Cyclic ureas as ortho directing substituents

Article abstract of DOI:10.1039/b105420c

Six-membered cyclic ureas are shown to have a weak ortho directing ability when linked through nitrogen to benzene and pyridine rings.

Full text of DOI:10.1039/b105420c

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Cyclic ureas as ortho directing substituents
Jon-Paul Meigh,a Mercedes Álvarezb and John A. Joule*a
a Chemistry Department, The University of Manchester, Manchester, UK M13 9PL
b Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona,
08028 Barcelona, Spain
1
Received (in Cambridge, UK) 20th June 2001, Accepted 10th July 2001
First published as an Advance Article on the web 8th August 2001
Six-membered cyclic ureas are shown to have a weak ortho directing ability when linked through nitrogen to benzene
and pyridine rings.
including, by alternating the order of introduction of substitu-
ents onto the pyridine, ‘upside-down’ variants with respect to
the azaindole unit. We describe in this paper preliminary work
aimed at the introduction of a pyridine-3-substituent via
Introduction
The variolins, from the Antarctic sponge Kirkpatrickia vari-
alosa, are a small group of marine heterocyclic substances1 of
which variolins B and D are typical. In vitro studies showed
directed ortho metallation of a 2-substituted pyridine.
The lithiation of an aromatic or heteroaromatic molecule
regioselectively ortho to a particular group – Directed ortho
Metallation (DoM) – has become an invaluable tool for the
synthesis of aromatic/heteroaromatic molecules.5 Of the many
substituents which can act as ortho directing groups6 little
attention has been paid to ureas. We are aware of only four
reports,7–10 one of which appeared10 during the course of
the work described here: Seebach lithiated an N-allylurea
by deprotonation of the methylene group,7 Beak lithiated
N-benzyl-N,NЈ-dimethylurea at the benzylic position,8
Quéguiner lithiated N,N-dimethyl-NЈ-(quinolin-3-yl)urea at
C-4 using LDA,9 and finally, and most relevant to the present
variolin B to be the most active in tests which included assess-
ment of antiviral activity (Herpes simplex Type I, polio Type I);
variolin B is active against P388 leukemia cells.1 Each of the
variolins is based on a fused pyrimidino-7-azaindole – strictly a
pyrido[3Ј,2Ј:4,5]pyrrolo[1,2-c]pyrimidine. Noting the presence
of a heteroaryl unit located at the 3-position of the imbedded
7-azaindole, we have developed the use of palladium(0)-based
methodology for the coupling of 1-protected 3-trimethyl-
stannyl-7-azaindoles with aryl- and heteroaryl halides,2 evolved
a synthesis of the pyrrolo[1,2-c]pyrimidine system,3 which is
also imbedded in the variolin structures, and recently we have
described a total synthesis of deoxyvariolin B using these
principles.4
paper, Smith lithiated N,N-dimethyl-NЈ-(4-chlorophenyl)urea,
apparently (chlorine is also an ortho directing substituent) ortho
to the urea unit, using n-butyllithium at 0 ЊC. Smith also
showed that n-butyllithium failed to lithiate N,N-dimethyl-NЈ-
(4-fluorophenyl)urea, but that excess tert-butyllithium did effect
lithiation; this stronger base also brought about ring lithiation
of N,N-dimethyl-NЈ-(phenyl)urea, though accompanied by
N-methyl deprotonation and indeed, conditions were developed
to achieve efficient N-methyl lithiation only (two equivalents of
t-BuLi at Ϫ20 ЊC).10 There are no reports of lithiations of
N-aryl cyclic ureas.
An alternative retrosynthetic analysis to that used for previ-
ous work2,3,4 is shown in Scheme 1: here we propose that the
Results and discussion
It was our plan to utilise the carbonyl oxygen of 1-(pyridin-
2-yl)pyrimidin-2(1H)-ones or of 1-(pyridin-2-yl)-3,4,5,6-tetra-
hydropyrimidin-2(1H)-ones to assist lithiation of the pyridine
at C-3, generating species such as 3 or 4 (Scheme 2), and thereby
Scheme 1
Scheme 2
pyrrole ring would be formed at a late stage from a structure
such as 1 and that this would be developed from a pyridine 2 in
which the two pyrimidine substituents would be introduced
sequentially. A successful implementation of this route would
enable the development of a library of variolin analogues,
the introduction of suitable substituents. Subsequently the
carbonyl oxygen, having served its ortho assisting purpose, was
to provide the means for the introduction of an amino group at
C-9 of final targets.
2012
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105420c

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Syntheses of 1-arylpyrimidin-2(1H)-ones 5a and 5b
and 4-chloropicolinic acid chloride21 respectively, by conver-
sion to primary amides then Hofmann degradation.
1-(3-Methoxyphenyl)pyrimidin-2(1H)-one 5b was prepared11
from N-(3-methoxyphenyl)urea 6a by reaction with 1,1,3,3-
tetramethoxypropane, though in only 13% yield; the urea
6a was readily available12 from m-anisidine by reaction with
sodium cyanate. Although N-(pyridin-2-yl)urea 6b could be
prepared13 by simply heating 2-aminopyridine with urea (19%,
accompanied by N,NЈ-(dipyridin-2-yl)urea), or by heating
with phenyl carbamate14 (though always accompanied by
N,NЈ-(dipyridin-2-yl)urea), a better method was based on a
reported synthesis15 involving reaction of 2-aminopyridine
with N-chlorosulfonyl isocyanate, and the yield from this
route was improved (62%, see Experimental). Unfortunately,
attempts to convert N-(pyridin-2-yl)urea 6b into 1-(pyridin-
2-yl)pyrimidin-2(1H)-one 5c by reaction with 1,1,3,3-tetra-
Lithiations
It was the hope that the combined effects of the methoxy sub-
stituent and the pyrimidinone carbonyl oxygen would promote
ring lithiation at C-2 of the benzene ring in 5b. However, when
5b was treated with n-butyllithium at Ϫ78 ЊC then pivalalde-
hyde, an unresolvable mixture of products was produced, mass
spectroscopic analysis of which suggested that it contained
products of addition of the organolithium reagent to the
pyrimidin-2(1H)-one ring. Changing to tert-butyllithium, again
with attempted trapping using pivalaldehyde, the tendency for
addition to outweigh any possible deprotonation in this system
was confirmed, with the isolation of adduct 11 in 56% yield
after separation from the only other component of the product
mixture – unchanged starting material. Addition of Grignard
nucleophiles to pyrimidin-2(1H)-ones has been previously
described.11
methoxypropane met with failure. Disappointing results (see
later) in attempted lithiation of the 1-(aryl)pyrimidin-2(1H)-
ones led us to set aside further attempts to prepare 1-(pyridin-2-
yl)-substituted examples.
It was clear that lithiation of 1-arylpyrimidin-2(1H)-ones
was not a viable proposition – they are too susceptible to
organometallic addition in the pyrimidin-2(1H)-one ring.
Accordingly we turned to an examination of the saturated
cyclic ureas 10a–f. In order to determine optimum conditions,
lithiation of 10b, in which there was expected to be co-
operativity between the methoxy and heterocycle in directing
ability, was examined. Two mol equivalents of the base were
required, the first to remove the N-hydrogen. At Ϫ78 ЊC no ring
lithiation took place and thus, following quenching with excess
iodomethane, only the N-methylated product 12a was obtained.
Looking for a better method for the synthesis of 1-(aryl)-
pyrimidin-2(1H)-ones, we investigated the use of triarylbis-
muth reagents,16,17 which had been shown to arylate simple
amides and ureas.18 As a trial, it was shown that reaction of
pyridin-2-one with triphenylbismuth gave 1-phenylpyridin-
2(1H)-one in 68% yield. Turning to pyrimidin-2(1H)-one 7,19
reactions with triphenylbismuth and tris(3-methoxyphenyl)-
bismuth were successful in bringing about N-arylation and
thus the formation of 5a and 5b respectively, though only in
moderate yields.
Syntheses of 1-aryl/heteroaryl-3,4,5,6-tetrahydropyrimidin-
2(1H)-ones 10a–f
Following work by Cram,20 the route shown in Scheme 3 was
Treatment of 10b with 2.5 equivalents of n-butyllithium
at the much higher temperature of 0 ЊC was successful in
ring lithiation, and after quenching with iodomethane, the
N,C-dimethylated product 12b was obtained in 92% yield.
Comparable trappings with trimethylsilyl chloride, pivalalde-
hyde and benzoyl chloride produced 12c (68%), 12d (56%) and
12e (13%) respectively.
The temperature required for these lithiations is considerably
higher than is typical in DoM lithiations – it was clear that the
urea unit did not have a strong effect and indeed when the
demethoxy-analogue 10a was treated with n-butyllithium
under the same conditions, no ring lithiation occurred and only
the N-methylated product 12f was obtained. The methoxy-
compound 10c, isomeric to 10a, was lithiated however, though
the products of trapping with trimethylsilyl chloride proved
difficult to isolate. It was clear that the crude material contained
two isomeric products, in addition to starting material; one of
these, 12g, was isolated and fully characterised. Examination of
the spectroscopic data for the mixture of products made it clear
that the second product was the isomer 12h and that the two
trimethylsilyl derivatives had been formed in roughly equal
Scheme 3
used to prepare the tetrahydropyrimidin-2(1H)-ones, 10a–f in
good yields. Thus, reaction of the aromatic/heteroaromatic
amines 8 with 3-chloropropyl isocyanate led to ureas 9 from
which, by base-catalysed intramolecular N-alkylation, the
target products 10 were formed smoothly.
2-Amino-4-methoxypyridine 8e and 2-amino-4-chloro-
pyridine 8f were prepared from methyl 4-methoxypicolinate21
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021
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proportions. Apparently a methoxy group and the cyclic urea
have approximately equivalent ortho directing abilities.
formamide was dried over 4 Å molecular sieves. The molarities
of organolithiums were determined prior to use by titration.23a
All other chemicals were purified using the appropriate stand-
ard procedure as described in ref. 23b.
Turning to the pyridin-2-yl urea 10d, treatment with n-butyl-
lithium, even at Ϫ78 ЊC, produced complex mixtures in which,
by MS and NMR analysis it was clear that butyl addition had
occurred, probably at pyridine C-6, though nothing could be
fully characterised. With 10e it was hoped that the co-operative
effects of the two substituents would allow ring lithiation.
Reaction with n-butyllithium at Ϫ78 ЊC then quenching
with iodomethane led straightforwardly to the N-methylated
derivative 13a – there had been no ring lithiation.
1-Phenylpyrimidin-2(1H)-one 5a
Method 1. 1,1,3,3-Tetramethoxypropane (24.2 ml, 147.1
mmol, 2.0 eq.) was added dropwise, over a 1 h period, to a
solution of N phenylurea (10 g, 73.5 mmol, 1.0 eq.) in methanol
(50 ml) and conc. HCl (12 M, 20 ml). The addition resulted in
the formation of a white particulate suspension, which turned
bright yellow on stirring at ambient temperature. Stirring was
continued for a further 72 h and the reaction progress followed
by TLC. After this time, the solution, which had become dark
red in appearance was allowed to stand, resulting in the precipi-
tation of a yellow semi-solid mass. The volatile components
were removed under reduced pressure and the product dis-
solved in sat. aq. Na2CO3, then acidified (pH 5) with 2.5 M
H2SO4. The resulting aqueous solution was extracted with
chloroform (5 × 30 ml) (insoluble, sticky, light brown coloured
material (ca. 8 g) was precipitated at this stage), the combined
organic extracts were dried and concentrated in vacuo, to reveal
a bright orange coloured semi-solid (13.6 g). Repeated flash
column chromatography on neutral Al2O3 (eluting with 2–6%
MeOH–CH2Cl2) gave 5a as pale yellow coloured plates (2.4 g,
19%), mp 154–156 ЊC from EtOAc. Lit.24 155–156 ЊC; Rf 0.32
(6% MeOH–CH2Cl2; SiO2) (HRMS found: Mϩ, 172.0635.
C10H8N2O requires M, 172.06366) (Anal. found: C, 69.3; H,
5.2; N, 15.8%. C10H8N2O requires: C, 69.8; H, 4.7; N, 16.3%);
λmax (EtOH): 230, 292 nm (ε 14200, 11300); νmax (film): 3054,
1669 (br), 1613 cmϪ1; 1H-NMR (300 MHz, CDCl3): δ 6.34 (1H,
dd, J 7, 4, H-5), 7.33–7.45 (5H, m, C6H5), 7.67 (1H, dd, J 7, 3,
H-6), 8.74 (1H, dd, J 4, 3, H-4); 13C-NMR (75 MHz, CDCl3):
δ 104.5, 126.0, 129.2, 129.6, 140.2, 148.0, 155.6, 166.9; m/z (CI):
190 (M ϩ 18, 3%), 174 (M ϩ 2, 18), 173 (M ϩ 1, 100).
Application of the lithiation conditions (Ϫ78 0 ЊC) which
had been successful for 10b produced a very complex mixture,
analysis of which clearly showed both products from butyl
addition and from butyl addition accompanied by C-/N-methyl-
ations. Operating at Ϫ40 ЊC did allow the isolation of the target
dimethylated product 13b but only in poor yield.
It occurred to us that intramolecular co-ordination of
lithium by the pyridine nitrogen 14 might be both preventing
ortho assistance and encouraging nucleophilic butyl addition.
To test this idea, 10d was treated with one equivalent of
n-butyllithium at Ϫ78 ЊC, then with trimethylsilyl chloride (to
form a presumed O-silyl derivative) and then with a further
equivalent of n-butyllithium. Quenching with iodomethane
allowed the isolation of exclusively C-monomethylated product
13c in 37% yield.
Experimental
Method 2. A slurry of pyrimidin-2(1H)-one (7) (500 mg, 5.21
mmol, 1.0 eq.), triphenylbismuth (3.44 g, 7.82 mmol, 1.5 eq.),
anhydrous Cu(OAc)2 (1.42 g, 7.82 mmol, 1.5 eq.) and NEt3
(0.73 ml, 5.21 mmol, 1.5 eq.) in anhydrous CH2Cl2 (8 ml) was
stirred at rt in a flask equipped with a CaCl2 guard tube. After a
period of 20 h, the solution became gelatinous and changed
from deep blue to light green, grey copper() salts were clearly
visible. The reaction mixture was diluted with CH2Cl2 (10 ml),
material absorbed onto silica gel and the product isolated
by flash column chromatography (eluting with 6% MeOH–
CH2Cl2). Recrystallisation from hot EtOAc afforded 5a as
white plates (256 mg, 28%), mp 155–156 ЊC.
Flash column chromatography was performed using Merck
Kieselgel 60 (230–400 mesh). Organic solutions were dried over
anhydrous MgSO4. Solid products were dried under reduced
pressure using P4O10 as a desiccant. Proton nuclear magnetic
resonance (1H-NMR) spectra were recorded on Inova-300
Athos (300 MHz) and Unity 500 (500 MHz) spectrometers.
Complex signals which ‘appear’ simple are described as: e.g.
‘apparent quintet’, and an average J value given to the nearest
whole number. Carbon nuclear magnetic resonance (13C-NMR)
spectra were recorded on an Inova-300 Athos spectrometer
running at 75 MHz. All chemical shifts (δ) are quoted in parts
per million (ppm) downfield from tetramethylsilane (TMS).
Signal splittings are reported as singlet (s), doublet (d), double
doublet (dd), triplet (t), quartet (q), multiplet (m), and broad
(br); J values are given in Hertz (Hz). UV spectra were recorded
on a Hewlett Packard 8452A diode array spectrophotometer
and are given in nm with ε (in dm3 molϪ1 sϪ1) in parentheses. IR
spectra were recorded on an Ati Mattson Genesis Series FTIR
spectrometer; only absorptions of importance to structure
determination are listed; br = broad, sh = shoulder. Mass
spectra were recorded on a Fisons VG Trio 2000 (EI/CI{NH3})
(abundance relative to the base peak given in parentheses as a
percentage; only fragment ions of intensity >10% of the base
peak are cited) and a Concept IS (MM/FAB) spectrometer for
accurate mass determinations. Melting points (ЊC) were
recorded on a Reichart heated stage microscope and are un-
corrected. Flash column chromatography was carried out
according to the method of Still,22 using Merck 9385 silica gel
60 (230–400 mesh) [or neutral alumina]. All ethers were dried
over sodium wire and distilled under an atmosphere of dry
argon using benzophenone as an indicator of degree of
hydration. Dichloromethane (for reactions), pyridine, and
triethylamine were distilled from calcium hydride. Dimethyl-
N-(3-Methoxyphenyl)urea 6a
To a warm (40 ЊC) solution of freshly distilled m-anisidine (60
ml, 0.5 mol) in glacial acetic acid (140 ml) and water (260 ml)
was added sodium cyanate (70 g, 1.1 mol, 2.0 eq.) in water (200
ml) with vigorous stirring. The addition caused considerable
frothing and gave rise to the separation of a white precipitate.
The mixture was stirred for 2 h, whilst it cooled to rt, before
being left to stand overnight. The resultant solid was collected
by vacuum filtration, washed with cold water (3 × 50 ml) to
remove any excess AcOH and dried to leave light brown needles
(89 g, 99%). Recrystallisation from hot water (800 ml) with the
aid of decolourising charcoal (ca. 4 g), yielded 6a as fine, white
needles (75 g, 78%), mp 132–133 ЊC from water. Lit.11 134–
135 ЊC: Rf 0.47 (10% MeOH–CH2Cl2; SiO2) (HRMS found:
Mϩ, 166.0745. C8H10N2O2 requires M, 166.07422) (Anal.
found: C, 57.4; H, 6.3; N, 16.9%. C8H10N2O2 requires: C, 57.8;
H, 6.1; N, 16.9%); λmax (EtOH): 218, 242, 280 nm (ε 17049,
14378, 2868); νmax (KBr): 3564–3114 (br), 1666 cmϪ1; 1H-NMR
(300 MHz, d6-DMSO): δ 3.72 (3H, s, OCH3), 5.85 (2H, br s,
NH2), 6.49 (1H, dd, J 8, 2, H-4), 6.89 (1H, dd, J 8, 2, H-6), 7.13
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(1H, s, H-2), 7.15 (1H, apparent t, J 8, H-5), 8.53 (1H, br s,
NH); 13C-NMR (75 MHz, d6-DMSO): δ 55.2, 103.9, 106.8,
110.5, 129.7, 142.1, 156.3, 160.0; m/z (CI): 184 (M ϩ 18, 78%),
167 (M ϩ 1, 100), 124 (36).
Anhydrous bismuth trichloride (5.0 g, 15.86 mmol, 1.0 eq.) was
added slowly to the cooled mixture through a flame dried,
sealed powder addition funnel under a steady stream of argon.
Over this time, gentle heat was applied to ensure reflux, con-
tinued for a further hour once the addition was complete. The
cold reaction mixture was poured slowly into 100 ml of ice–
water, with vigorous stirring, the mixture was filtered under
reduced pressure and the ether layer was retained. The residue
on the filter, and the aqueous layer were extracted with ether
(3 × 10 ml). Evaporation of the combined ether extracts
revealed a yellow semi-solid, which crystallised as an off-white
solid (4.1 g, 49%) on cooling to 0 ЊC. Recrystallisation from 60–
80 petroleum ether afforded tris(3-methoxyphenyl)bismuth as
white needles (2.9 g, 34%, mp 79–80 ЊC from 60–80 petroleum
ether); Rf 0.92 (6% MeOH–CH2Cl2; SiO2) (HRMS found: Mϩ,
530.1306. C21H21BiO3 requires M, 530.12946) (Anal. found: C,
47.8; H, 4.0%. C21H21BiO3 requires: C, 47.8; H, 4.0%); λmax
1-(3-Methoxyphenyl)pyrimidin-2(1H)-one 5b
Method 1. 1,1,3,3-Tetramethoxypropane (16.0 ml, 96.4
mmol, 2.0 eq.) was added to a stirred solution of N-(3-
methoxyphenyl)urea 6a (8.0 g, 48.2 mmol, 1.0 eq.) in methanol
(30 ml) and conc. HCl (12 M, 15 ml), addition resulted in the
formation of an orange particulate suspension, which gradually
became homogeneous and deep red in colour on stirring at
ambient temperature for 30 min. Stirring was continued for a
further 72 h, then the volatile components were removed under
high vacuum and the resultant solid neutralised (pH 8) by dis-
solving in sat. aq. KHCO3. Extraction with CH2Cl2 (a sticky,
light brown coloured material (ca. 6 g) was precipitated at this
stage) gave the crude product as an orange coloured solid (12.3
g) which was found to contain five UV active components by
TLC. This material was taken up into 3 M HCl (20 ml) and
extracted with CH2Cl2 (3 × 20 ml portions), the aqueous layer
was neutralised with solid K2CO3 and extracted with a further
portion of CH2Cl2 (30 ml). The combined organic extracts
were dried and concentrated in vacuo, to give a bright orange
solid (3.87 g), containing product, still contaminated with five
other compounds (TLC). It was possible to separate some of
the components by flash column chromatography on neutral
alumina (eluting with 5–10% MeOH–CH2Cl2). Only two
components could be characterised, one was 5b as pale orange
coloured plates (1.3 g, 13%), mp 112–116 ЊC from EtOAc. Lit.11
114–115 ЊC from CHCl3–hexane.
1
(EtOH): 206, 286 nm (ε 35614, 10013); H-NMR (300 MHz,
d6-DMSO): δ 3.37 (9H, s, 3 × OCH3), 6.88 (3H, dd, J 7, 2,
3 × H-4), 7.29 (3H, d, J 7, 3 × H-6), 7.35 (3H, apparent s,
3 × H-2), 7.37 (3H, apparent t, J 7, 3 × H-5); 13C-NMR (75
MHz, d6-DMSO): δ 55.2, 113.1, 123.6, 129.7, 131.6, 161.5; m/z
(CI): 548 (M ϩ 18, 8%), 531 (M ϩ 1, 18), 441 (15), 440 (100),
423 (38).
N-(Pyridin-2-yl)urea 6b
Chlorosulfonyl isocyanate (0.97 ml, 10.64 mmol, 1.0 eq.) was
added dropwise over a 30 min period to a stirred solution of
2-aminopyridine (1.0 g, 10.64 mmol, 1.0 eq.) in anhydrous
acetonitrile (10 ml) at 0 ЊC. A vigorous reaction ensued, which
appeared to be complete after 20 min. The mixture was warmed
to rt and stirring was continued for a further 3 h. Excess aq. sat.
KHCO3 (10 ml) was added and the mixture was stirred at rt for
16 h. The resultant suspension was evaporated to dryness
revealing an off-white solid, which was taken-up in boiling 95%
EtOH (10 ml) and filtered whilst hot. The filtrate was concen-
trated to approximately one quarter of its volume and refriger-
ated overnight to afford the title compound as white plates (905
mg, 62%), mp 164–165 ЊC from 95% EtOH; Rf 0.47 (10%
MeOH–CH2Cl2; SiO2) (HRMS found: Mϩ, 137.0587. C6H7N3O
requires M, 137.05891) (Anal. found: C, 52.4; H, 5.1; N, 30.3%.
C6H7N3O requires: C, 52.6; H, 5.1; N, 30.6%); λmax (EtOH):
234, 282 nm (ε 1073, 331); νmax (KBr): 3312–2994 (br), 1708
Method 2. A slurry of pyrimidin-2(1H)-one (7) (190 mg, 1.98
mmol), tris(3-methoxyphenyl)bismuth (2.10 g, 3.96 mmol,
2.0 eq.), anhydrous Cu(OAc)2 (719 mg, 3.96 mmol, 2.0 eq.)
and NEt3 (0.42 ml, 2.97 mmol, 1.5 eq.) in anhydrous CH2Cl2
(8.0 ml) was stirred at rt in a flask equipped with a CaCl2 guard
tube. After a period of 24 h, the solution had changed from
deep blue, to light green in colour and grey copper() salts could
be observed. The reaction mixture was diluted with CH2Cl2
(10 ml) and the product isolated by flash column chromato-
graphy, following pre-absorption of the mixture onto silica gel
(eluting with 1–6% MeOH–CH2Cl2). Recrystallisation from
EtOAc afforded the title compound as off-white coloured plates
(145 mg, 36%), mp 112–113 ЊC from EtOAc; Rf 0.32 (6%
MeOH–CH2Cl2; SiO2) (HRMS found: Mϩ, 202.0743. C11H10-
N2O2 requires M, 202.07422) (Anal. found: C, 63.2; H, 5.0; N,
10.9%. C11H10N2O2ؒEtOAc requires: C, 63.4; H, 5.7; N, 11.4%);
λmax (EtOH): 218, 274 nm (ε 14712, 8448); νmax (film): 3497,
1
(br), 1601 (br) cmϪ1; H-NMR (300 MHz, d6-DMSO): δ 6.89
(1H, apparent br t, J 7, H-5), 6.95–7.10 (2H, br s, NH2), 7.35
(1H, apparent d, J 8, H-3), 7.71 (1H, apparent t, J 7, H-4),
8.14 (1H, apparent d, J 5, H-6), 9.04 (1H, br s, NH); 13C-NMR
(75 MHz, d6-DMSO): δ 112.0, 117.2, 138.4, 147.2, 153.9, 155.8;
m/z (CI): 138 (M ϩ 1, 65%), 121 (15), 95 (100).
1
3435, 1671 (br), 1605 (br) cmϪ1; H-NMR (500 MHz, CDCl3):
δ 3.85 (3H, s, OCH3), 6.40 (1H, dd, J 6.5, 4.0, H-5), 6.96 (1H,
apparent s, H-2Ј), 6.97 (1H, ddd, J 8.0, 3.0, 1.0, H-4Ј), 7.00 (1H,
dd, J 8.0, 1.0, H-6Ј), 7.42 (1H, dt, J 1.0, 8.0, H-5Ј), 7.73 (1H, dd,
J 6.5, 3.0, H-6), 8.70 (1H, dd, J 4.0, 3.0, H-4); 13C-NMR (75
MHz, CDCl3): δ 55.5, 103.9, 111.9, 115.0, 118.0, 130.3, 141.1,
148.0, 155.5, 160.2, 166.8; m/z (CI): 220 (M ϩ 18, 5%), 203
(M ϩ 1, 100), 124 (16).
1-Phenyl-2(1H)-pyridone
A slurry of pyridin-2(1H)-one (250 mg, 2.63 mmol, 1.0 eq.),
triphenylbismuth (2.3 g, 5.26 mmol, 2.0 eq.), anhydrous
Cu(OAc)2 (715 mg, 3.94 mmol, 1.5 eq.) and NEt3 (0.55 ml,
3.94 mmol, 1.5 eq.) in anhydrous CH2Cl2 (5.0 ml) was stirred at
rt in a flask equipped with a CaCl2 guard tube. After 15 min, the
solution became gelatinous and changed from deep blue to light
green. More Cu(OAc)2 (240 mg, 1.32 mmol, 0.5 eq.) and
CH2Cl2 (3.0 ml) were added and stirring continued for a further
48 h, after which TLC analysis indicated no further conversion.
The reaction mixture was diluted with CH2Cl2 (10 ml) and the
mixture was absorbed onto silica gel. 1-Phenyl-2-pyridone was
isolated by flash column chromatography (eluting with 1–5%
MeOH–CH2Cl2) and recrystallised from hot EtOAc, giving
light brown needles (307 mg, 68%), mp 123–124 ЊC from
EtOAc. Lit.25 mp 123–125 ЊC; Rf 0.40 (6% MeOH–CH2Cl2;
SiO2) (HRMS found: Mϩ, 171.0681. C11H9NO requires M,
171.06841) (Anal. found: C, 76.5; H, 5.5; N, 7.7%. C11H9NO
requires: C, 77.2; H, 5.3; N, 8.2%); λmax (EtOH): 222, 310 nm
Tris(3-methoxyphenyl)bismuth
A flame dried 2-necked 100 ml flask, fitted with a reflux con-
denser and rubber septum was charged with “bright” mag-
nesium turnings (2.3 g, 95.15 mmol, 6.0 eq.) under a dry argon
atmosphere. The turnings were covered with anhydrous Et2O
(50 ml) and 3-bromoanisole (12.0 ml, 95.15 mmol, 6.0 eq.), was
added at a rate to maintain slow reflux; gentle warming was
necessary to initiate the reaction which turned dark brown in
colour as the magnesium was consumed. After a period of 30
min, boiling stopped, so the mixture was heated at gentle reflux
for a further 30 min until all the magnesium went into solution.
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021
2015

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(ε 13692, 7496); νmax (film): 1659 (br) cmϪ1
;
1H-NMR (300
4 h and the mixture stirred at rt overnight allowing the ammonia
MHz, CDCl3): δ 6.28 (1H, dt, J 2, 7, H-5), 6.70 (1H, dd, J 7, 2,
H-3), 7.37–7.54 (7H, m, 5 × PhH, H-4 and H-6); 13C-NMR (75
MHz, CDCl3): δ 105.8, 121.8, 126.5, 128.4, 129.3, 137.9, 139.8,
140.9, 162.3; m/z (CI): 172 (M ϩ 1, 100%).
to evaporate. Evaporation of the THF afforded the amide as
small, light brown coloured needles, which by TLC and
1H-NMR analysis were judged to be of sufficient purity for the
next step (10 g, 79%); mp 143–144 ЊC from EtOAc. Lit.27
162–163 ЊC; Rf 0.62 (10% MeOH–CH2Cl2 with a few drops
of NEt3) (HRMS found: Mϩ, 156.0092. C6H5ClN2O requires
M, 156.00904) (Anal. found: C, 44.1; H, 2.1; N, 15.4%.
C6H5ClN2OؒH2O requires: C, 43.5; H, 3.7; N, 16.9%); λmax
(EtOH): 250, 268 nm (ε 952, 1266); νmax (KBr): 3366–3177 (br),
4-Methoxypicolinamide
Ammonia (ca. 300 ml) was condensed into a flask containing a
solution of methyl 4-methoxypicolinate21 (10.6 g, 63.5 mmol) in
MeOH (300 ml), then the mixture was refluxed for 5 h. The
NH3 was allowed to evaporate, the remaining mixture concen-
trated to dryness, and the crude product, an off-white solid (9.0
g), recrystallised from EtOAc giving the amide as large
off-white plates (8.2 g, 85%), mp 145–146 ЊC. Lit.26 149–150 ЊC;
Rf 0.79 (6% MeOH–CH2Cl2 with a few drops of NEt3; SiO2)
(HRMS found: Mϩ, 152.0590. C7H8N2O2 requires M,
152.05857) (Anal. found: C, 54.8; H, 5.3; N, 18.2%. C7H8N2O2
requires: C, 55.3; H, 5.3; N, 18.4%); λmax (EtOH): 240, 248 nm
1
1710 (br), 1609 cmϪ1; H-NMR (300 MHz, d6-DMSO): δ 7.73
(1H, dd, J 5.2, 1.9, H-5), 7.85 (1H, br s, NH), 8.03 (1H, d, J 1.9,
H-3), 8.23 (1H, br s, NH), 8.61 (1H, d, J 5.4, H-6); 13C-NMR
(75 MHz, d6-DMSO): δ 122.4, 126.7, 144.8, 150.4, 152.4, 165.2;
m/z (CI): 176 (37Cl, M ϩ 18, 26%), 174 (35Cl, M ϩ 18, 46), 159
(37Cl, M ϩ 1, 36), 157 (35Cl, M ϩ 1, 100).
2-Amino-4-chloropyridine 8f
(ε 9034, 14915); νmax (KBr): 3411, 3189, 1687 (br) cmϪ1
;
To a solution of KOH (17.9 g, 319.5 mmol, 10.0 eq.) in water
(90 ml) at 0–5 ЊC, bromine (3.3 ml, 63.9 mmol, 2.0 eq.) was
added dropwise with stirring, followed by 4-chloropicolinamide
(5.0 g, 32.0 mmol, 1.0 eq.) rapidly. Most of the material went
into solution, however, 1,4-dioxane (50 ml) was added in order
to ensure that a homogeneous solution was obtained. The
resulting solution was stirred at rt for 30 min, then heated at
55 ЊC for 60 min. The mixture was cooled and glacial AcOH
(10 ml) was added dropwise, when an exothermic reaction took
place with CO2 evolution and a cream coloured precipitate
formed. The mixture was heated at 50–55 ЊC for a further
30 min, causing the precipitate to dissolve, the solution was
then allowed to cool. KOH (ca. 7 g) was added and the resulting
white suspension extracted with CH2Cl2 (3 × 150 ml). The
combined organic extracts were dried and concentrated in
vacuo to reveal the crude product amine as a pale yellow solid
(3.1 g). Recrystallisation of this material from Et2O–hexane
(2 : 1) afforded the amine as bright white plates (2.1 g, 51%), mp
95–96 ЊC from Et2O–hexane (2 : 1). Lit.28 130–131 ЊC; Rf 0.49
(10% MeOH–CH2Cl2; SiO2) (HRMS found: Mϩ, 128.0141.
C5H5ClN2 requires M, 128.01412) (Anal. found: C, 46.4; H, 4.1;
N, 21.3; Cl, 27.3%. C5H5ClN2 requires: C, 46.7; H, 3.9; N, 21.8;
Cl, 27.6%); λmax (CHCl3): 246, 294 nm (ε 1473, 1127); νmax(film):
1H-NMR (300 MHz, d6-DMSO): δ 3.90 (3H, s, OCH3), 7.15
(1H, dd, J 5.7, 2.7, H-5), 7.57 (1H, d, J 2.7, H-3), 7.01 (1H, br s,
NH), 8.14 (1H, br s, NH), 8.44 (1H, d, J 5.7, H-6); 13C-NMR
(75 MHz, d6-DMSO): δ 55.9, 108.0, 112.8, 150.2, 152.7, 166.2,
166.8; m/z (CI): 153 (M ϩ 1, 100%), 136 (14), 109 (32), 108 (10).
2-Amino-4-methoxypyridine 8e
A solution of KOH (29.9 g, 532.9 mmol, 10.0 eq.) in water
(150 ml) was cooled (0–5 ЊC) and to this was added bromine
(5.5 ml, 106.6 mmol, 2.0 eq.) dropwise with stirring, followed by
4-methoxypicolinamide (8.1 g, 53.3 mmol, 1.0 eq.) rapidly.
Most of the material went into solution, however, 1,4-dioxane
(50 ml) was added (slowly) in order to ensure that a homo-
geneous mixture was obtained. The resulting solution was
stirred at rt for 30 min, then heated at 55 ЊC for 60 min. Heating
was stopped and glacial AcOH (25 ml) was added dropwise
with vigorous stirring, an exothermic reaction took place with
CO2 evolution and a cream coloured precipitate formed. The
resulting suspension was heated at 55 ЊC for a further 30 min,
causing the precipitate to dissolve. Once cool, KOH (ca. 18 g)
was added and the resulting white suspension extracted with
CH2Cl2 (3 × 150 ml). The combined organic extracts were dried
and concentrated in vacuo to leave the crude product amine as a
pale yellow solid (3.62 g). Recrystallisation from Et2O furnished
8e as off-white plates (2.97 g, 45%), mp 113–114 ЊC from Et2O.
Lit.21 116–117 ЊC; Rf 0.37 (2 : 2 : 1; PhMe–EtOAc–MeOH;
SiO2) (HRMS found: Mϩ, 124.0639. C6H8N2O requires M,
124.0637) (Anal. found: C, 57.8; H, 6.6; N, 22.5%. C6H8N2O
requires: C, 58.1; H, 6.5; N, 22.6%); λmax (CHCl3): 250, 280 nm
1
3450, 3171, 3154, 1625 cmϪ1; H-NMR (300 MHz, CDCl3):
δ 4.74 (2H, br s, NH2), 6.52 (1H, br s, H-3), 6.66 (1H, br d, J 5.4,
H-5), 7.79 (1H, d, J 5.4, H-6); 13C-NMR (75 MHz, CDCl3):
δ 108.1, 114.4, 144.9, 149.0, 159.1; m/z (CI): 148 (37Cl, M ϩ 18,
6%), 146 (35Cl, M ϩ 18, 20%), 131 (37Cl, M ϩ 1, 30), 129 (35Cl,
M ϩ 1, 100).
(ε 1582, 1470); νmax (film): 3460, 3299, 3123, 1634, 1608 cmϪ1
;
N-(3-Chloropropyl)-NЈ-phenylurea 9a
1H-NMR (300 MHz, CDCl3): δ 3.81 (3H, s, OCH3), 4.72 (2H,
br s, NH2), 6.00 (1H, d, J 2.2, H-3), 6.28 (1H, dd, J 5.9, 2.2,
H-5), 7.90 (1H, d, J 5.9, H-6); 13C-NMR (75 MHz, CDCl3):
δ 54.9, 92.3, 102.5, 148.7, 160.0, 167.3; m/z (CI): 125 (M ϩ 1,
100%), 124 (12).
Aniline (2.0 g, 1.96 ml, 21.48 mmol, distilled from KOH) in
anhydrous CH2Cl2 (20 ml) was treated with 3-chloropropyl
isocyanate (3.30 ml, 32.21 mmol, 1.5 eq.) under N2, and the
resulting solution was stirred at rt for 48 h. Evaporation left a
colourless oil that solidified on standing to give a sticky light
brown solid, which on washing with Et2O gave the crude prod-
uct as a white powder (5.32 g). Recrystallisation from EtOAc
afforded 9a as bright white needles (3.81 g, 92%), mp 120–
121 ЊC from EtOAc; Rf 0.68 (2 : 2 : 1; PhMe–EtOAc–MeOH)
(HRMS found: Mϩ, 212.0721. C10H13ClN2O requires M,
212.07163) (Anal. found: C, 56.1; H, 6.5; N, 13.2; Cl, 17.1%.
C10H13ClN2O requires: C, 56.5; H, 6.2; N, 13.2; Cl, 16.7%); λmax
(CHCl3): 254, 276 nm (ε 12487, 4209); νmax (film): 3323, 2959,
2926, 1688 cmϪ1; 1H-NMR (300 MHz, d6-DMSO): δ 1.92 (2H,
apparent quintet, J 6, CH2), 3.23 (2H, apparent q, J 6, CH2N),
3.69 (2H, t, J 6.0, CH2Cl), 6.30 (1H, br t, J 5.0, alkyl NH), 6.90
(1H, dt, J 1.0, 7.3, ArH), 7.23 (2H, t, J 7.3, ArH), 7.41 (2H, d,
J 7.3, ArH), 8.49 (1H, s, aromatic NH); 13C-NMR (75 MHz,
d6-DMSO): δ 33.1, 36.9, 43.4, 118.0, 121.4, 129.0, 140.8, 155.7;
m/z (CI): 232 (37Cl, M ϩ 18, 2%), 230 (35Cl, M ϩ 18, 6), 215
4-Chloropicolinamide
A mixture of picolinic acid (10 g, 81.3 mmol), NaBr (420 mg,
4.1 mmol) and SOCl2 (30 ml, 406.5 mmol) in a 500 ml, 3-necked
round-bottomed flask, equipped with a reflux condenser and
CaCl2 drying tube was heated to reflux for 24 h (after 3 h the
mixture turned black and started to solidify, a further 15 ml of
SOCl2 was required in order for stirring to be resumed). The
excess SOCl2 was evaporated and the resultant brown solid was
suspended in anhydrous THF (250 ml). The flask was fitted
with a dry ice condenser and vented to a mineral oil bubbler, the
mixture was cooled to Ϫ78 ЊC and ammonia (excess) was con-
densed into the THF solution. Once an approximately equal
volume of NH3 to THF was achieved, the vent was closed and
the dark blue suspension was stirred at Ϫ20 to Ϫ10 ЊC for 3 to
2016
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021

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(37Cl, M ϩ 1, 30), 214 (15), 213 (35Cl, M ϩ 1, 100), 177 (21), 94
1682 (br) cmϪ1 1H-NMR (300 MHz, CDCl3): δ 2.15 (2H,
;
(16), 93 (12).
apparent quintet, J 7, CH2), 3.60 (2H, apparent q, J 6,
CH2N), 3.70 (2H, t, J 6.5, CH2Cl), 6.87 (1H, d, J 8.0, H-3), 6.92
(1H, apparent t, J 5, H-5), 7.62 (1H, apparent t, J 8, H-4), 8.21
(1H, apparent d, J 5, H-6), 8.64 (1H, s, NH), 9.60 (1H, br s,
NH); 13C-NMR (75 MHz, CDCl3): δ 32.7, 36.9, 42.6, 111.9,
116.7, 138.2, 145.9, 153.3, 156.4; m/z (CI): 216 (37Cl, M ϩ 1,
35%), 214 (35Cl, M ϩ 1, 100%), 212 (35), 178 (20).
N-(3-Chloropropyl)-NЈ-(3-methoxyphenyl)urea 9b
To a solution of m-anisidine (2.0 g, 1.82 ml, 16.24 mmol,
pre-distilled from KOH) in anhydrous CH2Cl2 (100 ml), under a
dry nitrogen atmosphere was added 3-chloropropyl isocyanate
(2.50 ml, 24.36 mmol, 1.5 eq., dropwise), the resulting solution
was stirred at rt. A slight exotherm was observed and following
a 15 min period the solution turned cloudy, stirring was con-
tinued for a further 72 h. Evaporation left a colourless oil that
solidified on standing to give a sticky light brown solid, which
on washing with Et2O gave crude urea as a white powder (4.47
g). Recrystallisation from EtOAc gave 9b as white needles (3.81
g, 97%), mp 92–94 ЊC from EtOAc; Rf 0.08 (2% MeOH–
CH2Cl2; SiO2) (HRMS found: Mϩ, 242.0819. C11H15ClN2O2
requires M, 242.0822) (Anal. found: C, 54.3; H, 6.5; N, 11.2; Cl,
15.0%. C11H15ClN2O2 requires: C, 54.4; H, 6.2; N, 11.5; Cl,
14.6%); λmax (CHCl3): 250, 282 nm (ε 14599, 5688); νmax (film):
N-(3-Chloropropyl)-NЈ-(4-methoxypyridin-2-yl)urea 9e
To a solution of 2-amino-4-methoxypyridine 8e (3.47 g, 27.97
mmol) in anhydrous CH2Cl2 (50 ml), under a dry N2 atmos-
phere was added 3-chloropropyl isocyanate (4.29 ml, 41.96
mmol, 1.5 eq.), then the resulting solution was stirred at rt for
48 h. Evaporation left a pale yellow oil which solidified on
standing to yield the crude product as a white powder (6.42 g),
recrystallisation from EtOAc afforded 9e as sticky white needles
(5.99 g, 88%), mp 97–98 ЊC from EtOAc; Rf 0.63 (2 : 2 : 1;
PhMe–EtOAc–MeOH) (HRMS found: Mϩ, 243.0770. C10H14-
ClN3O2 requires M, 243.07745) (Anal. found: C, 48.2; H, 6.1;
N, 16.2%. C10H14ClN3O2 requires: C, 49.3; H, 5.8; N, 17.2%);
λmax (CHCl3): 252, 272, 314 nm (ε 1360, 1420, 108); νmax (film):
3333, 2986, 2938, 2753, 1654 (br), 1606 cmϪ1; H-NMR (300
1
MHz, CDCl3): δ 1.98 (2H, apparent quintet, J 7, CH2), 3.39
(2H, t, J 6.5, CH2N), 3.59 (2H, t, J 6.5, CH2Cl), 3.78 (3H, s,
OCH3), 5.60 (1H, br s, NH), 6.64 (1H, dd, J 8.0, 2.0, H-4), 6.82
(1H, dd, J 8.0, 2.0, H-6), 7.01 (1H, t, J 2.0, H-2), 7.20 (1H, t,
J 8.0, H-5), 7.26 (1H, br s, NH); 13C-NMR (75 MHz, CDCl3):
δ 32.6, 37.4, 42.4, 55.1, 106.3, 109.0, 112.7, 129.8, 139.8, 156.4,
160.2; m/z (CI): 262 (37Cl, M ϩ 18, 3%), 260 (35Cl, M ϩ 18, 8),
245 (37Cl, M ϩ 1, 31), 244 (15), 243 (35Cl, M ϩ 1, 100), 207 (21),
124 (19), 123 (12).
1
3223 (br), 2901, 1686 (br), 1607 cmϪ1; H-NMR (300 MHz,
CDCl3): δ 2.13 (2H, apparent quintet, J 7, CH2), 3.57 (2H,
apparent q, J 7, CH2N), 3.69 (2H, t, J 6.5, CH2Cl), 3.88 (3H, s,
OCH3), 6.33 (1H, d, J 2.2, H-3), 6.51 (1H, dd, 5.9, 2.2, H-5),
8.02 (1H, d, J 5.9, H-6), 8.35 (1H, br t, alkyl NH), 9.58 (1H,
br s, aromatic NH); 13C-NMR (75 MHz, CDCl3): δ 32.7, 37.0,
42.5, 55.2, 95.2, 105.7, 147.0, 154.9, 156.3, 167.2; m/z (CI): 246
(37Cl, M ϩ 1, 37%), 244 (35Cl, M ϩ 1, 100), 208 (14), 151 (14),
125 (18).
N-(3-Chloropropyl)-NЈ-(4-methoxyphenyl)urea 9c
A solution of p-anisidine (1.82 g, 14.80 mmol, dried by azeo-
troping with anhydrous benzene) in anhydrous CH2Cl2 (20 ml),
under a dry N2 atmosphere, was treated with 3-chloropropyl
isocyanate (2.30 ml, 22.20 mmol, 1.5 eq.), then the resulting
dark brown solution was stirred at rt for 72 h, after which
evaporation of the CH2Cl2 revealed a purple coloured oil that
solidified on standing to give a sticky solid. Washing with Et2O
left a lilac powder (3.61 g). Recrystallisation from EtOAc gave
9c as lilac needles (3.30 g, 92%), mp 120–121 ЊC from EtOAc;
Rf 0.58 (2 : 2 : 1; PhMe–EtOAc–MeOH) (HRMS found: Mϩ,
242.0822. C11H15ClN2O2 requires M, 242.0822) (Anal. found:
C, 54.4; H, 6.5; N, 11.3; Cl, 14.7%. C11H15ClN2O2 requires: C,
54.4; H, 6.2; N, 11.5; Cl, 14.6%); λmax (EtOH): 252, 284 nm
N-(3-Chloropropyl)-NЈ-(4-chloropyridin-2-yl)urea 9f
To a solution of 2-amino-4-chloropyridine 8f (2.0 g, 15.56
mmol) in anhydrous CH2Cl2 (50 ml), under a dry nitrogen
atmosphere was added 3-chloropropyl isocyanate (2.4 ml, 23.35
mmol, 1.5 eq.), then the resulting solution was stirred at rt for
48 h. Evaporation revealed a pale yellow oil which solidified on
standing to yield the crude product as a white powder (4.01 g),
recrystallisation from EtOAc gave 9f as off-white needles
(3.32 g, 86%), mp 114–115 ЊC from EtOAc; Rf 0.67 (2 : 2 : 1;
PhMe–EtOAc–MeOH) (HRMS found: Mϩ, 247.0277.
C9H11Cl2N3O requires M, 247.02791) (Anal. found: C, 42.7; H,
4.4; N, 16.3; Cl, 29.2%. C9H11Cl2N3O requires: C, 43.6; H, 4.5;
N, 16.9; Cl, 28.6%); λmax (CHCl3): 248, 286 nm (ε 9369, 5999);
(ε 12384, 3869); νmax (film): 3307, 3049, 2961, 1628, 1607 cmϪ1
;
1H-NMR (300 MHz, d6-DMSO): δ 1.89 (2H, apparent quintet,
J 7, CH2), 3.21 (2H, apparent q, J 7, CH2N), 3.69 (2H, apparent
t, J 7, CH2Cl), 3.71 (3H, s, OCH3), 6.09 (1H, br t, J 6.0, alkyl
NH), 6.82 (2H, dd, J 7.0, 2.0, H-3 and H-5), 7.30 (2H, dd, J 7.0,
2.0, H-2 and H-6), 8.28 (1H, s, aromatic NH); 13C-NMR (75
MHz, d6-DMSO): δ 33.2, 36.9, 43.5, 55.5, 114.2, 119.8, 134.0,
154.3, 155.9; m/z (CI): 262 (37Cl, M ϩ 18, 1%), 260 (35Cl,
M ϩ 18, 3), 245 (37Cl, M ϩ 1, 28), 244 (14), 243 (35Cl, M ϩ 1,
100), 207 (12), 124 (12), 123 (11).
νmax (film): 3205, 3036, 2998, 2928, 1688 (br) cmϪ1; H-NMR
1
(300 MHz, CDCl3): δ 2.13 (2H, apparent quintet, J 7, CH2),
3.60 (2H, t, J 6.5, CH2N), 3.69 (2H, t, J 6.5, CH2Cl), 6.91 (1H,
dd, J 6.0, 2.0, H-5), 7.04 (1H, d, J 2.0, H-3), 8.09 (1H, d, J 6.0,
H-6), 9.40 (1H, br t, alkyl NH), 9.72 (1H, s, aromatic NH);
13C-NMR (75 MHz, CDCl3): δ 32.6, 37.0, 42.5, 111.9, 117.3,
145.5, 146.8, 154.3, 156.3; m/z (CI): [252 (9%), 250 (60), 248
(M ϩ 1, 100), characteristic 9 : 6 : 1 structure for 2 × Cl], 214
(25), 212 (10), 129 (10).
N-(3-Chloropropyl)-NЈ-(pyridin-2-yl)urea 9d
1-Phenyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one 10a
To a solution of 2-aminopyridine (1.1 g, 11.65 mmol) in
anhydrous CH2Cl2 (50 ml), under dry N2 was added 3-chloro-
propyl isocyanate (1.8 ml, 17.48 mmol, 1.5 eq.) then the result-
ing solution was stirred for 96 h. Evaporation left a pale yellow
oil which solidified on standing to afford the crude product as a
white powder (2.8 g). Recrystallisation from 40–60 petroleum
ether provided 9d as fine white needles (2.3 g, 93%), mp
57–58 ЊC from 40–60 petroleum ether; Rf 0.60 (2 : 2 : 1; PhMe–
EtOAc–MeOH) (HRMS found: Mϩ, 213.0671. C9H12ClN3O
requires M, 213.06688) (Anal. found: C, 50.6; H, 6.1; N, 19.7%.
C9H12ClN3O requires: C, 50.6; H, 5.7; N, 19.7%); λmax (CHCl3):
248, 284 nm (ε 1640, 1437); νmax (film): 3224–2963, 3081, 2963,
To a stirred solution of urea 9a (4.96 g, 23.39 mmol) in
anhydrous 2-methylpropan-2-ol (50 ml) at 30 ЊC, t-BuOK
(10.48 g, 93.55 mmol, 4.0 eq.) was added, and the resulting
off-white suspension stirred at this temperature whilst being
protected by a CaCl2 drying tube. After 22 h, the pH of the
solution was adjusted to 5 by careful addition of 1 M HCl
(ca. 70 ml). The 2-methylpropan-2-ol was evaporated and the
resulting off-white residue was partitioned between CH2Cl2
(80 ml) and water (20 ml). The aqueous layer was re-extracted
with CH2Cl2 (3 × 10 ml) and the combined organic extracts
were washed with brine (1 × 20 ml), dried and then concen-
trated in vacuo to yield a light yellow oil which solidified on
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021
2017

View Online
standing to reveal an off-white solid (3.32 g). Recrystallisation
from EtOAc afforded 10a as off-white needles (3.18 g, 76%),
that were collected by vacuum filtration, washed with Et2O and
dried; mp 212–214 ЊC from EtOAc, Lit.29 202–203 ЊC; Rf 0.46
(2 : 2 : 1; PhMe–EtOAc–MeOH) (HRMS found: Mϩ, 176.0946.
C10H12N2O requires M, 176.09496) (Anal. found: C, 68.0; H,
7.1; N, 16.0%. C10H12N2O requires: C, 68.2; H, 6.9; N, 15.9%);
λmax (CHCl3): 254 nm (ε 13218); νmax (film): 3220 (br), 3061,
2950, 1654 (br) cmϪ1; 1H-NMR (300 MHz, CDCl3): δ 2.11 (2H,
apparent quintet, J 6, H-5), 3.44 (2H, apparent t, J 6, H-4), 3.72
(2H, apparent t, J 6, H-6), 5.45 (1H, br s, NH), 7.20 (1H, appar-
ent tt, J 7, 2, ArH), 7.35 (4H, m, ArH); 13C-NMR (75 MHz,
CDCl3): δ 22.4, 40.6, 48.7, 125.3, 125.6, 128.7, 143.7, 155.7;
m/z (CI): 194 (M ϩ 18, 5%), 178 (18), 177 (M ϩ 1, 100).
quintet, J 6, H-5), 3.41 (2H, apparent dt, J 2, 6, H-4), 3.64 (2H,
apparent t, J 6, H-6), 3.82 (3H, s, OCH3), 5.77 (1H, br s, NH),
6.90 (2H, d, J 8.9, H-3Ј and H-5Ј), 7.23 (2H, dd, J 7, 2, H-2Ј and
H-6Ј); 13C-NMR (75 MHz, CDCl3): δ 22.4, 40.6, 49.2, 55.4,
114.1, 127.2, 136.7, 156.0, 157.3; m/z (CI): 207 (M ϩ 1, 100%)
(EI) 206 (Mϩ, 27), 136 (100), 120 (35), 92 (15), 77 (20), 49 (27).
1-(Pyridin-2-yl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one 10d
To a stirred solution of urea 9d (2.5 g, 11.74 mmol) in
anhydrous 2-methylpropan-2-ol (100 ml) at 30 ЊC, t-BuOK
(5.3 g, 46.95 mmol, 4.0 eq.) was added, then the solution was
stirred at this temperature and protected from moisture. After
18 h, the pH of the solution was adjusted to 5 by careful add-
ition of 1 M HCl (ca. 40 ml) then the 2-methylpropan-2-ol was
evaporated. The resulting off-white residue was partitioned
between CH2Cl2 (80 ml) and water (20 ml) and the aqueous
layer was extracted with additional CH2Cl2 (3 × 10 ml). The
combined organic extracts were washed with brine (1 × 20 ml),
dried and concentrated in vacuo to reveal a pale yellow oil which
solidified on standing to yield the crude product as an off-white
solid (2.1 g). Recrystallisation from EtOAc afforded 10d as off-
white plates (1.3 g, 63%) which were washed with Et2O, mp
143–144 ЊC from EtOAc; Rf 0.28 (2 : 2 : 1; PhMe–EtOAc–
MeOH; SiO2) (HRMS found: Mϩ, 177.0901. C9H11N3O
requires M, 177.09021) (Anal. found: C, 61.0; H, 6.4; N, 23.7%.
C9H11N3O requires: C, 61.0; H, 6.3; N, 23.7%); λmax (CHCl3):
250, 282 nm (ε 1243, 1029); νmax (film): 3233 (br), 3079, 2965,
1-(3-Methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one
10b
t-BuOK (6.20 g, 55.25 mmol, 4.0 eq.) was added to a stirred
solution of urea 9b (3.40 g, 14.02 mmol) in anhydrous 2-methyl-
propan-2-ol (200 ml) at 30 ЊC, then the resulting white sus-
pension was stirred at this temperature and protected from
moisture. After 16 h, the pH of the solution was adjusted to
5 by careful addition of 1 M HCl (ca. 45 ml), this resulted in
the formation of a white precipitate (probably KCl). The
2-methylpropan-2-ol was evaporated under reduced pressure
and the resulting white residue partitioned between CH2Cl2
(50 ml) and water (10 ml). The aqueous layer was extracted with
CH2Cl2 (3 × 15 ml) and the combined organic extracts washed
with brine (1 × 30 ml) and dried. Filtration, followed by evap-
oration yielded a light brown oil, which solidified on standing
to an off-white solid (2.91 g). Slow recrystallisation of this
material from EtOAc gave 10b as large off-white needles, which
were filtered, washed with Et2O, and dried (2.28 g, 79%), mp
149–150 ЊC from EtOAc; Rf 0.50 (2 : 2 : 1; PhMe–EtOAc–
MeOH; SiO2) (HRMS found: Mϩ, 206.1058. C11H14N2O2
requires M, 206.10552) (Anal. found: C, 63.7; H, 7.0; N, 13.7%.
C11H14N2O2 requires: C, 64.1; H, 6.8; N, 13.6%); λmax (CHCl3):
244, 280 nm (ε 3000, 7475); νmax (film): 3302–3219 (br), 3068,
2950, 1654 (br) cmϪ1; 1H-NMR (300 MHz, CDCl3): δ 2.12 (2H,
apparent quintet, J 6, H-5), 3.45 (2H, apparent dt, J 2, 6, H-4),
3.71 (2H, apparent t, J 6, H-6), 3.83 (3H, s, OCH3), 5.07 (1H, br
s, NH), 6.77 (1H, dd, J 8.4, 2.6, H-4Ј), 6.94 (2H, m, H-2Ј and
H-6Ј), 7.30 (1H, dd, J 8.4, 1.8, H-5Ј); 13C-NMR (75 MHz,
CDCl3): δ 22.4, 40.6, 48.7, 55.2, 111.2, 111.6, 117.8, 129.3,
144.8, 155.5, 159.8; m/z (CI): 207 (M ϩ 1, 100%), (EI) 206 (Mϩ,
51), 136 (100), 92 (15), 77 (20), 49 (27).
1671 (br) cmϪ1 1H-NMR (300 MHz, CDCl3): δ 2.10 (2H,
;
apparent quintet, J 6, H-5), 3.44 (2H, apparent dt, J 2, 6, H-4),
4.03 (2H, t, J 5.9, H-6), 5.39 (1H, br s, NH), 7.00 (1H, dt, J 1.0,
5.0, H-5Ј), 7.65 (1H, dt, J 2.0, 8.0, H-4Ј), 7.93 (1H, d, J 8.0,
H-3Ј), 8.37 (1H, dd, J 5, 1, H-6Ј); 13C-NMR (75 MHz, CDCl3):
δ 22.1, 40.7, 44.6, 118.8, 119.3, 136.6, 147.0, 154.6, 155.5; m/z
(CI): 178 (M ϩ 1, 100%) (EI) 177 (Mϩ, 100), 176 (15), 148 (13),
133 (16), 121 (36), 119 (99), 107 (45), 94 (24), 78 (46).
1-(4-Methoxypyridin-2-yl)-3,4,5,6-tetrahydropyrimidin-2(1H)-
one 10e
To a stirred solution of urea 9e (4.00 g, 16.49 mmol) in
anhydrous 2-methylpropan-2-ol (100 ml) at 30 ЊC, t-BuOK
(7.81 g, 69.57 mmol, 4.2 eq.) was added and then the mixture
was stirred at this temperature whilst protected from moisture,
for 24 h. The pH of the solution was adjusted to 5 by careful
addition of 1 M HCl (ca. 60 ml) then the 2-methylpropan-2-ol
was evaporated leaving an off-white residue which was par-
titioned between CH2Cl2 (80 ml) and water (20 ml). The aque-
ous layer was extracted with CH2Cl2 (3 × 10 ml), the combined
organic extracts were washed with brine (1 × 20 ml), dried and
concentrated in vacuo to reveal a pale yellow oil which solidified
on standing to yield an off-white solid (1.69 g). Recrystallis-
ation of this material from EtOAc afforded 10e as white
plates (1.35 g, 40%) that were washed with Et2O, mp 105–
106 ЊC from EtOAc; Rf 0.29 (2 : 2 : 1; PhMe–EtOAc–MeOH)
(HRMS found: Mϩ, 207.1005. C10H13N3O2 requires M,
207.10077) (Anal. found: C, 57.7; H, 6.3; N, 20.2%. C10H13N3O2
requires: C, 58.0; H, 6.3; N, 20.3%); λmax (CHCl3): 256, 280 nm
1-(4-Methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one
10c
To a stirred solution of urea 9c (3.30 g, 13.61 mmol) in
anhydrous 2-methylpropan-2-ol (50 ml) at 30 ЊC, t-BuOK
(6.10 g, 54.43 mmol, 4.0 eq.) was added, and the resulting off-
white suspension stirred at this temperature and protected from
moisture. After 16 h, the pH of the solution was adjusted to 5
by careful addition of 1 M HCl (ca. 45 ml), the 2-methyl-
propan-2-ol was evaporated and the resulting off-white residue
partitioned between CH2Cl2 (80 ml) and water (20 ml), the
aqueous layer was extracted with CH2Cl2 (3 × 10 ml) and the
combined organic extracts washed with brine (1 × 20 ml), dried
and concentrated in vacuo to afford a purple oil which solidified
on standing to yield a grey–brown solid (2.23 g). Recrystallis-
ation from 96% EtOH furnished the title compound as off-
white needles (2.03 g, 72%) which were washed with Et2O, mp
210–211 ЊC from 96% EtOH; Rf 0.40 (2 : 2 : 1; PhMe–EtOAc–
MeOH) (HRMS found: Mϩ, 206.1057. C11H14N2O2 requires M,
206.10552) (Anal. found: C, 64.1; H, 6.9; N, 13.5%. C11H14N2O2
requires: C, 64.1; H, 6.8; N, 13.6%); λmax (CHCl3): 252, 282 nm
(ε 13210, 5712); νmax (film): 3211, 3062, 2938, 1664 (br), 1610
(ε 1663, 1625); νmax (film): 3233 (br), 3252, 2965, 1669 (br) cmϪ1
;
1H-NMR (300 MHz, CDCl3): δ 2.05 (2H, apparent quintet, J 6,
H-5), 3.39 (2H, apparent dt, J 2, 6, H-4), 3.99 (2H, apparent t,
J 6, H-6), 5.90 (1H, br s, NH), 6.56 (1H, dd, J 5.7, 2.4, H-5Ј),
7.50 (1H, d, J 2.4, H-3Ј), 8.14 (1H, d, J 5.7, H-6Ј); 13C-NMR (75
MHz, CDCl3): δ 22.1, 40.6, 44.8, 55.1, 103.7, 107.2, 147.7,
155.5, 156.2, 166.1; m/z (CI): 208 (M ϩ 1, 100%).
1-(4-Chloropyridin-2-yl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one
10f
A 1.0 M solution of t-BuOK in t-BuOH (60.0 ml, 60.0 mmol,
3.5 eq.) was added dropwise to a stirred solution of urea 9f
(4.27 g, 17.22 mmol) in anhydrous 2-methylpropan-2-ol (5.0 ml)
1
(sh) cmϪ1; H-NMR (300 MHz, CDCl3): δ 2.07 (2H, apparent
2018
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021

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at 30 ЊC, then the mixture was stirred at this temperature whilst
protected from moisture, for 24 h. The pH of the solution was
adjusted to 5 by careful addition of 1 M HCl (ca. 45 ml), the
2-methylpropan-2-ol was evaporated and the resulting off-white
residue partitioned between CH2Cl2 (80 ml) and water (20 ml).
The aqueous layer was extracted with CH2Cl2 (3 × 10 ml), the
combined organic extracts were washed with brine (1 × 20 ml),
dried and concentrated in vacuo to reveal a pale yellow oil which
solidified on standing to yield an off-white solid (2.98 g).
Recrystallisation of this material from EtOAc afforded the title
compound as off-white plates (2.26 g, 62%) that were washed
with Et2O, mp 149–150 ЊC; Rf 0.38 (6% MeOH–CH2Cl2 con-
taining a few drops of NEt3) (HRMS found: Mϩ, 211.05116.
C9H10ClN3O requires M, 207.1077) (Anal. found: C, 50.6; H,
4.9; N, 19.5; Cl, 16.6%. C9H10ClN3O requires: C, 51.1; H, 4.8;
N, 19.9; Cl, 16.8%); λmax (CHCl3): 246, 280 nm (ε 1136, 511);
with argon and anhydrous THF (5.0 ml) was added. The
mixture was stirred at Ϫ78 ЊC and n-BuLi (1.56 M, 1.94 ml,
3.03 mmol, 2.5 eq.) was added dropwise (over 20 min). After
60 min, the solution became yellow and homogeneous in
appearance; it was stirred for a further 7 h at this temperature
then treated with dry iodomethane and the mixture allowed to
warm to room temperature overnight. The resulting homo-
geneous mixture was quenched with saturated aq. NH4Cl
solution (3 ml), the THF was evaporated and the aqueous
solution partitioned between CH2Cl2 (5 ml) and water (2 ml).
The aqueous layer was extracted with CH2Cl2 (3 × 5 ml), the
combined organic extracts were washed with brine (1 × 5 ml),
dried and concentrated in vacuo to afford 12a as an orange
coloured oil (162 mg, 61%); Rf 0.60 (2 : 2 : 1; PhMe–EtOAc–
MeOH) (HRMS found: Mϩ, 220.1209. C12H16N2O2 requires
M, 220.12117); λmax (CHCl3): 248, 280 nm (ε 12128, 4053);
1
νmax (film): 3317, 3240 (br), 3091, 3072, 2940, 1673 (br) cmϪ1
;
νmax (film): 2938, 2866, 1642 (br), 1601 (sh) cmϪ1; H-NMR
1H-NMR (300 MHz, CDCl3): δ 2.05 (2H, apparent quintet, J 6,
H-5), 3.40 (2H, apparent dt, J 2, 6, H-4), 3.97 (2H, apparent t,
J 6, H-6), 6.33 (1H, br s, NH), 6.97 (1H, dd, J 5.4, 1.8, H-5Ј),
8.06 (1H, d, J 1.8, H-3Ј), 8.21 (1H, d, J 5.4, H-6Ј); 13C-NMR
(75 MHz, CDCl3): δ 22.0, 40.5, 44.6, 118.8, 119.0, 143.9, 147.5,
155.3, 155.4; m/z (CI): 214 (37Cl, M ϩ 1, 31%), 212 (35Cl,
M ϩ 1, 100).
(300 MHz, CDCl3): δ 2.14 (2H, apparent quintet, J 6, H-5), 3.02
(3H, s, NCH3), 3.40 (2H, apparent t, J 6, H-4), 3.71 (2H, appar-
ent t, J 6, H-6), 3.82 (3H, s, OCH3), 6.73 (1H, dd, J 8.0, 1.0,
H-4Ј), 6.87 (1H, apparent d, J 8, H-6Ј), 6.89 (1H, apparent s,
H-2Ј), 7.24 (1H, t, J 8.0, H-5Ј); 13C-NMR (75 MHz, CDCl3):
δ 22.6, 35.6, 48.0, 48.7, 55.2, 110.9, 111.4, 117.6, 129.0, 145.4,
155.3, 159.7; m/z (CI): 221 (M ϩ 1, 100%).
1-(2-Methyl-3-methoxyphenyl)-3-methyl-3,4,5,6-tetrahydro-
pyrimidin-2(1H)-one 12b
3,4-Dihydro-1-(3-methoxyphenyl)-4-(2,2-dimethylethyl)-
pyrimidin-2(1H)-one 11
Following a procedure similar to that described above, tetra-
hydropyrimidin-2(1H)-one 10b (250 mg, 1.21 mmol) was
treated with n-BuLi (1.56 M, 1.95 ml, 3.03 mmol, 2.5 eq.)
initally at Ϫ78 ЊC and then at 0 ЊC for 2 h, and the solution
treated with iodomethane at Ϫ78 ЊC giving 12b as a pale yellow
oil (284 mg, 92%); Rf 0.65 (2 : 2 : 1; PhMe–EtOAc–MeOH)
(HRMS found: Mϩ, 234.1366. C13H18N2O2 requires M,
234.13682); λmax (CHCl3): 242, 274 nm (ε 7214, 4878); νmax
To a suspension of dried 1-(3-methoxyphenyl)-3,4,5,6-tetra-
hydropyrimidin-2(1H)-one 10b (314 mg, 1.56 mmol, 1.0 eq.)
in anhydrous THF (6.0 ml) at Ϫ78 ЊC, t-BuLi (1.3 M, 1.2 ml,
1.56 mmol, 1.0 eq.) was added (dropwise), under a dry argon
atmosphere (all glassware was flame-dried prior to use). The
resulting solution was stirred at Ϫ78 ЊC for 60 min; during
this time the 1-(3-methoxyphenyl)pyrimidin-2(1H)-one went
into solution and an orange–red colour developed. Addition
of (pre-distilled) pivalaldehyde (0.17 ml, 1.56 mmol, 1.0 eq.)
caused the coloration to dissipate, suggesting that an anion had
been trapped. The mixture was stirred for a further 60 min at
Ϫ78 ЊC, before it was allowed to warm gradually to room tem-
perature overnight. Following this, the mixture was quenched
with saturated aq. NH4Cl (ca. 3 ml) to remove any unreacted
t-BuLi, water (5 ml) was added and the resulting aqueous solu-
tion extracted with CH2Cl2 (3 × 10 ml). The combined organic
extracts were dried and concentrated in vacuo to reveal an off-
(film): 2931, 2857, 1639 (br) cmϪ1 1H-NMR (300 MHz,
;
CDCl3): δ 2.06–2.24 (5H, br s, CH2 and ArCH3), 3.02 (3H, s,
NCH3), 3.39–3.49 (3H, m), 3.56–3.65 (1H, m), 3.84 (3H, s,
OCH3), 6.79 (1H, apparent d, J 8, H-4Ј), 6.83 (1H, apparent d,
J 8, H-6Ј), 7.17 (1H, t, J 8.1, H-5Ј); 13C-NMR (75 MHz,
CDCl3): δ 10.7, 22.7, 35.5, 48.0, 49.1, 55.6, 108.7, 120.0, 125.0,
126.4, 143.7, 158.3; m/z (CI): 235 (M ϩ 1, 100%).
1-(2-Trimethylsilyl-3-methoxyphenyl)-3,4,5,6-tetrahydro-
pyrimidin-2(1H)-one 12c
1
white solid (300 mg), which was found by H-NMR and TLC
analyses to be of approximate composition 4 : 1, C-4 addi-
tion product 11 to unreacted starting material. Flash column
chromatography on silica eluting with CH2Cl2 up to 5%
MeOH–CH2Cl2, gave the addition product as off-white plates
(228 mg); Rf 0.65 (6% MeOH–CH2Cl2; SiO2) (HRMS found:
Mϩ, 261.1607. C15H20N2O2 requires M, 261.1603); νmax (film):
Following a similar procedure to that described above,
tetrahydropyrimidin-2(1H)-one 10b (250 mg, 1.21 mmol) was
treated with n-BuLi (1.56 M, 1.95 ml, 3.03 mmol, 2.5 eq.)
initially at 0 ЊC and then at 0 ЊC for 2 h, and the resulting lithio-
derivative reacted with trimethylsilyl chloride (0.38 ml, 3.03
mmol, 2.5 eq.) at Ϫ78 ЊC giving an off-white solid (303 mg).
Recrystallisation from EtOAc afforded 12c as bright white
plates (230 mg, 68%, from two crops), mp 177–178 ЊC
from EtOAc; Rf 0.36 (2 : 2 : 1; PhMe–EtOAc–MeOH) (HRMS
found: M ϩ 1, 279.1525. C14H22N2O2Si requires M ϩ 1,
279.1529) (Anal. found: C, 60.2; H, 8.2; N, 9.7%. C14H22N2O2Si
requires: C, 60.4; H, 8.0; N, 10.1%); λmax (CHCl3): 248, 282 nm
(ε 9328, 14561); νmax (film): 3224 (br), 3062, 2941, 1659 (br)
cmϪ1; 1H-NMR (300 MHz, CDCl3): δ 0.00 (9H, s, Me3Si), 1.65–
1.90 (2H, m, CH2), 3.07–3.21 (3H, m), 3.24–3.33 (1H, m), 3.49
(3H, s, OCH3), 4.79 (1H, br s, NH), 6.47 (2H, d, J 8.0, H-4Ј and
H-6Ј), 7.04 (1H, t, J 8.0, H-5Ј); 13C-NMR (75 MHz, CDCl3):
δ 0.7, 22.1, 40.4, 50.2, 55.2, 108.8, 120.7, 127.1, 131.3, 149.5,
156.1, 165.1; m/z (CI): [281 (5%), 280 (22), 279 (100), M ϩ 1,
30Si, 29Si and 28Si respectively], 207 (15).
3246 (br), 3106, 2959, 2868, 2836, 1690 (br), 1602 cmϪ1
;
1H-NMR (300 MHz, CDCl3): δ3.80 (1H, br d, J 4.1, H-4), 3.84
(3H, s, OCH3), 4.81 (1H, br s, NH), 4.95 (1H, complex m, dd,
J 8.1, 4.1 after shaking with D2O, H-5), 6.34 (1H, d, J 8.1, H-6),
6.83 (1H, br d, J 8.5, H-4Ј), 6.88 (1H, br s, H-2Ј), 6.90 (1H,
br d, J 8.5, H-6Ј), 7.30 (1H, m, H-5Ј); 13C-NMR (75 MHz,
d6-DMSO): δ 24.7, 36.5, 55.3, 62.0, 100.3, 112.0, 112.3, 118.3,
129.5, 129.9, 141.7, 153.2, 159.9; m/z (CI): 278 (M ϩ 18, 4%),
262 (15), 261 (M ϩ 1, 100), 259 (6), 203 (5).
1-(3-Methoxyphenyl)-3-methyl-3,4,5,6-tetrahydropyrimidin-
2(1H)-one 12a
Tetrahydropyrimidin-2(1H)-one 10b (250 mg, 1.21 mmol) was
added to a 25 ml 3-necked round-bottomed flask equipped with
a magnetic stirring bar, septum, stopper and a rota-flow®
valve. The flask and its contents were placed under vacuum and
the tetrahydropyrimidinone was carefully heated until molten,
the flask was then flame-dried. Once cool, the flask was flushed
1-[2-(1-Hydroxy-2,2-dimethylpropyl)-3-methoxyphenyl]-3,4,5,6-
tetrahydropyrimidin-2(1H)-one 12d
Using the typical procedure (above), 1-(3-methoxyphenyl)-
J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021
2019

View Online
3,4,5,6-tetrahydropyrimidin-2(1H)-one 10b (500 mg, 2.42
mmol) was lithiated with n-BuLi (1.56 M, 3.88 ml, 6.07 mmol,
2.5 eq.) at 0 ЊC and then at 0 ЊC for 2 h, and reacted at Ϫ78 ЊC
with pivalaldehyde giving a white powder (481 mg), which was
recrystallised from EtOAc, affording the title compound as
opaque plates (400 mg, 56%, from two crops), mp 205–206 ЊC
from EtOAc; Rf 0.29 (2 : 2 : 1; PhMe–EtOAc–MeOH) (HRMS
found: Mϩ, 292.1796. C16H24N2O3 requires M, 292.17868)
(Anal. found: C, 65.3; H, 8.4; N, 9.6%. C16H24N2O3 requires: C,
65.7; H, 8.3; N, 9.6%); λmax (CHCl3) 250, 280 nm (ε 11153,
15246); νmax (film): 3548 (br), 3312–3237 (br), 2950, 2904, 2867,
1H-NMR (300 MHz, CDCl3): δ 2.12 (2H, CH2), 3.02 (3H, s,
NCH3), 3.39 (2H, m), 3.70 (2H, m), 7.11–7.21 (2H, m, ArH),
7.23–7.36 (3H, m, ArH); 13C-NMR (75 MHz, CDCl3): δ 22.6,
35.6, 48.0, 48.6, 124.8, 125.3, 128.4, 135.9, 144.3; m/z (CI): 191
(M ϩ 1, 100%).
1-(4-Methoxy-2-trimethylsilylphenyl)-3,4,5,6-tetrahydro-
pyrimidin-2(1H)-one 12g
Following the method described above, tetrahydropyrimidin-
2(1H)-one 10c (298 mg, 1.45 mmol) was treated with n-BuLi
(1.6 M, 2.26 ml, 3.62 mmol, 2.5 eq.) at Ϫ78 ЊC and after bring-
ing to 0 ЊC for 2 h, reacted at Ϫ78 ЊC with trimethylsilyl chlor-
ide (0.46 ml, 3.62 mmol, 2.5 eq.) causing the orange colour to
dissipate after 20 min. The solution was allowed to warm to
room temperature overnight, saturated aq. NH4Cl solution
(3 ml) added, THF was evaporated and the resulting aq. mix-
ture partitioned between CH2Cl2 (10 ml) and water (5 ml). The
aqueous layer was extracted with CH2Cl2 (3 × 10 ml), the com-
bined organic extracts were shaken with brine (10 ml), dried
and concentrated in vacuo to leave the crude product as a light
brown solid (248 mg). Attempted purification by flash silica
column chromatography failed. Separation by reversed phase
preparative HPLC on silica gel (eluting with 80 : 20 MeOH–
H2O at a flow rate of 15 ml minϪ1) gave unreacted starting
material(HPLCyield:51%), then1-(4-methoxy-2-trimethylsilyl-
phenyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one 12g as a glassy
solid (4.7 mg, HPLC yield: 23%) (HRMS found: M ϩ 1,
1
1664 (br) cmϪ1; H-NMR (300 MHz, CDCl3): δ 1.89 (9H, s,
(CH3)3C), 2.00–2.07 (1H, m), 2.11–2.20 (1H, m), 3.44–3.53 (3H,
m), 3.57–3.64 (1H, m), 3.87 (3H, s, OCH3), 4.29 (1H, d, J 11.8,
OH), 4.49 (1H, d, J 11.8, CH), 5.10 (1H, br s), 6.89 (1H, d,
J 8.0, H-4Ј), 6.96 (1H, d, J 8.0, H-6Ј), 7.28 (1H, apparent t, J 8,
H-5Ј); 13C-NMR (75 MHz, CDCl3): δ 22.4, 27.0, 37.8, 40.8,
50.3, 55.1, 79.2, 110.1, 122.7, 126.7, 128.3, 128.4, 143.4, 156.3,
158.7; m/z (CI): 310 (M ϩ 18, 1%), 293 (M ϩ 1, 100), 276 (15),
275 (94), 235 (10), 207 (20).
1-(2-Benzoyl-3-methoxyphenyl)-3-benzoyl-3,4,5,6-tetrahydro-
pyrimidin-2(1H)-one 12e
Following the usual procedure tetrahydropyrimidin-2(1H)-one
10a (250 mg, 1.21 mmol) was lithiated with n-BuLi (1.6 M, 1.89
ml, 3.03 mmol, 2.5 eq.) at 0 ЊC, and the resulting species reacted
at Ϫ98 ЊC with benzoyl chloride (0.35 ml, 3.03 mmol, 2.5 eq.),
work up giving an orange semi-solid (728 mg), which was found
to contain three closely running components by TLC (2 : 2 : 1;
PhMe–EtOAc–MeOH; SiO2). Repeated flash column chrom-
atography on silica gel (eluting with CH2Cl2 up to 5% MeOH–
CH2Cl2) afforded 12e as white plates (67 mg, 13%), mp
161–162 ЊC from EtOAc; Rf 0.71 (2 : 2 : 1; PhMe–EtOAc–
MeOH) (HRMS found: Mϩ, 414.1573. C25H22N2O4 requires M,
414.15795) (Anal. found: C, 64.0; H, 4.4; N, 5.8%. C25H22-
N2O4ؒ3H2O requires: C, 64.1; H, 6.0; N, 6.0%); λmax (CHCl3):
1
279.1532. C14H22N2O2Si requires M ϩ 1, 279.1529); H-NMR
(300 MHz, CDCl3): δ 0.00 (9H, s, Me3Si), 1.68–1.75 (1H, m),
1.81–1.95 (1H, m), 3.12–3.19 (3H, m), 3.24–3.32 (1H, m), 3.50
(3H, s, OCH3), 4.71 (1H, br s, NH), 6.60 (1H, dd, J 9, 3, H-5Ј),
6.76 (1H, d, J 3, H-3Ј), 6.81 (1H, d, J 9, H-6Ј); 13C-NMR (75
MHz, CDCl3): δ Ϫ0.4, 22.3, 40.9, 50.4, 55.3, 115.2, 121.2, 129.1,
140.5, 141.3, 149.5, 156.8, 157.9; m/z (CI): [281 (5%), 280 (20),
279 (100), M ϩ 1, 30Si, 29Si and 28Si, respectively]. Finally 1-(3-
trimethylsilyl-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-
2(1H)-one 12h (HPLC yield: 26%) was eluted contaminated
with the 2-isomer 12g.
248 nm (ε 13307); νmax (film): 3064, 2965, 2893, 1677 (br) cmϪ1
;
1H-NMR (300 MHz, CDCl3): δ 2.15 (2H, m), 3.68 (3H, s,
OCH3), 3.75 (2H, br s, H-4), 3.86 (2H, br s, H-6), 6.93 (2H,
apparent dd, J 8, 2, ArH), 7.00 (2H, apparent t, J 8, ArH), 7.11
(2H, d, J 8.2, ArH), 7.23–7.29 (1H, m, ArH), 7.40–7.52 (3H,
m, ArH), 7.60–7.68 (1H, m, ArH), 7.86 (2H, d, J 8.2, ArH);
13C-NMR (75 MHz, CDCl3): δ 22.3, 43.1, 50.8, 110.5, 120.7,
127.3, 127.4, 128.3, 128.4, 129.5, 130.0, 131.1, 133.3, 136.6,
137.3, 141.0, 152.8, 157.6, 173.0, 195.7; m/z (CI): 432 (M ϩ 18,
3%), 415 (M ϩ 1, 100), 105 (18).
1-(4-Methoxypyridin-2-yl)-3-methyl-3,4,5,6-tetrahydro-
pyrimidin-2(1H)-one 13a
Following the usual drying procedure described above, a stirred
solution of tetrahydropyrimidin-2(1H)-one 10e (200 mg, 0.97
mmol) in anhydrous THF (5 ml), was treated with n-BuLi
(1.6 M, 0.72 ml, 1.16 mmol, 1.2 eq. -dropwise) at Ϫ78 ЊC under
an atmosphere of dry N2. The resulting mixture was stirred for
60 min, where it became yellow in colour, and anhydrous
iodomethane (72 µl, 1.16 mmol, 1.2 eq.) was added dropwise.
Stirring was continued at Ϫ78 ЊC for 60 min, the reaction mix-
ture was then warmed to rt over 3 h. The mixture was quenched
with sat. aq. NH4Cl (3 ml), the THF was evaporated and the
resulting aqueous suspension partitioned between CH2Cl2 (10
ml) and water (2 ml). The aqueous layer was extracted with
CH2Cl20 (3 × 5 ml), the combined organic extracts were shaken
with brine (10 ml), dried and concentrated in vacuo to afford
13a as a yellow coloured oil (178 mg, 83%), no further purifi-
cation was necessary; Rf 0.38 (2 : 2 : 1; PhMe–EtOAc–MeOH)
(HRMS found: Mϩ, 221.1165. C11H15N3O2 requires M,
1-Phenyl-3-methyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one 12f
Following the usual drying procedure tetrahydropyrimidin-
2(1H)-one 10a (250 mg, 1.42 mmol) was treated with n-BuLi
(1.23 M, 2.88 ml, 3.55 mmol, 2.5 eq.) at Ϫ78 ЊC and the result-
ing pale yellow mixture warmed to 0 ЊC where it was stirred for
a period of 2 h. Over this time a yellow colour developed, how-
ever the mixture did not become homogeneous. Cooling to
Ϫ78 ЊC, followed by the dropwise addition of dry iodomethane
(0.22 ml, 3.55 mmol, 2.5 eq.) caused the yellow colour to fade
(over 5 min) and the mixture was slowly warmed to room tem-
perature overnight. The reaction mixture was quenched with
sat. aq. NH4Cl (2 ml), the THF was evaporated, and the aque-
ous mixture partitioned between CH2Cl2 (10 ml) and water
(3 ml). The aqueous layer was re-extracted with CH2Cl2 (3 × 5
ml), the combined organic extracts were shaken with brine (10
ml), dried and concentrated in vacuo to yield the crude product
as an orange coloured semi-solid (268 mg). Extensive chrom-
atography, eluting with CH2Cl2 up to 1% MeOH–CH2Cl2 gave
the major component 12f as a colourless oil (187 mg, 69%),
Lit.30 72 ЊC; Rf 0.49 (6% MeOH–CH2Cl2) (HRMS found: Mϩ,
190.1107. C11H14N2O requires M, 190.11061); λmax (CHCl3):
1
221.11642); νmax (film): 2936, 2872, 1652 (br) cmϪ1; H-NMR
(300 MHz, CDCl3): δ 2.08 (2H, apparent quintet, J 6, H-5), 3.03
(3H, s, NCH3), 3.38 (2H, apparent t, J 6, H-4), 3.84 (3H, s,
OCH3), 3.99 (2H apparent t, J 6, H-6), 6.54 (1H, dd, J 5.8, 2.0,
H-5Ј), 7.47 (1H, d, J 2.0, H-3Ј), 8.10 (1H, d, J 5.8, H-6Ј); 13C-
NMR (75 MHz, CDCl3): δ 22.4, 35.8, 45.1, 48.2, 55.3, 102.9,
107.5, 146.7, 155.1, 156.4, 166.4; m/z (CI): 222 (M ϩ 1, 100%).
1-(3-Methyl-4-methoxypyridin-2-yl)-3-methyl-3,4,5,6-
tetrahydropyrimidin-2(1H)-one 13b
246 nm (ε 12602); νmax (film): 2935, 2861, 1643 (br) cmϪ1
;
Following the usual drying procedure, a stirred solution of
2020 J. Chem. Soc., Perkin Trans. 1, 2001, 2012–2021

View Online
tetrahydropyrimidin-2(1H)-one 10e (101 mg, 0.49 mmol) in
anhydrous THF (3 ml), was treated with n-BuLi (1.12 M, 1.1
ml, 1.22 mmol, 2.5 eq., dropwise) at Ϫ78 ЊC under an atmos-
phere of dry N2. The resulting mixture was stirred for 25 min,
then warmed to Ϫ40 ЊC, where it gradually became dark orange
in colour. After a period of 2 h, the mixture was cooled to
Ϫ78 ЊC and anhydrous iodomethane (76 µl, 1.22 mmol, 2.5 eq.)
was added dropwise. Stirring was continued at Ϫ78 ЊC for 2 h,
the reaction mixture was then warmed to room temperature
overnight. The mixture was quenched with sat. aq. NH4Cl
(3 ml), the THF was evaporated and the resulting aqueous sus-
pension partitioned between CH2Cl2 (10 ml) and water (2 ml).
The aqueous layer was re-extracted with CH2Cl2 (3 × 5 ml), the
combined organic extracts were shaken with brine (10 ml),
dried and concentrated in vacuo to afford an orange semi-solid
(134 mg). Careful resolution by flash column chromatography
on silica gel (eluting with CH2Cl2 up to 5% MeOH–CH2Cl2)
afforded 13b as a yellow oil (20 mg, 16%); Rf 0.38 (2 : 2 : 1;
PhMe–EtOAc–MeOH) (HRMS found: Mϩ, 235.1323.
C12H17N3O2 requires M, 235.13207); νmax (film): 2928, 2873,
unreacted: 1-(4-methoxypyridin-2-yl)-3,4,5,6-tetrahydropyrim-
idin-2(1H)-one 10e (20 mg); 13c as a pale yellow coloured oil
(40 mg, 37%); Rf 0.08 (HRMS found: Mϩ, 221.1167.
C11H15N3O2 requires M, 221.11642); νmax (film): 3439 (br), 2936,
2872, 1657 (br) cmϪ1; 1H-NMR (300 MHz, CDCl3): δ 1.81 (5H,
m, CH2 and py-CH3), 3.08–3.18 (2H, m, H-4), 3.57 (3H, s,
OCH3), 3.62–3.72 (2H, m), 4.85 (1H, br s, NH), 6.40 (1H, d,
J 5.6, H-5Ј), 7.94 (1H, d, J 5.6, H-6Ј); 13C-NMR (75 MHz,
CDCl3): δ 10.6, 22.4, 40.8, 46.8, 55.7, 104.9, 120.0, 147.3, 150.8,
154.8, 165.3; m/z (CI): 222 (M ϩ 1, 100%).
References
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1647 (br) cmϪ1; H-NMR (300 MHz, CDCl3): δ 2.13 (3H, s,
py-CH3), 2.18–2.22 (2H, m, CH2), 3.02 (3H, s, NCH3), 3.38–
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Following the usual drying procedure, a stirred solution of
tetrahydropyrimidin-2(1H)-one (10e) (101 mg, 0.49 mmol) in
anhydrous THF (3 ml), was treated with n-BuLi (1.12 M, 0.44
ml, 0.49 mmol, 1.0 eq.) dropwise at Ϫ78 ЊC under an atmos-
phere of dry N2. The resulting mixture was stirred for 35 min,
where it became yellow in colour, and anhydrous trimethylsilyl
chloride (62 µl, 0.49 mmol, 1.0 eq.) was added dropwise.
Stirring was continued at Ϫ78 ЊC for 30 min, the reaction mix-
ture was then warmed to rt over 60 min. A white suspen-
sion formed which was cooled back to Ϫ78 ЊC and treated
with n-BuLi (1.12 M, 0.44 ml, 0.49 mmol, 1.0 eq., dropwise).
After stirring for 30 min the suspension was allowed to
warm (slowly) to Ϫ16 ЊC, where it became homogeneous
and yellow in colour, then finally to 0 ЊC where it was stirred
for 2 h. After this period, the resulting dark yellow solution was
cooled to Ϫ78 ЊC, anhydrous iodomethane (30 µl, 0.49 mmol,
1.0 eq.) was added dropwise and the mixture allowed to
warm to room temperature overnight. The reaction mixture
was quenched with sat. aq. NH4Cl(aq) (3 ml), the THF was
evaporated and the resulting aqueous suspension partitioned
between CH2Cl2 (10 ml) and water (2 ml). The aqueous
layer was extracted with CH2Cl2 (3 × 5 ml), the combined
organic extracts were shaken with brine (10 ml), dried and
concentrated in vacuo to yield the crude product as a dark
brown foam (106 mg). TLC analysis showed this to be a
complex mixture containing at least four components. The
mixture was resolved by flash column chromatography on
silica gel (eluting with CH2Cl2 up to 4% MeOH–CH2Cl2
containing a few drops of NEt3). In order of elution, the follow-
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methyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (13a) (16 mg);
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