[2-(Hydroxymethyl)cyclohexyl]uracil (5a); Typical
Procedure
( )-cis-1-[2-(Hydroxymethyl)cyclohexyl]-5-chlorouracil (10);
Typical Procedure
A mixture of imide 4a (600 mg, 2.68 mmol) and 2 M H2SO4 (18
mL) was refluxed for 3 h. After cooling, it was neutralized with 2 M
NaOH, the solvent was evaporated under vacuum (by forming an
azeotropic mixture with EtOH–toluene) and the resulting residue
was purified by FC (CHCl3–MeOH, 98:2) to give 5a; yield: 450 mg
(86%); mp 188–190 °C. The same procedure was used to get 5a
from 4b (600 mg, 2.26 mmol); yield: 450 mg (90%). Compound 5a
was also obtained in 60% yield from 5b by hydrolysis of the ben-
zoyl derivative 5b with 1 M MeONa–MeOH at r.t. overnight.
NCS (32 mg, 0.24 mmol) in HOAc (1.8 mL) was added to a solution
of the uracil derivative 5a (48 mg, 0.21 mmol) in HOAc (2.9 mL) at
r.t. The mixture was heated at 80 °C for 6 h, the solvent was evapo-
rated (azeotropic mixture with EtOH–toluene), and the residue was
re-dissolved in 0.5 M NaOH and neutralized with 0.5 M HCl. The
solvent was evaporated under vacuum (azeotropic mixture with
EtOH–toluene) and the residue was chromatographed on silica gel
[hexane–i-PrOH, 96:4] to give 10; yield: 28 mg (51%); mp: 193–
195 °C.
IR (KBr): 3383, 3010, 2922, 2855, 1698, 1281 cm–1.
IR (KBr): 3205, 3068, 2943, 1772, 1205, 1045 cm–1.
1H NMR (DMSO-d6): d = 1.25–2.08 [m, 9 H, (CH2)4 + CHCO],
3.30–3.35 (m, 1 H, HCHO), 3.44–3.49 (m, 1 H, HCHO), 4.32–4.38
(m, 2 H, CHN + OH), 5.50 (d, J = 8.9 Hz, 1 H, H-5), 7.45 (d, J = 8.9
Hz, 1 H, H-6), 11.10 (s, 1 H, NH).
1H NMR (DMSO-d6): d = 1.28–1.86 [m, 7 H, (CH2)3 + HCH], 2.02–
2.18 (m, 2 H, HCH + CHCO), 3.41–3.50 (m, 2 H, CH2O), 4.31–4.35
(m, 1 H, CHN), 4.40 (t, J = 4.8 Hz, 1 H, OH), 7.89 (s, 1 H, H-6),
11.07 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 19.8, 25.3, 25.8, 26.8, 38.8, 57.3, 58.1,
100.2 (5), 144.0 (6), 151.4 (2), 164.6 (4).
13C NMR (DMSO-d6): d = 20.3, 25.2, 26.1, 27.5, 40.9 (2¢), 57.8 (1¢),
58.6 (7¢), 105.9 (5), 140.9 (6), 150.5 (2), 159.4 (4).
MS: m/z (%) = 224 (32) [M+], 193 (16) [M+ – CH3O], 150 (9), 113
MS: m/z (%) = 260 (2) [M + 2]+, 258 (7) [M+], 149 (52) [(M + 2)+ -
+
(100) [M+ – C7H11O], 95 (24), 79 (22), 67 (23), 63 (22).
C7H11O], 147 (14) [M+ – C7H11O], (6) [(M + 2) – C7H12O], 111
(54) [C7H11O], 109 (60), 97 (89), 95 (100).
HRMS (EI): m/z [M+] calcd for C11H15ClN2O3: 258.0771; found:
HRMS (EI): m/z [M+] calcd for C11H16N2O3: 224.1161; found:
224.1163.
258.0777.
X-Ray Crystal Analysis of 5a
Formula: C11H16N2O3. Crystal Data: Monoclinic, space group Cc,
a = 17.481 (4), b = 15.673 (4), c = 18.203 (4) Å, b = 115.64 (5)°,
V = 4496.3 (18) Å3, Z = 16, Dc = 1. Mg m–3, F(000) = 1920, m =
0.097 mm–1, T = 293 K. Data collection: Structure of a single crys-
tal of ca. 0.47 × 0.19 × 0.08 mm was performed on a Bruker Smart
CCD-1000 area detector diffractometer using graphite monochro-
mated MoK radiation, l = 0.71073 Å. Absorption corrections were
carried out using SADABS.23 The structure was resolved by direct
methods. Structure Refinement: The structure was refined by a full-
matrix least-squares based on F2, using anisotropic displacement
parameters for all non-hydrogen atoms24 to wR2 = 0.1913, R1 =
0.0982 for 286 parameters and 5052 independent reflections; max.
( )-cis-1-[2-(Hydroxymethyl)cyclohexyl]-5-iodouracil (11);
Typical Procedure
Iodine monochlorure (41.4 mg, 0.25 mmol) was added to a stirred
solution of 5a (38 mg, 0.17 mmol) in MeOH (4 mL). The resulting
solution was heated at 50 °C for 1.5 h. The solution was cooled and
decolorized by careful washing with the minimum required volume
of 2% NaHSO3–H2O solution. The solvent was evaporated under
vacuum and the residue purified by FC [hexane–i-PrOH, 98:2];
yield: 12 mg (29%); mp: 189–191 °C.
IR (KBr): 3432, 3045, 2932, 2841, 1716, 1670, 1278, 1051 cm–1.
1H NMR (DMSO-d6): d = 1.43–1.99 [m, 7 H, (CH2)3 + HCH], 2.23–
2.33 (m, 2 H, HCH + CHCO), 3.51–3.60 (m, 1 H, HCHO), 3.68–
Synthesis 2004, No. 15, 2517–2522 © Thieme Stuttgart · New York

2522
D. Viña et al.
PAPER
(7) (a) Farina, V.; Hauck, S. I. Synlett 1991, 157. (b) Robins,
3.88 (m, 1 H, HCHO), 4.47–4.51 (m, 1 H, CHN), 4.57 (t, J = 5.1 Hz,
1 H, OH), 8.05 (s, 1 H, H-6), 11.89 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.2, 25.3, 26.2, 27.3, 57.7 (1¢), 58.4 (7¢),
67.9, 74.7, 147.6 (6), 151.1 (2), 160.9 (4).
M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854.
(c) Tsvetkov, A. V.; Latyshev, G. V.; Lukashev, N. V.;
Beletskaya, I. P. Tetrahedron Lett. 2002, 43, 2787.
(8) Sheally, Y. F.; O’Dell, C. A. J. Heterocycl. Chem. 1976, 13,
1041.
(9) Hronowski, L. J.; Szarek, W. A. Can. J. Chem. 1985, 63,
2787.
(10) Mitsunobu, O. Synthesis 1981, 1.
MS: m/z (%) = 350 (53) [M+], 239 (43) [M+ – C7H11O], 238 (90)
[M+ – C7H12O], 195 (91), 181 (83), 95 (100), 83 (19), 85 (46).
HRMS (EI): m/z [M+] calcd for C11H15IN2O3: 350.0126; found:
350.0127.
(11) Nativ, E.; Rona, P. Isr. J. Chem. 1972, 40, 55.
(12) Gyarmati, Z.; Liljeblad, A.; Rintola, M.; Bernáth, G.;
Kanerva, L. T. Tetrahedron: Asymmetry 2003, 14, 3805.
(13) Santana, L.; Teijeira, M.; Uriarte, E. J. Heterocycl. Chem.
1999, 36, 1.
(14) Katagiri, N.; Muto, M.; Nomura, M.; Higashikawa, T.;
Kaneko, C. Chem. Pharm. Bull. 1991, 39, 1112.
(15) (a) Tietze, L.; Schemeider, C.; Pretor, M. Synthesis 1993,
1079. (b) Fernández, F.; García-Mera, X.; Morales, M.;
Rodríguez-Borges, J. E. Synthesis 2001, 239.
(16) Péter, M.; Van der Eycken, J.; Bernáth, G.; Fülöp, F.
Tetrahedron: Asymmetry 1998, 9, 2339.
(17) Bera, S.; Nair, V. Tetrahedron 2002, 58, 4865.
(18) Kinast, G.; Tietze, L.-F. Chem. Ber. 1976, 109, 3626.
(19) Complete crystallographic data have been deposited at the
Cambridge Crystallogrphic Data Centre under the number
CCDC-235125. Copies can be obtained free of charge from
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
(20) Awano, H.; Shuto, S.; Baba, M.; Kira, T.; Shigeta, S.;
Matsuda, A. Bioorg. Med. Chem. Lett. 1994, 4, 367.
(21) Robins, M. J.; Barr, P. J.; Giziewicz, J. Can. J. Chem. 1982,
60, 554.
Acknowledgment
We thank the Spanish Ministry of Science and Technology (SAF
2003-02222) and the Xunta de Galicia (PGIDT02BTF2031PR) for
financial support. D. V. is grateful to the Spanish Ministry of Sci-
ence and Technology for a pre-doctoral grant (FPU).
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Synthesis 2004, No. 15, 2517–2522 © Thieme Stuttgart · New York