Base-catalyzed synthesis of bicyclic 4-aminopyrimidines from the reaction of dinitriles with mononitriles

Article abstract of DOI:10.1016/j.tet.2011.03.098

A convenient method for the synthesis of bicyclic 4-aminopyrimidines is described, involving the reaction of dinitriles with mononitriles in the presence of catalytic potassium tert-butoxide. These reactions proceed via the Thorpe-Ziegler cyclization of t

Full text of DOI:10.1016/j.tet.2011.03.098

Tetrahedron 67 (2011) 3839e3845
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Base-catalyzed synthesis of bicyclic 4-aminopyrimidines from the reaction
of dinitriles with mononitriles
,
Serghei Chercheja a, Juliet K. Simpson b, Hon Wai Lam a
*
a EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the synthesis of bicyclic 4-aminopyrimidines is described, involving the reaction
Received 13 January 2011
Received in revised form 9 March 2011
Accepted 28 March 2011
Available online 2 April 2011
of dinitriles with mononitriles in the presence of catalytic potassium tert-butoxide. These reactions proceed
via the ThorpeeZiegler cyclization of the dinitrile to form an intermediate b-cyanoenamine, which then
undergoes annulation with the mononitrile in situ.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
4-Aminopyrimidine
Dinitrile
Nitrile
Cyclization
Base catalysis
1. Introduction
cyanoenamines. However, the principal challenge with this ap-
proach that must be overcome is minimization of side products
resulting from self-coupling of one or both of the reaction partners.
In this article, the successful implementation of this strategy is
described.
Bicyclic 4-aminopyrimidines 4 are important heterocyclic scaf-
folds for drug discovery.1 However, conventional methods for their
synthesis are often lengthy, cumbersome, and not amenable to late-
stage modification.1 An attractive alternative route lies in the cy-
clization of a dinitrile 1 to provide a b-cyanoenamine 2, which can
then react with a mononitrile 3 in situ to provide the target
2. Results and discussion
structure 4 (Scheme 1).
Our studies began with evaluation of various conditions in the
reaction of adiponitrile (1a) with benzonitrile (3a). The best results
were obtained by heating a mixture of 1a (1.5 equiv), 3a (1.0 equiv),
and t-BuOK (20 mol %) in p-xylene at 120 ꢀC for 4 h. Under these
conditions, aminopyrimidine 5a was isolated in 81% yield (Eq. 1),
the structure of which was confirmed by X-ray crystallography
(Fig. 1).6 Side products 65 and 77 resulting from self-coupling of
N
NH2
R
3
CN
CN
N
X
X
X
CN
n
n
n
NH2
N
4
R
1
2
Scheme 1. Proposed route to bicyclic 4-aminopyrimidines.
Both steps of this sequence are well-known: the classical
ThorpeeZiegler cyclization of dinitriles,2 and annulation of
b-cya-
noenamines with nitriles.3 Surprisingly however, the integration of
these two steps into a one-pot domino reaction has not, to our
knowledge, been described.4,5 The realization of such a process
would provide a convenient entry into bicyclic 4-aminopyrimidines
4 without having to isolate and purify the intermediate
b-
* Corresponding author. Tel.: þ44 131 650 4831; fax: þ44 131 650 6453; e-mail
address: h.lam@ed.ac.uk (H.W. Lam).
Fig. 1. X-ray crystal structures of 5a and 5q.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.098

3840
S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
Table 1
adiponitrile were also detected in the reaction mixture, but they
were easily removed by column chromatography.
Reaction of adiponitrile (1a) with aromatic and heteroaromatic mononitrilesa
NH2
N
t-BuOK (20 mol %)
CN
CN
N
(1)
+
p-xylene, 120 °C, 4 h
Ph
3a
N
Ph
5a, 81%
1a
(1.5 equiv)
NH2
NH2
Entry
Product
Yieldb (%)
N
N
N
N
1
2
3
4
5
6
7
8
R¼H 5a
81
75
80
90
82
28
83
65
38
21
0
N
+
+
R¼t-Bu 5b
R¼Ph 5c
N
CN
6
NH2
N
7
R¼Cl 5d
(trace)
(trace)
NH2
R¼Br 5e
R¼F 5f
R¼CF3 5g
R¼OMe 5h
R¼NH2 5i
R¼NMe2 5j
R¼OH 5k
R¼CO2Me 5l
Next, further investigation of the reaction scope was undertaken
N
using the aforementioned experimental protocol. These experi-
ments demonstrated that reaction of adiponitrile (1a) with various
aromatic (entries 1e10 and 13e15) and heteroaromatic nitriles
(entries 16e18) was successful to provide bicyclic 4-amino-
pyrimidines (Table 1). In addition to benzonitrile itself (entry 1),
benzonitriles containing alkyl (entry 2), aryl (entry 3), chloro (entry
4), bromo (entry 5), and trifluoromethyl (entry 7) substituents at
the 4-position were among the better substrates, giving products in
75e90% yield. 4-Fluorobenzonitrile underwent cyclization in low
yield (28%) due to the formation of side products resulting from
displacement of the fluorine through SNAr reactions.8 In contrast, 3-
fluorobenzonitrile afforded 5m in excellent yield (96%) under the
same conditions (entry 13). 3-Methoxybenzonitrile was also an
effective substrate (entry 14). The reaction between adiponitrile
(1a) and benzonitriles bearing electron-donating groups at the 4-
position resulted in lower yields (21e65%) of the products (entries
8e10), with incomplete consumption of 4-amino-subsituted
nitriles observed even after a reaction time of 20 h (entries 9 and
10). These results are as expected due to the lower electrophilicities
of these substrates. Unsurprisingly, 4-cyanophenol failed to un-
dergo reaction even in the presence of 2.0 equiv of t-BuOK (entry
11), presumably due to the phenoxide anion formed under the basic
conditions deactivating the nitrile group toward nucleophilic
attack. Attempted cyclization of adiponitrile (1a) with methyl 4-
cyanobenzoate (3l) resulted in none of the desired bicyclic 4-ami-
nopyridine 5l being detected (entry 12). Instead, a complex mixture
of products was formed, from which Claisen condensation product
8 (12% yield based on mononitrile) was isolated (Eq. 2). Evidently,
the presence of the electrophilic ester substituent was detrimental
to the desired reaction.
9c
10c
11d
12
R
R
0e
NH2
N
13
14
R¼F 5m
96
86
R¼OMe 5n
N
NH2
N
15
16
17
5o
5p
85
31
N
NH2
N
N
N
NH2
N
5q
5r
22
41
N
N
NH2
N
18f
O
N
a
Reactions were conducted using 1.95 mmol of adiponitrile (1a) and 1.30 mmol
of mononitrile in p-xylene (1 mL).
N
CN
b
Isolated yield of product, based on mononitrile as the limiting reagent.
c
O
Reaction time of 20 h.
d
Using 2.0 equiv of t-BuOK with respect to 4-cyanophenol (3k).
e
See text and Eq. 2.
f
t-BuOK (20 mol %)
CN
CN
CN
CN
Reaction conducted in 2 mL of p-xylene. The yield of 5r in a reaction conducted
+ unidentified
products
+
(2)
p-xylene, 120 °C, 4 h
in 1 mL of p-xylene was 26%.
CO2Me
3l
8, 12%
1a
Heteroaromatic nitriles were problematic substrates, providing
lower yields of products (entries 16e18) along with numerous side
products. In the case of 2-furonitrile, halving the concentration of
the reaction was beneficial, increasing the yield of 5r from 26 to 41%
(entry 18). The structure of 4-pyridyl-substituted product 5q was
further confirmed by X-ray crystallography (Fig. 1).6
Table 2 presents the results of reaction of adiponitrile (1a) with
aliphatic mononitriles. Here, the presence of acidic a-protons in the
mononitrile was expected to present chemoselectivity problems.
Although benzyl cyanide (entry 1) was a competent substrate under
the standard conditions employed inTable 1, cyclohexanecarbonitrile
(entry 2) and valeronitrile (entry 3) had to be used in a large excess
(10.0 equiv with respect to adiponitrile) for satisfactory yields of
bicyclic 4-aminopyridines 9b and 9c, respectively. Presumably,
competitive pathways resulting from self-condensation of the
mononitrile reduce the efficiencies of these reactions.
Finally, the use of dinitriles other than adiponitrile (1a) was
investigated (Table 3). In the presence of 50 mol % of t-BuOK,
higher homologue pimelonitrile (1b) underwent cyclization with
benzonitrile and 4-(trifluoromethyl)benzonitrile to provide prod-
ucts 10a and 10b in 90% and 57% yields, respectively (entries 1

S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
3841
Table 3
Table 2
Reaction of various dinitriles with a range of benzonitrilesa
Reaction of adiponitrile (1a) with aliphatic mononitrilesa
Dinitriles
Entry
Product
Yieldb
(%)
CN
CN
CN
CN
CN
CN
Me
N
1c
NH2
N
1d
1b
1c
9a
9b
53c
48
Entry
Product
Yield (%)
Ph
NH2
N
N
NH2
1
2
R¼H 10a
90
57
N
N
R¼CF3 10b
N
2
R
NH2
N
Me
N
3
4
R¼H 10c
R¼Br 10d
90
92
NH2
N
N
3
9c
56
R
N
n-Bu
NH2
N
a
Reactions were conducted using 1.30 mmol of adiponitrile (1a) and 13.0 mmol
of mononitrile in the absence of solvent.
5b
6b
R¼H 10e
38
40
R¼t-Bu 10f
b
N
Isolated yield of product, based on adiponitrile (1a) as the limiting reagent.
Reaction was conducted using 1.95 mmol (1.5 equiv) of adiponitrile (1a) and
c
R
1.30 mmol of benzyl cyanide (3s) in p-xylene (1 mL). Reported yield is based on
a
benzyl cyanide as the limiting reagent.
Reactions were conducted using 1.95 mmol of adiponitrile (1a) and 1.30 mmol
of mononitrile in p-xylene (1 mL).
b
Using 20 mol % of t-BuOK.
and 2). Conversions were significantly lower when only 20 mol %
of t-BuOK was employed. We were pleased to observe that dini-
trile 1c containing a methylamino substituent in the tether also
underwent smooth cyclization to form products 10c and 10d in
a PerkineElmer Spectrum One FT-IR instrument as a thin film. Flash
chromatography was carried out in air on pre-packed ISOLUTEÒ
Flash Si II silica columns using an automated Biotage FlashMasterÔ
II purification system. High resolution mass spectra were recorded
on a Bruker Apex IV instrument or a Thermofisher LTQ Orbitrap XL
spectrometer. 1H NMR spectra were recorded on a Bruker AVA400
(400 MHz) or a Bruker DPX360 (360 MHz) spectrometer. Chemical
high yields, without evidence of b-elimination (entries 3 and 4).
However, the reactions of 1,2-phenylenediacetonitrile (1d) were
less efficient (entries 5 and 6). Here, high conversions were ob-
served using only 20 mol % of t-BuOK, but in addition to the
desired bicyclic 4-aminopyrimidines, numerous other side prod-
ucts were also detected.
shifts (d) are quoted in parts per million (ppm) downfield of tet-
ramethylsilane, using residual protonated solvent as internal
standard (CDCl3 at 7.27 ppm and DMSO-d6 at 2.50 ppm). Abbrevi-
ations used in the description of resonances are: s (singlet),
d (doublet), t (triplet), q (quartet), br (broad), m (multiplet). Cou-
pling constants (J) are quoted to the nearest 0.1 Hz. Assignments
were made using COSY, HMQC, HMBC, and ROESY experiments.
Proton-decoupled 13C NMR spectra were recorded on a Bruker
AVA400 (100.6 MHz) spectrometer or a Bruker DPX360 (90.6 MHz)
3. Conclusion
In conclusion, catalytic potassium tert-butoxide promotes the
direct synthesis of bicyclic 4-aminopyrimidines from the reaction of
dinitriles withmononitriles. Thismethodtoleratesa rangeofreaction
partners to provide diverse bicyclic 4-aminopyrimidines in a more
convenient and expedient fashion compared with existing methods.
spectrometer. Chemical shifts (d) are quoted in parts per million
(ppm) downfield of tetramethylsilane, using deuterated solvent as
internal standard (CDCl3 at 77.0 ppm and DMSO-d6 at 39.5 ppm).
Assignments were made using the DEPT sequence with secondary
pulses at 90ꢀ and 135ꢀ.
4. Experimental
4.1. General
All commercially available reagents were dried before use. Solid
reagents were dried under high vacuum for several hours. Liquid
reagents were dried with 3 A molecular sieves. Anhydrous p-xylene
4.2. Base-catalyzed reaction of adiponitrile with
mononitriles: general procedure A
ꢀ
was purchased from SigmaeAldrich. All reactions were performed
in a Carousel 12 Plus Reaction Station under nitrogen. Melting
points were recorded on a Gallenkamp melting point apparatus and
are uncorrected. Infra-red spectra were recorded on
To a solution of adiponitrile (219 mL, 1.95 mmol) and the ap-
propriate mononitrile (1.30 mmol) in p-xylene (1 mL) in a carousel
tube was added t-BuOK (29.2 mg, 0.26 mmol) in one portion. The
reaction vessel was heated in a carousel to 120 ꢀC for 4 h. After

3842
S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
cooling to room temperature, CH2Cl2 (ca. 30 mL) was used to
transfer the mixture onto a silica cartridge for purification.
and purified by flash chromatography (0% EtOAc/cyclo-
hexane/100% EtOAc/cyclohexane) to give a white solid (310 mg,
82%). Mp 177e179 ꢀC; IR (film) 3654, 3291 (NH), 3145, 2954, 2913,
4.2.1. 2-Phenyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamine
2182, 1625, 1586, 1564, 1457, 1389, 1009, 776 cmꢁ1 1H NMR
;
(5a). The title compound was prepared according to general pro-
(400 MHz, CDCl3) d 8.23e8.20 (2H, m, ArH), 7.57e7.54 (2H, m, ArH),
cedure A using benzonitrile (133
m
L, 1.30 mmol) and purified by
4.81 (2H, br s, NH2), 2.98 (2H, t, J¼7.8 Hz, CH2Ar), 2.74 (2H, t,
flash chromatography (0% EtOAc/cyclohexane/100% EtOAc/cy-
clohexane) to give a white solid (223 mg, 81%). Mp 131e133 ꢀC; IR
(film) 3319 (NH), 3184, 2957, 1622, 1589, 1568, 1435, 1397, 758,
J¼7.5 Hz, CH2Ar), 2.22e2.08 (2H, m, CH2CH2Ar); 13C NMR
(100.6 MHz, CDCl3)
d 173.3 (C), 162.7 (C), 159.4 (C), 137.4 (C), 131.0
(2ꢂ CH), 129.6 (2ꢂ CH), 124.3 (C), 114.2 (C), 34.2 (CH2), 26.8 (CH2),
21.6 (CH2); HRMS (ES) exact mass calcd for C13H13N3Br [MþH]þ:
290.0293, found: 290.0294.
702 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.33e8.30 (2H, m, ArH),
7.44e7.42 (3H, m, ArH), 4.91 (2H, br s, NH2), 3.00e2.96 (2H, m,
CH2Ar), 2.73e2.69 (2H, m, CH2Ar), 2.18e2.09 (2H, m, CH2CH2Ar);
13C NMR (90.6 MHz, CDCl3)
d
173.2 (C),163.7 (C),159.4 (C),138.5 (C),
4.2.6. 2-(4-Fluorophenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5f). The title compound was prepared according to gen-
eral procedure A using 4-fluorobenzonitrile (157 mg, 1.30 mmol)
and purified by flash chromatography (0% EtOAc/cyclo-
hexane/50% EtOAc/cyclohexane) to give a white solid (84 mg,
28%). Mp 186e188 ꢀC; IR (film) 3294 (NH), 3159, 1621, 1603, 1573,
129.7 (CH), 128.2 (2ꢂ CH), 127.9 (2ꢂ CH), 113.9 (C), 34.2 (CH2), 26.7
(CH2), 21.6 (CH2); HRMS (ES) exact mass calcd for C13H14N3
[MþH]þ: 212.1182, found: 212.1181.
4.2.2. 2-(4-tert-Butylphenyl)-6,7-dihydro-5H-cyclopentapyrimidin-
4-ylamine (5b). The title compound was prepared according to
1510, 1390, 1217, 1159, 849, 782 cmꢁ1
;
1H NMR (400 MHz, DMSO-
general procedure
A
using 4-tert-butylbenzonitrile (220
mL,
d6) 8.33e8.30 (2H, m, ArH), 7.26e7.21 (2H, m, ArH), 6.69 (2H, br s,
d
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane) to give a white solid
(261 mg, 75%). Mp 149e151 ꢀC; IR (film) 3315 (NH), 3178, 2960,
NH2), 2.79 (2H, t, J¼7.7 Hz, CH2Ar), 2.67 (2H, t, J¼7.3 Hz, CH2Ar),
2.04e1.97 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, DMSO-d6)
d
171.2 (C), 163.2 (C, d, JF¼246.4 Hz), 160.9 (C), 160.1 (C), 135.0 (C, d,
2868, 1611, 1579, 1560, 1447, 1392, 906, 850, 787, 728 cmꢁ1
;
1H
JF¼2.7 Hz), 129.5 (2ꢂ CH, d, JF¼8.5 Hz), 114.9 (2ꢂ CH, d, JF¼21.4 Hz),
113.5 (C), 33.7 (CH2), 26.9 (CH2), 21.1 (CH2); HRMS (ES) exact mass
calcd for C13H13N3F [MþH]þ: 230.1094, found: 230.1095.
NMR (400 MHz, CDCl3)
d
8.19 (2H, d, J¼8.5 Hz, ArH), 7.46 (2H, d,
J¼8.5 Hz, ArH), 4.99 (2H, br s, NH2), 3.00 (2H, t, J¼7.8 Hz, CH2Ar),
2.75 (2H, t, J¼7.4 Hz, CH2Ar), 2.24e2.11 (2H, m, CH2CH2Ar), 1.35
(9H, s, C(CH3)3); 13C NMR (100.6 MHz, CDCl3)
d
173.2 (C), 163.8 (C),
4.2.7. 2-(4-Trifluoromethylphenyl)-6,7-dihydro-5H-cyclo-
pentapyrimidin-4-ylamine (5g). The title compound was prepared
according to general procedure A using 4-(trifluoromethyl)benzo-
nitrile (222 mg, 1.30 mmol) and purified by flash chromatography
(0% EtOAc/cyclohexane/100% EtOAc/cyclohexane) to give a white
solid (300 mg, 83%). Mp 155e157 ꢀC; IR (film) 3494, 3430, 3351
(NH), 3291, 3237, 3129, 2957, 2181, 1628, 1567, 1460, 1320, 1157,
159.3 (C), 153.0 (C), 135.5 (C), 127.7 (2ꢂ CH), 125.2 (2ꢂ CH), 113.6
(C), 34.7 (C), 34.2 (CH2), 31.3 (3ꢂ CH3), 26.7 (CH2), 21.6 (CH2);
HRMS (ES) exact mass calcd for C17H22N3 [MþH]þ: 218.1808,
found: 218.1805.
4.2.3. 2-Biphenyl-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl-
amine (5c). The title compound was prepared according to general
procedure A using 4-phenylbenzonitrile (233 mg, 1.30 mmol) and
purified by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane) to give a white solid (297 mg, 80%). Mp 235 ꢀC
(decomp.); IR (film) 3462, 3310 (NH), 3129, 1630, 1588, 1460, 1396,
1108, 1062, 784 cmꢁ1 1H NMR (360 MHz, CDCl3)
; d 8.46e8.44 (2H,
m, ArH), 7.69e7.67 (2H, m, ArH), 4.85 (2H, br s, NH2), 3.02e2.97 (2H,
m, CH2Ar), 2.77e2.73 (2H, m, CH2Ar), 2.21e2.15 (2H, m, CH2CH2Ar);
13C NMR (90.6 MHz, CDCl3)
d 173.3 (C), 162.2 (C), 159.4 (C), 141.7 (C),
131.3 (C, q, JF¼32.2 Hz), 128.2 (2ꢂ CH), 125.1 (2ꢂ CH, q, JF¼3.4 Hz),
124.2 (C, q, JF¼272.3 Hz), 114.7 (C), 34.2 (CH2), 26.7 (CH2), 21.5
(CH2); HRMS (ES) exact mass calcd for C14H13N3F3 [MþH]þ:
280.1062, found: 280.1067.
859, 760, 695 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 8.37 (2H, d,
J¼8.3 Hz, ArH), 7.75e7.72 (4H, m, ArH), 7.51e7.47 (2H, m, ArH),
7.40e7.37 (1H, m, ArH), 6.68 (2H, br s, NH2), 2.82 (2H, t, J¼7.7 Hz,
CH2Ar), 2.69 (2H, t, J¼7.4 Hz, CH2Ar), 2.07e1.99 (2H, m, CH2CH2Ar);
13C NMR (100.6 MHz, DMSO-d6)
d
171.3 (C),161.6 (C),160.1 (C),141.0
4.2.8. 2-(4-Methyoxyphenyl)-6,7-dihydro-5H-cyclopentapyrimidin-
(C), 139.7 (C), 137.6 (C), 129.0 (2ꢂ CH), 128.0 (2ꢂ CH), 127.7 (CH),
126.6 (2ꢂ CH), 126.4 (2ꢂ CH), 113.7 (C), 33.7 (CH2), 27.0 (CH2), 21.1
(CH2); HRMS (ES) exact mass calcd for C19H18N3 [MþH]þ: 288.1501,
found: 288.1492.
4-ylamine (5h). The title compound was prepared according to
general procedure
A using 4-methoxybenzonitrile (173 mg,
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane/20% MeOH/CH2Cl2) to
give a white solid (204 mg, 65%). Mp 242e244 ꢀC (decomp.); IR
(film) 3471, 3317 (NH), 3179, 2955,1613,1588,1434,1395,1383, 907,
4.2.4. 2-(4-Chlorophenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5d). The title compound was prepared according to general
procedure A using 4-chlorobenzonitrile (179 mg, 1.30 mmol) and
purified by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane) to give a white solid (319 mg, 90%). Mp
158e160 ꢀC; IR (film) 3429, 3349 (NH), 3136, 2920, 2179, 1612, 1587,
728, 700 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 8.22 (2H, d,
J¼8.8 Hz, ArH), 6.97 (2H, d, J¼8.8 Hz, ArH), 6.62 (2H, br s, NH2), 3.79
(3H, s, OCH3), 2.77 (2H, t, J¼7.7 Hz, CH2Ar), 2.66 (2H, t, J¼7.4 Hz,
CH2Ar), 2.02e1.98 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, DMSO-
d6)
d
171.1 (C), 161.7 (C), 160.6 (C), 160.0 (C), 131.0 (C), 129.0 (2ꢂ CH),
1564, 1454, 1409, 1085, 1010, 776 cmꢁ1
8.25e8.22 (2H, m, ArH), 7.42e7.38 (2H, m, ArH), 4.94 (2H, br s, NH2),
3.01e2.97 (2H, t, J¼7.8 Hz, CH2Ar), 2.76e2.73 (2H, t, J¼7.4 Hz, CH2Ar),
2.21e2.14 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, CDCl3)
173.1
;
1H NMR (400 MHz, CDCl3)
113.4 (2ꢂ CH), 112.9 (C), 55.2 (CH3), 33.7 (CH2), 26.9 (CH2), 21.1
(CH2); HRMS (ES) exact mass calcd for C14H16N3O [MþH]þ:
242.1293, found: 242.1291.
d
d
(C), 162.5 (C), 159.4 (C), 136.9 (C), 135.7 (C), 129.3 (2ꢂ CH), 128.3 (2ꢂ
CH), 114.1 (C), 34.2 (CH2), 26.7 (CH2), 21.5 (CH2); HRMS (ES) exact
mass calcd for C13H13N3Cl [MþH]þ: 246.0798, found: 246.0800.
4.2.9. 2-(4-Aminophenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5i). The title compound was prepared according to
a modification of general procedure A using 4-aminobenzonitrile
(154 mg, 1.30 mmol) for an increased reaction time of 20 h and
purified by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane/20% MeOH/CH2Cl2) to give a white solid
(112 mg, 38%). Mp 199e201 ꢀC (decomp.); IR (film) 3326 (NH), 3191,
4.2.5. 2-(4-Bromophenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5e). The title compound was prepared according to gen-
eral procedure A using 4-bromobenzonitrile (237 mg, 1.30 mmol)

S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
3843
2961; 1608; 1568; 1452, 1433, 1387, 1172, 786 cmꢁ1
;
1H NMR
3.89 (3H, s, OCH3), 2.99 (2H, t, J¼7.8 Hz, CH2Ar), 2.74 (2H, t, J¼7.4 Hz,
CH2Ar), 2.20e2.12 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, CDCl3)
(400 MHz, DMSO-d6) 8.02e8.00 (2H, m, ArH), 6.58e6.56 (2H, m,
d
ArH), 6.41 (2H, br s, NH2), 5.37 (2H, br s, NH2), 2.74 (2H, t, J¼7.6 Hz,
CH2Ar), 2.64 (2H, t, J¼7.2 Hz, CH2Ar), 2.01e1.94 (2H, m, CH2CH2Ar);
d 173.2 (C), 163.5 (C), 159.7 (C), 159.3 (C), 140.0 (C), 129.2 (CH), 120.5
(CH), 116.3 (CH), 114.0 (C), 112.6 (CH), 55.3 (CH3), 34.2 (CH2), 26.7
(CH2), 21.6 (CH2); HRMS (ES) exact mass calcd for C14H16N3O
[MþH]þ: 242.1293, found: 242.1297.
13C NMR (100.6 MHz, DMSO-d6)
d 171.1 (C), 162.6 (C), 159.8 (C),
150.2 (C), 128.8 (2ꢂ CH), 126.1 (C), 113.0 (2ꢂ CH), 111.8 (C), 33.7
(CH2), 26.8 (CH2), 21.1 (CH2); HRMS (ES) exact mass calcd for
C13H15N4 [MþH]þ: 227.1297, found: 227.1287.
4.2.14. 2-Naphthalen-2-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5o). The title compound was prepared according to gen-
4.2.10. 2-(4-Dimethylaminophenyl)-6,7-dihydro-5H-cyclo-
pentapyrimidin-4-ylamine (5j). The title compound was prepared
according to a modification of general procedure A using 4-dime-
thylaminobenzonitrile (190 mg, 1.30 mmol) for an increased re-
action time of 20 h and purified by flash chromatography (0%
eral procedure A using naphthalene-2-carbonitrile (199 mg,
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane) to give a white solid
(288 mg, 85%). Mp 176e178 ꢀC; IR (film) 3325 (NH), 3183, 2957,
1613, 1568, 1451, 1433, 1400, 788 cmꢁ1; 1H NMR (400 MHz, DMSO-
EtOAc/cyclohexane/100%
EtOAc/cyclohexane/20%
MeOH/
d6)
d
8.85 (1H, s, ArH), 8.45 (1H, dd, J¼8.5, 1.5 Hz, ArH), 8.04e8.02
CH2Cl2) to give a white solid (68 mg, 21%). Mp 253e256 ꢀC
(decomp.); IR (film) 3484, 3298 (NH), 3183, 2905, 1604, 1572, 1381,
(1H, m, ArH), 7.96e7.92 (2H, m, ArH), 7.55e7.52 (2H, m, ArH), 6.75
(2H, br s, NH2), 2.85 (2H, t, J¼7.7 Hz, CH2Ar), 2.71 (2H, t, J¼7.3 Hz,
CH2Ar), 2.08e2.00 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz,
1176, 826, 783 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 8.14e8.12 (2H,
m, ArH), 6.73e6.70 (2H, m, ArH), 6.48 (2H, br s, NH2), 2.96 (6H, s,
N(CH3)2), 2.76 (2H, t, J¼7.7 Hz, CH2Ar), 2.65 (2H, t, J¼7.4 Hz, CH2Ar),
2.02e1.95 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, DMSO-d6)
DMSO-d6) d 171.4 (C), 163.2 (C), 161.8 (C), 160.2 (C), 136.0 (C), 133.7
(C), 132.8 (CH), 128.7 (CH), 127.5 (CH), 126.9 (CH), 126.7 (CH), 126.2
(CH), 125.2 (CH), 113.8 (C), 33.7 (CH2), 27.0 (CH2), 21.1 (CH2); HRMS
(ES) exact mass calcd for C17H16N3 [MþH]þ: 262.1339, found:
262.1337.
d
171.0 (C), 162.3 (C), 159.8 (C), 151.2 (C), 128.6 (2ꢂ CH), 126.2 (C),
112.0 (C), 111.2 (2ꢂ CH), 39.9 (2ꢂ CH3), 33.7 (CH2), 26.9 (CH2), 21.1
(CH2); HRMS (ES) exact mass calcd for C15H19N4 [MþH]þ: 255.1610,
found: 255.1601.
4.2.15. 2-Quinolin-3-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl-
amine (5p). The title compound was prepared according to gen-
4.2.11. 2-[(4-Cyanophenyl)carbonyl]hexanedinitrile (8). The title
compound was prepared according to general procedure A using
methyl 4-cyanobenzoate (210 mg, 1.30 mmol) and purified by flash
chromatography (0% EtOAc/cyclohexane/100% EtOAc/cyclohex-
ane) to give a colorless oil (38 mg, 12%). IR (film) 2927, 2238 (C^N),
2232 (C^N), 2225 (C^N), 1699, 1406, 1265, 1221, 983, 910,
eral procedure
A
using 3-quinolinecarbonitrile (200 mg,
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane/20% MeOH/CH2Cl2) to
give a white solid (105 mg, 31%). Mp 250e252 ꢀC (decomp.); IR
(film) 3395, 3306 (NH), 3180, 2905, 1639, 1581, 1562, 1465, 1428,
1394, 852, 786, 750 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 9.80
852 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
8.11e8.08 (2H, m, ArH),
(1H, d, J¼2.0 Hz, ArH), 9.11 (1H, d, J¼1.8 Hz, ArH), 8.13 (1H, d,
J¼7.8 Hz, ArH), 8.06 (1H, d, J¼8.5 Hz, ArH), 7.81e7.77 (1H, m, ArH),
7.66e7.62 (1H, m, ArH), 6.88 (2H, br s, NH2), 2.86 (2H, t, J¼7.7 Hz,
CH2Ar), 2.72 (2H, t, J¼7.4 Hz, CH2Ar), 2.09e2.01 (2H, m,
7.88e7.85 (2H, m, ArH), 4.39 (1H, dd, J¼7.9, 6.0 Hz, CHCN),
2.56e2.45 (2H, m, CH2CN), 2.25e2.12 (2H, m, CH2CH2CH2CN),
2.05e1.88 (2H, m, CH2CH2CN); 13C NMR (100.6 MHz, CDCl3)
d 188.6
(C), 136.5 (C), 133.0 (2ꢂ CH), 129.2 (2ꢂ CH), 118.5 (C), 118.0 (C), 117.3
(C),115.8 (C), 39.1 (CH), 27.6 (CH2), 22.6 (CH2),16.8 (CH2); HRMS (EI)
exact mass calcd for C14H11N3O [M]þ: 237.0897, found: 237.0900.
CH2CH2Ar); 13C NMR (100.6 MHz, DMSO-d6)
d 171.4 (C), 160.2 (C),
149.9 (CH), 148.0 (C), 134.3 (CH), 131.0 (CH), 130.1 (CH), 129.0 (CH),
128.7 (C), 127.3 (CH), 126.9 (C), 114.4 (C), 33.7 (CH2), 27.0 (CH2),
21.1 (CH2); HRMS (ES) exact mass calcd for C16H15N4 [MþH]þ:
263.1297, found: 263.1290.
4.2.12. 2-(3-Fluorophenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-
ylamine (5m). The title compound was prepared according to
general procedure A using 3-fluorobenzonitrile (139
m
L, 1.30 mmol)
4.2.16. 2-Pyridin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl-
amine (5q). The title compound was prepared according to general
procedure A using 4-cyanopyridine (135 mg, 1.30 mmol) and pu-
rified by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane/20% MeOH/CH2Cl2) to give a white solid
(60 mg, 22%). Mp 158e160 ꢀC; IR (film) 3324 (NH), 3182, 2957,1681,
and purified by flash chromatography (0% EtOAc/cyclo-
hexane/100% EtOAc/cyclohexane) to give a white solid (285 mg,
96%). Mp 116e118 ꢀC; IR (film) 3311 (NH), 3179, 2957, 2906, 1624,
1571, 1434, 1398, 1381, 851, 773 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
8.10e8.09 (1H, m, ArH), 8.03e7.99 (1H, m, ArH), 7.45e7.40 (1H, m,
ArH), 7.17e7.13 (1H, m, ArH), 5.09 (2H, br s, NH2), 2.99 (2H, t,
J¼7.8 Hz, CH2Ar), 2.74 (2H, t, J¼7.4 Hz, CH2Ar), 2.23e2.15 (2H, m,
1630, 1587, 1553, 1456, 1414, 1397, 777 cmꢁ1
CDCl3) 8.69e8.68 (2H, m, ArH), 8.18e8.16 (2H, m, ArH), 5.02 (2H,
br s, NH2), 2.98 (2H, t, J¼7.9 Hz, CH2Ar), 2.74 (2H, t, J¼7.4 Hz, CH2Ar),
2.18e2.15 (2H, m, CH2CH2Ar); 13C NMR (100.6 MHz, CDCl3)
173.3
;
1H NMR (400 MHz,
d
CH2CH2Ar); 13C NMR (100.6 MHz, CDCl3)
d 173.3 (C), 163.0 (C, d,
JF¼244.3 Hz), 162.5 (C, d, JF¼3.1 Hz), 159.3 (C), 140.9 (C, d,
JF¼7.8 Hz), 129.6 (CH, d, JF¼7.9 Hz), 123.5 (CH, d, JF¼2.8 Hz), 116.5
(CH, d, JF¼21.4 Hz), 114.8 (CH, d, JF¼23.0 Hz), 114.4 (C), 34.2 (CH2),
26.7 (CH2), 21.6 (CH2); HRMS (ES) exact mass calcd for C13H13N3F
[MþH]þ: 230.1094, found: 230.1096.
d
(C),161.4 (C), 159.5 (C),150.0 (2ꢂ CH), 145.8 (C), 122.0 (2ꢂ CH),115.5
(C), 34.1 (CH2), 26.8 (CH2), 21.5 (CH2); HRMS (ES) exact mass calcd
for C12H13N4 [MþH]þ: 213.1140, found: 213.1135.
4.2.17. 2-Furan-2-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl-
4.2.13. 2-(3-Methyoxyphenyl)-6,7-dihydro-5H-cyclopentapyrimidin-
amine (5r). The title compound was prepared according to a mod-
4-ylamine (5n). The title compound was prepared according to
ification of general procedure A using 2-furonitrile (114 mL,
general procedure
A
using 3-methoxybenzonitrile (159
m
L,
1.30 mmol) in double (2 mL) the standard amount of p-xylene and
purified by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane) to give a white solid (107 mg, 41%). Mp
174e175 ꢀC (decomp.); IR (film) 3491, 3316 (NH), 3185, 2956, 1646,
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane) to give a white solid
(270 mg, 86%). Mp 166e168 ꢀC; IR (film) 3429, 3314 (NH), 3175,
2960, 2841, 1648, 1570, 1454, 1432, 1394, 1378, 1235, 1043,
1562, 1459, 1395, 1020, 781, 753 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
775 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.93e7.89 (2H, m, ArH),
d
7.55e7.53 (1H, m, ArH), 7.18 (1H, d, J¼3.3 Hz, ArH), 6.50e6.49 (1H,
7.37e7.33 (1H, m, ArH), 6.99e6.97 (1H, m, ArH), 4.85 (2H, br s, NH2),
m, ArH), 5.01 (2H, br s, NH2), 2.97 (2H, t, J¼7.8 Hz, CH2Ar), 2.72 (2H,

3844
S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
t, J¼7.4 Hz, CH2Ar), 2.15e2.08 (2H, m, CH2CH2Ar); 13C NMR
1.30 mmol) and purified by flash chromatography (0% EtOAc/
cyclohexane/100% EtOAc/cyclohexane) to give a white solid
(263 mg, 90%). Mp 121e123 ꢀC; IR (film) 3319 (NH), 2937, 1613,
(100.6 MHz, CDCl3)
d 172.9 (C), 159.3 (C), 156.5 (C), 152.6 (C), 143.9
(CH), 113.8 (C), 111.7 (CH), 111.6 (CH), 34.2 (CH2), 26.8 (CH2), 21.4
(CH2); HRMS (ES) exact mass calcd for C11H12N3O [MþH]þ:
202.0980, found: 202.0981.
1587, 1565, 1556, 1445, 1401, 759, 702 cmꢁ1 1H NMR (360 MHz,
;
CDCl3)
d 8.31e8.28 (2H, m, ArH), 7.46e7.40 (3H, m, ArH), 4.90 (2H,
br s, NH2), 2.83e2.80 (2H, m, CH2Ar), 2.43e2.37 (2H, m, CH2Ar),
1.89e1.86 (4H, m, CH2CH2CH2Ar); 13C NMR (90.6 MHz, CDCl3) 163.6
(C), 161.6 (C), 161.3 (C), 138.5 (C), 129.6 (CH), 128.2 (2ꢂ CH), 127.7
(2ꢂ CH), 109.9 (C), 32.1 (CH2), 22.4 (CH2), 22.3 (2ꢂ CH2); HRMS (ES)
exact mass calcd for C14H16N3 [MþH]þ: 226.1339, found: 226.1335.
4.2.18. 2-Benzyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamine
(9a). The title compound was prepared according to general pro-
cedure A using benzyl cyanide (150 mL, 1.30 mmol) and purified by
flash chromatography (0% EtOAc/cyclohexane/100% EtOAc/
cyclohexane/20% MeOH/CH2Cl2) to give a white solid (154 mg,
53%). Mp 185e187 ꢀC; IR (film) 3081, 2951, 1667, 1581, 1476, 1432,
4.3.2. 2-(4-Trifluoromethylphenyl)-5,6,7,8-tetrahydroquinazolin-4-
ylamine (10b). The title compound was prepared according to
1407, 690 cmꢁ1 1H NMR (360 MHz, CDCl3)
; d 7.38e7.34 (5H, m,
ArH), 4.89 (2H, br s, NH2), 4.05 (2H, s, CH2Ph), 2.91e2.89 (2H, m,
CH2Ar), 2.64e2.60 (2H, m, CH2Ar), 2.13e2.05 (2H, m, CH2CH2Ar);
general procedure B using pimelonitrile (251 mL, 1.95 mmol) and 4-
(trifluoromethyl)benzonitrile (222 mg, 1.30 mmol) and purified by
flash chromatography (0% EtOAc/cyclohexane/100% EtOAc/cy-
clohexane) to give a white solid (218 mg, 57%). Mp 152e154 ꢀC; IR
(film) 3496, 3298 (NH), 3183, 2936, 2863, 1624, 1566, 1456, 1332,
13C NMR (90.6 MHz, CDCl3)
d 172.7 (C), 167.9 (C), 159.6 (C), 139.1 (C),
129.0 (2ꢂ CH), 128.3 (2ꢂ CH), 126.2 (CH), 113.2 (C), 45.5 (CH2), 34.2
(CH2), 26.6 (CH2), 21.5 (CH2); HRMS (ES) exact mass calcd for
C14H16N3 [MþH]: 226.1339, found: 226.1336.
1158, 1126, 785 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.44e8.42 (2H,
m, ArH), 7.69e7.67 (2H, m, ArH), 4.87 (2H, br s, NH2), 2.84e2.81 (2H,
m, CH2Ar), 2.44e2.41 (2H, m, CH2Ar), 1.93e1.87 (4H, m,
4.2.19. 2-Cyclohexyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl-
amine (9b). The title compound was prepared according to
a modification of general procedure A in that: (i) 10 equiv of
cyclohexanecarbonitrile (1.54 mL, 13.0 mmol) was used, and (ii) the
reaction was conducted in the absence of solvent. Purification was
carried by flash chromatography (0% EtOAc/cyclohexane/100%
EtOAc/cyclohexane) to give a white solid (135 mg, 48%). Mp
196e198 ꢀC; IR (film) 3315 (NH), 3186, 2929, 2852, 1638, 1577, 1460,
CH2CH2CH2Ar); 13C NMR (100.6 MHz, CDCl3)
d 163.9 (C), 161.6 (C),
159.9 (C), 141.9 (C), 131.2 (C, q, JF¼33.2 Hz), 128.0 (2ꢂ CH), 125.1 (2ꢂ
CH, q, JF¼3.7 Hz), 124.3 (C, q, J¼272.6 Hz), 110.7 (C), 32.1 (CH2), 22.5
(CH2), 22.3 (CH2), 22.2 (CH2); HRMS (ES) exact mass calcd for
C15H15N3F3 [MþH]þ: 294.1218, found: 294.1215.
4.3.3. 6-Methyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
4-ylamine (10c). The title compound was prepared according to
general procedure B using 3-[(2-cyanoethyl)methylamino]propio-
1404 cmꢁ1 1H NMR (CDCl3)
; d 4.81 (2H, br s, NH2), 2.86 (2H, t,
J¼7.8 Hz, CH2Ar), 2.70e2.60 (3H, m, CH2Ar and CH2CHCH2),
2.15e1.97 (2H, m, (CH2)5), 1.96e1.84 (2H, m, (CH2)5), 1.84e1.73 (2H,
m, (CH2)5), 1.69e1.66 (1H, m, (CH2)5), 1.61e1.51 (2H, m, (CH2)5),
nitrile (206 mg, 1.95 mmol) and benzonitrile (133 mL, 1.30 mmol)
and purified by flash chromatography (0% EtOAc/cyclo-
hexane/100% EtOAc/cyclohexane/20% MeOH/CH2Cl2) to give
a white solid (280 mg, 90%). Mp 118e119 ꢀC; IR (film) 3332 (NH),
1.43e1.15 (3H, m, (CH2)5); 13C NMR (CDCl3)
d 173.2 (C), 172.6 (C),
159.3 (C), 112.9 (C), 47.4 (CH), 34.2 (CH2), 31.9 (2ꢂ CH2), 26.6 (CH2),
26.3 (2ꢂ CH2), 25.9 (CH2), 21.5 (CH2); HRMS (ES) exact mass calcd
for C13H20N3 [MþH]þ: 218.1657, found: 218.1650.
3188, 2937, 2787, 1627, 1590, 1558, 1450, 1400, 1375, 758, 700 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d 8.32e8.23 (2H, m, ArH), 7.49e7.38
(3H, m, ArH), 6.64 (2H, br s, NH2), 3.29e3.21 (2H, m, NCH2Ar),
2.75e2.72 (2H, m, NCH2CH2), 2.66e2.64 (2H, m, NCH2CH2), 2.39
4.2.20. 2-Butyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamine
(9c). The title compound was prepared according to a modification
of general procedure A in that: (i) 10 equiv of valernonitrile (1.36 mL,
13.0 mmol) was used, and (ii) the reaction was conducted in the
absence of solvent. Purification was carried out by flash chroma-
tography (0% EtOAc/cyclohexane/100% EtOAc/cyclohexane) to give
a white solid (140 mg, 56%). Mp 142e143 ꢀC; IR (film) 3309 (NH),
(3H, s, NCH3); 13C NMR (100.6 MHz, DMSO-d6)
d 160.4 (C), 160.1 (C),
159.7 (C), 138.3 (C), 129.6 (CH), 128.1 (2ꢂ CH), 127.3 (2ꢂ CH), 108.3
(C), 51.9 (CH2), 51.6 (CH2), 45.7 (CH3), 31.8 (CH2); HRMS (ES) exact
mass calcd for C14H17N4 [MþH]þ: 241.1453, found: 241.1452.
4.3.4. 2-(4-Bromophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]
pyrimidin-4-ylamine (10d). The title compound was prepared
according to general procedure B using 3-[(2-cyanoethyl)methyl-
amino]propionitrile (206 mg, 1.95 mmol) and 4-bromobenzonitrile
(182 mg, 1.30 mmol) and purified by flash chromatography (0%
3131, 2952, 2928, 2862, 1657, 1574, 1468, 1408 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
4.98 (2H, br s, NH2), 2.86 (2H, t, J¼7.8 Hz, CH2Ar),
2.69e2.63 (4H, m, CH2Ar and CH2CH2CH2CH3), 2.11e2.04 (2H, m,
CH2CH2Ar), 1.73e1.65 (2H, m, CH2CH2CH3), 1.41e1.32 (2H, m,
CH2CH3), 0.89 (3H, t, J¼7.3 Hz, CH3); 13C NMR (100.6 MHz, CDCl3)
EtOAc/cyclohexane/100%
EtOAc/cyclohexane/20%
MeOH/
d
172.6 (C), 169.9 (C), 159.3 (C), 112.7 (C), 39.1 (CH2), 34.1 (CH2), 31.3
CH2Cl2) to give a white solid (293 mg, 92%). Mp 169e171 ꢀC; IR
(film) 3317 (NH), 3181, 2942, 2792, 1629, 1557, 1583, 1453, 1420,
(CH2), 26.6 (CH2), 22.7 (CH2), 21.5 (CH2),13.9 (CH3); HRMS (ES) exact
mass calcd for C11H18N3 [MþH]þ: 192.1501, found: 192.1497.
1401, 1377, 785, 730 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
8.21e8.18 (2H, m, ArH), 7.64e7.62 (2H, m, ArH), 6.70 (2H, br s,
4.3. Base-catalyzed reaction of various dinitriles with various
mononitriles: general procedure B
NH2), 3.26e3.20 (2H, m, NCH2Ar), 2.74e2.71 (2H, m, NCH2CH2),
2.68e2.61 (2H, m, NCH2CH2), 2.38 (3H, s, NCH3); 13C NMR
(100.6 MHz, DMSO-d6)
d 160.4 (C), 159.7 (C), 159.2 (C), 137.5 (C),
To a solution of the appropriate dinitrile (1.95 mmol) and the
appropriate mononitrile (1.30 mmol) in p-xylene (1 mL) in a car-
ousel tube was added t-BuOK (73 mg, 0.65 mmol) in one portion.
The reaction vessel was heated in a carousel to 120 ꢀC for 4 h. After
cooling to room temperature, CH2Cl2 (ca. 30 mL) was used to
transfer the mixture onto a silica cartridge for purification.
131.1 (2ꢂ CH), 129.3 (2ꢂ CH), 123.3 (C), 108.6 (C), 51.9 (CH2), 51.5
(CH2), 45.7 (CH3), 31.7 (CH2); HRMS (ES) exact mass calcd for
C14H16N4Br [MþH]þ: 319.0558, found: 319.0560.
4.3.5. 2-Phenyl-9H-indeno[2,1-d]pyrimidin-4-ylamine (10e). The ti-
tle compound was prepared according to a modification of general
procedure B in that t-BuOK (29.2 mg, 0.26 mmol) was used, using
1,2-phenylenediacetonitrile (305 mg, 1.95 mmol) and benzonitrile
4.3.1. Phenyl-5,6,7,8-tetrahydroquinazolin-4-ylamine (10a). The ti-
tle compound was prepared according to general procedure B using
(133
mL, 1.30 mmol). Purification was carried out by flash chroma-
pimelonitrile (251 mL, 1.95 mmol) and benzonitrile (133 mL,
tography (0% EtOAc/cyclohexane/50% EtOAc/cyclohexane) to give

S. Chercheja et al. / Tetrahedron 67 (2011) 3839e3845
3845
a violet solid (128 mg, 38%). Mp 196e198 ꢀC; IR (film) 3308 (NH),
3169, 2923, 1588, 1548, 1451, 1390, 1265, 905, 729, 713 cmꢁ1 1H
NMR (400 MHz, CDCl3) 8.52e8.38 (2H, m, ArH), 7.64e7.60 (1H, m,
ArH), 7.58e7.40 (5H, m, ArH), 7.41e7.31 (1H, m, ArH), 5.33 (2H, br s,
NH2), 4.02 (2H, s, CH2); 13C NMR (100.6 MHz, CDCl3)
173.0 (C),
162.6 (C), 157.4 (C), 139.9 (C), 138.1 (C), 137.6 (C), 130.1 (CH), 128.4
(2ꢂ CH), 128.2 (2ꢂ CH), 127.2 (CH), 126.4 (CH), 125.2 (CH), 120.8
(CH), 114.4 (C), 39.3 (CH2); HRMS (ES) exact mass calcd for C17H14N3
[MþH]þ: 260.1188, found: 260.1188.
References and notes
;
1. (a) Arban, R.; Benedetti, R.; Bonanomi, G.; Capelli, A.; Castiglioni, E.; Contini, S.;
Degiorgis, F.; Di Felice, P.; Donati, D.; Fazzolari, E.; Gentile, G.; Marchionni, C.;
Marchioro, C.; Messina, F.; Micheli, F.; Oliosi, B.; Pavone, F.; Pasquarello, A.;
Perini, B.; Rinaldi, M.; Sabbatini, F. M.; Vitulli, G.; Zarantonello, P.; Di Fabio, R.;
St-Denis, Y. ChemMedChem 2007, 2, 528e540; (b) Simmen, K. A.; Lin, T.-I.; Lenz,
O.; Surleraux, D. L. N. G.; Raboisson, P. J.-M. B. PCT Int. Appl., WO 2006035061
A1, 2006. (c) Dugar, S.; Chakravarty, S.; Conte, A.; Axon, J.; McEnroe, G. PCT Int.
Appl., WO 2004087056 A2, 2004. (d) Capelli, A. M.; Marchionni, C.; Micheli, F.;
Pasquarello, A.; Perini, B.; St-Denis, Y. PCT Int. Appl., WO 2002088095 A1, 2002.
d
d
€
(e) Schindler, U.; Schonafinger, K.; Strobel, H. Ger. Offen. DE 19853278 A1,
2000.
4.3.6. 2-(4-tert-Butylphenyl)-9H-indeno[2,1-d]pyrimidin-4-ylamine
(10f). The title compound was prepared according to a modifica-
tion general procedure B in that t-BuOK (29.2 mg, 0.26 mmol) was
used, using 1,2-phenylenediacetonitrile (305 mg, 1.95 mmol) and
2. Seminal references: (a) Ziegler, K.; Eberle, H.; Ohlinger, H. Justus Liebigs Ann.
Chem. 1933, 504, 94e130; (b) Baron, H.; Remfry, F. G. P.; Thorpe, J. F. J. Chem. Soc.
1904, 85, 1726e1761. For a review, see: (c) Schaefer, J. P.; Bloomfield, J. J. Org.
React. 1967, 15, 1e203 For selected recent examples, see: (d) Francis, J. E.; Ben-
nett, D. A.; Hyun, J. L.; Rovinski, S. L.; Amrick, C. L.; Loo, P. S.; Murphy, D.; Neale,
R. F.; Wilson, D. E. J. Med. Chem. 1991, 34, 2899e2906; (e) Yoshizawa, K.; Toyota,
S.; Toda, F. Green Chemistry 2002, 4, 68e70; (f) Winkler, M.; Martínkova, L.; Knall,
A. C.; Krahulec, S.; Klempier, N. Tetrahedron 2005, 61, 4249e4260; (g) Michae-
lidou, S. S.; Koutentis, P. A. Tetrahedron 2010, 66, 685e688.
3. For representative examples, see: (a) Taylor, E. A.; Borror, A. L. J. Org. Chem.
1961, 26, 4967e4974; (b) Smyrl, N. R.; Smithwick, R. W., III. J. Heterocycl. Chem.
1982, 19, 493e496; (c) Hanefeld, U.; Rees, C. W.; White, A. J. P.; Williams, D. J. J.
Chem. Soc., Perkin Trans. 1 1996, 1545e1552; (d) Seijas, J. A.; Pilar Vazquez-Tato,
M.; Monsterrat, M. Tetrahedron 2000, 41, 2215e2217; (e) Hess, S.; Muller, C. E.;
4-tert-butylbenzonitrile (220 mL, 1.30 mmol). Purification was car-
ꢁ
ried out by flash chromatography (0% EtOAc/cyclohexane/50%
EtOAc/cyclohexane) to give a yellow solid (163 mg, 40%). Mp
207e209 ꢀC; IR (film) 3306 (NH), 3177, 2962, 1618, 1581, 1548, 1460,
1396, 797, 734, 715 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.38e8.36
(2H, m, ArH), 7.58 (1H, d, J¼7.3 Hz, ArH), 7.51 (2H, d, J¼8.6 Hz, ArH),
7.49e7.45 (1H, m, ArH), 7.40 (1H, t, J¼7.3 Hz, ArH), 7.35e7.29 (1H,
m, ArH), 5.41 (2H, br s, NH2), 3.99 (2H, s, CH2), 1.39 (9H, s, C(CH3)3);
ꢁ
€
Frobenius, W.; Reith, U.; Klotz, K.-N.; Eger, K. J. Med. Chem. 2000, 43,
4636e4646.
4. For examples of trimerization of nitriles to 4-aminopyrimidines, reactions that
13C NMR (100.6 MHz, CDCl3)
d 172.9 (C), 162.6 (C), 157.4 (C), 153.3
(C), 139.8 (C), 137.7 (C), 135.3 (C), 127.9 (2ꢂ CH), 127.1 (CH), 126.2
(CH), 125.3 (2ꢂ CH), 125.1 (CH), 120.6 (CH), 114.1 (C), 39.2 (CH2),
34.8 (C), 31.2 (3ꢂ CH3); HRMS (ES) exact mass calcd for C21H22N3
[MþH]þ: 316.1814, found: 316.1817.
proceed presumably via the annulation of b-cyanoenamines with nitriles, see:
(a) Reynolds, G. A.; Humphlett, W. J.; Swamer, F. W.; Hauser, C. R. J. Org. Chem.
1951, 16, 165e172; (b) Cairns, T. L.; Larchar, A. W.; McKusick, B. C. J. Am. Chem.
Soc. 1952, 74, 5633e5636; (c) Burns, T. P.; Rieke, R. D. J. Org. Chem. 1987, 52,
3674e3680; (d) Takaya, H.; Naota, T.; Murahasahi, S. J. Am. Chem. Soc. 1998,
120, 4244e4245; (e) Baxendale, I. R.; Ley, S. V. J. Comb. Chem. 2005, 7,
483e489.
5. For the formation of a bicyclic aminopyrimidine from 2 equiv of the same
dinitrile (adiponitrile), see: Thompson, Q. E. J. Am. Chem. Soc. 1958, 80,
5483e5487.
6. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 804388e804389. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
7. Yamamoto, K. Yuki Gosei Kagaku Kyokaishi 1971, 29, 510e514.
8. For examples of SNAr reactions of 4-fluorobenzonitrile with nitrile anions, see:
(a) McEvoy, F. J.; Albright, J. D. J. Org. Chem. 1979, 44, 4597e4603; (b) Caron, S.;
Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712e713 For examples of
SNAr reactions of 4-fluorobenzonitrile with other carbon nucleophiles, see: (c)
Bordwell, F. G.; Hughes, D. L. J. Am. Chem. Soc. 1986, 108, 5991e5997; (d) Suzuki,
Y.; Toyota, T.; Imada, F.; Sato, M.; Miyashita, A. Chem. Commun. 2003, 1314e1315;
(e) Ueno, M.; Yonemoto, M.; Hashimoto, M.; Wheatley, A. E. H.; Naka, H.; Kondo,
Y. Chem. Commun. 2007, 2264e2266.
Acknowledgements
This work was funded by the EPSRC and GlaxoSmithKline under
the Array Chemistry Initiative. We thank Dr. Fraser J. White at the
School of Chemistry, University of Edinburgh for assistance with
X-ray crystallography. The EPSRC National Mass Spectrometry
Service Centre at the University of Wales, Swansea, is gratefully
acknowledged for providing high resolution mass spectra.
Supplementary data
Copies of 1H and 13C NMR spectra for new compounds. Sup-
plementary data associated with this article can be found in the
online version at doi:10.1016/j.tet.2011.03.098.