Application of the intramolecular aza-Wittig reaction to the synthesis of pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2006.03.091

Pyrido[2,3-d]pyrimidines are synthesized in a two-step procedure from amides and tetrazolo[1,5-a]pyridine-8-carbonyl chloride. Reaction of the crude imides with triphenylphosphine effects an intramolecular aza-Wittig reaction to afford a variety of substi

Full text of DOI:10.1016/j.tetlet.2006.03.091

Tetrahedron Letters 47 (2006) 3361–3363
Application of the intramolecular aza-Wittig reaction to
the synthesis of pyrido[2,3-d]pyrimidines
*
Johann Chan and Margaret Faul
Chemistry Process Research and Development, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
Received 9 March 2006; accepted 14 March 2006
Abstract—Pyrido[2,3-d]pyrimidines are synthesized in a two-step procedure from amides and tetrazolo[1,5-a]pyridine-8-carbonyl
chloride. Reaction of the crude imides with triphenylphosphine effects an intramolecular aza-Wittig reaction to afford a variety
of substituted pyrido[2,3-d]pyrimidines in good to moderate yields (30–76%).
ꢀ
2006 Elsevier Ltd. All rights reserved.
The beginnings of the aza-Wittig reaction are rooted in
the work of Staudinger who synthesized the first imino-
phosphorane by reaction of tertiary phosphines and
O
N
O
R1
R1
N
H
N
H
Eguchi
1
organic azides in the early 1900s. The reaction of
N
N
N
iminophosphoranes with carbonyl compounds, parti-
cularly in an intramolecular sense, provides an effective
approach to C@N bond formation. Consequently, the
use of iminophosphoranes as a synthetic intermediate
toward a variety of nitrogen containing heterocycles
PPh3
+
O
Cl
R2
1
Cl
R2
O
R1
R2
N
2
vs.
has become commonplace.
N
N
O
In the course of our investigations in the area of auto-
3
Cl
immune diseases, we required an alternative route to
N
synthesize compounds that contained a pyrido[2,3-d]-
pyrimidine core. Eguchi had previously reported that
iminophosphoranes derived from 2-aminonicotinic-
amides react with a variety of acid chlorides to furnish
N
2
N3
N3
O
R2
O
N
R1
+
O
4
pyrido[2,3-d]pyrimidines in excellent yields. The
H
N
R1
R2
reaction was believed to proceed through an intermole-
cular aza-Wittig reaction followed by cyclization of the
resultant imidoyl chloride 1 (Scheme 1). However, this
method requires 200 mol % acyl chloride, and is limited
to situations where the acyl chloride is stable or simple
to prepare. Furthermore, this method is not applicable
Scheme 1. Synthesis of pyrido[2,3-d]pyrimidines.
5
1
2
cyclic pyridopyrimidines. To this end, we were pleased
to find that the intramolecular aza-Wittig reaction
indeed furnished the desired compounds in good to
moderate yields. Herein, we report the participation of
tetrazolo[1,5-a]pyridine-8-carbonyl chloride (4) in the
synthesis of pyrido[2,3-d]pyrimidines by way of an
intramolecular aza-Wittig reaction.
to substrates in which R and R are tethered. An alter-
native method that could overcome these drawbacks
would be to perform the coupling between pyridine acyl
chloride 2 and various amides, thus allowing access to
Keywords: Tetrazolo[1,5-a]pyridine-8-carbonyl chloride; aza-Wittig;
Pyrido[2,3-d]pyrimidines; Iminophosphoranes.
*
Corresponding author. Tel.: +1 805 313 5264; fax: +1 805 375
532; e-mail: johannc@amgen.com
The synthesis of tetrazolo[1,5-a]pyridine-8-carbonyl
chloride (4) is summarized in Scheme 2. Beginning with
4
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.091

3362
J. Chan, M. Faul / Tetrahedron Letters 47 (2006) 3361–3363
O
O
N
O
to generate pyrido[2,3-d]pyrimidines in good to moder-
ate yields (Table 1). N-acylation of the amide was
8
OH NaN3
DMSO
OH (COCl)2
Cl
achieved through the use of Et N/DMAP which affor-
3
ded the desired imides (Scheme 3). Interestingly, the
treatment of amides with NaH/THF or NaH/DMF fol-
lowed by the addition of tetrazolo[1,5-a]pyridine-8-car-
bonyl chloride (4) gave a mixture of N- and O-coupled
products. The crude imide was used directly in the
cyclization to generate the desired products (Table 1).
Entries 1, 2, and 3 illustrate the potential of this meth-
od to synthesize cyclic pyridopyrimidines, a class of
compounds that are particularly challenging to access
N
Cl
N
cat. DMF
CH2Cl2
N
N
N N
N N
3
4
Scheme 2. Synthesis of tetrazolo[1,5-a]pyridine-8-carbonyl chloride.
2
-chloronicotinic acid, treatment with sodium azide
afforded tetrazole 3 in 65% yield. Notably, the equili-
brium in water between tetrazole 3 and its isomeric 2-
azidopyridine lies exclusively at the tetrazole, consistent
with the earlier characterization data reported for this
compound. Reaction of 3 with oxalyl chloride afforded
tetrazolo[1,5-a]pyridine-8-carbonyl chloride (4) in 95%
isolated yield as a fine powder that is stable when stored
at ꢀ20 ꢁC under argon (Scheme 2).
9
using existing technologies. Electron-rich aromatic
1
groups were well tolerated at R ; however, coupling
6
of amides possessing electron-deficient aromatic groups
1
at R (p-iodophenyl, p-cyanophenyl) suffered from poor
1
0
conversion primarily due to imide hydrolysis. Alkyl
groups larger than methyl suffered from poor conver-
7
2
sion. With respect to R , aromatic, aliphatic groups
In a two-step process, amides were coupled with tetra-
zolo[1,5-a]pyridine-8-carbonyl chloride (4) and cyclized
and hydrogen were suitable substrates (entries 4, 5,
and 6).
Table 1. Two-step approach to the synthesis of pyrido[2,3-d]pyrimidines
O
O
i) 20% DMAP, Et N
3
R1
H
Cl
CH2Cl2
N
N
R2
R1
+
R2
N
ii) PPh , toluene
N
N
N
N
3
O
N
110 °C
Entry
1
Amide
Product
Yield (%)
53
O
O
N
H
N
N
N
N
O
2
3
N
71
76
N
H
O
N
O
N
N
N
O
H
N
N
N
O
H
N
Me
a
4
72
Me
N
O
O
OBn
H
N
b
5
N
N
53
30
O
BnO
Me
N
N
N
O
H
N
Me
H
6
O
N
a
Difficulty purifying from P(O)Ph
Reaction conducted in THF at 60 ꢁC.
3
in hexanes:ethyl acetate chromatography.
b

J. Chan, M. Faul / Tetrahedron Letters 47 (2006) 3361–3363
3363
O
N
5. An analogous approach to the quinazolinones have been
undertaken see: (a) Takeuchi, H.; Eguchi, S. Tetrahedron
Lett. 1989, 30, 3313; (b) Takeuchi, H.; Hagiwara, S.;
Eguchi, S. Tetrahedron 1989, 20, 6375; (c) Luheshi, A. B.;
Salem, S. M.; Smalley, R. K. Tetrahedron Lett. 1990, 31,
Cl
N
N
N
-N
N
N
N+
N
N
N N
6
561; (d) Eguchi, S.; Takeuchi, H.; Matsushita, Y.
O
O
+
Heterocycles 1992, 33, 153.
O
R2
R2
6. (a) Pollak, A.; Polane, S.; Stanovnik, B.; Tisler, M.
Monatsh. Chem. 1972, 103, 1591; (b) Cmoch, P.; Stefa-
niak, L.; Webb, G. A. Magn. Reson. Chem. 1997, 35,
237.
O
N
R1
O
N
R1
H
N
R1
R2
5a
5b
7
. Representative procedure: To a solution of 2-chloronico-
tinic acid (40.0 g, 254 mmol) in DMSO (150 mL) was
added sodium azide (16.5 g, 254 mmol) and the resulting
mixture heated to 90 ꢁC for 3 h. The precipitated product
was poured into 500 mL of acetone and filtered. The white
filter cake was washed with an additional 1.5 L of acetone,
and dried in a vacuum oven (room temperature) to obtain
3 (27.3 g, 65%) as a white solid. Synthesis of acyl chloride:
To a slurry of the acid 3 (17.8 g, 108 mmol) in dichloro-
methane (150 mL) was added DMF (0.1 mL) followed by
oxalyl chloride (18.9 mL, 217 mmol) slowly. The reaction
mixture was stirred for 3 h, concentrated in vacuo, and
washed 2· with hexane (50–75 mL). The slurry was
concentrated in vacuo to afford 4 (19.6 g, 98%) as a fine
O
N
N
R1
Ph P
PPh3
N2
3
- P(O)PPh3
R2
N
N
O
-
R2
N
O
N
R1
6
Scheme 3. Proposed mechanism to pyrido[2,3-d]pyrimidine formation.
Although no mechanistic studies have been conducted,
one reasonable proposal for this sequence begins with
the standard coupling to form imide 5a/5b. Treatment
of 5a/5b with triphenylphosphine could trap-out the
desired iminophosphorane 6 from the equilibrium
*
gray powder. Compounds 3 and 4 have not been tested
for their propensity as explosives.
8
. Synthesis of pyridopyrimidine representative procedure
(entry 3): To a solution of azepan-2-one (226 mg, 2 mmol)
in dichloromethane (5 mL) was added triethylamine
(0.84 mL, 6 mmol), tetrazolo[1,5-a]pyridine-8-carbonyl
chloride (4) (746 mg, 4 mmol), and DMAP (45 mg,
1
1
mixture. Cyclization of iminophosphorane 6 would
then lead to the desired product.
0
.2 mmol) and stirred for 16 h. The reaction mixture was
In summary, a new approach to the synthesis of
pyridopyrimidines has been developed. Utilizing tetr-
azolo[1,5-a]pyridine-8-carbonyl chloride (4), imides were
conveniently synthesized and transformed via an aza-
Wittig reaction to furnish pyrido[2,3-d]pyrimidines in
good to moderate yields. This two-step procedure offers
an attractive alternative to conventional methods, and is
particularly useful for the generation of cyclic
pyridopyrimidines.
diluted with dichloromethane (125 mL) and washed with
1
was dried (MgSO ), filtered and concentrated in vacuo to
afford crude imide. The crude imide was transferred to a
M HCl (75 mL) and 2· water (75 mL). The organic layer
4
1
5 mL sealed tube and taken up in toluene (5 mL).
Triphenylphosphine (640 mg, 1.2 mmol) was added and
the reaction mixture heated to 110 ꢁC for 16 h. The
solution was concentrated in vacuo and purified by silica
gel chromatography (4:1 ethylacetate:hexanes ! 100%
ethyl acetate) to afford the desired pyridopyrimidine
(
330 mg, 76%).
9. Dunn, A. D.; Kinnear, K. I.; Norrie, R. Z. Chem. 1986,
6, 290.
Acknowledgements
2
1
0. The conclusion of imide hydrolysis as opposed to poor
reactivity was made based on the isolation of amide formed
with tetrazolo[1,5-a]pyridine-8-carbonyl chloride (4) (cross-
product). In the case of poor reactivity, the cross-product
would not be observed.
We would like to thank Randy Jensen for NMR
assistance.
References and notes
1
2
. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
. (a) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 209; (b) Wamhoff, H.; Richardt, G.;
St o¨ lben, S. Adv. Heterocycl. Chem. 1995, 64, 159; (c)
Fresneda, P. M.; Molina, P. Synlett 2004, 1, 1.
. Collins, T. L.; Johnson, M. G.; Ma, J.; Medina, J.C.;
Miao, S.; Schneider, M.; Tonn, G. CXCR3 Antagonists.
International Patent 075863, September 10, 2004.
N
N
N
N
N
O
N
hydrolysis
N
N
O
N
R1
R2
O
NH
R1
3
cross-product
4
. Okawa, T.; Toda, M.; Eguchi, S.; Kakehi, A. Synthesis
11. Lowe-Ma, C. K.; Nissan, R. A.; Wilson, W. S. J. Org.
Chem. 1990, 55, 3755.
1
998, 1467.