The synthesis of C2-symmetric and axially chiral compounds for recognition and catalysis

Article abstract of DOI:10.1016/S0040-4020(00)00803-6

Axially chiral amidines and guanidines, some possessing C₂-symmetry, have been targeted as potential chiral catalysts for reactions of α,β-unsaturated carboxylic acids or esters. The key step in each synthesis required the coupling of two sterically demanding aromatic compounds to form atropisomeric biaryl species. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00803-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8735±8746
The Synthesis of C2-Symmetric and Axially Chiral Compounds for
Recognition and Catalysis
*
John Clews, Anthony D. M. Curtis and Hugh Malkin
School of Chemistry and Physics, Lennard-Jones Laboratories, Keele University, Keele, Staffordshire ST5 5BG, UK
Received 23 June 2000; revised 18 August 2000; accepted 30 August 2000
AbstractÐAxially chiral amidines and guanidines, some possessing C2-symmetry, have been targeted as potential chiral catalysts for
reactions of a,b-unsaturated carboxylic acids or esters. The key step in each synthesis required the coupling of two sterically demanding
aromatic compounds to form atropisomeric biaryl species. q 2000 Elsevier Science Ltd. All rights reserved.
Guanidines and amidines have been used widely as recogni-
tion elements for anionic substrates; they remain protonated
over a wide pH range and form organised hydrogen bonded
complexes. In particular, the symmetrical heterocyclic core
(1) forms the basis of many compounds designed to recog-
nise carboxylate, phosphate and nitronate functionalities.
Mendoza et al employed a guanidinium moiety in the design
of a compound for the ef®cient resolution of l-tryptophan
and l-phenylalanine,1,2 and in a catalyst designed to induce
chirality in the Michael reactions of a,b-unsaturated esters.3
Davis et al employed a bicyclic amidinium in the recog-
nition of nitronate species in pursuit of a system for the
induction of chirality in the Henry reaction;4 this was
subsequently realised by Najera et al. using an acyclic
guanidinium species.5 Axially chiral biaryl amidinium
species have been investigated previously.6
the axially chiral targets using a biaryl coupling required an
aromatic residue. However, the steric bulk of the blocking
group in the target molecules must not hinder the approach
of the guest a,b-unsaturated substrate, nor must it prevent
the substrate from being able to access and associate with
the binding site on the host amidine or guanidine. Essen-
tially, the incoming substrate must be able to `see' the
binding site. The ability of the target molecules to accom-
modate a,b-unsaturated substrates and, hence, induce
asymmetry in reactions of the substrates was assessed
using very simple molecular modelling techniques.7
A
rigid tricyclic amidine or guanidine moiety was chosen to
serve as the recognition site for two series of compounds
possessing axial chirality. Atropisomers can exist for all the
target compounds due to restricted rotation around the biaryl
C±C bond. However, different conformations can be
envisaged for each atropisomer of most of the target hosts
and this became important in our later investigations.
The aim of this current work was to design a compound that
would recognise and bind speci®cally an a,b-unsaturated
substrate, either an oxoanion or a neutral species, and
behave as a temporary, catalytic chiral auxiliary. The axial
chirality of the compound must enable attack on an
a,b-unsaturated substrate from one face only, attack from
the other face being hindered by a large blocking group
(Fig. 1).
Conformation A of the atropisomer of C2-symmetric
compound (2) was energetically favoured over conforma-
tion B. The tricyclic moiety of conformation A and the
methyl group of conformation B provide facial selectivity
in each case. In both cases, the recognition site is accessible
(Figs. 2 and 3). The C2-symmetric bis(amidine) (3) gave
similar results, the favoured conformation having a dihedral
angle of 478.
The blocking group must be of a size suf®cient to effect
good facial selectivity; our chosen strategy of assembling
Keywords: guanidines; amidines; molecular recognition; axial chirality.
* Corresponding author. Tel.: 144-1782-583040; fax: 144-1782-712378;
e-mail: a.d.m.curtis@chem.keele.ac.uk
Figure 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00803-6

8736
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
Figure 2.
The corresponding diprotonated bis(guanidine) (4) and
bis(amidine) (5) were examined, as these species would
actually bind oxoanion substrates. Protonation of either
compound (2) or (3) increases the dihedral angle between
the two tricyclic moieties to 1248 for (4) and 1358 for (5),
presumably through mutual repulsion of the protonated
basic centres. The favoured atropisomeric conformations
of compounds (4) and (5) still have recognition sites that
are blocked from one face.
A naphthyl moiety was chosen as the directing group in a
series of axially chiral compounds. The naphthyl group
provides effective facial discrimination in the favoured
atropisomeric conformations of guanidine (6) (dihedral
angle 688) and amidine (7) (dihedral angle 628). Modelling
also con®rmed that the rotational mobility about the biaryl
axes of guanidine (8) (dihedral angle 1078) and amidine (9)
(dihedral angle 1038) is extremely restricted by the addition
of a second ortho methyl substituent.
Figure 3.
The dihedral angles of the preferred atropisomeric confor-
mations of protonated compounds (10) (dihedral angle 618),
(11) (dihedral angle 688), (12) (dihedral angle 1038) and (13)
(dihedral angle 1058) are virtually unchanged from their
nonprotonated counterparts.

J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
8737
Scheme 1. (a) Br2, AcOH. (b) I2 AcOH. (c) 20% COCl2 in toluene, 608C. (d) (19), DMF, 1008C, N2. (e) (Me3Sn)2, Pd(PPh3)2Cl2, THF, 808C, N2.
methylbenzoic acid (14) afforded 2-amino-3-bromo-5-
methylbenzoic acid (15) exclusively. Similarly, iodination
of compound (14) yielded iodide (16). Treatment of
bromide (15) or iodide (16) with phosgene (as a solution
in toluene) afforded isatoic anhydrides (17) and (18),
respectively, in quantitative yield. Condensation of
anhydrides (17) and (18) with 2-methylthio-1,4,5,6-tetra-
hydropyrimidine (19) delivered the desired tricyclic
compounds (20) and (21) in 44% and 65% yield, respec-
tively. Bromide (20) was subsequently reacted with hexa-
methylditin to give stannane (22). The above route to
pyrimido[2,1-b]quinazoline derivatives was adopted in
favour of the direct fusion of 2-methylthio-1,4,5,6-tetra-
hydropyrimidine (19) with anthranilic acids (15) and (16)
as the latter process gave unsatisfactory yields with these
substrates.
The modelling has demonstrated that a tricyclic amidine/
guanidine based skeleton can support a facial directing
group without sterically hindering the binding site. These
positive results encouraged the synthesis of the proposed
compounds.
The ®rst series of compounds investigated possess C2-
symmetry. We envisaged that a convergent strategy could
be employed, using a common building block to give both
partners for a biaryl bond forming reaction. The synthesis of
pyrimido[2,1-b]quinazoline derivatives was achieved in
good yield (Scheme 1). Thus, bromination of 2-amino-5-
The synthesis of C2-symmetric compound (3) via a biaryl
bond forming reaction was investigated using Stille, Suzuki
and Ullmann protocols. Only the reaction of bromide (20)
with stannane (22) using Stille methodology delivered
compound (3), albeit in very low (3%) yield (Scheme 2).
The palladium catalysed coupling reaction was attempted
Scheme 2.

8738
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
Scheme 3. (a) PhI, Pd(PPh3)4, 1,4-dioxane, re¯ux, 48 h. (b) PhB(OH)2, Pd(PPh3)2Cl2, 1,4-dioxane, Na2CO3 (aq), re¯ux, 24 h.
many times using different catalysts and conditions, but the
majority of experiments yielded the reduced compound (23)
(previously prepared using an alternative procedure8) in
high yield, together with recovered bromide (20).
Quantitative methylation of bromide (20) gave the protected
building block (25) (Scheme 4). Subsequent reaction of
compound (25) with hexamethylditin delivered stannane
(26) in 47% (based on recovered starting material); no
coupled product was detected in the product mixture.
Stannane (26) was reacted with iodobenzene using
palladium catalysis to yield the coupled product (27) in
25% yield, though the major product was again reduced
starting material (28) (prepared for reference by methylation
of compound (23)). However, reaction of methylated
bromide (25) with stannane (26) under analogous conditions
did not yield the desired C2-symmetric compound (29), the
compounds isolated from the reaction being recovered
bromide (25) and reduced material (28).
Stannane (22) was reacted with iodobenzene using similar
conditions to yield coupled product (24) in 25% yield, and
with phenylboronic acid to give (24) in 31% yield (Scheme
3).
Many examples of Stille couplings of sterically demanding
substrates are cited in the literature.9,10,11,12 We considered
possible reasons (other than steric hindrance) for the
repeated isolation of reduced material from the cross-
coupling reactions. The metallated intermediate can only
be acquiring a proton from the solvent, atmosphere or
from the starting materials themselves. Rigorous pre-
cautions were always taken to ensure that anhydrous
conditions were employed under an inert atmosphere. We
decided subsequently to protect the secondary amine func-
tion in bromide (20) to remove the acidic proton from the
starting material. There is precedent for this manoeuvre in
the work of Stille et al.13 Our main concern was not ease of
cleavage of the protecting group: rather, we required a group
that would not increase the steric constraints of the reaction
too greatly. After establishing that the cross-coupling
reaction was viable, alternative protecting groups could be
examined.
Suzuki methodology was also employed but with a similar
Scheme 4. (a) NaH, THF, Mel. (b) (Me3Sn)2, Pd(PPh3)4, 1,4-dioxane, 1208C, 4 h. (c) Phl, Pd(PPh3)4, 1,4-dioxane, re¯ux, 3 h.

J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
8739
Scheme 5. (a) Ac2O, AcOH, re¯ux, 30 min. (b) Fuming HNO3, 08C. (c) Aqueous HBr, re¯ux, 12 h. (d) Aqueous HBr, NaNO2, CuBr, 08C. (e) MeOH, H2SO4,
re¯ux, 14 h.
outcome to the reactions of bromide (25) and stannane (26)
as described above. Isolation of the boronic acid (30) from
reaction of bromide (25) with butyllithium, quenching of the
anion with trimethyl borate and subsequent hydrolysis
proved dif®cult. Homocoupling was attempted using the
method described by Keay et al., by in situ formation of
the boronic acid (30) and subsequent addition of a palladium
catalyst;14 again, the major product isolated was reduced
material (28).
the reaction was not the desired homocoupled compound;
rather, sul®de (33) was isolated in 60% yield. Similar results
have been reported previously by Tamborski and Chen and
by Soulen and Grif®th for the attempted homocoupling of
¯uorinated aryls.15,16
An alternative, divergent strategy was employed for the
synthesis of C2-symmetric compound (34), relying upon
the preparation of biphenyl (35) as the key intermediate.
In an alternative strategy, (20) was reacted with 2-bromo-
nitrobenzene under palladium catalysed Ullmann coupling
conditions. The nitrobenzene derivative was expected to be
an active coupling partner in the Ullmann reaction, deliver-
ing the anticipated product (31) in high yield. However, the
reaction did not deliver the desired biaryl product, instead
giving N-arylated compound (32) in 36% yield, together
with 2,20-dinitrobiphenyl, unreacted bromide (20) and
reduced compound (23).
Synthesis of compound (35) was achieved in six steps from
3-amino-4-methylbenzoic acid (36) (Scheme 5). Acylation
of the acid (36) gave amide (37), nitration of which gave
two regioisomeric compounds in
a 4:1 ratio. The
regioisomers were readily separated by fractional crystal-
lisation, giving the desired compound (38) in 71% yield.
Cleavage of the amide using hydrobromic acid delivered
salt (39). Subsequent diazotisation and Sandmeyer
bromination gave 3-bromo-4-methyl-2-nitrobenzoic acid
(40) in 80% yield. Esteri®cation was necessary as the
Ullmann coupling shows low tolerance to the presence of
free carboxylic acid functions; this was best achieved using
acid catalysis to give methyl ester (41) in 98% yield.
We assume that N-alkylation occurred because of the acidic
proton in bromide (20). A different result was obtained from
the attempted homocoupling of methylated bromide (25) in
DMSO under Ullmann conditions. The major product from

8740
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
Scheme 6. (a) Fe, EtOH, conc. HCl, re¯ux, 12 h. (b) KOH, MeOH, re¯ux 12 h.
Homocoupling of (41) under Ullmann conditions yielded
the desired biphenyl compound (35) in 63% yield. However,
this reaction proved to be rather capricious and varying
amounts of debrominated material (42) were always
isolated in preparations using freshly activated copper
powder, anhydrous reagents and high temperatures.17 This
is in contrast with results obtained by Kanojia et al. in the
coupling of sterically demanding substrates under identical
conditions.18
of a compound with two substituents ortho to the bromide
substituent. Hence, reduction of key biphenyl (35) was not
attempted because of the small amount available. However,
the chemistry outlined above indicates that the divergent
strategy provides a promising route to C2-symmetric target
(34). Not only does this route avoid the coupling of two
sterically demanding tricyclic units but the synthesis of
intermediate biphenyl (35) is achieved without the need to
use expensive catalysts.
After encountering problems in our attempts to prepare
biaryl compounds with C2-symmetry, we directed our
efforts towards the preparation of simpler compounds with
axial chirality. Compound (7) was chosen as the target. No
repulsion between the two basic centres found in
compounds (3) and (34) would be present in the correspond-
ing naphthyl substituted compound (7). Furthermore,
coupling of bromide (20) and the naphthyl moiety should
not present so many problems in terms of steric effects.
The next step after the homocoupling of bromide (41) was
the reduction of the nitro groups in (35) to amines and
saponi®cation of the methyl esters to yield bis(aminoacid)
(43). Compound (43) could then be further elaborated to
give compound (34) using the methodology employed for
the synthesis of bromide (20). Reduction of 2,20-dinitro-
1,10-biphenyl to the corresponding diamine in high yield
has been reported using the conditions of West.19,20 Bromide
(41) was chosen as a model to test our strategy (Scheme 6):
compound (41) was reduced using West conditions to
give amine (44) in 87% yield, subsequent saponi®cation
delivered aminoacid (45) in good yield.
1-Bromo-2-methylnaphthalene (46) was converted into
boronic acid (47) via the Grignard intermediate (Scheme
7).21 Boronic acid (47) was then coupled with the bromide
(20) under optimised Suzuki coupling conditions to give
compound (7) in 27% yield.
Naphthyl substituted compound (7) obviously exists as
enantiomeric atropisomers: 1H NMR nOe experiments
indicated that the preferred conformation of this compound
is as depicted. Although racemisation is possible, there is
much literature precedent suggesting that the energy
required to rotate through the biaryl bond of 2-substituted
1,10-biaryl systems is high enough to make this unfavour-
able and, therefore, pure enantiomers can be stored at room
temperature for long periods of time. In light of these and
other studies, axially chiral compound (7) would not be
prone to racemisation under mild reaction conditions.
Compound (7) was resolved into its enantiomeric forms
by analytical chiral HPLC but attempts to effect a classical
resolution have so far been unsuccessful.
As with the convergent route, it proved dif®cult to homo-
couple the sterically demanding bromide (41); it should be
noted that the present strategy relies upon the homocoupling
Protonated axially chiral compound (11) proved to be a
Scheme 7. (a) Mg, THF, heat 1 h; B(OMe)3, RT, 2 h; aqueous HCl, RT 4 h. (b) (20), Pd(PPh3)2Cl2, 1,4-dioxane, 2 M aqueous ethanolic Ba(OH)2, re¯ux, 24 h,
Ar.

J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
8741
suitable system for the recognition of anionic substrates
(association constant K for sodium acetate in CDCl3 is
solid, mp 2058C (lit22 2078C); (Found: C, 41.47; H, 3.21;
N, 5.87. C8H9BrNO2 requires C, 41.74; H, 3.48; N, 6.09%);
1
8.9£102 M21, measured by analysis of H NMR spectra of
n
max (KBr disc) 3471, 3367, 2918, 1680, 1573, 1548, 1465,
1421, 1310, 1273, 1237, 1067, 939, 869, 791 and 708 cm21
protonated (11) in the presence of varying amounts of
sodium acetate). A strong association with neutral esters
;
dH (270 MHz, d6DMSO) 7.60 (1H, d, Jˆ2.0 Hz, H-2), 7.49
(1H, d, Jˆ2.0 Hz, H-4), 2.17 (3H, s, Me); m/z (EI) 231 (67
M1), 229 (69 M1), 213 (99), 211 (100), 184 (27), 182 (23),
132 (15), 104 (36), 77 (41%).
1
was also evidenced by signi®cant changes in the H NMR
spectra of protonated compound (11) in the presence of
ethyl acetate. This implies that reduction to the guanidine
may not be necessary for catalytic activity. We are currently
studying the use of protonated species (11) as an asymmetric
catalyst in several important reactions of a,b-unsaturated
substrates and will report our ®ndings in due course.
2-Amino-3-iodo-5-methylbenzoic acid (16). To a stirred
solution of 2-amino-5-methylbenzoic acid (14) (5 g,
33 mmol) in glacial acetic acid (50 mL) was added iodine
crystals (9 g, 35 mmol). The mixture was heated at re¯ux
for three days. The mixture was cooled to room temperature
and petroleum ether (bp 40±608C) (30 mL) was added. The
mixture was ®ltered, the ®ltrate was concentrated in vacuo,
and dichloromethane was added to give the title compound
(16) (1.37 g, 16%) as a yellow solid, mp 2118C; (Found: C,
34.73; H, 2.69; N, 5.1; C8H8INO2 requires C, 34.68; H, 2.91;
N, 5.06%);.nmax (Nujol) 3417, 3376, 3314, 1787, 1726,
1660, 1576, 1537, 1502, 1378, 1321, 1304, 1239, 1170,
Experimental
Melting points were determined using a Reithert Ko¯er
melting point microscope apparatus and are uncorrected.
Microanalyses were carried out using a Perkin±Elmer 240
elemental analyser. Infrared spectra were obtained using a
Perkin±Elmer Paragon 100 FT-IR spectrometer; samples
were analysed either as potassium bromide discs, as mulls
in Nujol or as solutions in CHCl3. Nuclear magnetic reso-
nance (NMR) spectra were acquired using either a Jeol
GSX270 FT-NMR at 270 MHz or a Bruker DPX300
FT-NMR at 300 MHz; samples were analysed as solutions
in CDCl3 or d6-DMSO solution. Low resolution mass
spectra were acquired using a AEI MS12 mass spectrometer
(EI, 70 eV) or by the EPSRC Mass Spectrometry Service
(Swansea). High resolution mass spectra were recorded by
the EPSRC Mass Spectrometry Service (Swansea) and the
mass spectrometry service at Reading University.
934, 898, 872, 792, 762, 722 and 700 cm21
; dH
(270 MHz, CDCl3) 7.75 (1H, d, Jˆ2.0 Hz, H-2), 7.69 (1H,
d, Jˆ2.0 Hz, H-4) 2.21 (2H, s, NH), 2.17 (3H, s, Me); m/z
(EI) 277 (100 M1), 260 (22), 259 (88), 230 (11), 209 (11),
164 (5), 146 (16), 132 (13), 105 (12), 104 (19), 77 (35%).
8-Bromo-6-methyl-1H-3,1-benzoxazine-2,4-dione (17).
2-Amino-5-methyl-benzoic acid (15) (15.0 g, 65 mmol)
was dissolved in a solution of 20% phosgene in toluene
(50 mL) and stirred at 608C for 24 h. A further amount of
a solution of 20% phosgene in toluene (50 mL) was added
and heating continued. Aliquots (0.5 mL) were taken at 6 h
intervals and heating continued until no starting material
remained by 1H NMR. The solvent was evaporated in
vacuo to yield the title compound (16.70 g, 100%) (17) as
an off-white solid, mp 249±2508C; (Found: C, 42.22, H,
2.11, N, 5.45; C9H6BrNO3 requires C, 42.19, H, 2.34, N,
5.47%); nmax (Nujol) 3217, 1787, 1723, 1612, 1378, 1328,
1256, 1207, 1142, 1054, 1006, 929, 880, 850, 801, 742, 723
and 708 cm21; dH (270 MHz, d6DMSO) 11.01 (1H, s, NH)
7.89 (1H, d, Jˆ2.0 Hz, H-5), 7.77 (1H, d, Jˆ2.0 Hz, H-7),
2.33 (3H, s, Me); m/z (EI) 257 (21 M1) 255 (22 M1) 213
(96), 211 (100), 184 (27), 182 (26), 132 (21), 104 (29), 103
(26), (77) (53), 76 (29%).
All solvents were puri®ed and distilled before use. Aceto-
nitrile was doubly distilled from P2O5 and then stored in a
Ê
dark bottle over 4 A molecular sieves. THF and dioxan were
dried by re¯uxing over sodium until benzophenone held a
purple colour. Dimethyl sulphoxide was passed through a
Ê
column (20 g/L) of activated 3 or 4 A molecular sieves.
Thin layer chromatography was carried out using foil
backed alumina or silica plates. Flash column chromato-
graphy was carried out using Janssen silica gel (particle
size 0.035±0.07 mm). Chromatotron radial chromatography
was performed on plates prepared using silica gel 60 PF254
.
Activation of copper powder/copper bronze
8-Iodo-6-methyl-1H-3,1-benzoxazine-2,4-dione (18). 2-
Amino-3-iodo-5-methylbenzoic acid (16) (1.3 g, 4.7
mmol) was dissolved in a solution of 20% phosgene in
toluene (50 mL) and stirred at 608C for 24 h. A further
amount of a solution of 20% phosgene in toluene (50 mL)
was added and heating continued. Aliquots (0.5 mL) were
taken at 6 h intervals and heating continued until no starting
material remained by 1H NMR. The solvent was evaporated
in vacuo to yield the title compound (18) (1.4 g, 100%) as a
cream solid, mp 231±2338C; nmax (CHCl3) 3254, 1789,
1723, 1610, 1501, 1329, 1254, 1216, 1141, 1056, 1008,
927, 880, 826, 698, 670 and 615 cm21; dH (270 MHz,
CDCl3) 7.92 (1H, d, Jˆ2.0 Hz, H-5), 7.89 (1H, d,
Jˆ2.0 Hz, H-7), 2.38 (3H, s, Me); m/z (EI) 303 (100 M1),
260 (32), 230 (39), 151 (10), 133 (39), 132 (57), 104 (43),
103 (55), 92 (61), 91 (91), 78 (20), 77 (59%); HRMS (CI,
NH3) M1 found 302.9404. C9H6INO3 requires 302.9392.
Copper bronze or copper powder (1 g) was treated with a
2% solution of iodine in acetone (50 mL) for 5±10 min. The
copper was ®ltered off and washed with a 50% solution of
concentrated hydrochloric acid in acetone (25 mL). The
resulting slurry was ®ltered and washed with acetone.
The copper was then dried in vacuo at 3008C for 4 h. The
activated copper was used immediately.
2-Amino-3-bromo-5-methylbenzoic acid (15). To a stirred
solution of 2-amino-5-methyl-benzoic acid (14) (25 g,
166 mmol) in glacial acetic acid (250 mL) at room tempera-
ture was added bromine (10 mL, 198 mmol) dropwise. A
yellow precipitate formed immediately and the suspension
was stirred for a further 3 h. The precipitate was ®ltered,
washed with distilled water (250 mL) and dried in vacuo to
give the title compound (15) (37 g, 97%) as an off-white

8742
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
10-Bromo-8-methyl-1,2,3,4-tetrahydropyrimido[2,1-b]-
quinazolin-6-one (20). To a stirred solution of 8-bromo-6-
11.08; C15H21N3OSn requires C, 47.65; H, 5.6; N, 11.11%);
nmax (KBr disc) 3290, 1665, 1578, 1475, 1444, 1369, 1282,
methyl-1H-3,1-benzoxazine-2,4-dione
(17)
(12.8 g,
1223, 1161, 1118, 1019, 800, 175 and 696 cm21; dH
(270 MHz, CDCl3) 7.85 (1H, m, H-7), 7.50 (1H, d,
Jˆ2.0 Hz, H-9), 5.00 (1H, br s, NH), 4.08 (2H, m, CH2),
3.48 (2H, m, CH2), 2.38 (3H, s, ArMe), 2.11 (2H, m, CH2),
0.29 (9H, t, Jˆ26 Hz, SnMe3); m/z (EI) 379 (3 M11H), 334
(19), 277 (23), 262 (100), 215 (42), 183 (100), 108 (59), 77
(13%).
50 mmol) in dimethylformamide (250 mL) was added
2-methylsulfanyl-1,4,5,6-tetrahydropyrimidine (19) (6.5 g,
50 mmol). The mixture was heated to 1008C for 4 h and a
stream of nitrogen was bubbled continuously through the
mixture. The mixture was cooled and distilled water
(500 mL) was added to give an off white precipitate. The
precipitate was ®ltered, washed with water (2£50 mL), then
petroleum ether (bp 40±608C) (2£50 mL). The precipitate
was dissolved in dichloromethane (250 mL), the solution
was dried over magnesium sulphate and the solvent evapo-
rated in vacuo to give an off-white solid. Recrystallisation
(dichloromethane±diethyl ether) gave the title compound
(20) (6.47 g, 44%) as a white crystalline solid, mp 2528C;
8-Methyl-10-(80-methyl-60-oxy-10,20,30,40-tetrahydropyr-
imido[2,1-b]quinazolin-100-yl)-1,2,3,4-tetrahydropyri-
mido[2,1-b]quinazolin-6-one (3). 10-Bromo-8-methyl-
1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one
(0.117 g, 0.4 mmol), 10-(Trimethylstannyl)-8-methyl-
1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one (22)
(20)
n
max (KBr disc) 3297, 2947, 1664, 1622, 1579, 1488, 1294,
(0.15 g, 0.4 mmol) and bis(triphenylphosphine) palladium(II)
dichloride (56 mg) were dissolved in dry 1,4-dioxane
(20 mL) under argon. The mixture was heated at re¯ux for
48 h and then cooled to room temperature. The mixture was
®ltered and the solvent evaporated in vacuo to give an
orange solid. Puri®cation of the crude product by chromato-
graphy (33% ethyl acetate/petroleum ether (bp 40±608C),
then methanol) gave the title compound (3) (5 mg, 3%) as a
yellow solid, mp 297±3008C; nmax (KBr disc) 3404, 1683,
1592, 1477, 1438, 1318, 1291, 1101, 787, 746 and
692 cm21; dH (270 MHz, CDCl3) 7.89 (2H, d, Jˆ2.0 Hz,
2£H-7), 7.29 (2H, d, Jˆ2.0 Hz, 2£H-9), 3.97 (4H, t,
Jˆ4.0 Hz, CH2), 3.16 (4H, br t, Jˆ5.5 Hz, CH2), 2.32
(6H, s, Me), 1.93 (4H, m, CH2); m/z (EI) 428 (88 M1),
427 (80), 413 (24), 388 (14), 387 (14), 344 (17), 330 (21),
293 (27), 290 (27), 281 (24), 278 (41), 277 (100%); HRMS
(CI, NH3) M12H found 427.1872. C24H23N6O2 requires
427.1882.
1232, 1219, 1018, 814, 790 and 675 cm21; dH (270 MHz,
CDCl3) 7.87 (1H, d, Jˆ2.0 Hz, H-7), 7.69 (1H, d, Jˆ2.0 Hz,
H-9), 5.63 (1H, br s; NH), 4.09 (2H, t, Jˆ6.5 Hz, CH2), 3.48
(2H, t, Jˆ6.5 Hz, CH2), 2.36 (3H, s, Me), 2.11 (2H, m,
CH2); m/z (EI) 295 (93 M1), 293 (100 M1), 240 (12), 238
(14), 213 (17), 211 (19), 129 (12), 103 (23), 77 (15), 76
(10%); HRMS (CI, NH3) M11H found 294.0229.
C12H12BrN3O requires 294.0242.
10-Iodo-8-methyl-1,2,3,4-tetrahydropyrimido[2,1-b]quin-
azolin-6-one (21). To a stirred solution of 8-iodo-6-methyl-
1H-3,1-benzoxazine-2,4-dione (18) (1.3 g, 3.8 mmol) in
dimethylformamide (25 mL) was added 2-methylsulfanyl-
1,4,5,6-tetrahydropyrimidine (19) (0.5 g, 3.8 mmol). The
mixture was heated to 1008C for 4 h and a stream of nitrogen
was bubbled continuously through the mixture. The mixture
was cooled and distilled water (50 mL) was added to give a
pale yellow precipitate. The precipitate was ®ltered, washed
with water (2£50 mL), then petroleum ether (bp 40±608C)
(2£50 mL). The precipitate was dissolved in dichloro-
methane (75 mL), the solution was dried over magnesium
sulphate and the solvent evaporated in vacuo to give an off-
white solid. Recrystallisation (dichloromethane±diethyl
ether) gave the title compound (21) (0.84 g, 65%) as a
pale yellow solid, mp 241±2438C; (Found: C, 41.98; H,
3.69; N, 12.19; C12H12IN3O requires C, 42.25; H, 3.55; N,
12.32%); nmax (KBr disc) 3299, 1664, 1623, 1578, 1496,
8-Methyl-1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-
6-one (23). 2-Amino-5-methylbenzoic acid (14) (1.0 g,
6.6 mmol) and 2-methylsulfanyl-1,4,5,6-tetrahydropyrimi-
dine (19) (840 mg, 6.6 mmol) were ground separately into
®ne powders and then thoroughly mixed together to give a
creamy paste. The mixture was heated at 1608C for 30 min
under argon to give a viscous dark brown oil. Puri®cation of
the crude product by chromatography (50% ethyl acetate/
petroleum ether (bp 40±608C), then methanol) followed by
crystallisation (ethanol) gave the title compound (23)
(596 mg, 42%) as an off-white crystalline solid, mp 241±
2428C; nmax (CHCl3) 3443, 3285, 1664, 1578, 1489, 1475,
1446, 1371, 1341, 1318, 1294, 1216, 1166, 1115, 1100,
1473, 1371, 1317, 1292, 1235 and 790 cm21
; dH
(270 MHz, CDCl3) 7.93 (1H, d, Jˆ2.0 Hz, H-7), 7.86 (1H,
d, Jˆ2.0 Hz, H-9), 4.05 (2H, t, Jˆ6.0 Hz, CH2), 3.46 (2H, t,
Jˆ6.0 Hz, CH2), 2.32 (3H, s, Me), 2.08 (2H, m, CH2); m/z
(EI) 341 (100 M1), 286 (24), 259 (32), 214 (30), 132 (19),
103 (28), 83 (27), 77 (24), 55 (34%).
1044, 1019, 974, 930, 888, 875, 812, 708 and 669 cm21
;
dH (270 MHz, CDCl3) 7.82 (1H, s, H-7), 7.32 (1H, d,
Jˆ8.0 Hz, H-10), 7.08 (1H, d, Jˆ8.0 Hz, H-9), 6.07 (1H,
br s; NH), 4.01 (2H, t, Jˆ6.0 Hz, CH2), 3.42 (2H, t,
Jˆ6.0 Hz, CH2), 2.29 (3H, s, Me), 2.02 (2H, t, Jˆ6.0 Hz,
CH2); m/z (EI) 215 (33), 165 (20), 151 (60), 133 (100), 116
(28), 106 (29), 104 (49), 78 (26), 77 (29%); HRMS (CI,
NH3) M11H found 216.1134. C12H14N3O requires
216.1137.
10-(Trimethylstannyl)-8-methyl-1,2,3,4-tetrahydropyri-
mido[2,1-b]quinazolin-6-one (22). 10-Bromo-8-methyl-
1,2,3,4-tetrahydro-2H-pyrimido[2,1-b]quinazolin-6-one (20)
(2.0 g, 6.8 mmol), hexamethylditin (2.9 g, 9 mmol) and
bis(triphenylphosphine) palladium(II) dichloride (0.4 g,
0.58 mmol) were dissolved in 1,4-dioxane (50 mL) under
Argon. The stirred mixture was heated at 1208C for 4 h
and then cooled to room temperature. The mixture was
®ltered and the solvent evaporated in vacuo to give a
brown solid. Puri®cation of the crude product by chromato-
graphy (CH2Cl2) gave the title compound (22) (2.39 g, 93%)
as a yellow solid, mp 2168C; (Found: C, 47.60; H, 5.55; N,
8-Methyl-10-phenyl-1,2,3,4-tetrahydropyrimido[2,1-b]-
quinazolin-6-one (24). Stille conditions: Iodobenzene
(70 mg, 0.34 mmol, 0.39 mL), 10-(trimethylstanyl)-8-methyl-
1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one (22)
(100 mg, 0.34 mmol), and tetrakis(triphenylphosphine)

J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
8743
palladium(0) (20 mg) were added to anhydrous 1,4-dioxane
(3 mL) and the mixture was heated at re¯ux for 3 h under
argon. The mixture was cooled to room temperature and
®ltered. The ®ltrate was diluted with dichloromethane
(150 mL) and the solution was washed with brine
(100 mL) and water (50 mL). The organic solution was
dried over magnesium sulphate and the solvent evaporated
in vacuo to yield a brown oil. Puri®cation of the crude
product by chromatography (50% ethyl acetate/petroleum
ether (bp 40±608C)) gave the title compound (24) (21 mg,
25%) as an off-white solid, mp 202±2058C; (Found: C,
74.30; H, 5.97; N, 14.19; C18H17N3O requires C, 74.20; H,
5.88; N, 14.42%); nmax (KBr disc) 3443, 3240, 3167, 1672,
1611, 1483, 1442, 1370, 1318, 1298, 1279, 1222, 1161, 800,
758 and 699 cm21; dH (300 MHz, CDCl3) 7.99 (1H, s, H-7),
7.74 (2H, d, Jˆ7.5 Hz, 2£Ar), 7.45 (1H, d, Jˆ2 Hz, H-9),
7.38 (2H, t, Jˆ7.5 Hz, Ar), 7.28 (1H, t, Jˆ7.5 Hz, Ar), 7.12
(1H br s, NH), 3.94 (2H, t, Jˆ6.0 Hz, CH2), 2.80 (2H, t,
Jˆ6.0 Hz, CH2), 2.43 (3H, s, Me), 1.78 (2H, m, CH2); m/z
(EI) 291 (100 M1), 277 (42), 217 (27), 180 (36), 152 (25),
133 (21), 86 (56), 84 (95), 77 (60%).
254 (14), 253 (14), 252 (16), 213 (13), 211 (17), 129 (16),
104 (9), 103 (30), 102 (18), 69 (48%).
1,8-Dimethyl-10-(trimethylstannyl)-1,2,3,4-tetrahydro-
pyrimido[2,1-b]quinazolin-6-one (26). 10-Bromo-1,8-
dimethyl-1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one
(25) (0.4 g, 1.3 mmol), hexamethylditin (0.55 g, 1.7 mmol)
and tetrakis(triphenylphosphine) palladium(0) (100 mg)
were dissolved in 1,4-dioxane (10 mL) under argon. The
stirred mixture was heated at 1208C for 4 h and then cooled
to room temperature. The mixture was ®ltered and the
solvent evaporated in vacuo to give a grey solid. Puri®cation
of the crude product by chromatography (20% ethyl acetate/
petroleum ether (bp 40±608C)) gave the title compound (26)
(240 mg, 47%) as a white solid, mp 241±2448C; nmax (KBr
disc) 1671, 1579, 1504, 1449, 1412, 1341, 1313, 1292,
1246, 1182, 1065, 956 and 880 cm21; dH (270 MHz,
CDCl3) 7.61 (1H, s, H-7), 7.28 (1H, s, H-9), 3.89 (2H, t,
Jˆ6.0 Hz, CH2), 3.22 (2H, t, Jˆ6.0 Hz, CH2), 2.97 (3H, s,
NMe), 2.15 (3H, s, ArMe), 1.89 (2H, m, CH2), 0.09 (9H, t,
Jˆ26.5 Hz, SnMe3); m/z (EI) 393 (7 M11H), 392 (3 M1),
378 (100), 376 (88), 374 (51), 189 (7%); HRMS (CI, NH3)
M11H found 394.0952. C16H24N3OSn requires 394.0940.
Suzuki conditions: To a solution of 10-bromo-8-methyl-
1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one
(20)
(200 mg, 0.68 mmol) in anhydrous 1,4-dioxane (10 mL)
was added bis(triphenylphosphine) palladium(II) dichloride
(40 mg) and the mixture stirred at room temperature for
20 min under argon. A solution of phenylboronic acid
(83 mg, 0.68 mmol) in 2 M aqueous sodium carbonate
(1 mL) was added and the mixture was heated at re¯ux
for 24 h. The mixture was cooled to room temperature and
®ltered. The ®ltrate was diluted with dichloromethane
(150 mL) and the solution was washed with brine
(50 mL). The mixture was dried over magnesium sulphate
and the solvent evaporated in vacuo to give a pale yellow
solid. Puri®cation of the crude product by chromatography
(50% ethyl acetate/petroleum ether (bp 40±608C)) gave the
title compound (24) (63 mg, 31%) as an off-white solid,
identical by IR and 1H NMR spectroscopy to material
obtained using Stille conditions.
1,8-Dimethyl-10-phenyl-1,2,3,4-tetrahydropyrimido[2,1-
b]quinazolin-6-one (27). Iodobenzene (67 mg, 0.32 mmol,
0.37 mL), 1,8-dimethyl-10-(trimethylstannyl)-1,2,3,4-tetra-
hydropyrimido[2,1-b]quinazolin-6-one
(26)
(100 mg,
0.32 mmol), and tetrakis(triphenylphosphine) palladium(0)
(20 mg) were added to anhydrous 1,4-dioxane (3 mL) and
the mixture was heated at re¯ux for 3 h under argon. The
mixture was cooled to room temperature and ®ltered.
The ®ltrate was diluted with dichloromethane (150 mL)
and the solution was washed with brine (100 mL) and
water (50 mL). The organic solution was dried over mag-
nesium sulphate and the solvent evaporated in vacuo to
yield a red oil. Puri®cation of the crude product by chroma-
tography (petroleum ether (bp 40±608C), then ethyl acetate)
gave the title compound (27) (21 mg, 25%) as an off-white
solid, mp 214±2168C; nmax (KBr disc) 1658, 1582, 1512,
1477, 1407, 1315, 1287, 1229, 893, 801, 718 and 695 cm21
;
10-Bromo-1,8-dimethyl-1,2,3,4-tetrahydropyrimido[2,1-
b]quinazolin-6-one (25). 10-Bromo-8-methyl-1,2,3,4-
tetrahydropyrimido[2,1-b]quinazolin-6-one (20) (500 mg,
1.7 mmol) was dissolved in anhydrous THF (5 mL) at
room temperature. Sodium hydride (136 mg, 3.4 mmol,
60% dispersion in oil) was added slowly to the stirred solu-
tion, followed by methyl iodide (284 mg, 2.0 mmol). The
mixture was stirred in the dark for 24 h. The mixture was
diluted with iced water (20 mL) and saturated aqueous
sodium carbonate (20 mL) was added. The mixture was
extracted with dichloromethane (2£150 mL), the organic
phase was dried over magnesium sulphate and the solvent
evaporated in vacuo to yield the title compound (25)
(522 mg, 100%) as a white solid, mp 2638C; (Found: C,
50.61; H, 4.57; N, 13.59; C13H14BrN3O requires C, 50.67;
H, 4.58; N, 13.64%); nmax (CHCl3) 1662, 1637, 1618, 1581,
1560, 1541, 1508, 1478, 1458, 1411, 1361, 1340, 1312,
1290, 1217, 1047, 958, 929, 876, 845 and 626 cm21; dH
(270 MHz, CDCl3) 7.76 (1H, s, H-7), 7.62 (1H, s, H-9),
4.02 (2H, t, Jˆ6.0 Hz, CH2), 3.44 (2H, t, Jˆ6.0 Hz, CH2),
3.25 (3H, s NMe), 2.29 (3H, s, ArMe), 2.03 (2H, m, CH2);
m/z (EI) 309 (100 M1), 307 (100 M1), 280 (48), 278 (47),
dH (300 MHz, CDCl3) 7.91 (1H, br s, H-7), 7.71 (2H, d,
Jˆ7.5 Hz, Ar), 7.46 (1H, d, Jˆ2.0 Hz, H-9), 7.41 (2H, t,
Jˆ7.5 Hz, Ar), 7.32 (1H, t, Jˆ7.5 Hz, Ar), 4.12 (2H, t,
Jˆ7.0 Hz, CH2), 3.41 (2H, t, Jˆ7.0 Hz, CH2), 3.10 (3H, s,
NMe) 2.43 (3H, s, ArMe), 2.08 (2H, m, CH2); m/z (EI) 305
(100 M1), 276 (27), 125 (15), 111 (26), 97 (38), 85 (28), 71
(41%); HRMS (CI, NH3) M11H found 306.1609.
C19H20N3O requires 306.1606.
1,8-Dimethyl-1,2,3,4-tetrahydropyrimido[2,1-b]quina-
zolin-6-one (28). 8-Methyl-1,2,3,4-tetrahydropyrimido[2,1-
b]quinazolin-6-one (23) (215 mg, 1.0 mmol) was dissolved
in anhydrous THF (5 mL) at room temperature. Sodium
hydride (80 mg, 2.0 mmol, 60% dispersion in oil) was
added slowly to the stirred solution, followed by methyl
iodide (170 mg, 1.2 mmol). The mixture was stirred in the
dark for 24 h. The mixture was diluted with iced water
(20 mL) and saturated aqueous sodium carbonate (20 mL)
was added. The mixture was extracted with dichloro-
methane (2£50 mL), the organic phase was dried over
magnesium sulphate and the solvent evaporated in vacuo
to yield the title compound (28) (296 mg, 96%) as a white

8744
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
solid, mp 2208C; nmax (KBr) 1661, 1504, 1410, 1380, 1313,
1295, 1198 and 839 cm21; dH (300 MHz, CDCl3) 7.79 (1H,
d, Jˆ0.5 Hz, H-7), 7.30 (1H, dd, Jˆ8.5 and 0.5 Hz, H-10),
7.17 (1H, d, Jˆ8.5 Hz, H-9), 4.04 (2H, t, Jˆ6.0 Hz, CH2),
3.37 (2H, t, Jˆ6.0 Hz, CH2), 3.16 (3H, s NMe), 2.31 (3H, s,
ArMe), 2.02 (2H, m, CH2); m/z (EI) 229 (100 M1), 200 (77),
174 (20), 133 (20), 104 (15), 77 (13%); HRMS (CI, NH3)
M11H found 230.1296. C13H16N3O requires 230.1293.
¯ask equipped for re¯ux was added acetic anhydride
(10 mL) slowly in 4±5 portions. An off-white precipitate
formed after a few minutes. The mixture was stirred for a
further 30 min, cooled to room temperature and ®ltered. The
precipitate was washed with diethyl ether (2£150 mL) and
dried in vacuo to give the title compound (37) (12.5 g, 98%)
as an off-white solid, mp 272±2748C (lit23 275±2768C);
nmax (KBr disc) 3236, 3023, 1684, 1646, 1618, 1581,
1545, 1430, 1412, 1375, 1323, 1303, 1273, 1235, 1139,
1104, 1022, 937, 905, 848 and 746 cm21; dH (270 MHz,
d6DMSO) 9.38 (1H, br s, CO2H); 8.01 (1H, br s, H-2),
7.60 (1H, d, Jˆ8.0 Hz, H-6), 7.28 (1H, d, Jˆ8.0 Hz, H-5),
2.24 (3H, s, COMe), 2.06 (3H, s, ArMe); m/z (EI) 193 (33
M1), 151 (100), 136 (37), 119 (29), 106 (40), 91 (40%);
HRMS (CI, NH3) M11H found 194.0815. C10H12NO3
requires 194.0817.
10-Bromo-8-methyl-1-(20-nitrophenyl)-1,2,3,4-tetrahydro-
pyrimido[2,1-b]quinazolin-6-one (32). To a stirred solu-
tion of 10-bromo-8-methyl-1,2,3,4-tetrahydropyrimido[2.1-
b]quinazolin-6-one (20) (100 mg, 0.34 mmol) and 2-bromo-
nitrobenzene (68 mg, 0.34 mmol) in dry dimethyl sulphox-
ide (3 mL) was added freshly activated copper bronze
(42 mg, 0.68 mmol). The stirred mixture was heated at
1208C for 8 h under argon. The mixture was cooled to
room temperature, diluted with chloroform (100 mL) and
the solution was washed with brine (2£100 mL). The
organic layer was dried over magnesium sulphate and the
solvent evaporated in vacuo to give a yellow/brown solid.
Puri®cation of the crude product by chromatography (ethyl
acetate) gave the title compound (32) (80 mg, 63%) as a pale
yellow solid, mp 2838C; (Found: C, 51.91; H, 3.67; N,
13.44; C18H15BrN4O3 requires C, 52.06; H, 3.64; N,
13.49%); nmax (CHCl3) 3020, 1670, 1574, 1559, 1540,
1531, 1507, 1498, 1480, 1458, 1442, 1355, 1314, 1216,
771 and 669 cm21; dH (270 MHz, CDCl3) 8.04 (1H, dd,
Jˆ7.5 and 1.5 Hz, H-30), 7.74 (1H, d, Jˆ1.0 Hz, H-7),
7.64 (1H, dt, Jˆ7.5 and 1.5 Hz, H-40), 7.51 (1H, d,
Jˆ1.0 Hz, H-90), 7.38 (2H, m, H-50 and H-60), 4.17 (2H,
br t, Jˆ6.0 Hz, CH2), 3.85 (2H, br m, CH2), 2.33 (2H, br m,
CH2), 2.25 (3H, s, Me); m/z (EI) 417 (6), 415 (6), 371 (15),
369 (15), 296 (100), 294 (96), 240 (11), 238 (13), 213 (21),
211 (23), 116 (14), 102 (17), 77 (22%).
3-Acetylamino-4-methyl-2-nitrobenzoic acid (38). To an
solution of 3-acetylamino-4-methylbenzoic acid (37)
(11.5 g, 59 mmol) cooled to 08C was added fuming nitric
acid (22 mL) slowly over 90 min, not allowing the tempera-
ture of the mixture to rise above 58C. The mixture was
stirred at 08C for 2 h. The mixture was poured on to ice
(110 g) and left to stand for 12 h. The precipitate was
®ltered, washed with cold water (100 mL) and dried in
vacuo to give a pale yellow solid. Recrystallisation of the
crude product (glacial acetic acid) gave the title compound
(38) (10 g, 71%) as a white solid, mp 1578C (lit24 155±
1568C); (Found: C, 50.55; H, 4.21; N, 11.79; C10H10N2O5
requires C, 50.42; H, 4.23; N, 11.76%); nmax (KBr disc)
3345, 2930, 1720, 1645, 1547, 1519, 1375, 1269, 1206,
1177, 1144, 1044, 852, 804, 790, 776 and 625 cm21; dH
(270 MHz, d6DMSO) 10.35 (1H, br s, CO2H), 7.86 (1H,
d, Jˆ8.0 Hz, H-6), 7.08 (1H, d, Jˆ8.0 Hz, H-5), 2.47 (3H,
s, COMe), 2.23 (3H, s, ArMe); m/z (EI) 220 (31), 196 (61),
161 (22), 152 (20), 103 (38), 77 (19), 43 (100%).
1,8-Dimethyl-10-methylsulfanyl-1,2,3,4-tetrahydropyri-
mido[2,1-b]quinazolin-6-one (33). To a solution of 10-
bromo-1,8-dimethyl-1,2,3,4-tetrahydropyrimido[2,1-b]quina-
zolin-6-one (25) (150 mg, 0.48 mmol) in dry dimethyl
sulphoxide (3 mL) was added freshly activated copper
bronze (75 mg) and the mixture was heated at re¯ux for
18 h under argon. The solution was cooled to room tempera-
ture and ®ltered. The ®ltrate was diluted with ethyl acetate
(100 mL) and washed with brine (2£100 mL), aqueous
ammonia (5 mL) and water (2£50 mL). The organic phase
was dried over magnesium sulphate and the solvent evapo-
rated in vacuo to give a pale yellow solid. Puri®cation of the
crude product by chromatography (50% ethyl acetate/
petroleum ether (bp 40±608C)) gave the title compound
(33) (107 mg, 81%) as a white solid, mp 2718C; (Found:
C, 60.79; H, 5.97; N, 15.32; C14H17N3OS requires C, 61.06;
H, 6.22; N, 15.26%); nmax (KBr disc) 2966, 1660, 1507,
3-Amino-4-methyl-2-nitrobenzoic acid hydrobromide
(39). A solution of 3-acetylamino-4-methyl-2-nitrobenzoic
acid (38) (10 g, 42 mmol) in aqueous hydrobromic acid
(48% w/v) (150 mL) was heated at re¯ux for 12 h. The
mixture was cooled to room temperature and the solvent
evaporated in vacuo to give a yellow/orange solid. Recrys-
tallisation of the crude product (acetone/petroleum ether (bp
40±608C)) gave the title compound (39) (9.7 g, 100%) as an
orange solid, mp 1728C (lit.25173±1758C); (Found: C,
34.79; H, 3.25; N, 10.32; C8H9BrN2O4 requires C, 34.68;
H, 3.27; N, 10.11%); nmax (KBr disc) 3480, 3372, 2925,
1706, 1618, 1519, 1443, 1332, 1256 and 1198 cm21; dH
(270 MHz, d6DMSO) 7.24 (1H, d, Jˆ7.5 Hz, H-6), 6.84
(1H, d, Jˆ7.5 Hz, H-5), 2.19 (3H, s, ArMe); m/z (EI) 276
(2 M1), 226 (2), 196 (27), 169 (3), 148 (4), 133 (3), 121 (5),
105 (8), 104 (8), 82 (94), 81 (38), 80 (100), 79 (39%).
1443, 1365, 1310, 1295, 1203 and 827 cm21
; dH
(270 MHz, CDCl3) 7.55 (1H, d, Jˆ1.5 Hz, H-7), 7.03 (1H,
d, Jˆ1.5 Hz, H-9), 4.02 (2H, t, Jˆ6.0 Hz, CH2), 3.38 (2H, t,
Jˆ6.0 Hz, CH2), 2.40 (3H, s SMe), 2.32 (3H, s, NMe), 2.02
(2H, m, CH2); m/z (EI) 275 (100 M1), 229 (90), 215 (30),
201 (35), 161 (10), 121 (10), 106 (20) 78 (30%).
3-Bromo-4-methyl-2-nitrobenzoic acid (40). To a solution
of 3-amino-4-methyl-2-nitrobenzoic acid hydrobromide
(39) (25 g, 109 mmol) aqueous hydrobromic acid (48%
w/v) (300 mL) at 58C was added a solution of sodium nitrite
(13.5 g, 195 mmol) in water (15 mL) slowly, maintaining
the temperature between 5±108C. The mixture was shaken
after each addition of the sodium nitrite solution until all red
fumes were absorbed. Copper powder (1.5 g) was added to
the mixture and the mixture heated very cautiously on a
3-Acetylamino-4-methylbenzoic acid (37). To a stirred
solution of 3-amino-4-methylbenzoic acid (36) (10 g,
66 mmol) in glacial acetic acid (70 mL) contained in a

J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
8745
water bath. Upon evolution of nitrogen the ¯ask was cooled
immediately to 08C. After vigorous evolution of nitrogen
had subsided the ¯ask was heated at 308C for 3 h. The
mixture was cooled by the slow addition of iced water
until a pale yellow precipitate formed. The precipitate was
®ltered and dried in vacuo to give the title compound (40)
(17 g, 80%) as a pale yellow solid, mp 232±2348C; (Found:
C, 36.85; H, 2.21; N, 5.37; C8H6BrNO4 requires C, 36.95; H,
2.33; N, 5.39%); nmax (Nujol) 1706, 1598, 1547, 1416,
1378, 1291, 1249, 1190, 1162, 1016, 935, 844, 797, 779,
722, 702 and 622 cm21; dH (270 MHz, d6DMSO) 8.27 (1H,
d, Jˆ8.5 Hz, H-6). 7.99 (1H, d, Jˆ8.5 Hz, H-5), 2.78 (3H, s,
Me); m/z (EI) 261 (55), 259 (64), 231 (14), 229 (18), 215
(13), 213 (18), 187 (15), 185 (17), 171 (11), 169 (13), 133
(15), 132 (12), 106 (36), 105 (34), 90 (22), 89 (38), 78 (100),
77 (77%).
(500 mg, 1.8 mmol) in absolute ethanol (50 mL) and
concentrated hydrochloric acid (0.5 mL) was added iron
pin dust (300 mg, (170 g/mol for each nitro group)) in 4
portions, allowing 5 min between each addition. The
mixture was heated at re¯ux for 12 , cooled to room
temperature and made alkali using a 1 M sodium hydroxide
solution in 50% aqueous ethanol. The mixture was ®ltered,
the ®ltrate was washed with brine (50 mL) and extracted
with dichloromethane (2£50 mL). The organic phase was
dried over magnesium sulphate and the solvent evaporated
in vacuo to give the title compound (44) (380 mg, 87%) as
an off-white solid, mp 198±2008C; nmax (KBr disc) 3487,
3364, 2951, 1698, 1621, 1574, 1465, 1436, 1277, 1242,
1208, 1097 and 1008 cm21; dH (300 MHz, CDCl3) 7.74
(1H, d, Jˆ8.0 Hz, H-6), 6.47 (1H, d, Jˆ8.0 Hz, H-5), 5.66
(2H, br s, NH2), 3.85 (3H, s, CO2Me), 2.27 (3H, s, ArMe);
m/z (EI) 246 (93 M11H), 245 (69 M1), 244 (100 M11H),
243 (64 M1), 213 (32), 211, (32), 104 (7), 77 (7%); HRMS
(CI, NH3) M11H found 243.9971. C9H11BrNO2 requires
243.9973.
Methyl 3-bromo-4-methyl-2-nitrobenzoate (41). To a
solution of 3-bromo-4-methyl-2-nitrobenzoic acid (40)
(1 g, 3.8 mmol) in anhydrous methanol (3.8 mmol, 3 mL)
was added concentrated sulphuric acid (0.5 mL) The
mixture was heated at re¯ux for 14 h. The mixture was
cooled to room temperature and diluted with dichloro-
methane (50 mL). The mixture was washed with water
(2£50 mL), the organic phase was dried over magnesium
sulphate and the solvent evaporated in vacuo to give a pale
yellow solid. Puri®cation of the crude product by chromato-
graphy (ethyl acetate) and crystallisation (dichloromethane/
petroleum ether (bp 60±808C)) gave the title compound (41)
(1.02 g, 98%) as an off-white solid, mp 2398C; (Found: C,
39.40; H, 2.91; N, 5.24; C9H8BrNO4 requires C, 39.44; H,
2.94; N, 5.11%); nmax (KBr disc) 1734, 1548, 1438, 1364,
2-Amino-3-bromo-4-methylbenzoic acid (45). To a solu-
tion of methyl 2-amino-3-bromo-4-methylbenzoate (44)
(200 mg, 0.82 mmol) in 75% aqueous methanol (50 mL)
was added potassium hydroxide (45 mg, 0.8 mmol) slowly.
The mixture was heated at re¯ux for 12 h. The mixture was
cooled to room temperature, diluted with water (100 mL)
and extracted with ethyl acetate (2£150 mL). The organic
phase was dried over magnesium sulfate and the solvent
evaporated in vacuo to give the title compound (45)
(164 mg, 87%) as an off-white solid, mp 2088C; nmax
(KBr disc) 3471, 3367, 2921, 1684, 1572, 1549, 1466,
1421, 1311, 1274, 1238, 870, 792 and 709 cm21; dH
(270 MHz, CDCl3) 7.75 (1H, d, Jˆ8.0 Hz, H-6), 7.62 (1H,
d, Jˆ8.0 Hz, H-5), 6.47 (2H, br s, NH2), 2.17 (3H, s, ArMe);
m/z (EI) 231 (74 M1), 229 (74 M1), 213 (100), 211 (85),
184 (16), 183 (13), 182 (9), 132 (5), 104 (37), 77 (31%);
HRMS (CI, NH3) M11H found 229.9812. C8H9BrNO2
requires 229.9817.
1296, 1244, 1201, 1163, 976, 845, 777, 718 and 702 cm21
;
dH (270 MHz, CDCl3) 7.92 (1H, d, Jˆ8.0 Hz, H-d). 7.42
(1H, d, Jˆ8.0 Hz, H-5), 3.90 (3H, s, CO2Me), 2.54 (3H, s,
ArMe); m/z (EI) 275 (60), 273 (60), 244 (88), 242 (88), 214
(15), 212 (15), 170 (19), 168 (20), 133 (26), 91 (54), 90 (77),
89 (100), 77 (39), 63 (77%).
2,20-Dinitro-6,60-dimethyl-3,30-dimethoxycarbonylbi-
phenyl (35). Methyl 3-bromo-4-methyl-2-nitrobenzoate
(41) (100 mg, 0.36 mmol) and freshly activated copper
powder (457 mg, 7.2 mmol) were mixed thoroughly. A
further portion of copper powder (229 mg, 3.6 mmol) was
placed on top of the mixture and the mixture was heated at
2158C for 72 h. The mixture was dissolved in methanol and
the solution was ®ltered. The solvent was evaporated in
vacuo to give an orange solid. Puri®cation of the crude
product by ¯ash chromatography (50% ethyl acetate/petro-
leum ether (bp 40±608C)) gave the title compound (35)
(44 mg, 63%) as an off-white solid, mp 1018C; nmax (KBr
disc) 2961, 1733, 1607, 1552, 1538, 1435, 1368, 1280, 1240
and 1088 cm21; dH (270 MHz, CDCl3) 7.90 (2H, d,
Jˆ8.0 Hz, 2£H-4), 7.45 (2H, d, Jˆ8.0 Hz, 2£H-5), 3.81
(3H, s, CO2Me), 2.08 (3H, s, ArMe); m/z (EI) 357 (21),
342 (39), 326 (36), 310 (100), 252 (43), 178 (39), 165
(90), 152 (68), 139 (42), 115 (25), 89 (29), 59 (60%); m/z
(CI, NH3) 406 (43 M11NH4), 359 (10), 329 (100), 271
(18%); HRMS (CI, NH3) M11NH41 found 406.1240.
C18H20N3O8 requires 406.1250.
2-Methyl-1-naphthylboronic acid (47). To freshly acti-
vated magnesium turnings (1.04 g, 42.7 mmol) was added
a solution of 1-bromo-2-methylnaphthalene (46) (8.6g,
38.8 mmol) in anhydrous THF (25 mL). The mixture was
stirred and heated gently for 1 h. Trimethylborate (4.44 g,
42.7 mmol) was added slowly and the mixture was stirred at
room temperature for 2 h. 1 M aqueous hydrochloric acid
(12 mL) was added slowly to give a grey precipitate. The
mixture was stirred at room temperature for a further 4 h,
diluted with dichloromethane (100 mL) and washed with
distilled water (2£50 mL). The organic phase was dried
over magnesium sulphate and the solvent evaporated in
vacuo to give a yellow oil. The oil was dissolved in petro-
leum ether (bp 60±808C) (20 mL) and concentrated aqueous
hydrochloric acid (1 mL) was added. The mixture was stir-
red at room temperature for 3 h, during which time a white
precipitate formed. The precipitate was ®ltered and dried in
vacuo to give the title compound (47) (5.7 g, 79%) as a
white solid, mp 125±1288C (lit21 1278C); nmax (KBr)
3318, 3045, 1595, 1565, 1510, 1427, 1398, 1347, 1333,
1297, 1265, 1162, 1141, 1067, 980, 810, 785, 742, 678
and 629 cm21; dH (270 MHz, CDCl3) 7.63±7.72 (3H, m,
Ar), 7.29±7.39 (2H, m, Ar), 7.17 (1H, m, Ar), 5.05 (2H, s,
Methyl 2-amino-3-bromo-4-methylbenzoate (44). To a
solution of methyl 3-bromo-4-methyl-2-nitrobenzoate (41)

8746
J. Clews et al. / Tetrahedron 56 (2000) 8735±8746
B(OH)2), 2.45 (3H, s, ArMe); m/z (EI) 186 (100 M1), 168
(72), 167 (48), 142 (71), 141 (83), 115 (45%); HRMS (CI,
NH3) M1 found 186.0844. C11H11BO2 requires 186.0852.
Professor T. R. Kelly for his invaluable scienti®c
contribution.
References
8-Methyl-10-(20-methyl-10-naphthyl)-1,2,3,4,-tetrahydro-
pyrimido[2,1-b]quinazolin-6-one (7). To a stirred solution
of 10-bromo-8-methyl-1,2,3,4-tetrahydropyrimido[2,1-b]-
quinazolin-6-one (20) (100 mg, 0.34 mmol) and bis(tri-
Â
1. Galan, A.; Andreu, D.; Echavarren, A. M.; Prados, P.; de
Mendoza, J. J. Am. Chem. Soc. 1992, 114, 1511±1512.
Â
2. de Mendoza, J.; Alcazar, V.; Botana, E.; Galan, A.; Lu, G.;
phenylphosphine)
palladium(II)
chloride
(20 mg)
Magrans, O.; Martin-Portugues, M.; Prados, P.; Salmeron, A.;
Sanchez-Quesada, J.; Steel, C.; Segura, M. Pure Appl. Chem.
1997, 69, 577±582.
dissolved in anhydrous 1,4-dioxan (5 mL) was added a
mixture of 2-methyl-1-naphthylboronic acid (47) (63 mg,
0.36 mmol) dissolved in a 2 M 50% aqueous ethanolic solu-
tion of barium hydroxide (5 mL). The mixture was heated at
re¯ux for 24 h under argon. The mixture was cooled to room
temperature and diluted with dichloromethane (100 mL).
The mixture was ®ltered and the ®ltrate was washed with
water (50 mL). The organic phase was dried over magne-
sium sulphate and the solvent evaporated in vacuo to give a
pale yellow/orange solid. The reduced by-products were
precipitated using dichloromethane and petroleum ether
(bp 40±608C) and ®ltered. The ®ltrate was concentrated in
vacuo to give a red/orange solid. Puri®cation of the crude
product by ¯ash chromatography (20% ethyl acetate/petro-
leum ether (bp 60±808C)) gave the title compound (7)
(33 mg, 27%) as a white solid, mp 136±1378C, nmax
(CHCl3) 3439, 1664, 1599, 1487, and 1216 cm21; m/z (EI)
355 (77 M1), 340 (100), 256 (36), 228 (77), 170 (31%); m/z
(CI, NH3) 356 (100% M111); HRMS (EI) M1 found
355.1676. C23H21N3O requires 355.1685.
 Â
3. Alcazar, V.; Moran, J. R.; de Mendoza, J. Tetrahedron Lett.
1995, 36, 3941±3944.
4. Boyle, P. H.; Convery, M. A.; Davies, A. P.; Hosken, G. D.;
Murray, B. A. J. Chem. Soc., Chem. Commun. 1994, 1875±1876.
  Â
5. Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetrahedron:
Asymmetry 1994, 5, 1393±1402.
6. Lehr, S.; Schultz, K.; Bauch, M.; Gobel, M. W. Angew. Chem.
Int. Ed. Engl. 1994, 33, 984±986.
7. Chem3D version 5.0 from CambridgeSoft was employed for the
modelling studies. For a description of the MM2 force®eld used in
this program, please refer to the User's Guide.
8. Glowka, M. L.; Olczak, A.; Korzycka, L. J. Chem. Crystallogr.
1994, 24, 725±730.
9. Saa, J. M.; Martorell, G. J. Org. Chem. 1993, 58, 1963±1966.
10. Roth, G. P.; Farina, V.; Liebeskind, L. S.; Pena-Cubrera, E.
Tetrahedron Lett. 1995, 36, 2191±2194.
11. Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J. Org. Chem. 1994, 59, 5905±5911.
1H NMR data for the predominant atropisomeric conforma-
tion of compound (7): dH (300 MHz, CDCl3) 7.95 (1H, s,
H-7), 7.71 (1H, br t, Jˆ6.5 Hz, Ar), 7.34 (1H, d, Jˆ8.5 Hz,
Ar) 7.29±7.33 (2H, m, 2£Ar), 7.22 (1H, s, H-9), 7.19 (2H, br
t, Jˆ6.0 Hz, 2£Ar), 3.97 (2H, t, Jˆ6.0 Hz, CH2), 5.15 (1H,
br s, NH), 3.12 (2H, br t, Jˆ6.0 Hz, CH2), 2.36 (3H, s,
ArMe), 2.10 (3H, s, ArMe), 1.92 (2H, m, CH2).
12. Hoye, T. R.; Chen, M. J. Org. Chem. 1996, 61, 7940±7942.
13. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110,
4051±4053.
14. Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem.
1996, 61, 9556±9559.
15. Chen, G. J.; Tamborski, C. J. Fluorine Chem. 1989, 43, 207±
228.
16. Grif®th, J. R.; Soulen, R. L. J. Fluorine Chem. 1989, 44, 195±
202.
1H NMR data for the minor atropisomeric conformation of
compound (7): dH (300 MHz, CDCl3) 7.95 (1H, s, H-7),
7.71 (1H, br t, Jˆ6.5 Hz, Ar), 7.34 (1H, d, Jˆ8.5 Hz, Ar),
7.29±7.33 (2H, m, 2£Ar), 7.22 (1H, s, H-9), 7.19 (2H, br t,
Jˆ6.5 Hz, 2£Ar) 4.00 (2H, t, Jˆ6.0 Hz, CH2), 2.99±3.13
(2H, m, CH2), 2.42 (3H, s, ArMe), 2.17 (3H, s, ArMe), 1.87
(2H, m, CH2).
17. Peltier, D.; Pichevin, A. Bull. Soc. Chim. Fr. 1960, 1141±
1147.
18. Kanojia, R. M.; Ohemeng, K. A.; Schwender, C. F.; Barrett,
J. F. Tetrahedron Lett. 1995, 36, 8553±8556.
19. West, R. W. J. Chem. Soc. 1925, 127, 494±495.
20. Heaney, H.; Lees, P. Tetrahedron 1968, 24, 3717±3723.
21. Lawesson, S. O. Acta Chem. Scand. 1957, 11, 1075±1076.
22. Fisher, T. H.; Dershem, S. M.; Prewitt, M. L. J. Org. Chem.
1990, 55, 1040±1043.
Acknowledgements
23. Weinstein, B.; Crews, O. P.; Leaffer, M. A.; Baker, B. R.;
Goodman, L. J. Org. Chem. 1962, 27, 1389±1395.
24. Levine, S. G.; Wani, M. C. J. Org. Chem. 1965, 30, 3185±
3190.
We thank the School of Chemistry and Physics, Keele
University for a studentship (H. M.), the EPSRC Mass Spec-
trometry Service (Swansea) and the Mass Spectrometry
Service at Reading University for recording HRMS and
25. Bolhoer, W. A.; Balwin, J. J. US Patent 3691166, 1969 (Merck
& Co. Inc.); Chem. Abstr. 1972, 77, 152±222.