The anion of 3-methyl-2-pyridin-4-yl-1,3-oxazine

Article abstract of DOI:10.1081/SCC-120021505

n-Butyllithium at -78°C readily abstracts the methine proton from the title compound. The anion reacts efficiently with a range of electrophiles to provide 4-pyridyl ketones upon acid hydrolysis.

Full text of DOI:10.1081/SCC-120021505

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The Anion of 3-Methyl-2-pyridin-4-yl- 1,3-oxazine
a
b
b
b
Peter Sheldrake , Elizabeth Tyrrell , Shirin Mintias & Imran Shahid
a
Department of Synthetic Chemistry , GlaxoSmithKline Pharmaceuticals , Old Powder Mills
Nr. Leigh, Tonbridge, Kent, UK
b
School of Chemical and Pharmaceutical Sciences , Kingston University , Kingston, Surrey,
UK
Published online: 17 Aug 2006.
To cite this article: Peter Sheldrake , Elizabeth Tyrrell , Shirin Mintias & Imran Shahid (2003) The Anion of 3-Methyl-2-
pyridin-4-yl- 1,3-oxazine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:13, 2263-2268, DOI: 10.1081/SCC-120021505
To link to this article: http://dx.doi.org/10.1081/SCC-120021505
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 13, pp. 2263–2268, 2003
The Anion of 3-Methyl-2-pyridin-4-yl-
1,3-oxazine
1
,
2,
2
Peter Sheldrake, * Elizabeth Tyrrell, * Shirin Mintias,
2
and Imran Shahid
1
Department of Synthetic Chemistry, GlaxoSmithKline
Pharmaceuticals, Old Powder Mills Nr. Leigh,
Tonbridge, Kent, UK
School of Chemical and Pharmaceutical Sciences,
2
Kingston University, Kingston,
Surrey, UK
ABSTRACT
ꢁ
n-Butyllithiumat ꢀ78 C readily abstracts the methine proton from
the title compound. The anion reacts efficiently with a range of
electrophiles to provide 4-pyridyl ketones upon acid hydrolysis.
*
Correspondence: Peter Sheldrake, Department of Synthetic Chemistry,
GlaxoSmithKline Pharmaceuticals, Old Powder Mills Nr. Leigh, Tonbridge,
Kent, UK; E-mail: peters@icr.ac.uk. Elizabeth Tyrrell, School of Chemical and
Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston, Surrey,
UK; E-mail: E.Tyrrell@kingston.ac.uk.
2
263
DOI: 10.1081/SCC-120021505
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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Sheldrake et al.
Scheme 1.
[
1]
In a previous article the reactions of the anion derived from
-dimethoxymethyl-pyridine with a range of electrophiles were described.
4
Acid hydrolysis of the adducts that resulted then provided a convenient
methodology for the synthesis of 4-pyridyl ketones. However, the acid
catalyzed hydrolysis was not effective when the anion had been captured
with an aldehyde or had been acylated. Such pyridines protonate first on
the pyridine nitrogen, making acid catalyzed processes at a remote loca-
tion difficult. A pyridine derivative such as the oxazine 2 would be expected
to protonate first on the oxazine nitrogen so facilitating hydrolysis.
In this communication we describe how 3-methyl-2-pyridin-4-yl-1,3-
oxazine 2 may also be readily alkylated or reacted with other electro-
philes and thus provide an alternative procedure for the synthesis of
[
2]
4
-pyridyl ketones, hydroxyketones, and diketones. The oxazine 2 was
readily formed in high yield by simply stirring pyridine-4-carboxaldehyde
[
in 3-methylaminopropan-1-ol (Sch. 1).
3]
1
Anion formation was achieved by exposure of the oxazine 2 to
n-butyllithium at low temperature. Then, for example, alkylation with
iodoethane provided 3 as an oil in good yield. The relative purity of
1
the crude product, as judged by H NMR spectroscopy, coupled with
its instability to column chromatography meant that the hydrolysis
step was carried out without further purification. Thus heating 3 with
aqueous acetic acid effected the hydrolysis step in high yield to afford
1-pyridin-4-yl-propan-1-one 4 as an oil. The noteworthy feature of this
synthesis was that alkylation occurred exclusively at carbon and not at
[
4]
the pyridine nitrogen atom. Having optimized the three steps we inves-
tigated the generality of the reaction with a variety of simple alkylation
and acylation reactions the results of which are shown in Table 1.
Fromthese data it can be seen that the oxazine 2 acts as a synthe-
tically useful umpolung reagent forming the stabilized anion which then
readily and efficiently reacts with a range of alkyl and acyl electrophiles.
In the case of alkylation reactions the hydrolysis step provides the

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3
-Methyl-2-pyridin-4-yl-1,3-oxazine
2265
Table 1.
Oxazine %
Ketone %
Electrophile
CH
CH CH CH I
3
CH
2
I
76
82
85
84
83
87
90
80
95
83
51
70
85
96
3
2
2
CH (CH ) Br
84
88
3
3
2
2 3
CH
CH
2 4
(CH ) Br
¼ CHCH
2
Br
82
pNO C H CHO
4
decomposed
30 (over 2 steps)
decomposed
decomposed
71
2
6
pMeSC
H
6 4
CHO
PhCHO
PhCOCl
p-FC
p-MeSC
PhCH COCl
6
H
4
CO
2
Me
Me
6
4
H CO
2
93
decomposed
2
ketones in good reproducible yields. Reaction of the anion with aromatic
aldehydes is possible, but only in one case was the hydrolysis product
isolated and then only in poor yield. Acylation of the anion occurred in
generally good yield, again exclusively on carbon. In two cases the dike-
tone was obtained in useful yield fromthe hydrolysis, but the hydrolysis
lacks generality in these examples. The instability of the a–hydroxy and
a–oxo carbonyl compounds formed is due to the considerable destabiliz-
ing effect of the pyridine ring which leaves hydrolysis products susceptible
to nucleophilic attack. This is in marked contrast with the analogous
phenyl compounds.
In summary, we have shown that the oxazine 2 is a convenient
umpolung derivative of pyridine-4-aldehyde, easier to form and cleave
[1]
than the acetal and with the potential to provide functionalized
products.
EXPERIMENTAL
3
-Methylaminopropan-1-ol. This was prepared by a variation of the
[3]
literature method. 3-Chloropropan-1-ol (100 g 1.06 mol) was dissolved
in methylamine solution, 33% in IMS (750 mL) and left at ambient
temperature for six days. Potassium hydroxide (69.7 g 1.06 mol) was

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266
Sheldrake et al.
added and stirred until dissolved. The mixture was heated to coagulate
the precipitate and then filtered. The solid was washed with warmethanol
(
200 mL) and the filtrates were evaporated to leave a cloudy oil (104.4 g).
The oil was distilled at reduced pressure (about 6 mm Hg) and after a
ꢁ
short forerun the product was collected at 60–67 C. Yield 61.6 g 65%.
NMR 1.68 (2H, quintet), 2.42 (3H, s), 2.83 (2H, tr), 3.81 (2H, tr).
3-Methyl-2-pyridin-4-yl-1,3-oxazine 2. 3-Methylaminopropan-1-ol
5.0g 56 mmol) was stirred and cooled in an ice bath to 5 C. Pyridine-
ꢁ
(
4
1
-aldehyde (6.0g 56 mmol) was added in a slow dropwise manner. After
0 min in the cold bath the reaction was stirred for a further 1 h at
ambient temperature. The reaction was diluted with dichloromethane,
washed twice with water and then with 1M sodiumhydrogen carbonate
solution. The organic solution was dried over sodiumsulfate and evapo-
rated to leave the oxazine 2 (9.17 g 92%) which was used in the next
reactions without further purification.
ꢀ1
lmax (neat) cm : 3040, 2880, 2800, 1580, 1380, 1260, 1200.
d (300 MHz; CDCl ): 1.32–1.40 (1H, dm, CH), 2.00 (3H, s, N-CH ),
H
3
3
2.04–2.22 (1H, m, CH) 2.73–2.83 (1H, td J 12, 4 Hz, CH), 3.02–3.09 (1H,
dm, CH), 3.65–3.74 (1H, td J 12, 4 Hz, CH), 4.07–4.14 (IH, dm, CH),
4
4
.63 (1H, s, CH), 7.29–7.32 (2H, dd J 4, 1 Hz,¼CH), 7.62–7.64 (2H, dd J
,1 Hz,¼CH). ꢀ (74.45 MHz; CDCl ) 22.46 (t), 37.38 (q), 53.54 (t), 67.94
C
3
þ
(
1
t), 93.71 (d), 122. 21 (d), 148.07 (s), 149.87 (d). EI m/z: (Found M ,
79.1184, C H N O requires 179.1184), UV (MeOH) ꢁ 259 nm.
Generation and reaction of the anion of 2. The oxazine 2 (1.07 g
1
0
14
2
max
6
.03 mmol) was dissolved in dry THF (10 mL) and the solution was
ꢁ
cooled under nitrogen to ꢀ78 C. n-Butyllithiumsolution (2.5 M in
hexane, 2.65 mL, 6.63 mmol) was added and the solution stirred for
15 min. The electrophile (6.6 mmol) was added and the reaction stirred
ꢁ
for 1 h at ꢀ78 C. The reaction was removed from the cold bath and
quenched with 1M sodiumhydrogen carbonate solution. Ethyl acetate
(
15 mL) was added and the layers shaken and separated. The aqueous
was again extracted with ethyl acetate (15 mL). The combined organic
layers were washed with brine, dried (anhydrous sodiumsulfate) and
evaporated to give the crude product. The crude product could be pur-
ified by flash chromatography. Often it was suitable for hydrolysis with-
out further purification.
2-Ethyl-3-N-methyl-2-pyridin-4-yl-1,3-oxazine 3. Using ethyl iodide
on a 6 mmol scale, a yield of 76% was obtained.
ꢀ
1
lmax (neat) cm : 2960, 2880, 2840, 1593, 1492, 1432, 1339, 1281,
198.
d (300 MHz; CDCl ): 0.22–0.27(3H, t J 8 Hz, CH ), 0.64–0.70 (1H,
1
H
3
3
dm, CH), 1.256–1.35 (1H, sextet J 8 Hz, CH), 1.49–1.62 (1H, sextet J 8 Hz,

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3
-Methyl-2-pyridin-4-yl-1,3-oxazine
2267
CH), 1.87–1.89 (1H, mCH), 2.29 (3H,s, N-CH ), 2.42–2.48 (1H, m, CH),
3
2.73–2.83 (1H, m, CH), 3.38–3.56 (2H, m, CH and CH), 7.11–7.13 (2H, dd
J 4, 1 Hz,¼CH), 8.27–8.29 (2H, dd J 4,1 Hz,¼CH). ꢀ (74.45 MHz; CDCl )
C
3
7
.39 (q), 18.74 (t), 33.58 (t), 35.23 (q), 48.11 (t), 62.17 (t), 92.57 (s), 123. 35
þ
(d), 149.79 (d), 151.09 (s). EI m/z: (Found M , 207.1508, C H N O
1
requires 207.1508) 136, 130, UV (MeOH) ꢁmax 258 nm.
2
18
2
2
-(4-Fluorobenzoyl)-3-methyl-2-pyridin-4-yl-1,3-oxazine. Obtained in
3% yield on a 3 mmol scale.
dH 1.42 (1H br d), 2.04 (1H, m), 2.35 (3H, s), 3.10 (1H, d of t), 3.41
1H, t of d), 3.8 (1H, t of d), 4.04 (1H, m), 6.98 (2H, t J¼9 Hz), 7.52 (2H,
d J¼7 Hz), 8.18 (2H, dd J¼7 Hz, 9 Hz), 8.60 (2H, d J¼7 Hz).
-(4-Methylthiobenzoyl)-3-methyl-2-pyridin-4-yl-1,3-oxazine. Obtained
8
(
2
in 51% yield on a 10 mmol scale.
ꢀH 1.40 (1H, br d), 2.05 (1H, br m), 2.34 (3H, s, NMe), 2.48 (3H, s,
SMe), 3.12 (1H, d of t), 3.44 (1H, t of d), 3.82 (1H, t of d), 4.02 (1H, br d
of t), 7.12 (2H, d J¼8.5 Hz), 7.54 (2H, d J¼7 Hz), 8.06 (2H, d J¼8.5 Hz),
8
.60 (2H, d J¼7 Hz).
Hydrolysis of alkylated, hydroxyalkylated or acylated oxazines. The
oxazine (about 6 mmol) was dissolved in a mixture of acetic acid:water
7
ꢁ
:3 (10 mL) and heated at 70–80 C for 30 min. Most of the solvent was
evaporated and water (25 mL) was added. The product was extracted into
dichloromethane (3 ꢂ 10 mL). The combined extracts were washed with
water, sodiumhydrogen carbonate solution; dried over sodiumsulfate
and evaporated. The crude product was purified on a flash column.
1-Pyridin-4-yl-propan-1-one 4. On a 4 mmol scale a yield of 96% was
obtained.
ꢀ
1
lmax (neat) cm : 3000, 2880, 2840, 1695, 1560, 1480, 1420, 1380,
220, 1200, 745.
d (300 MHz; CDCl ): 1.14–1.19 (3H, t J 7 Hz, CH ), 2.19–2.99 (2H,
1
H
3
3
q J 7 Hz, CH ), 7.67 7.69 (2H, dd J 4, 1 Hz,¼CH), 8.73–8.75 (2H, d J
2
4
Hz,¼CH). ꢀ (74.45 MHz; CDCl ) 7.70 (q), 32.16 (t), 121. 07 (d), 142.73
C
3
þ
(s), 150.69 (d), 189.00 (s). EI m/z 135 M , 106, 78 (100%), 51. UV
MeOH) ꢁmax 275 nm.
(
1-(4-Methylthiophenyl)-2-pyridin-4-ylethanedione. Obtained in 93%
yield on a 4 mmol scale.
dH 2.54 (3H, s, SMe), 7.34 (4H, overlapping d), 7.78 (2H, d J¼7 Hz),
7.88 (2H, d J¼8.5 Hz).
ACKNOWLEDGMENT
We thank Professor Keith Jones for helpful advice and comments.

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268
Sheldrake et al.
REFERENCES
. Sheldrake, P. Syn. Commun. 1993, 1967.
. A brief investigation of the corresponding oxazolidine derived from
commercially available 2-methylaminoethanol was undertaken.
1
2
ꢀ
However the anion appears to be unstable even at À78 C and only
very low alkylation yields were obtained.
. Lehn, J.-M.; Linscheid, P.; Riddell, F.G. Bull. Soc. Chim. France
3
4
1968, 1172.
. For C vs. N alkylations of similar anions see Anders, E.; Opitz, A.
and Bauer, W. Synthesis 1991, 1221.
Received in the UK September 9, 2002