Direct synthesis of substituted pyrimidines and quinazolines

Article abstract of DOI:10.1055/s-2007-990932

A variety of N-vinyl and N-aryl amides were converted in one step into the corresponding pyrimidine and quinazoline derivatives, respectively. Amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by nitrile

Full text of DOI:10.1055/s-2007-990932

PRACTICAL SYNTHETIC PROCEDURES
823
Direct Synthesis of Substituted Pyrimidines and Quinazolines
S
ynthesis of Substitute
a
d
Pyrimidin
t
e
s
and
t
Q
uina
h
z
olines ew D. Hill, Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Fax +1(617)2521504; E-mail: movassag@mit.edu
Received 20 July 2007
PSP
No116
Abstract: A variety of N-vinyl and N-aryl amides were converted in one step into the corresponding pyrimidine and quinazoline deriva-
tives, respectively. Amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by nitrile addi-
tion to the activated amide derivative and annulation provides the desired azaheterocycles.
Key words: amide, nitrile, pyrimidine, quinazoline, annulation
Tf2O
Me
2-ClPyr
O
O
Me
HN
N
+
CH2Cl2
–78 °C to 23 °C
Me
Me
Me
N
O
N
Me
86%
1
2
3
Scheme 1
ClPyr)11 to be optimal for direct condensation of amides
and nitriles en route to pyrimidine derivatives. The single-
Introduction
Due to the presence of pyrimidines and quinazolines in step conversion of amide 1 and nitrile 2 to pyrimidine 3 is
many pharmaceuticals, natural products, and fine materi- illustrative of this methodology (Scheme 1). Various base
als, important contributions have been reported concern- additives were examined but were less effective than 2-
ing synthetic methodology for their preparation.1 ClPyr, as shown in optimization studies conducted using
Condensation reactions between amines and carbonyl de- amide 4 and nitrile 5 (Table 1). Superstoichiometric 2-
rivatives or intermolecular cycloaddition approaches are ClPyr was found to have an inhibitory effect on conver-
common to many of these synthetic methodologies.1,2 sion of 4 and 5 into the quinazoline 6 (Table 1, entry 12).
1
Cross-coupling chemistry has recently enabled the intro- Under optimal reaction conditions, data from in situ H,
duction of substituents on existing activated azahetero- 13C, and 19F NMR, and IR monitoring studies suggest that
cycles.3 We describe here a convergent and single-step activation of an amide substrate (7 in Scheme 2) with
procedure for the synthesis of a variety of pyrimidine and Tf2O and 2-ClPyr leads to a mixture of intermediate 8 and
quinazoline derivatives from N-vinyl and N-aryl amides, triflate adduct 9.4 Subsequent s-nucleophilic addition of
respectively.4
nitrile 10 is expected to give nitrilium ion 11 followed by
rapid annulation with concomitant loss of 2-ClPyr·HOTf
to afford the pyrimidine 12 (Scheme 2).
Both N-vinyl and N-aryl amides are readily available and
attractive starting materials for azaheterocycle synthesis.5
Based on observations made while pursuing a two-step
synthesis of pyridine derivatives,6 we envisioned amide
activation, subsequent nitrile s-nucleophilic addition, fol-
lowed by annulation of the corresponding nitrilium ion to
give access to a wide variety of pyrimidine derivatives.7
Nitriles, including optically active derivatives, are com-
mercially available, can be accessed by dehydration of
amides,8 or prepared by hydrocyanation of carbonyl de-
rivatives and serve as versatile starting materials for aza-
heterocycle synthesis.
Scope and Limitations
A variety of quinazoline and pyrimidine derivatives were
prepared from readily available amide and nitrile sub-
strates using this chemistry (Table 2). While cyclization
of electron-rich N-aryl amides and nitriles typically pro-
ceeded with mild heating (45 °C), increasing the reaction
temperature to 140 °C in a microwave reactor lowered re-
action times and often increased isolated yields (Table 2,
entries 3, 5–8, 10–14). The electron-deficient N-aryl sub-
strate, shown in entry 3 of Table 2, required reaction tem-
peratures of 140 °C to obtain complete conversion to the
product. The use of a formamide substrate failed to give
the desired pyrimidine due to competing isocyanide for-
We found the reagent combination of trifluoromethane-
sulfonic anhydride (Tf2O)9,10 and 2-chloropyridine (2-
SYNTHESIS 2008, No. 5, pp 0823–0827
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-990932; Art ID: Z17607SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

824
M. D. Hill, M. Movassaghi
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Single-Step Conversion of Amide 4 to Quinazoline 6a
was required; however, less reactive systems benefited
from mild warming to 45 °C (Table 2, entry 18).
OMe
Tf2O
base
additive
Importantly, an optically active N-vinyl amide and an op-
tically active nitrile were converted into the correspond-
ing pyrimidines without any loss in optical activity and
without desilylation in the course of the reaction (Table 2,
entries 21–22). However, in the case of the less reactive
optically active N-aryl amides (98% ee) used in entries 23
and 24 of Table 2, the need for heating the reaction mix-
ture to obtain the desired quinazolines afforded products
in racemic form.
OMe
HN
+
CH2Cl2
–78 °C to 45 °C
N
N
O
N
4
5
6
Entry
1
Base additive
none
Base (equiv)
Yield (%) of 6
0
29
0
Minor adjustments of the reaction conditions can extend
the scope of this chemistry to less reactive substrates. For
example, superstoichiometric amount of the nitrile com-
ponent was necessary to achieve satisfactory yields with
the less reactive substrates (Table 2, entries 9, 18, and 22).
Excess nitrile was also beneficial with sterically crowded
substrates (Table 2, entry 21). Aliphatic nitriles were
more reactive than benzonitrile derivatives when this
chemistry was conducted at 45 °C. However, when reac-
tions were heated to 140 °C this observable difference sig-
nificantly decreased.
2
Et3N
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.2
3.0
3
i-Pr2NEt
14
26
28
19
59
54
63
72
90
81
4
pyridine
5
2,6-lutidine
2,4,6-collidine
ethyl nicotinate
3-bromopyridine
2-bromopyridine
2-chloropyridine
2-chloropyridine
2-chloropyridine
6
7
8
9
An efficient and convergent single-step synthesis of a
wide range of pyrimidine and quinazoline derivatives
from readily available amide and nitrile substrates is dis-
cussed. A wide range of substrates was applicable to this
methodology. This methodology does not require isola-
tion of activated intermediates nor does it call for stoichi-
ometric Lewis acid additives post amide activation.
Epimerizable N-vinyl amide and nitrile substrates may be
used as substrates in this chemistry to give the desired aza-
heterocyclic products without loss in optical activity.
10
11
12
a Reaction conditions: amide 4 (1 equiv), nitrile 5 (1.1 equiv), Tf2O
(1.1 equiv), base additive, CH2Cl2, –78 °C → 45 °C, 16 h.
mation (Table 2, entry 10). Electron-rich and electron-de-
ficient benzonitriles were successfully used as substrates
in this chemistry (Table 2, entries 11–13). A variety of N-
vinyl amides gave access to pyrimidine derivatives with
alkyl- or benzonitriles as nucleophiles (Table 2, entries
15–22). In the case of N-vinyl amides, often no heating
Procedure
The synthesis of pyrimidines and quinazolines directly from the
corresponding nitrile and N-vinyl or N-aryl amides, respectively, is
described.
R2
R2
N
R4
R3
R3
10
HN
N
Tf2O
2-ClPyr
R1
O
R1
N
R4
12
7
Tf2O, 2-ClPyr
– TfOH
TfO– R2
R2
R2
N
R4
R3
H
R3
H
R3
–OTf
+
N
10
N
N
–OTf
TfO
R1
+
N
+
N
+
N
R1
R1
– 2-ClPyr
– TfOH
R4
8
9
11
–OTf
Cl
Cl
Scheme 2
Synthesis 2008, No. 5, 823–827 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Direct Synthesis of Substituted Pyrimidines and Quinazolines
825
Table 2 Synthesis of Pyrimidines and Quinazolines
Entry Amide
Nitrile
Conditions Yield (%)a
R2
R2
R3
R3
R4
O
N
N
R1
N
H
R1
N
R4
1
2
R1 = Ph, R2 = H, R3 = OMe
R1 = Ph, R2 = H, R3 = H
R4 = c-C6H11
B
B
C
B
C
C
C
C
B
C
C
C
C
C
89
R4 = c-C6H11
71
61
87b
69
81
73
80
88c
0
3
R1 = Ph, R2 = CF3, R3 = H
R4 = c-C6H11
4
R1 = 4-MeOC6H4, R2 = H, R3 = OMe
R1 = 4-NO2C6H4, R2 = H, R3 = OMe
R1 = t-Bu, R2 = H, R3 = OMe
R1 = c-C6H11, R2 = H R3 = OMe
R1 = N(CH2CH2)2O, R2 = H, R3 = H
R1 = cyclohex-1-enyl, R2 = H, R3 = OMe
R1 = H, R2 = H, R3 = H
R4 = c-C6H11
5
R4 = c-C6H11
6
R4 = c-C6H11
7
R4 = c-C6H11
8
R4 = c-C6H11
9
R4 = c-C6H11
10
11
12
13
14
R4 = c-C6H11
R1 = Ph, R2 = H, R3 = OMe
R1 = Ph, R2 = H, R3 = OMe
R1 = Ph, R2 = H, R3 = OMe
R1 = Ph, R2 = H, R3 = OMe
R4 = 4-NO2C6H4
R4 = 4-MeOC6H4
R4 = 4-CO2EtC6H4
R4 = (E)-C6H4CH=CH
86
88
74
68
O
O
R4
O
R4
N
N
Ph
N
H
Ph
N
15
16
17
R4 = c-C6H11
R4 = t-Bu
A
A
A
92
86d
77
R4 = (CH2)3C≡CH
Ph
O
O
N
N
N
18
19
R4 = c-C6H11
B
A
Ph
Ph
N
N
N
cC6H11
Ph
Ph
N
H
89c,e
S
R4 = c-C6H11
S
N
H
Ph
cC6H11
86
NH
O
20
21
R4 = c-C6H11
A
NTIPS
Ph
Ph
N
H
Ph
cC6H11
70f
O
O
N
O
N
Ph
B
Ph
N
Ph
N
OTBS
H
OTBS
71e,g (96% ee)
Synthesis 2008, No. 5, 823–827 © Thieme Stuttgart · New York

826
M. D. Hill, M. Movassaghi
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Synthesis of Pyrimidines and Quinazolines (continued)
Entry Amide
Nitrile
Conditions Yield (%)a
O
OTIPS
O
O
N
22
B
Me
N
Me
N
H
N
Me
Me
OTIPS
OMe
59e,g (93% ee)
OMe
OTIPS
O
N
23
C
C
Me
N
H
Me
N
Me
N
Me
OH
58h (rac)
OMe
OMe
O
N
cC6H11
24
Me
N
H
Me
N
cC6H11
N
Me
Me
85 (rac)
a Isolated yields; all entries are an average of two experiments. Optimal reaction conditions used uniformly unless otherwise noted: Tf2O (1.1
equiv), 2-ClPyr (1.2 equiv), nitrile (1.1 equiv), CH2Cl2; Conditions: A = 23 °C, 1 h; B = 45 °C, 16 h; C = microwave, 140 °C, 20 min.
b Time = 18 h.
c Nitrile = 5.0 equiv.
d Gram-scale reaction.
e Time = 1 h.
f TBAF (1 equiv) was used to desilylate the product.
g Nitrile = 3.0 equiv.
h TBAF (2 equiv) was used to desilylate the product.
4-tert-Butyl-2-phenyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimi-
dine (3); Typical Procedure
HRMS (ESI): m/z [M + H]+ calcd for C17H21N2O [M + H]+:
269.1654; found: 269.1653.
Trifluoromethanesulfonic anhydride (894 mL, 5.41 mmol, 1.10
equiv) was added via a syringe over 3 min to a flame-dried flask
containing a stirred mixture of amide 1 (1.00 g, 4.92 mmol,
1 equiv), nitrile 2 (491 mg, 5.90 mmol, 1.20 equiv), and 2-chloro-
pyridine (559 mL, 5.90 mmol, 1.20 equiv) in CH2Cl2 (16 mL) at
–78 °C. After 5 min, the mixture was placed in an ice-water bath for
10 min and warmed to 0 °C. The resulting solution was allowed to
warm to r.t. After 1 h, aq 1 N NaOH (5 mL) was introduced to neu-
tralize the trifluoromethanesulfonate salts. CH2Cl2 (50 mL) was
added to dilute the mixture and the layers were separated. The or-
ganic layer was washed with aq CuSO4 (10% w/w) to remove the 2-
chloropyridine, dried (Na2SO4), and filtered. The volatiles were re-
moved under reduced pressure, and the residue was purified by
flash column chromatography (eluent: 10% EtOAc and 1% Et3N in
hexanes; column: 12 × 4 cm) on neutralized silica gel to give the py-
rimidine 3 as a clear oil; yield: 1.13 g (86%); Rf = 0.67 (EtOAc–hex-
anes, 20:80).
Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C,
76.13; H, 7.52; N, 10.34.
Acknowledgment
M.M. is a Firmenich Assistant Professor of Chemistry and a Beck-
man Young Investigator. M.D.H. acknowledges an AMGEN gra-
duate fellowship. This study was supported by NSF (547905). We
acknowledge additional support from DRCRF (39-04), Glaxo-
SmithKline, Merck, and Boehringer Ingelheim Pharmaceutical Inc.
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Direct Synthesis of Substituted Pyrimidines and Quinazolines
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Synthesis 2008, No. 5, 823–827 © Thieme Stuttgart · New York