Effect of substituent structure on pyrimidine electrophilic substitution

Article abstract of DOI:10.1016/j.tet.2007.04.063

In an investigation into the electrophilic nitrosation reactions of a series of 4,6-disubstituted pyrimidine derivatives, a subtle interplay between the electronic nature of the C-4 and C-6 substituents and reactivity was found where these were chloro-, mono- or disubstituted amino groups. Effects such as the presence of an aryl group or two alkyl groups on the amino moiety impede the progress of the reaction despite the presence of a second activating group.

Full text of DOI:10.1016/j.tet.2007.04.063

Tetrahedron 63 (2007) 5394–5405
Effect of substituent structure on pyrimidine electrophilic
substitution
*
Christiaan W. van der Westhuyzen, Amanda L. Rousseau and Christopher J. Parkinson
Discovery Chemistry, CSIR Biosciences, Building T5, Pinelands Site, Ardeer Road, Pinelands 1645, South Africa
Received 12 January 2007; revised 30 March 2007; accepted 19 April 2007
Available online 25 April 2007
Abstract—In an investigation into the electrophilic nitrosation reactions of a series of 4,6-disubstituted pyrimidine derivatives, a subtle
interplay between the electronic nature of the C-4 and C-6 substituents and reactivity was found where these were chloro-, mono- or disub-
stituted amino groups. Effects such as the presence of an aryl group or two alkyl groups on the amino moiety impede the progress of the
reaction despite the presence of a second activating group.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Purine and pyrimidine ring systems form the backbone
of many important biological molecules, such as nucleic
acids, cofactors and various toxins. The ability of these
molecules to interact with proteins has been extensively
exploited in the preparation of inhibitors specific against
certain conditions, such as Gleevec (cancer) or aronixil
(atherosclerosis), for example. The privileged nature of the
purine/pyrimidine structure in terms of their shape and hy-
drogen-bonding characteristics make them ideal starting
points in the search for new chemical entities of biological
significance.
2.1. Generation of substituted 4-amino-5-nitroso-
pyrimidines, followed by amination at C-6
As a starting point, we chose to use 4,6-dichloropyrimidine 1
both for its availability and the well-documented selectivity
obtainable by a sequential introduction of different nucleo-
philes to substitute the chlorine atoms on the ring.1,2 We
planned to use combinations of a primary and a secondary
amine for each pyrimidine, in order to probe the selectivity
hereof against selected targets (Scheme 1).
Cl
Cl
HNR1R2
Our research, focussing on biologically relevant metal ions
in binding sites of receptors, led us to look at these structures
as potential inhibitory compounds from the point of view of
ion chelation in the receptor. Both pyrimidines, in the guise
of the 4,5-diamino or 4,5,6-triamino structures, and purines
could potentially function within this paradigm. With judi-
cious use of substituents on the amino moieties of the pyrim-
idines, we wanted to generate a diverse selection of the
products for screening against a battery of potential targets
in the infectious disease area.
iPrOH, Δ
N
N
Base
N
1
Cl
N
2
NR1R2
NaNO2
H+
NR3R4
NO
Cl
HNR3R4
toluene, Δ
NO
N
N
conditions
N
NR1R2
N
NR1R2
N6
N
N6
N
N5
N4
4
3
N5
N4
N
N
Scheme 1. General preparation of bisaminated 5-nitrosopyrimidines 4.
Refluxing a mixture of 1, the amine of choice and triethyl-
amine,1 or alternatively, two-fold excess of the amine
in question in isopropyl alcohol according to literature
methods2 afforded the required aminopyrimidines 2a–h for
all the primary and secondary aliphatic amines employed
Keywords: Pyrimidine; Nitrosation; Alkyl substituted; Aryl substituted.
* Corresponding author. Tel.: +27 11 605 2135; fax: +27 11 608 3200;
e-mail: cwvdwesthuyzen@csir.co.za
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.063

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
Table 1. Amination of 1 and nitrosation reactions of amines 2a–j Table 2. Aminations of chlorides 3a–c
5395
Cl
a R1 = Me, R2 = H, R3,R4 = -NMe2
NR3R4
NO
a R1 = Me, R2 = H
f NR1,R2 = prolin-1-yl (Me ester)
g NR1,R2 = -N(CH3)2
b R1 = Me, R2 = H, NR3,R4 = pyrrolidin-1-yl
c R1 = Bn, R2 = H, R3,R4 = -NMe2
X
N
b R1= Bn, R2 = H
N
c R1 = CH2CH2OH, R2 = H
h NR1,R2 = morpholin-1-yl
d R1 = Bn, R2 = H, NR3,R4 = pyrrolidin-1-yl
e R1 = Bn, R2 = H, NR3,R4 = morpholin-1-yl
f R1 = CH2CH2OH, R2 = H, R3,R4 = -NMe2
N
NR1R2
d R1 = CH(Bn)CO2Me, R2 = H i NR1,R2 = 4-BrPhNH-
N
NR1R2
e NR1,R2 = pyrrolidin-1-yl
j NR1,R2 = 2-PyNH-
2 X=H
3 X=NO
4
g R1 = CH2CH2OH, R2 = H, NR3,R4 = pyrrolidin-1-yl
Amine
Amination of 1
Nitrosation of 2a–i
Dimethylamine
Pyrrolidine
No. Yield (%)
Morpholine
No. Yield (%)
No.
Yield
(%)
No.
Yield (%)/
methoda
No.
Yield (%)
3a
3b
3c
4a
4c
4f
59
91
72
4ba
4d
83
94
37
n/a
4e
—
85
—
Methylamine
Benzylamine
Ethanolamine
L-Phenylalanine methyl ester 2d
Pyrrolidine
L-Proline methyl ester
Dimethylamine
Morpholine
4-Bromoaniline
2-Aminopyridine
2a
2b
2c
75
85
78
11
3a
3b
3c
3d
3e
3f
3g
3h
3i
88/A
90/B
80/A
0/A
0/A, B
0/A, B
0/A, B
0/B
4ga
n/a
n/a¼not attempted.
a
Neat, 150 ꢀC, 1h.
2e
2f
2g
2h
2i
98
83
Quant.
92
67
In the instance of a secondary amine, ortho substitution
occurs, while tertiary anilines favour direct electrophilic ni-
trosation in the para-position without the intermediacy of a
nitramine.6 Inability to form the nitramine intermediate may
be the reason for the failure of the nitrosation reaction in
products 2e–h, with direct para-substitution being precluded
in this system. Nitramine generation from secondary aryl-
amines using nitrous acid is also known.5 A possible expla-
nation for the failure of the reaction using 2i may lie in the
slightly poorer electrophilicity of the pyrimidine ring at
C-5 due to the chlorine substituent at C-6. Furthermore,
the lower basicity of the arylamine nitrogen at C-4 due to be-
ing bound to two aromatic rings may hinder the formation
of a stable nitramine intermediate. Following this line of
thought, it would appear that displacement of both the chlo-
rine atoms first, and then nitrosation would avoid these
difficulties in the case of amines 2e–i.
0/A, C
—
2j
0b
3j
a
A: Glacial AcOH, NaNO2; B: concd HCl, NaNO2; C: concd H2SO4,
NaNO2.
Toluene, KOBut, 130 ꢀC, sealed tube.
b
in generally good yield (Table 1). The aromatic amines used
proved unpredictable, with 4-bromoaniline readily forming
2i, while 2-aminopyridine refused to react with 1 even under
forcing conditions (potassium tert-butoxide, toluene, pres-
sure tube, 130 ꢀC).
To facilitate the introduction of the second amine in 2a–i,
electrophilic substitution at C-5 with an electron-withdraw-
ing group was attempted to activate the remaining C–Cl
bond to nucleophilic displacement. Otherwise, forcing con-
ditions need to be employed,3 and we sought to avoid this if
possible. In this instance, nitrosation was chosen due to the
ease of introducing the group, and its facile reduction. Nitro-
sation was attempted under classical conditions4 (glacial
acetic acid or mineral acid, aqueous sodium nitrite, room
temperature), with the nitroso products 3a–c precipitating
out of solution as brilliant yellow, water insoluble products
in good yield, at least in the case of secondary amines 2a–c.
Surprisingly, phenylalaninyl derivative 2d failed to react
under these conditions. We assumed that this was due to its
insolubility in the slightly aqueous medium used in that case,
or possibly a slight attenuation of the amino group donor
ability through the inductive effect of the adjacent carbonyl.
In the instance of the tertiary amines 2e–h, as well as N-aryl
product 2i, nitrosation failed. Similarly, when 2e–h were
treated with sodium nitrite in sulfuric acid in which they re-
mained soluble in the presence of aqueous sodium nitrite, no
reaction occurred, indicating that contact was not the issue.
2.2. Generation of 4,6-diaminopyrimidines, and
subsequent electrophilic substitution reactions
In the cases where nitrosation proved problematic, the dis-
placement of the second chlorine moiety in 2e–i was accom-
plished under forcing conditions (toluene, 130 ꢀC, pressure
tube, 18 h) using the required primary or secondary amines.3
When using secondary amines as nucleophiles for reaction
with secondary amines 2a–d, yields of 4,6-disubstituted py-
rimidines 5a–f were modest in most cases attempted, while
the reaction with dimethylamine proving problematic due to
its volatility (Table 3). In the instance of proline derivative
2d, the corresponding amide 5e was isolated from the reac-
tion with pyrrolidine.
NR3R4
a R1 = Me, R2= H, NR3,R4 = morpholin-1-yl
b R1 = Bn, R2= H, NR3,R4 = morpholin-1-yl
c R1 = CH2CH2OH, R2 = H, NR3,R4 = morpholin-1-yl
d R1 = Me, R2 = H, NR3,R4 = pyrrolidin-1-yl
e R1 = -CH(Bn)CON(C4H8),
N
Chlorides 3a–c were subsequently treated with each of the
desired secondary amines in dichloromethane at room tem-
perature, smoothly generating the substituted 4,6-di-amino-
5-nitrosopyrimidines 4a–g (Table 2). The exceptions were
products 4b and 4g, which were prepared by heating 3a
and 3c in neat pyrrolidine at 150 ꢀC for 1 h.
N
NR1R2
5
R2 = H, NR3,R4 = pyrrolidin-1-yl
f R1 = -CH(Bn)CO2Me, R2 = H, R3 = R4 = Me
Similarly, treating tertiary amines 2e and 2f with primary
aliphatic amines gave modest yields of bisamines 6a–c
(Table 4). No reaction was noted for the poorly basic 2-amino-
pyridine or 4-bromoaniline in the absence of strong base,
namely potassium tert-butoxide, affording bisamines 6d–f
Mechanistically, the nitrosation requires the formation of an
intermediate nitramine, with the migration of the nitroso
group to the ortho- or para-position of an aromatic ring.5

5396
C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
Table 3. Amination of secondary amines 2a–d
Amine
2a
2b
2c
2d
No.
%
No.
%
No.
%
No.
%
Morpholine
Pyrrolidine
Dimethylamine
5aa
5da
n/a
77
35
—
5ba,c
n/a
55
—
—
5ca
n/a
n/a
75
—
—
n/a
—
26
17
5eb,d
5fb
n/a
n/a¼not attempted.
a
Fused at 250 ꢀC.
b
Boiled in toluene in a sealed tube at 130 ꢀC.
Potassium tert-butoxide added.
Isolated as the 2-hydroxyethyl amide.
c
d
Table 4. Amination of tertiary amines 2e and fa
NR3R4
a R1 = Bn, R2 = H, R3,R4 = pyrrolidin-1-yl
N
N
N
N
HNO3
NO2
b R1= CH2CH2OH, R2 = H, NR3,R4 = pyrrolidin-1-yl
c R1 = CH2CH2OH, R2 = H,
N
N
N
H2SO4
R3,R4 = prolin-1-yl (ethanolamine amide)
d R1 = 4-BrPh-, R2 = H, NR3,R4 = pyrrolidin-1-yl
e R1 = 4-BrPh-, R2 = H,
NR3,R4 = prolin-1-yl (free acid form)
f R1 = 2-Py, R2 = H, R3,R4 = pyrrolidin-1-yl
N
NR1R2
N
H
N
N
H
N
6
6f
7
Sponge
Nickel
Amine
2e
2f
No.
Yield
No.
Yield
N
N
NH2
Benzylamine
6a
46
50
37
15a
n/a
—
54
20a
—
Ethanolamine
4-Bromoaniline
2-Aminopyridine
6b
6cc
6db
6fb
6eb,d
n/a
N
N
H
N
Scheme 2. Nitration of 6f and reduction of the nitro group.
n/a¼not attempted.
a
Boiled in toluene in a sealed tube at 130 ꢀC.
Potassium tert-butoxide added.
b
c
d
in aqueous sulfuric acid with sodium dithionite, affording
a readily filterable solid (Scheme 3).
Isolated as the pyrrolidin-1-yl amide.
Isolated as the free acid.
NR3R4
NO
NR3R4
NH2
Dithionite
H2SO4, Δ
in poor yield. Under these conditions, the amination of 2f
afforded amide 6c with ethanolamine, while the poorly basic
4-bromoaniline afforded the free acid 6e.
N
N
R1 = H
N
NR1R2
N
NR1R2
8
4
It was reasoned that the presence of a secondary amine in
products 5a–f and 6a–f, along with the additional electro-
philic activation afforded by the second amino moiety,
should be sufficient to allow electrophilic nitrosation to oc-
cur at C-5. However, attempted nitrosation of 6d and 6e as
test cases failed in both acetic acid and concentrated mineral
acid, despite their solubility in the latter case.
CH(OEt)3
Ac2O
Δ
NR3R4
N
N
N
N
R2
9
To assure ourselves of the nucleophilicity of pyrimidines
5a–f and 6a–f, a stronger electrophile was used as a test case
(Scheme 2). Nitration of 6f using 65% nitric acid in concen-
trated sulfuric acid afforded 5-nitropyrimidine 7 (83% yield).
Reduction hereof in boiling ethanol using sponge nickel
occurred readily, but the amino product decomposed when
the filtrate was concentrated after removing the catalyst.
This would therefore support the assumption that a stronger,
softer electrophile would be better suited to react directly
with these bisamines at C-5.
Scheme 3. Reduction and cyclisation of bisaminated 5-nitroso-pyrimidines
4b–g.
Recrystallisation produced pure products 8b–g in modest
to good yields (Table 5). Portions of the resultant triamines
8b–g were treated with triethyl orthoformate and acetic anhy-
dride, producing purines 9a–e. Ethanolamine derivatives
8e and 8f produced complex mixtures of products along
with the desired systems, the mixtures were not purified suf-
ficiently for conclusive characterisation.
2.3. Reduction of 5-nitrosopyrimidines 4b–f, and ring
closure of the amines
Interestingly, the analysis of the chlorides 2a–h,j, 3a–c and
4a–f proved problematic showing great instability under
electrospray mass spectral conditions in most cases. This
also adds credence to the observed reactivity of these
Reduction of nitroso products 4b–g was readily accom-
plished by treating a warm mixture of the nitroso product

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
5397
at a flow rate of 1 cm3/min. Mass spectra were recorded in
the ES+ mode using a 32 V source on a Waters LCT-Pre-
miere TOF MS system with MassLynx V 4.1 software. Sam-
ples were dissolved in methanol containing reserpine
(100 pg/mL) and recorded by direct infusion at a flow rate
of 20 mL/min. The ion abundances were controlled by dilu-
tion or by altering the capillary voltages. Infrared spectra
were recorded on a Bruker Tensor 22 system. Melting points
were determined with a Reichert Hotstage microscope and
are uncorrected. Standard workup refers to extraction with
an organic solvent, followed by drying with magnesium
sulfate, and vacuum distillation of the solvent on a rotary
evaporator.
Table 5. Reduction of 4b–g and cyclisation of the 5-amino compounds 8b–g
NR3R4
X
NR3R4
b R2 = Me, NR3,R4 = pyrrolidin-1-yl
c R2= Bn, R3,R4 = -NMe2
d R2= Bn, NR3,R4 = pyrrolidin-1-yl
e R2= Bn, NR3,R4 = morpholin-1-yl
f R2 = CH2CH2OH, R3,R4 = -NMe2
g R2 = CH2CH2OH, NR3,R4 = pyrrolidin-1-yl
N
N
N
N
N
NHR2
N
R2
4 X = NO
8 X = NH2
9
Nitroso product
Dithionite reduction
Cyclisation
Yield (%)
No.
Yield (%)
No.
4b
4c
4d
4e
4f
8b
8c
8d
8e
8f
86
80
87
70
54
71
9b
9c
9d
9e
9f
67
88
80
68
Mixture
Mixture
4.2. General method for the monoamination of 4,6-
dichloropyrimidine (1)
4g
8g
9g
structures in the above instances. Furthermore, the purines
9b–e showed similar trends, consistently adding water under
the mild ionisation conditions employed to afford stable
formamides in the ion trap, along with detectable amounts
of the product derived by the loss of formamide in all
instances.
A solution of 1 in isopropyl alcohol (1.0 M) containing
either amine (2.1 equiv) or a mixture of amine (1.2 equiv)
and triethylamine (1.2 equiv) was refluxed for 1–5 h, until
all the starting material was consumed. The solvent was re-
moved under vacuum, and the resulting viscous mass parti-
tioned between water and ethyl acetate or dichloromethane.
Extraction and standard workup, followed by column chro-
matography afforded the pure products. In this manner the
following products were obtained:
3. Conclusion
In summary, we have uncovered a series of unexpected and
obscure effects influencing the electrophilic nitrosation of
activated pyrimidines. These include structural factors (the
inability of trisubstituted amino moieties to promote electro-
philic nitrosation in the presence of a competing deactivator
2e–h,j and in bisactivated cases 5a–f and 6a–f), despite the
precedent for this with trisubstituted anilines, as well as pos-
sible electronic factors contributing to a similar inability
with N-aryl substituted 4-aminopyrimidines. Interestingly,
the presence of a C-6 N-alkyl amino moiety in 5a–f and
6a–f does not promote nitrosation in the presence of a C-4
N,N-dialkyl- or N-aryl group on the same pyrimidine system,
despite the mechanistic precedent for the promotion of nitro-
sation in the presence of such functionality.
4.2.1. 6-Chloro-N-methylpyrimidin-4-amine (2a).7 Com-
pound 1 (10.03 g, 67.12 mmol), isopropyl alcohol (168 cm3),
methylamine hydrochloride (5.06 g, 74.97 mmol) and tri-
ethylamine (10.3 cm3, 73.8 mmol) afforded, after column
chromatography using 10% ethyl acetate/hexane as eluent,
2a (7.26 g, 75%) as a white crystalline solid. Recrystallised
to white needles, mp 136–138 ꢀC (hexane), lit.7b 137–
138 ꢀC (hexane); Rf (50% ethyl acetate/hexane) 0.42; nmax
(KBr pellet) 3253, 3111, 1627, 1574, 1434, 1388, 1331,
1228, 1145, 1099, 981, 893, 839, 747 cmꢂ1; dH (200 MHz,
CDCl3) 8.33 (1H, s, H-2), 6.35 (1H, s, H-5), 5.72 (1H, br
s, NH) and 2.94 (3H, d, NHMe, J 5.2); dC (50 MHz,
CDCl3) 164.0 (C-6), 160.8 (C-4), 158.2 (C-2), 101.3 (br,
C-5) and 28.2 (NHMe); tR 3.10 min (B); HRMS (ES):
MH+, found 144.0322. C5H7ClN3 requires 144.0323.
4. Experimental
4.2.2. N-Benzyl-6-chloropyrimidin-4-amine (2b).3a,8
Compound 1 (10.04 g, 67.36 mmol), isopropyl alcohol
(168 cm3), benzylamine (8.07 cm3, 73.84 mmol) and tri-
ethylamine (10.3 cm3, 73.8 mmol) afforded, after column
chromatography using 10% ethyl acetate/hexane as eluent,
2b (12.66 g, 85%) as an orange solid. Recrystallised to white
rhomboid needles, mp 119–120 ꢀC (hexane), lit.3a 121 ꢀC
(ethyl acetate/petroleum ether); Rf (20% ethyl acetate/hex-
ane) 0.26; nmax (KBr pellet) 3218, 3073, 2991, 2857, 1594,
1494, 1400, 1346, 1314, 1156, 1099, 979, 936, 907, 824,
757, 740, 696 cmꢂ1; dH (200 MHz, CDCl3) 8.09 (1H, s,
H-2), 7.19–7.43 (5H, m, aryl H), 6.42 (1H, br s, NH), 6.36
(1H, s, H-5) and 4.50 (2H, d, PhCH2, J 5.4); dC (50 MHz,
CDCl3) 163.2 (C-6), 159.7 (C-4), 158.2 (C-2), 136.8 (quater-
nary aryl C), 128.8, 127.9 and 127.4 (aryl C), 101.9 (br, C-5)
and 45.6 (PhCH2); tR 14.28 min (B); m/z (ES) 221 (40), 220
(36, MH+), 219 (100, M+), 218 (65), 185 (15), 106 (96), 91
(98), 79 (37), 77 (19), 65 (49), 52 (23), 51 (27%); HRMS
(ES): MH+, found 220.0726. C11H11ClN3 requires
220.0636.
4.1. General procedures
All starting materials used were commercially obtained and
used as obtained from the supplier without further purifica-
tion. Column chromatography was performed using Merck
Kiesel gel 60 (particle size 0.040–0.063 mm), while thin
layer chromatography was done on Merck aluminium-sup-
ported silica gel 60 F254. NMR spectra were recorded on
a Varian Gemini 200 NMR spectrometer operating at
200 MHz. Chemical shift data are recorded in parts per mil-
lion, and coupling constants are quoted in hertz. HPLC data
were recorded on a Waters Liquid Chromatograph system
using a Varian 9050 UV–vis detector operating at 254 nm.
All separations were done using a PhenomenexÒ LunaÔ
5m C-18(2) 150 mmꢁ4.60 mm column using an isocratic
elution system, detecting at 254 nm. Solvents used were
either pure methanol (A) or 50% methanol: 25 mM aqueous
ammonium acetate buffer at pH 4 (B) as indicated, eluting

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C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
4.2.3. 2-[(6-Chloropyrimidin-4-yl)amino]ethanol (2c).9
Compound (10.08 g, 67.64 mmol) in isopropyl
4.2.6. Methyl 1-(6-chloropyrimidin-4-yl)pyrrolidine-
2-carboxylate (2f).11 A solution of L-proline (14.26 g,
0.12 mol) in methanol (100 cm3) was treated with hydrogen
chloride gas for 30 min, then left to stir for 1 h. The solution
was then concentrated to dryness, and the methyl ester hy-
drochloride was used without characterisation. A solution
hereof, 1 (15.01 g, 0.10 mol) and triethylamine (31.3 cm3,
0.23 mol) in isopropyl alcohol (100 cm3) was treated as
per the general method. Chromatography (using 20% ethyl
acetate/hexane as eluent) afforded 2f, a viscous orange oil
(19.74 g, 81%); Rf (20% ethyl acetate/hexane) 0.29; dH
(200 MHz, CDCl3) 8.39 (1H, s, H-2), 6.39 (1H, br s, H-5),
4.63 (1H, br s, COCH), 3.73 (3H, s, OMe), 3.81–3.28 (2H,
two overlapping br s, NCH2) and 2.41–1.95 [4H, m,
(CH2)2]; dC (50 MHz, CDCl3) 172.8 (CO), 160.9 (C-6),
159.8 (C-4), 158.0 (C-2), 101.2 (C-5), 59.8 (OMe), 52.2
(COCH), 46.5 (NCH2), 30.1 and 24.1 [(CH2)2]; tR
5.27 min (B). The product could not be purified sufficiently
and was used as-is without further characterisation.
1
alcohol (168 cm3) containing ethanolamine (4.25 cm3,
70.48 mmol) and triethylamine (10.3 cm3, 73.8 mmol) af-
forded, after column chromatography using 10% ethyl
acetate/hexane as eluent, 2c (9.19 g, 78%) as a beige
solid. Recrystallised to white needle clusters, mp 110–
112 ꢀC (ethyl acetate/hexane), lit.9 115–116 ꢀC (ethyl
acetate); Rf (ethyl acetate) 0.40; nmax (KBr pellet) 3600–
3100 (br), 2920, 1614, 1403, 1334, 1090, 997, 954, 910,
877, 817, 746, 689 cmꢂ1; dH (200 MHz, CDCl3+DMSO-
d6) 8.22 (1H, s, H-2), 6.45 (1H, br s, NH), 6.35 (1H, s,
H-5), 3.70 (2H, t, OCH2, J 5.0) and 3.41 (3H, br s, OH
and NHCH2); dC (50 MHz, CDCl3+DMSO-d6) 163.8
(C-6), 158.4 (C-2 and C-4), 103.3 (br, C-5), 61.1
(OCH2) and 44.2 (NHCH2); tR 2.40 min (B); HRMS
(ES): MH+, found 174.0482. C6H9ClN3O requires
174.0429.
4.2.4. Methyl (2R)-2-[(6-chloropyrimidin-4-yl)amino]-
3-phenylpropanoate (2d).10 Compound
1
(10.04 g,
4.2.7. 6-Chloro-N,N-dimethylpyrimidin-4-amine (2g).12
Compound 1 (15.03 g, 0.10 mol), dimethylamine (60% in
water, 9.20 cm3, 0.12 mol) and triethylamine (17.07 cm3,
0.12 mol) in isopropyl alcohol (100 cm3) were treated as
per the general method. Chromatography (using 10–20%
ethyl acetate/hexane as eluent) afforded beige crystals of
2g (16.73 g, quant.). Recrystallised to white blocks, mp
99–100 ꢀC (ethyl acetate/hexane), lit.12b 102–103 ꢀC (hep-
tane); Rf (20% ethyl acetate/hexane) 0.29; nmax (KBr pellet)
3080, 2932, 1582, 1499, 1398, 1344, 1299, 1184, 1107, 989,
966, 858, 738 cmꢂ1; dH (200 MHz, CDCl3) 8.38 (1H, s,
H-2), 6.39 (1H, s, H-5) and 3.14 (6H, s, NMe2); dC
(50 MHz, CDCl3) 159.2 (C-6), 158.9 (C-4), 158.0 (C-2),
101.3 (C-5) and 37.8 (NMe2); tR 4.48 min (B); HRMS
(ES): MH+, found 158.0490. C6H9ClN3 requires 158.0485.
67.38 mmol), isopropyl alcohol (168 cm3), L-phenylalanine
methyl ester hydrochloride [freshly prepared from L-phenyl-
alanine (12.32 g, 74.57 mmol) in methanol (75 cm3) that
was treated with hydrogen chloride gas] and triethylamine
(19.6 cm3, 0.14 mol) afforded, after column chromato-
graphy using 10–20% ethyl acetate/hexane as eluent, 2d
(2.08 g, 11%) as an orange oil; Rf (20% ethyl acetate/
hexane) 0.28; nmax (solid ATR) 3241, 3091, 2953, 1743,
1572, 1498, 1455, 1236, 1116, 1091, 842, 756, 695 cmꢂ1
;
dH (200 MHz, CDCl3) 8.35 (1H, s, H-2), 7.01–7.35
(5H, m, aryl H), 6.36 (1H, s, H-5), 5.79 (1H, br d, NH,
J 7.6), 4.68–5.21 (1H, br m, CHCO), 3.75 (3H, s, OCH3)
3.24 (1H, dd, PhCHaHb, J 5.6 and 13.8) and 3.41 (1H,
dd, PhCHaHb, J 6.4 and 14.0); dC (50 MHz, CDCl3) 172.0
(CO), 162.1 (C-6), 159.1 (C-4), 158.3 (C-2), 135.5 (quater-
nary aryl C), 129.1, 128.5 and 127.1 (aryl C), 103.9 (br, C-5),
54.6 (OCH3), 52.3 (PhCH2) and 37.8 (CHCO); tR 1.87 min
(A); m/z (ES) 291 (6, M+), 234 (26, MH+ꢂCO2Me),
232 (75), 202 (60), 200 (98), 168 (26), 163 (27), 162
(100), 142 (37), 140 (79), 131 (23), 129 (22), 113 (51),
103 (29), 91 (70), 77 (21), 65 (23), 51 (19%); HRMS
(ES): MH+, found 292.0944. C14H15ClN3O2 requires
292.0853.
4.2.8. 4-(6-Chloropyrimidin-4-yl)morpholine (2h).12a
Compound 1 (15.00 g, 0.10 mol) and morpholine (18.00 g,
0.21 mol) in isopropyl alcohol (100 cm3) were treated as
per the general method. Concentration of the extract af-
€
forded a crystalline solid. This was washed on a Buchner
funnel with saturated aqueous sodium bicarbonate, followed
by the minimum of ethyl acetate to remove water to yield
beige crystals of 2h (18.30 g, 92%). Recrystallised to white
needles, mp 154–155 ꢀC (ethyl acetate/hexane), lit.12a 151–
152 ꢀC (ethyl acetate/hexane); Rf (20% ethyl acetate/hex-
ane) 0.26; nmax (KBr pellet) 3070, 2970, 2870, 1584, 1526,
1492, 1343, 1112, 982, 856 cmꢂ1; dH (200 MHz, CDCl3)
8.39 (1H, s, H-2), 6.48 (1H, s, H-5), 3.91–3.72 [4H, m,
O(CH2)2] and 3.70–3.41 [4H, m, N(CH2)2]; dC (50 MHz,
CDCl3) 162.6 (C-6), 160.2 (C-4), 158.0 (C-2), 101.4 (C-5),
66.3 [O(CH2)2] and 44.2 [N(CH2)2]; tR 1.91 min (A); m/z
(ES) 201 (20), 200 (17), 199 (58, M+), 198 (38), 170 (38),
169 (25), 168 (93), 156 (25), 154 (27), 142 (67), 116 (31),
114 (100), 87 (33), 86 (24), 52 (25%); HRMS (ES): MH+,
found 200.0633. C8H11ClN3O requires 200.0591.
4.2.5. 6-Chloro-4-pyrrolidin-1-ylpyrimidine (2e). Com-
pound
1
(15.00 g, 0.10 mol), pyrrolidine (9.37 cm3,
0.112 mol) and triethylamine (17.1 cm3, 0.12 mol) in iso-
propyl alcohol (100 cm3) were treated as per the general
method. Column chromatography (using 10–20% ethyl ace-
tate/hexane as eluent) afforded beige crystals of 2e (17.85 g,
98%). Recrystallised to white needles, mp 93–94 ꢀC (ethyl
acetate/hexane); Rf (20% ethyl acetate/hexane) 0.28; nmax
(KBr pellet) 2984, 2871, 1593, 1494, 1416, 1349, 1326,
1177, 1094, 1012, 964, 811, 742 cmꢂ1; dH (200 MHz,
CDCl3) 8.36 (1H, s, H-2), 6.25 (1H, s, H-5), 3.58 and 3.31
[4H, 2 overlapping br s, N(CH2)2] and 2.12 [4H, br s,
(CH2)2]; dC (50 MHz, CDCl3) 160.9 (C-6), 158.9 (C-4),
158.0 (C-2), 101.0 (C-5), 46.3 [N(CH2)2] and 25.3
[(CH2)2]; tR 7.13 min (B); m/z (ES) 185 (21), 183 (48,
M+), 156 (39), 155 (63), 154 (100), 121 (18), 120 (33), 70
(27), 52 (18%); HRMS (ES): MH+, found 184.0676.
C8H11ClN3 requires 184.0642.
4.2.9. N-(4-Bromophenyl)-6-chloropyrimidin-4-amine
(2i).13 Compound 1 (9.98 g, 67.01 mmol) in isopropyl alco-
hol (168 cm3) containing 4-bromoaniline (12.10 g,
69.50 mmol) and triethylamine (10.3 cm3, 73.8 mmol) was
heated as per the general procedure. An equal volume of
water and ethyl acetate were then added, and the resultant

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
5399
suspension filtered off to yield 2i (12.73 g, 67%) as a beige
powder. Recrystallised to a beige powder, mp 220–222 ꢀC
(ethyl acetate/hexane); Rf (20% ethyl acetate/hexane) 0.35;
nmax (KBr pellet) 3286, 3152, 3066, 1628, 1596, 1569,
1505, 1488, 1456, 1403, 1327, 1284, 1265, 1228, 1096,
1073, 986, 845, 824, 808, 766 cmꢂ1; dH (200 MHz,
CDCl3) 9.11 (1H, br s, H-2), 8.05 (1H, s, NH), 7.17 (2H,
d, aryl H, J 8.8), 7.05 (2H, d, aryl H, J 9.0) and 6.40 (1H,
s, H-5); dC (50 MHz, CDCl3+DMSO-d6) 169.4 (C-6),
161.9 (C-4), 158.1 (C-2), 137.6 (quaternary aryl C), 131.7
and 122.7 (aryl C), 116.3 (quaternary aryl C) and 104.6
(C-5); tR 2.15 min (A); m/z (ES) 286 (34), 285 (68), 284
(100, M+), 283 (55), 282 (87%); HRMS (ES): M+, found
284.1569. C10H781Br35ClN3 requires 284.9491.
sodium hydroxide and partially concentrated to an orange
oil. This was seeded, and combined with the filtered solids
to afford 3c (8.54 g, 80%) as a pale orange powder. Recrys-
tallised to clumps of yellow blocks, mp 79–80 ꢀC (hexane);
Rf (20% ethyl acetate/hexane) 0.18; nmax (KBr pellet) 3377,
3094, 1569, 1455, 1384, 1138, 1080, 1054, 978, 803 cmꢂ1
;
dH (200 MHz, CDCl3) 8.86 (1H, br s, H-2), 8.05 (1H, s,
NH), 4.36 (2H, t, OCH2, J 5.5), 3.73 (2H, t, NHCH2,
J 5.6) and 2.25 (1H, br s, OH); dC (50 MHz, CDCl3) 162.5
(C-6), 158.2 (C-2 and C-4), 108.1 (C-5), 59.6 (OCH2) and
42.7 (NHCH2); tR 4.52 min (A); m/z (ES) 203 (14, M+),
176 (19), 174 (58, MH+ꢂNO), 172 (25), 156 (8), 145 (32),
144 (38), 143 (100), 142 (98), 130 (28%); HRMS (ES):
MH+ꢂNO, found 174.0468. C6H9ClN3O requires 174.0434.
4.3. General method for the nitrosation of pyrimidines
4.4. General method for the amination of 5-nitroso-
pyrimidines 3a–c
A solution of the pyrimidine in either acetic acid or hydro-
chloric acid (2 M) was treated dropwise with a solution of
sodium nitrite (1.8 equiv) in water (6.3 M). Evolution of
a brown gas occurs during addition, and a solid precipitate
forms over time. The solid is filtered off, washed with water
and dried under suction. In this manner, the following prod-
ucts were obtained.
A mixture of the pyrimidine in dichloromethane (2 M) was
treated with 2 equiv of the amine required dropwise, result-
ing in spontaneous heating. The mixture was stirred for 18 h
at room temperature. The resultant solution was concen-
trated and purified by column chromatography. In this man-
ner, the following products were obtained.
4.3.1. 6-Chloro-N-methyl-5-nitrosopyrimidin-4-amine
(3a). Chloride 2a (7.26 g, 50.58 mmol) in acetic acid
(26 cm3) was treated with a solution of sodium nitrite
(6.31 g, 91.38 mmol) in water (84 cm3) dropwise over
30 min. After stirring for 2 h, 3a was filtered off (7.68 g,
88%) as a yellow powder. Recrystallised to yellow rhomboid
blocks, mp 76–78 ꢀC (hexane); Rf (20% ethyl acetate/hex-
ane) 0.59; nmax (KBr pellet) 3095, 1568, 1490, 1455, 1212,
1145, 1079, 957, 888, 781 cmꢂ1; dH (200 MHz, CDCl3)
8.83 (1H, s, H-2), 8.06 (1H, s, NH) and 3.45 (3H, s,
NHMe); dC (50 MHz, CDCl3) 161.9 (C-4 and C-6), 158.4
(C-2), 107.9 (C-5) and 27.6 (NHMe); tR 9.10 min (B); m/z
(ES) 173 (1, MH+), 146 (33, MH+ꢂNO), 145 (21), 144
(100, M+ꢂNO), 143 (39), 130 (18%).
4.4.1. N,N,N0-Trimethyl-5-nitrosopyrimidine-4,6-di-
amine (4a). Pyrimidine 3a (0.97 g, 5.65 mmol), dichloro-
methane (2.9 cm3) and dimethylamine (33% in alcohol,
1.74 cm3, 12.75 mmol) afforded, after column chromato-
graphy using 10–30% ethyl acetate/hexane as eluent, a yel-
low solid, 4a (0.60 g, 59%) by the general method.
Recrystallised to beige blocks, mp 91–92 ꢀC (ethyl ace-
tate/hexane); Rf (20% ethyl acetate/hexane) 0.42; nmax
(KBr pellet) 2930, 1599, 1560, 1459, 1438, 1308, 1185,
1098, 1007, 975, 951, 833, 727 cmꢂ1; dH (200 MHz,
CDCl3) 8.52 (1H, s, H-2), 7.02 (1H, s, NH), 3.47 (3H, s,
NCH3) and 3.18 [6H, s, N(CH3)2]; dC (50 MHz, CDCl3)
163.1 (C-6), 160.1 (C-4), 157.4 (C-2), 87.4 (C-5), 37.5
[N(CH3)2] and 28.0 (NHCH3); HRMS (ES): MH+ꢂNO,
found 153.1136. C7H12N4 requires 153.1140.
4.3.2. N-Benzyl-6-chloro-5-nitrosopyrimidin-4-amine
(3b). Chloride 2b (12.48 g, 56.82 mmol) in concentrated hy-
drochloric acid (28 cm3) was treated with sodium nitrite
(7.11 g, 0.10 mol) in water (95 cm3) dropwise over
30 min. The pale beige powder that deposited over 18 h
was isolated, affording 3b (12.75 g, 90%). Recrystallised
to small yellow rhomboid blocks, mp 110–112 ꢀC (hexane);
Rf (20% ethyl acetate/hexane) 0.64; nmax (KBr pellet) 3093,
1568, 1497, 1458, 1410, 1392, 1128, 1058, 926, 887,
710 cmꢂ1; dH (200 MHz, CDCl3) 8.91 (1H, br s, H-2),
8.08 (1H, s, NH), 7.29 (5H, br s, aryl H) and 5.37 (2H, s,
PhCH2); dC (50 MHz, CDCl3) 162.1 (C-4 and C-6), 158.4
(C-2), 134.2 (quaternary aryl C), 128.6, 128.3 and 127.9
(aryl C), 108.0 (C-5) and 43.6 (PhCH2); tR 2.12 min (A);
m/z (ES) 222 (23), 221 (26), 220 (100), 219 (65, MH+ꢂNO),
218 (80), 106 (12%).
4.4.2. N-Methyl-5-nitroso-6-pyrrolidin-1-ylpyrimidin-4-
amine (4b). Pyrimidine 3a (0.97 g, 5.61 mmol) and neat
pyrrolidine (1.16 cm3, 13.91 mmol) was heated to 150 ꢀC
for 1 h. The resultant black solution was purified by chroma-
tography using 10–30% ethyl acetate/hexane as eluent to
yield a yellow solid, 4b (0.97 g, 83%). Recrystallised to yel-
low rhomboid plates, mp 93–95 ꢀC (ethyl acetate/hexane);
Rf (20% ethyl acetate/hexane) 0.28; nmax (KBr pellet)
3048, 2974, 2868, 1598, 1552, 1510, 1442, 1333, 1300,
1237, 1183, 1153, 1099, 1051, 1021, 960, 861, 819, 788,
728 cmꢂ1; dH (200 MHz, CDCl3) 8.44 (1H, s, H-2), 6.80
(1H, s, NH), 3.48 [4H, br s, N(CH2)2], 3.40 (3H, s,
NHCH3) and 1.78–2.13 [4H, br m, (CH2)2]; dC (50 MHz,
CDCl3) 160.7 (C-6), 159.5 (C-4), 157.8 (C-2), 88.1 (C-5),
46.5 [N(CH2)2], 27.8 (NHCH3) and 25.1 [(CH2)2]; tR
11.57 min (B); m/z (ES) 208 (1, MH+), 180 (10), 179
(100), 178 (89, MH+ꢂNO), 177 (49, M+ꢂNO), 150 (51),
149 (15), 123 (12%).
4.3.3. 2-[(6-Chloro-5-nitrosopyrimidin-4-yl)amino]etha-
nol (3c). Chloride 2c (9.19 g, 52.96 mmol) in acetic acid
(26 cm3), sodium nitrite (6.65 g, 96.32 mol) and water
(132 cm3) were treated as before. The solids that formed
over 18 h were isolated, and the solution extracted with ethyl
acetate. The organic phase was washed with 2 M aqueous
4.4.3. N-Benzyl-N0,N0-dimethyl-5-nitrosopyrimidin-4,6-
diamine (4c). Pyrimidine 3b (0.51 g, 2.04 mmol), dichloro-
methane (1 cm3) and dimethylamine (33% in alcohol,

5400
C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
1.00 cm3, 7.32 mmol) afforded, after column chromato-
graphy using 10–30% ethyl acetate/hexane as eluent,
a pale yellow solid, 4c (0.48 g, 91%) by the general method.
Recrystallised to clusters of yellow needles, mp 84–85 ꢀC
(ethyl acetate/hexane); Rf (20% ethyl acetate/hexane) 0.39;
nmax (KBr pellet) 3032, 2995, 2930, 1613, 1446, 1197,
1112, 995, 937, 895, 857, 818, 715 cmꢂ1; dH (200 MHz,
CDCl3) 8.57 (1H, s, H-2), 7.21–7.31 (5H, m, aryl H), 7.05
(1H, s, NH), 5.39 (2H, s, PhCH2) and 3.18 [6H, s,
N(CH3)2]; dC (50 MHz, CDCl3) 163.2 (C-6), 159.9 (C-4),
157.5 (C-2), 135.1 (quaternary aryl C), 128.3, 128.2 and
127.4 (aryl C), 87.6 (C-5), 43.7 (PhCH2) and 37.5
[N(CH3)2]; tR 2.17 min (A); HRMS (ES): MH+, found
258.1362. C13H16N5O requires 258.1355.
pellet) 3309, 2885, 1602, 1523, 1443, 1410, 1333, 1202,
1122, 1094, 1058, 1013, 983, 864, 840, 814, 762 cmꢂ1; dH
(200 MHz, CDCl3) 8.48 (1H, s, H-2), 6.97 (1H, s, NH),
4.30 (2H, t, OCH2, J 4.9), 3.69 (2H, t, NHCH2, J 4.9) and
3.19 [6H, s, N(CH3)2]; dC (50 MHz, CDCl3) 163.1 (C-6),
159.9 (C-4), 157.0 (C-2), 88.0 (C-5), 60.3 (OCH2), 44.1
(NHCH2) and 37.5 [N(CH3)2]; tR 3.87 min (B); HRMS
(ES): MH+, found 212.1154. C8H14N5O2 requires 212.1147.
4.4.7. 2-[(5-Nitroso-6-pyrrolidin-1-ylpyrimidin-4-yl)ami-
no]ethanol (4g). Pyrimidine 3c (0.96 g, 4.76 mmol) and
neat pyrrolidine (0.98 cm3, 11.85 mmol) were heated to
150 ꢀC for 1 h. The resultant black solution was purified
by chromatography using 20–50% ethyl acetate/hexane as
eluent to afford a beige solid, 4g (0.41 g, 37%). Recrystal-
lised to yellow needles, mp 162–164 ꢀC (ethyl acetate/hex-
ane); Rf (50% ethyl acetate/hexane) 0.26; nmax (KBr pellet)
3220, 3102, 2994, 2965, 2868, 2824, 1736, 1589, 1479,
1442, 1253, 1234, 1115, 1097, 1012, 978, 904, 803, 750,
702 cmꢂ1; dH (200 MHz, CDCl3) 8.49 (1H, s, H-2), 6.84
(1H, s, NH), 4.31 (2H, ca. t, OCH2, J 4.8), 3.70 (2H, ca. t,
NHCH2, J 4.9), 3.11–3.85 [4H, br m, N(CH2)2] and 1.82–
2.23 [4H, br m, (CH2)2]; dC (50 MHz, CDCl3) 160.9 (C-6),
159.5 (C-4), 157.3 (C-2), 89.0 (C-5), 60.4 (OCH2), 46.8
[br, N(CH2)2], 44.1 (NHCH2) and 25.3 [br, (CH2)2]; tR
6.43 min (B); m/z (ES) 237 (2, M+), 207 (28), 178 (28),
177 (100), 164 (19), 149 (27), 148 (22), 147 (19), 136
(19), 135 (18), 121 (30), 79 (20), 70 (32), 67 (17%);
HRMS (ES): MH+, found 238.1348. C10H16N5O2 requires
238.1304.
4.4.4. N-Benzyl-5-nitroso-6-pyrrolidin-1-ylpyrimidin-4-
amine (4d). Pyrimidine 3b (0.50 g, 2.00 mmol), dichloro-
methane (1 cm3) and pyrrolidine (0.34 cm3, 4.02 mmol) af-
forded, after column chromatography using 10–30% ethyl
acetate/hexane as eluent, a pale yellow solid, 4d (0.53 g,
94%) by the general method. Recrystallised to clusters of
yellow needles, mp 126–127 ꢀC (ethyl acetate/hexane); Rf
(20% ethyl acetate/hexane) 0.36; nmax (KBr pellet) 3035,
2974, 2866, 1598, 1549, 1509, 1475, 1439, 1333, 1319,
1219, 1097, 1078, 1051, 1007, 900, 822, 749, 722,
703 cmꢂ1; dH (200 MHz, CDCl3) 8.56 (1H, s, H-2), 7.15–
7.31 (5H, m, aryl H), 6.90 (1H, s, NH), 5.39 (2H, s,
PhCH2), 3.53 [4H, br s, N(CH2)2] and 1.87–2.21 [4H, br
m, (CH2)2]; dC (50 MHz, CDCl3) 160.9 (C-6), 159.4 (C-4),
157.7 (C-2), 135.1 (quaternary aryl C), 128.3, 128.1 and
127.3 (aryl C), 88.5 (C-5), 46.7 [N(CH2)2], 43.6 (PhCH2)
and 25.2 [(CH2)2]; tR 2.28 min (A); HRMS (ES): MH+,
found 284.1519. C15H18N5O requires 284.1511.
4.5. General method for the amination of
chloropyrimidines 2a–f
4.4.5. N-Benzyl-6-morpholin-4-yl-5-nitrosopyrimidin-
4-amine (4e). A mixture of pyrimidine 3b (1.46 g,
5.87 mmol) in dichloromethane (10 cm3) was treated with
morpholine (1.23 g, 14.1 mmol) dropwise, resulting in spon-
taneous heating. The mixture was stirred overnight at room
temperature. The resultant deep yellow solution was poured
into ethyl acetate (20 cm3) and washed with an equal volume
of water. The solvent was removed to generate a sticky solid
that was triturated in hexane. Compound 4e was collected as
a yellow solid by filtration (1.42 g, 85%). Recrystallised to
yellow needles, mp 122–124 ꢀC (ethyl acetate/hexane); Rf
(20% ethyl acetate/hexane) 0.33; nmax (solid ATR) 2868,
1658, 1438, 1221, 1102, 980, 901, 827, 694 cmꢂ1; dH
(200 MHz, CDCl3) 8.60 (1H, s, H-2), 7.26 (5H, br s, aryl
H), 7.14 (1H, s, NH), 5.39 (2H, s, PhCH2), 3.80 [4H, m,
O(CH2)2] and 3.72 [4H, m, N(CH2)2]; dC (50 MHz,
CDCl3) 163.5 (C-6), 161.0 (C-4), 157.5 (C-2), 135.0 (quater-
nary aryl C), 128.7, 128.5 and 127.7 (aryl C), 87.8 (C-5),
66.5 [O(CH2)2], 45.0 [N(CH2)2] and 43.5 (PhCH2); tR
2.11 min (A). Used without further characterisation.
A mixture of the chloride and the required amine (2.1 equiv)
were either fused at 250 ꢀC for 1 h or boiled in toluene
(0.5 M) in a sealed tube at 130 ꢀC for 18 h. Partitioning be-
tween water and ethyl acetate, drying and concentration, fol-
lowed by column chromatography, affording the following
products.
4.5.1. N-Methyl-6-morpholin-4-ylpyrimidin-4-amine
(5a). Chloride 2a (1.45 g, 10.11 mmol) and morpholine
(2.28 cm3, 22.23 mmol) were fused, affording a yellow pow-
der, 5a (1.51 g, 77%) after chromatography with 30–50%
ethyl acetate/hexane. Recrystallised to fine beige needles,
mp 130–132 ꢀC (ethyl acetate/hexane); Rf (ethyl acetate)
0.21; nmax (KBr pellet) 3249, 3102, 2968, 2856, 1599,
1442, 1234, 1112, 992, 801 cmꢂ1; dH (200 MHz, CDCl3)
8.14 (1H, s, H-2), 5.37 (1H, s, H-5), 5.05 (1H, br s, NH),
3.77 [4H, t, O(CH2)2, J 4.9], 3.54 [4H, t, N(CH2)2, J 4.9]
and 2.87 (3H, d, NHCH3, J 5.2); dC (50 MHz, CDCl3)
163.7 and 163.1 (C-4 and C-6), 157.2 (C-2), 79.9 (C-5),
66.5 [O(CH2)2], 44.5 [N(CH2)2] and 28.4 (NHCH3); tR
2.11 min (B); m/z (ES) 194 (100, M+), 193 (25), 164 (49),
163 (94), 149 (49), 137 (88), 136 (26), 109 (88), 82 (33),
81 (24), 57 (21%); HRMS (ES): MH+, found 195.1267.
C9H15N4O requires 195.1246.
4.4.6. 2-{[6-(Dimethylamino)-5-nitroso-pyrimidin-4-
yl]amino}ethanol (4f). Pyrimidine 3c (1.02 g, 5.03 mmol),
dichloromethane (2.5 cm3) and dimethylamine (33% in al-
cohol, 1.48 cm3, 10.86 mmol) afforded, after column chro-
matography using 20–50% ethyl acetate/hexane as eluent,
a yellow solid, 4f (0.76 g, 72%) by the general method. Re-
crystallised to yellow needles, mp 76–78 ꢀC (ethyl acetate/
hexane); Rf (50% ethyl acetate/hexane) 0.28; nmax (KBr
4.5.2. N-Benzyl-6-morpholin-4-ylpyrimidin-4-amine
(5b).8a Chloride 2b (2.29 g, 10.44 mmol) and morpholine
(2.00 cm3, 23.00 mmol) in the presence of potassium tert-
butoxide (1.28 g, 11.48 mmol) were fused at 250 ꢀC for

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
5401
1 h. This was taken up in ethyl acetate (50 cm3), washed with
water (50 cm3), dried (MgSO4) and concentrated to a brown
gum. Column chromatography (20–50% ethyl acetate/hex-
ane as eluent) afforded a tacky yellow solid. This was dis-
solved in acetone, and the solid precipitated with hexane
to afford 5b, a yellow powder (1.56 g, 55%). Recrystallised
to a beige powder, mp 160–162 ꢀC (ethyl acetate/hexane); Rf
(50% ethyl acetate/hexane) 0.21; nmax (KBr pellet) 3220,
3102, 2994, 2965, 2868, 2824, 1588, 1442, 1233, 1204,
1115, 1012, 978, 904, 803, 766, 750, 702 cmꢂ1; dH
(200 MHz, CDCl3) 8.16 (1H, s, H-2), 7.48–7.05 (5H, m,
aryl H), 5.39 (2H, br m, H-5 and NH), 4.46 (2H, d,
PhCH2, J 6.0), 3.74 [4H, t, O(CH2)2, J 4.9] and 3.48 [4H,
t, N(CH2)2, J 4.9]; dC (50 MHz, CDCl3) 162.9 and 162.8
(C-4 and C-6), 157.3 (C-2), 138.0 (quaternary phenyl C),
128.8, 127.5 and 127.2 (phenyl CH), 81.0 (C-5), 66.5
[O(CH2)2], 45.8 (PhCH2) and 44.5 [N(CH2)2]; tR 6.82 min
(B); HRMS (ES): MH+, found 271.1553. C15H19N4O re-
quires 271.1559.
804, 740, 700 cmꢂ1; dH (200 MHz, CDCl3) 8.18 (1H, br s,
H-2), 7.41–7.09 (5H, m, aryl H), 5.45 (1H, br d, NH,
J 8.8), 5.25 (1H, s, H-5), 5.03 (1H, dt, NHCH, J 14.2 and
6.0), 3.62–3.19 [3H, m, CONCHaHb(CH2)–], 3.38 [4H, t,
N(CH2)2, J 7.0], 3.13 (1H, dd, PhCHaHb, J 13.2 and 7.2),
3.02 (1H, dd, PhCHaHb, J 13.0 and 9.2), 2.80–2.42 [1H,
m, CONCHaHb(CH2)–], 2.13–1.82 and 1.82–1.44 [8h,
2ꢁm, 2ꢁ(CH2)2]; dC (50 MHz, CDCl3) 170.6 (CO), 161.2
and 160.2 (C-4 and C-6), 157.5 (C-2), 137.0 (quaternary
phenyl C), 129.4, 128.2 and 126.7 (phenyl CH), 82.9
(C-5), 53.8 (NHCH), 46.3 and 45.7 [CON(CH2)2], 46.2
[N(CH2)2], 39.7 (PhCH2), 25.3, 25.1 and 24.0 [2ꢁ(CH2)2];
tR 13.65 min (B); m/z (ES) 365 (1, M+), 292 (41), 274
(80), 268 (40), 267 (100), 204 (26), 203 (98), 164 (19),
121 (75), 70 (24), 55 (23%); HRMS (ES): MH+, found
366.2252. C21H28N5O requires 366.2294.
4.5.6. Methyl 2-{[6-(dimethylamino)pyrimidin-4-yl]-
amino}-3-phenylpropanoate (5f). Chloride 2d (0.98 g,
3.37 mmol), dimethylamine (33% in ethanol, 3.0 cm3,
22.0 mmol) and toluene (7 cm3) afforded an orange solid,
5f (0.21 g, 17%) after chromatography (ethyl acetate to
10% methanol/ethyl acetate as eluent). Recrystallised to
beige blocks, mp 145–147 ꢀC (ethyl acetate/hexane); Rf
(10% methanol/ethyl acetate) 0.63; nmax (KBr pellet) 3284,
2905, 2801, 1645, 1584, 1505, 1454, 1306, 1164, 1119,
974, 805, 716, 699 cmꢂ1; dH (200 MHz, CDCl3) 8.20 (1H,
br s, H-2), 7.38–7.11 (5H, m, aryl H), 5.47 (1H, br d, NH,
J 8.4), 5.38 (1H, s, H-5), 5.31 (1H, dt, NHCH, J 8.2 and
6.0), 3.10 (1H, dd, PhCHaHb, J 13.2 and 5.8), 3.08 (3H, s,
OCH3), 3.02 (1H, obscured dd? PhCHaHb, J 13.2 and
3.4), 2.08 and 2.73 (6H, 2ꢁs, 2ꢁCH3); dC (50 MHz,
CDCl3) 172.3 (CO), 162.5 and 161.6 (C-4 and C-6), 157.3
(C-2), 136.9 (quaternary phenyl C), 129.4, 128.3 and 126.7
(phenyl CH), 82.5 (C-5), 51.4 (OCH3), 39.8 (NHCH), 37.1
(PhCH2), 36.9 and 35.6 [N(CH3)2]; tR 6.20 min (B); m/z
(ES) 300 (15, M+), 224 (10, MH+ꢂPh), 207 (15), 206
(100), 178 (35%).
4.5.3. 2-[(6-Morpholin-4-ylpyrimidin-4-yl)amino]etha-
nol (5c). Chloride 2c (1.88 g, 10.84 mmol) and morpholine
(2.08 cm3, 23.84 mmol) were fused and purified by column
chromatography [10–20% methanol/ethyl acetate as eluent].
This afforded a waxy beige solid 5c (1.82 g, 75%). Recrys-
tallised to a beige powder, mp 123–124 ꢀC (ethyl acetate/
hexane); Rf (10% methanol/ethyl acetate) 0.35; nmax (KBr
pellet) 3500–3100 (br), 3355, 2963, 2858, 1598, 1543,
1491, 1448, 1230, 1115, 1060, 992, 782 cmꢂ1; dH
(200 MHz, CDCl3) 7.96 (1H, s, H-2), 5.65 (1H, br m,
NH), 5.35 (1H, s, H-5), 4.68 (1H, br s, OH), 3.59 [6H, t
and obscured m, O(CH2)2, J 4.8 and CH2OH], 3.34 [4H, t,
N(CH2)2, J 4.9] and 3.24 (2H, q, NHCH2, J 5.0); dC
(50 MHz, CDCl3) 169.2 and 162.4 (C-4 and C-6), 156.8
(C-2), 81.2 (C-5), 66.1 [O(CH2)2], 61.0 (CH2OH), 44.1
[N(CH2)2] and 43.8 (NHCH2); tR 1.91 min (B); HRMS
(ES): MH+, found 225.1354. C10H17N4O requires 225.1352.
4.5.4. N-Methyl-6-pyrrolidin-1-ylpyrimidin-4-amine
(5d). Chloride 2a (1.45 g, 10.11 mmol) and pyrrolidine
(1.86 cm3, 22.24 mmol) were fused. Column chromato-
graphy (10% methanol/ethyl acetate as eluent) afforded
5d, a pale brown solid (0.63 g, 35%). Recrystallised to
a beige powder, mp 180–181 ꢀC (ethyl acetate/hexane); Rf
(10% methanol/ethyl acetate) 0.44; nmax (KBr pellet) 2858,
4.5.7. N-Benzyl-6-pyrrolidin-1-ylpyrimidin-4-amine
(6a). A mixture of chloride 2e (0.98 g, 5.35 mmol), benzyl-
amine (1.24 cm3, 11.4 mmol) and toluene (5 cm3) afforded
6a, a beige solid (0.62 g, 46%) after chromatography (50%
ethyl acetate/hexane to ethyl acetate was used as the eluent).
Recrystallised to beige needles, mp 167–169 ꢀC (ethyl ace-
tate/hexane); Rf (ethyl acetate) 0.41; nmax (KBr pellet) 3210,
2962, 2858, 1590, 1446, 1338, 1279, 1100, 978, 796, 749,
699 cmꢂ1; dH (200 MHz, CDCl3) 8.15 (1H, s, H-2), 7.21–
7.40 (5H, m, aryl H), 5.30 (1H, br t, NH), 5.18 (1H, s,
H-5), 4.46 (2H, d, PhCH2, J 5.6), 3.39 [4H, br s, N(CH2)2]
and 1.90–2.05 [4H, m, (CH2)2]; dC (50 MHz, CDCl3)
162.1 (C-6), 160.6 (C-4), 157.5 (C-2), 138.4 (aryl quaternary
C), 128.6, 127.3 and 127.2 (aryl C), 80.6 (C-5), 46.2
[N(CH2)2], 45.9 (PhCH2) and 25.3 [(CH2)2]; tR 10.13 min
(B); HRMS (ES): MH+, found 255.1596. C15H19N4 requires
255.1610.
1539, 1148, 1099, 1021, 973, 795, 698 cmꢂ1
; dH
(200 MHz, CDCl3) 8.11 (1H, s, H-2), 5.13 (1H, s, H-5),
4.89 (1H, br s, NH), 3.52–3.28 [4H, m, O(CH2)2], 2.85
(3H, d, NHCH3, J 5.2) and 2.09–1.81 [4H, m, N(CH2)2];
dC (50 MHz, CDCl3) 162.8 and 160.7 (C-4 and C-6),
157.2 (C-2), 79.5 (C-5), 46.3 [O(CH2)2], 28.5 (NHCH3)
and 25.3 [N(CH2)2]; tR 2.25 min (B); HRMS (ES): MH+,
found 179.1292. C9H15N4 requires 179.1297.
4.5.5. N-(1-Benzyl-2-oxo-2-pyrrolidin-1-ylethyl)-6-pyr-
rolidin-1-ylpyrimidin-4-amine (5e). Chloride 2d (1.00 g,
3.43 mmol) and pyrrolidine (0.57 cm3, 6.89 mmol) in tolu-
ene (7 cm3) afforded an orange solid, 5e (0.33 g, 26%) after
chromatography (ethyl acetate to 10% methanol/ethyl ace-
tate as eluent). Recrystallised to a beige powder, mp 170–
171 ꢀC (ethyl acetate/hexane; dec.); Rf (10% methanol/ethyl
acetate) 0.63; nmax (KBr pellet) 3261, 3156, 2953, 2874,
1629, 1572, 1503, 1456, 1343, 1285, 1225, 1173, 973,
4.5.8. 2-[(6-Pyrrolidin-1-ylpyrimidin-4-yl)amino]ethanol
(6b). Chloride 2e (1.95 g, 5.10 mmol), ethanolamine
(1.89 cm3, 31.37 mmol) and toluene (20 cm3) gave
a beige-brown solid, 6b (1.10 g, 50%) after chromatography
(ethyl acetate to 10% methanol/ethyl acetate was used as the
eluent). Recrystallised to a beige blocks, mp 116–117 ꢀC

5402
C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
(ethyl acetate/hexane); Rf (10% methanol/ethyl acetate)
0.22; nmax (KBr pellet) 3249, 3097, 2943, 2858, 1600,
1539, 1509, 1435, 1340, 1283, 1222, 1080, 1022, 979,
790 cmꢂ1; dH (200 MHz, CDCl3) 8.07 (1H, s, H-2), 5.30
(1H, br t, NH), 5.18 (1H, s, H-5), 4.08 (1H, br s, OH), 3.78
(2H, t, CH2OH, J 4.6), 3.22–3.49 [6H, br m, N(CH2)2 and
CH2NH] and 1.90–2.05 [4H, m, (CH2)2]; dC (50 MHz,
CDCl3) 162.2 (C-6), 160.4 (C-4), 157.1 (C-2), 80.8 (C-5),
61.6 (CH2OH), 46.3 [N(CH2)2], 44.3 (CH2NH) and 25.2
[(CH2)2]; tR 2.17 min (B); HRMS (ES): MH+, found
209.1409. C10H17N4O requires 209.1402.
825, 809 cmꢂ1; dH (200 MHz, CDCl3+DMSO-d6) 9.73
(1H, br s, NH), 7.67 (1H, m, H-2), 7.46 (2H, m, aryl H),
7.28 (2H, m, aryl H), 5.07 (1H, ca. d, H-5, J 3.2), 4.23–
4.61 (1H, br m, NCHCO), 3.18–3.39 and 3.39–3.62 (2H,
2ꢁbr m, NCH2) and 1.82–2.25 [4H, m, (CH2)2]; dC
(50 MHz, CDCl3) 170.3 (CO), 161.6 (C-6), 159.6 (C-4),
147.2 (C-2), 137.0 (aryl quaternary C), 130.3 and 120.4
(aryl C), 114.6 (aryl quaternary C), 85.7 (C-5), 60.3
(NCHCO), 46.5 (NCH2), 29.4 and 22.7 [(CH2)2]; tR
11.30 min (B); m/z (ES) 364 (22, M+), 362 (24, M+), 192
(20), 165 (34), 164 (100), 70 (44), 68 (28%).
4.5.9. N-(2-Hydroxyethyl)-1-{6-[(2-hydroxyethyl)ami-
no]pyrimidin-4-yl}pyrrolidine-2-carboxamide (6c).
Chloride 2f (1.61 g, 6.67 mmol), ethanolamine (1.21 cm3,
20.0 mmol) and toluene (20 cm3) afforded a brown oil, 6c
(1.02 g, 54%) after chromatography (10–20% methanol/eth-
yl acetate as eluent); Rf (10% methanol/ethyl acetate) 0.23;
nmax (liquid ATR) 3288 (br), 2941, 2872, 1650, 1596, 1490,
1307, 1056, 979, 800 cmꢂ1; dH (200 MHz, CDCl3) 7.97 (1H,
s, H-2), 7.43 (1H, br t, CONH, J 5.0), 5.90 (1H, br t, NH,
J 5.6), 5.27 (1H, s, H-5), 4.20–4.35 (1H, br m, CHCO),
3.18–3.38 and 3.39–3.75 [10H, 2ꢁm, 2ꢁNH(CH2)2OH
and NCH2] and 1.74–2.20 [4H, m, (CH2)2]; dC (50 MHz,
CDCl3) 172.5 (CO), 162.1 (C-6), 160.1 (C-4), 156.4 (C-2),
81.3 (C-5), 60.4 (CHCO), 60.2 [2ꢁ(CH2)2OH], 46.6
(NCH2), 45.0 [NH(CH2)2], 41.3 [NH(CH2)2], 29.4 and
23.2 [(CH2)2]; tR 1.77 min (B); HRMS (ES): MH+, found
296.1732. C13H22N5O3 requires 296.1723.
4.5.12. N-Pyridin-2-yl-6-pyrrolidin-1-ylpyrimidin-4-
amine (6f). Chloride 2e (1.91 g, 10.40 mmol), 2-aminopyr-
idine (1.51 g, 16.07 mmol) and potassium tert-butoxide
(3.54 g, 31.51 mmol) in toluene (20 cm3) were mixed at
room temperature in a reaction tube. Instant heating oc-
curred, with the formation of a dense brown precipitate.
The tube was sealed and treated as before to yield 6f, a beige
powder (0.38 g, 15%) after chromatography (ethyl acetate to
10% methanol/ethyl acetate as eluent). Recrystallised to a
brown powder, mp 203–204 ꢀC (ethyl acetate/hexane; dec.);
Rf (ethyl acetate) 0.29; nmax (KBr pellet) 3345, 3258, 3167,
2965, 2879, 2181, 1592, 1547, 1459, 1417, 1365, 1342,
1324, 1285, 1148, 1052, 1029, 980, 791, 778, 688 cmꢂ1; dH
(200 MHz, CDCl3) 8.35 (1H, s, H-2), 8.30 (1H, dd, pyridine
H-6, J 2.0 and 7.0), 7.60 (1H, ca. ddd, pyridine H-4, J 7.2, 6.8
and 1.8), 7.32 (1H, d, pyridine H-3, J 8.2), 6.87 (1H, dd, pyr-
idine H-5, J 7.2 and 6.0), 6.78 (1H, s, H-5), 3.52 [4H, br s,
N(CH2)2] and 1.90–2.18 [4H, m, (CH2)2]; dC (50 MHz,
CDCl3) 161.0 (C-6), 158.1 (C-4), 157.5 (C-2), 153.8 (pyri-
dine C-2), 147.7 (pyridine C-6), 137.6 (pyridine C-4),
116.7 (pyridine C-3), 112.6 (pyridine C-5), 86.7 (C-5),
46.4 [N(CH2)2] and 25.3 [(CH2)2]; tR 5.17 min (B); HRMS
(ES): MH+, found 242.1409. C13H16N5 requires 242.1406.
4.5.10. N-4-Bromophenyl-6-pyrrolidin-1-ylpyrimidin-4-
amine (6d). Chloride 2e (1.93 g, 10.50 mmol), 4-bromo-
aniline (2.73 g, 15.87 mmol) and potassium tert-butoxide
(3.52 g, 31.37 mmol) in toluene (20 cm3) yielded a brown
powder after chromatography (ethyl acetate to 10% metha-
nol/ethyl acetate as eluent). This was partially dissolved in
a minimum of acetone and precipitated with hexane. The
solid was isolated by filtration to afford a beige powder,
6d (1.24 g, 37%). Recrystallised to beige needles, mp
108–110 ꢀC (ethyl acetate/hexane); Rf (ethyl acetate) 0.26;
nmax (KBr pellet) 2960, 2863, 1587, 1504, 1480, 1321,
1153, 962, 797 cmꢂ1; dH (200 MHz, CDCl3+DMSO-d6)
8.15 (1H, s, H-2), 7.58 (1H, br s, NH), 7.31 (2H, ca. d,
aryl H, J 6.6), 7.20 (2H, ca. d, aryl H, J 6.7), 5.55 (1H, s,
H-5), 3.32 [4H, br s, N(CH2)2] and 1.88–1.98 [4H, m,
(CH2)2]; dC (50 MHz, CDCl3) 160.4 (C-6), 159.7 (C-4),
157.4 (C-2), 138.8 (aryl quaternary C), 131.8 and 122.5
(aryl C), 115.2 (aryl quaternary C), 82.8 (C-5), 46.1
[N(CH2)2] and 25.0 [(CH2)2]; tR 2.23 min (A); m/z (ES)
322 (13), 321 (100, MH+), 320 (12), 319 (100%, MH+).
4.5.13. 5-Nitro-N4-pyridin-2-yl-6-pyrrolidin-1-ylpyrim-
idin-4-amine (7). A rapidly stirred suspension of pyrimidine
6f (0.28 g, 1.16 mmol) and concentrated sulfuric acid
(2.3 cm3) were mixed at 0 ꢀC in a conical flask. Nitric acid
(65%, 0.24 cm3, 2.4 mmol) was then added dropwise to
the mixture, affording a yellow-orange solution over time
that gradually turned deep orange. This was allowed to
warm to room temperature over 18 h. The mixture was
then decanted onto crushed ice, neutralised with concen-
trated ammonia and extracted with ethyl acetate. Drying of
the organic phase (MgSO4) and concentration, followed by
column chromatography of the residue using 10% ethyl ace-
tate/hexane afforded a yellow solid 7 (0.28 g, 83%). Recrys-
tallised to yellow needles, mp 155–157 ꢀC (ethyl acetate/
hexane); Rf (20% ethyl acetate/hexane) 0.25; nmax (KBr pel-
let) 3339, 2977, 2881, 1572, 1519, 1456, 1433, 1358, 1279,
1255, 1224, 1181, 846, 778 cmꢂ1; dH (200 MHz, CDCl3)
10.2 (1H, br s, NH), 8.42 (1H, dd, pyridine H-6, J 8.4 and
0.8), 8.35 (1H, dt, pyridine H-4, J 4.8 and 1.0), 8.23 (1H,
s, H-2), 7.71 (1H, ddd, H-5, J 8.8, 7.8 and 1.9), 7.04 (1H,
dd, H-3, J 7.2 and 4.8), 3.47 [4H, br s, N(CH2)2] and
1.96–2.05 [4H, m, (CH2)2]; dC (50 MHz, CDCl3) 156.9 (pyr-
idine C-2), 153.5 (C-6), 151.5 (C-4), 148.2 (pyridine C-6),
137.8 (pyridine C-4), 119.6 (C-2), 115.8 (pyridine C-5),
109.7 (pyridine C-3), 80.2 (C-5), 50.0 [N(CH2)2] and 25.2
[br, (CH2)2]; tR 2.18 min (A); HRMS (ES): MH+, found
287.1259. C13H15N6O2 requires 287.1256.
4.5.11. 1-{6-[(4-Bromophenyl)amino]pyrimidin-4-yl}-
pyrrolidine-2-carboxylic acid (6e). Chloride 2f (1.61 g,
6.66 mmol), 4-bromoaniline (1.75 g, 10.18 mmol) and
potassium tert-butoxide (2.26 g, 20.14 mmol) in toluene
(20 cm3) were mixed at room temperature in a reaction
tube. Instant heating occurred, with the formation of a dense
brown precipitate. The reaction was treated as before to yield
6e, a beige powder (0.47 g, 20%) after chromatography (eth-
yl acetate to 10% methanol/ethyl acetate as eluent). Recrys-
tallised to a beige powder, mp 264–265 ꢀC (ethyl acetate/
hexane); Rf (ethyl acetate) 0.15; nmax (KBr pellet) 3276,
3072, 2964, 2870, 1684, 1609, 1543, 1489, 1306, 1249,

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
5403
4.6. General procedure for nitroso reduction
(C-6)a, 157.9 (C-2), 138.7 (quaternary aryl C), 128.7,
127.6 and 127.5 (aryl C), 80.9 (C-5), 46.4 [N(CH2)2], 46.1
(CH2Ph) and 25.5 [(CH2)2]; tR 7.12 min (B); HRMS (ES):
MH+ꢂNH, found 255.1599. C15H19N4 requires 255.1610.
The 5-nitrosopyrimidine was suspended in water (1 M) and
treated with solid sodium dithionite (2 equiv) portionwise.
Aqueous sulfuric acid (50% v/v, 2.5–3 mass equiv) was
added dropwise, and the resulting mixture was heated at
130 ꢀC with stirring for 5 min. The reaction mixture became
colourless after this time, and was cooled on ice. The pH of
the mixture was adjusted to >10 with 2 M aqueous sodium
hydroxide, and extracted with dichloromethane. The com-
bined organic extracts were concentrated under reduced
pressure, and the crude product recrystallised from dichloro-
methane/hexane. The following compounds were prepared
by this method.
4.6.4. N4-Benzyl-6-morpholin-4-ylpyrimidine-4,5-di-
amine (8e). Pyrimidine 4e (1.35 g, 4.63 mmol) in water
(50 cm3), sodium dithionite (1.70 g, 9.74 mmol) and sulfuric
acid (50% w/w, 9.09 g) afforded 8e (0.90 g, 70%) as a white
solid. Recrystallised to a white powder, mp 184–185 ꢀC
(CH2Cl2/hexane); Rf (50% ethyl acetate/hexane) 0.20; nmax
(KBr pellet) 3242, 3170, 3097, 2861, 1583, 1401, 1322,
1286, 1105, 1021, 973, 915 cmꢂ1; dH (200 MHz, CDCl3)
8.20 (1H, s, H-2), 7.35 (5H, br s, aryl H), 5.41 (1H, s,
NH), 5.35 (2H, br s, NH2), 4.48 (2H, d, CH2Ph, J 5.8),
3.75 [4H, m, O(CH2)2] and 3.51 [4H, m, N(CH2)2]; dC
(50 MHz, CDCl3) 164.5 (C-6), 163.0.0 (C-4), 157.5 (C-2),
138.5 (quaternary aryl C), 129.0, 128.0 and 127.5 (aryl C),
81.5 (C-5), 66.5 [O(CH2)2], 46.0 (PhCH2) and 44.5
[N(CH2)2]; tR 6.33 min (B); HRMS (ES): MH+ꢂNH, found
271.1564. C15H19N4O requires 271.1559.
4.6.1. N4-Methyl-6-pyrrolidin-1-ylpyrimidine-4,5-di-
amine (8b). Pyrimidine 4b (0.82 g, 3.98 mmol) in water
(4 cm3), sodium dithionite (1.45 g, 8.36 mmol) and sulfuric
acid (50% v/v, 8.2 g) afforded 8b, a brown solid (0.66 g,
86%). Recrystallised to a beige powder, mp 165–167 ꢀC
(CH2Cl2/hexane); Rf (10% methanol/ethyl acetate) 0.44;
nmax (KBr pellet) 3242, 3170, 3097, 2861, 1600, 1578,
1408, 1333, 1283, 1145, 1098, 1021, 993, 973, 915, 794,
700 cmꢂ1; dH (200 MHz, CDCl3) 8.11 (1H, s, H-2), 5.13
(1H, s, NH), 4.76 (2H, br s, NH2), 3.36–3.48 [4H, m,
N(CH2)2], 2.85 (3H, d, NCH3, J 5.4) and 1.94–2.00 [4H,
m, (CH2)2]; dC (50 MHz, CDCl3) 163.4 (C-4)a, 161.8
(C-6)a, 157.8 (C-2), 79.9 (C-5), 46.5 [N(CH2)2], 28.7
(NCH3)b and 25.5 [(CH2)2]b; tR 2.23 min (B); HRMS (ES):
MH+ꢂNH, found 179.1303. C9H15N4 requires 179.1297.
4.6.2. N6-Benzyl-N4,N4-dimethylpyrimidine-4,5,6-tri-
amine (8c).14 Pyrimidine 4c (0.12 g, 0.48 mmol) in water
(0.48 cm3), sodium dithionite (0.17 g, 1.00 mmol) and sulfu-
ric acid (50% v/v, 1.21 g) afforded 8c, a beige solid
(91.9 mg, 80%). Recrystallised to a beige powder, mp
149–150 ꢀC (CH2Cl2/hexane), lit.13 181–185 ꢀC (metha-
nol); Rf (50% ethyl acetate/hexane) 0.18; nmax (KBr pellet)
3211, 3071, 2987, 2861, 2808, 1589, 1422, 1317, 1299,
1169, 977, 797, 750, 702 cmꢂ1; dH (200 MHz, CDCl3)
8.16 (1H, s, H-2), 7.26–7.35 (5H, m, aryl H), 5.30 and
5.10 (2H, 2ꢁbr s, NH2), 4.45 (2H, d, CH2Ph, J 5.8), 3.01
(6H, s, 2ꢁNCH3) and 1.78 (1H, br s, NH); dC (50 MHz,
CDCl3) 163.0 (C-4 and C-6), 157.6 (C-2), 138.7 (quaternary
aryl C), 128.8 and 127.5 (aryl C), 80.2 (C-5), 46.0 (CH2Ph)
and 37.4 (2ꢁNCH3); tR 4.82 min (B); m/z (ES) and 229 (31),
228 (100, M+ꢂNH), 227 (59), 213 (29), 199 (33), 123 (68),
106 (67), 96 (25), 91 (81), 81 (23), 65 (21), 57 (21%); HRMS
(ES): MH+ꢂNH, found 229.1469. C13H17N4 requires
229.1453.
4.6.5. 2-[5-Amino-6-(dimethylamino)pyrimidin-4-yl]-
aminoethanol (8f).15 Pyrimidine 4f (0.58 g, 2.73 mmol) in
water (2.7 cm3), sodium dithionite (1.00 g, 5.74 mmol) and
sulfuric acid (50% v/v, 5.8 g) afforded 8f, a white solid
(0.29 g, 54%). Recrystallised to a white powder, mp 110–
111 ꢀC (CH2Cl2/hexane), lit.15 119–120 ꢀC (benzene); Rf
(10% methanol/ethyl acetate) 0.31; nmax (KBr pellet) 3225,
3105, 2860, 2807, 1599, 1518, 1420, 1328, 1301, 1073,
1021, 986, 892, 791, 675 cmꢂ1; dH (200 MHz, CDCl3)
8.15 (1H, s, H-2), 5.36 and 5.00 (2H, 2ꢁbr s, NH2), 3.80
(2H, t, CH2OH, J 4.9), 3.42–3.50 (2H, m, CH2NH), 3.05
(6H, s, 2ꢁNCH3) and 2.87 (1H, br s, NH); dC (50 MHz,
CDCl3) 162.9 (C-4)a, 162.0 (C-6)a, 157.3 (C-2), 80.9
(C-5), 62.9 (CH2OH), 44.8 (CH2NH) and 37.5 (2ꢁNCH3);
tR 1.81 min (B); HRMS (ES): MH+ꢂNH, found 183.1241.
C8H15N4O requires 183.1246.
4.6.6. 2-[(5-Amino-6-pyrrolidin-1-ylpyrimidin-4-yl)ami-
no]ethanol (8g). Pyrimidine 4g (0.34 g, 1.45 mmol) in wa-
ter (1.45 cm3), sodium dithionite (0.53 g, 3.05 mmol) and
sulfuric acid (50% v/v, 3.5 g) afforded 8g, a brown solid
(0.23 g, 71%). Recrystallised to a beige powder, mp 117–
118 ꢀC (CH2Cl2/hexane); Rf (10% methanol/ethyl acetate)
0.27; nmax (KBr pellet) 3321, 3234, 2964, 2862, 1600,
1539, 1509, 1434, 1338, 1280, 1226, 1196, 1110, 1079,
1057, 1025, 977, 798 cmꢂ1; dH (200 MHz, CDCl3) 8.12
(1H, s, H-2), 5.22 (1H, s, NH2), 5.06 (1H, br s, NH2), 3.79
(2H, t, CH2OH, J 4.9), 3.30–3.48 [7H, m, CH2NH,
N(CH2)2 and NH] and 1.94–2.01 [4H, m, (CH2)2]; dC
(50 MHz, CDCl3) 162.6 (C-4)a, 160.7 (C-6)a, 157.5 (C-2),
81.4 (C-5), 62.5 (CH2OH), 46.5 [N(CH2)2], 44.7 (CH2NH)
and 25.5 [(CH2)2]; tR 1.97 min (B); HRMS (ES): MH+ꢂNH,
found 209.1408. C10H17N4O requires 209.1402.
4.6.3. N4-Benzyl-6-pyrrolidin-1-ylpyrimidine-4,5-di-
amine (8d). Pyrimidine 4d (0.41 g, 1.45 mmol) in water
(1.45 cm3), sodium dithionite (0.53 g, 3.04 mmol) and sulfu-
ric acid (50% v/v, 4.08 g) afforded 8d, a beige solid (0.34 g,
87%). Recrystallised to a beige powder, mp 165–169 ꢀC
(CH2Cl2/hexane); Rf (ethyl acetate) 0.32; nmax (KBr pellet)
3210, 2962, 2858, 1657, 1561, 1489, 1337, 1306, 1279,
1219, 1180, 1103, 1024, 978, 917, 795, 748, 698 cmꢂ1; dH
(200 MHz, CDCl3) 8.10 (1H, s, H-2), 7.25–7.35 (5H, m,
aryl H), 5.35 (1H, br s, NH), 5.14 (2H, s, NH2), 4.41 (2H,
d, CH2Ph, J 5.8), 3.36 [4H, br s, N(CH2)2] and 1.90–1.96
[4H, m, (CH2)2]; dC (50 MHz, CDCl3) 162.5 (C-4)a, 160.9
4.7. General procedure for ring closure of triamino-
pyrimidines 8b–g
The pyrimidine was suspended in a mixture of acetic anhy-
dride (5 mass equiv) and triethyl orthoformate (5 mass
equiv) and heated to reflux with stirring. All the starting ma-
terial dissolves upon heating. After 4 h at reflux, the mixture

5404
C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
was cooled and excess acetic anhydride and triethyl ortho-
formate were removed under reduced pressure. The crude
residue was purified by silica gel column chromatography
using ethyl acetate as eluent, then by recrystallisation from
dichloromethane/hexane mixtures. The following com-
pounds were prepared by this method:
(59.7 mg, 68%). Recrystallised to a beige powder, mp
104–105 ꢀC (CH2Cl2/hexane); Rf (50% ethyl acetate/hex-
ane) 0.22; nmax (solid ATR) 3034, 2965, 2857, 1683, 1577,
1482, 1446, 1211, 984, 968, 754 cmꢂ1; dH (200 MHz,
CDCl3) 8.49 (1H, s, H-2), 7.21–7.35 (5H, m, aryl H), 6.66
(1H, s, H-8), 5.18 (2H, s, CH2Ph), 3.74–3.80 [4H, m,
O(CH2)2] and 3.56–3.61 [4H, m, N(CH2)2]; dC (50 MHz,
CDCl3) 171.6 (C-6)a, 163.5 (C-4)a, 161.35 (C-8), 158.0
(C-2), 137.9 (quaternary aryl C), 128.8, 127.5 and 127.4
(aryl C), 96.9 (C-5), 66.6 [O(CH2)2], 50.4 (CH2Ph) and
44.6 [N(CH2)2]; tR 10.25 min (B); m/z (ES) 313 (8,
M++H2O), 312 (36), 270 (72), 269 (100), 239 (25), 213
(23), 106 (39), 91 (63), 65 (15%); HRMS (ES):
MH++H2OꢂNCHO, found 271.1591 (C15H19N4O requires
271.1559) and M++H2O, found 313.1695 (C16H19N5O2
requires 313.1539).
4.7.1. 9-Methyl-6-pyrrolidin-1-yl-9H-purine (9b). Tri-
amine 8b (66.6 mg, 0.35 mmol), acetic anhydride
(332.5 mg) and triethyl orthoformate (332.5 mg) afforded
a beige solid, 9b (47.1 mg, 67%). Recrystallised to beige
plates, mp 53–56 ꢀC (CH2Cl2/hexane); Rf (50% ethyl ace-
tate/hexane) 0.32; nmax (KBr pellet) 3087, 3050, 2973,
2871, 1657, 1595, 1509, 1458, 1349, 1327, 1287, 1180,
1101, 1021, 983, 968, 870, 865, 704, 632 cmꢂ1; dH
(200 MHz, CDCl3) 8.41 (1H, s, H-2), 6.29 (1H, s, H-8),
3.34–3.56 [4H, m, N(CH2)2], 3.31 (3H, s, NCH3) and
1.92–2.04 [4H, m, (CH2)2]; dC (50 MHz, CDCl3) 171.2
(C-6)a, 161.3 (C-4)a, 158.4 (C-8), 158.1 (C-2), 96.9 (C-5),
46.8 [N(CH2)2], 35.0 (NCH3) and 25.4 [(CH2)2]; tR
3.72 min (B); m/z (ES) 221 (M++H2O), 220 (40), 192 (25),
178 (47), 177 (100), 150 (45), 149 (75), 109 (30), 70
(40%); HRMS (ES): MH++H2OꢂNCHO, found 179.1228
(C9H15N4 requires 179.1297) and M++H2O, found
221.1425 (C10H15N5O requires 221.1277).
Acknowledgements
We would like to thank Dr. Paul Steenkamp (CSIR Biosci-
ences) and Dr. Talitha Hildebrand [Protechnik Laboratories,
a Division of Armscor Business (Pty) Ltd.] for their invalu-
able assistance in running the mass spectra and discussions
with regard to their interpretation.
4.7.2. 9-Benzyl-6-dimethylamino-9H-purine (9c).14,16
Triamine 8c (50.2 mg, 0.21 mmol), acetic anhydride
(251 mg)andtriethylorthoformate(251 mg)affordedabeige
solid, 9c (46.0 mg, 88%). Recrystallised to a beige powder,
mp 116–117 ꢀC (CH2Cl2/hexane), lit.14b 120–121 ꢀC (etha-
nol); Rf (10% methanol/ethyl acetate) 0.22; nmax (solid ATR)
2963, 1655, 1588, 1510, 1402, 1286, 1170, 1082, 982,
702 cmꢂ1; dH (200 MHz, CDCl3) 8.46 (1H, s, H-2), 7.23–
7.32 (5H, m, aryl H), 6.33 (1H, s, H-8), 5.11 (2H, s,
CH2Ph) and 3.04 (6H, s, 2ꢁNCH3); tR 9.27 min (B); m/z
(ES) 271 (9, M++H2O), 270 (41), 229 (10), 228 (83), 227
(100), 150 (19), 123 (24), 106 (56), 95 (42), 91 (70), 65
(20%); HRMS (ES): MH++H2OꢂNCHO, found 229.1478
(C13H17N4 requires 229.1453) and M++H2O, found
271.1592 (C14H17N5O requires 271.1433).
References and notes
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4.7.3. 9-Benzyl-6-pyrrolidin-1-yl-9H-purine (9d).14 Com-
pound 8d (39.6 mg, 0.15 mmol), acetic anhydride (143 mg)
and triethyl orthoformate (143 mg) afforded 9d (32.8 mg,
80%) as a wax [lit.14b 129–130.5 ꢀC (heptane)]; Rf (50% eth-
yl acetate/hexane) 0.19; nmax (neat film) 2946, 2870, 1667,
1580, 1504, 1450, 1381, 1220, 1045, 969, 847, 728 cmꢂ1
;
dH (200 MHz, CDCl3) 8.45 (1H, s, H-2), 7.24–7.28 (5H,
m, aryl H), 6.19 (1H, s, H-8), 5.11 (2H, s, CH2Ph), 3.18–
3.62 [4H, br s, N(CH2)2] and 1.90–2.06 [4H, m, (CH2)2];
dC (50 MHz, CDCl3) 171.2 (C-6)a, 161.3 (C-4)a, 158.4
(C-8)a, 158.4 (C-2), 138.0 (quaternary aryl C), 128.7,
127.7 and 127.4 (aryl C), 98.1 (C-5), 50.5 [N(CH2)2], 46.7
(CH2Ph) and 25.5 [(CH2)2]; tR 15.90 min (B); m/z (ES)
296 (17), 254 (56), 253 (100), 226(14), 225 (17), 106 (27),
91 (44%); HRMS (ES): MH++H2OꢂNCHO, found
255.1646 (C15H18N4 requires 255.1610) and M++H2O,
found 297.1736 (C16H19N5O requires 297.1590).
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Osamu, S. WO Patent 2004043926, 2004.
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4.7.4. 9-Benzyl-6-morpholin-1-yl-9H-purine (9e). Tri-
amine 8e (85 mg, 0.30 mmol), acetic anhydride (0.43 g) and
triethyl orthoformate (0.43 g) afforded a beige solid, 9e

C. W. van der Westhuyzen et al. / Tetrahedron 63 (2007) 5394–5405
5405
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