Isocyanate acting as a carbonyl precursor: Pyridyl group-assisted formation of 4H-pyrido[1,2-a]pyrimidin-4-ones from ketimines and isocyanates

Article abstract of DOI:10.1039/b516916j

By the reactions of ketimines bearing a pyridyl or a picolyl group on a nitrogen atom of the imine moiety with tosylisocyanate, 4H-pyrido[1,2-a] pyrimidin-4-one derivatives could be obtained in quantitative yields. In these reactions, tosylisocyanate acts

Full text of DOI:10.1039/b516916j

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Isocyanate acting as a carbonyl precursor: pyridyl group-assisted formation of
4H-pyrido[1,2-a]pyrimidin-4-ones from ketimines and isocyanates†
Yoichiro Kuninobu,* Shuhei Nishimura and Kazuhiko Takai*
Received 29th November 2005, Accepted 29th November 2005
First published as an Advance Article on the web 13th December 2005
DOI: 10.1039/b516916j
By the reactions of ketimines bearing a pyridyl or a pi-
colyl group on a nitrogen atom of the imine moiety with
tosylisocyanate, 4H-pyrido[1,2-a]pyrimidin-4-one derivatives
could be obtained in quantitative yields. In these reactions,
tosylisocyanate acts as a carbonyl precursor. The pyridyl or
picolyl group is a key functional group because it is not only
the constituent structure of the 4H-pyrido[1,2-a]pyrimidin-4-
one framework but also the promoter of the formation of a
ketene intermediate.
(1)
Several isocyanates were examined with the ketimine 1a. The
reaction did not occur with cyclohexylisocyanate. Arylisocyanate
bearing an electron donating group (para-methoxy) gave 3a in 49%
yield. In order to promote the dissociation of the amine moiety
from 4a, we carried out the reactions using 2,6-dimethylisocyanate
as a bulky substrate and tosylisocyanate, which has an excellent
dissociation ability. In the case of 2,6-dimethylisocyanate, the
yield was very low (7%). On the other hand, 3a was obtained
quantitatively with two equivalents of tosylisocyanate. In this
reaction, a urea derivative 5a, which was formed by the reaction
of an amine with an isocyanate, was formed as a side product
in quantitative yield. This result reveals that isocyanates act as a
carbonyl source and react with ketimines to give 4H-pyrido[1,2-
a]pyrimidin-4-one derivatives. The highly efficient transformation
of the isocyanate into a carbonyl group is confirmed by the fact
that this reaction needs only two equivalents of isocyanate since
one equivalent of isocyanate reacts with a ketimine and another
one equivalent reacts with an amine (byproduct).
Synthesizing carbonyl compounds is one of the most important
organic transformations in both laboratories and industries.1
Carbon monoxide and phosgene are often used as carbonyl
sources; however, they can be difficult to handle due to their
toxicity and gaseous form. Therefore, there have recently been
many reports on the synthesis of carbonyl compounds with sub-
stitutes for carbon monoxide and phosgene, such as formic acid,
formate, formamide, formic anhydride, aldehyde, metal carbonyl,
carbamoylsilane and carbamoylstannane.2 In addition, dialkyl
carbonates,3 carbonyl diimidazoles4 and dichloromethanimines
have be used as substituents for carbon monoxide and phosgene.
Instead of these substituents, we used isocyanates as carbonyl
sources. We report herein that 4H-pyrido[1,2-a]pyrimidin-4-one
derivatives are synthesized from ketimines and isocyanates.
There have been many reports on the synthesis of bioactive
heterocyclic compounds bearing heteroatoms at ring junction
positions.5,6 One example is a 4H-pyrido[1,2-a]pyrimidin-4-one
skeleton, and its 4H-pyrido[1,2-a]pyrimidin-4-one derivatives7
show valuable pharmacological properties and are used as suc-
cessful analgesic agents.7e,7i
A possible mechanism of the reaction is shown in Scheme 1:
(1) Isomerization of the ketimine 1a to enamine 6a; (2) nucle-
ophilic attack of the enamine 6a with tosylisocyanate to give
an amide intermediate 4b;9,10 (3) the dissociation of tosylamide
from 4b to give 7a having a ketene moiety; (4) intramolecular
cyclization of the ketene and imine moieties in 7a to give the
By the reaction of ketimine 1a (1.0 equiv.) with phenylisocyanate
2a (2.0 equiv.) in toluene at 135 ◦C for 24 h, the corresponding
4H-pyrido[1,2-a]pyrimidin-4-one derivative 3a and amide 4a were
obtained in 29 and 70% yields, respectively [eqn (1)].8
Division of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology, Okayama University, Tsushima, Okayama, 700-
8530, Japan. E-mail: kuninobu@cc.okayama-u.ac.jp, ktakai@cc.okayama-
u.ac.jp; Fax: 81 86 251 8094; Tel: 81 86 251 8095
† Electronic supplementary information (ESI) available: General ex-
perimental procedure and characterization data for 4H-pyrido[1,2-
a]pyrimidin-4-one derivatives. See DOI: 10.1039/b516916j
Scheme 1 Proposed mechanism of the formation of 4H-pyrido[1,2-
a]pyrimidin-4-one.
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Table 1 Reaction of ketimines with tosylisocyanate
Entry
Ketimine
Product
Yielda (%)
1b
2
3a
93% (>99%)
22% (24%)
3
4
5
6
7
3b (X = H)
3c (X = MeO)
3d (X = Me)
3e (X = Ph)
3f (X = Cl)
93% (>99%)
94% (>99%)
92% (>99%)
91% (>99%)
93% (>99%)
8
3g
87% (>99%)
9
10
3h (n = 1)
3i (n = 7)
74% (>99%)
92% (>99%)
11c
3j
75% (>99%)
a Isolated yield. 1H NMR yield is reported in parenthesis. b 135 ◦C. c 135 ◦C, 1 h.
4H-pyrido[1,2-a]pyrimidin-4-one derivative 3a.7f ,7h Since iso-
cyanate must be consumed by the reaction with tosylamine, which
is formed as a byproduct in step (3), this reaction needs two
equivalents of tosylisocyanate to ketimine.
4-one derivative 3j, which is a successful analgesic agent,7e was
obtained in 75% isolated yield (Table 1, entry 11).12
In summary, we succeeded in the synthesis of 4H-pyrido[1,2-
a]pyrimidin-4-one derivatives quantitatively by the reaction of
ketimines bearing a pyridyl or a picolyl group on a nitrogen atom
of the imine moiety with tosylisocyanate. In the reactions, the
pyridyl and picolyl groups have two functions. One is, of course,
these groups are the constituent structure of 4H-pyrido[1,2-
a]pyrimidin-4-one derivatives, the other is that these groups
promote the formation of a ketene intermediate. In addition,
the tosylisocyanate acts as a source of carbon monoxide. To our
knowledge, this is the first example of using an isocyanate as a
carbonyl precursor. Since the carbonylation using isocyanates is a
highly efficient in comparison with the conventional carbonylation
reactions,2 isocyanates are expected to be used as a carbonyl source
in a wide range of synthetic chemistries.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 14078219, “Reaction Control of
Dynamic Complexes”) from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan. We thank Dr Masaichi
Saito (Department of Chemistry, Saitama University) for acquir-
ing HR-MS spectra.
Next, we investigated the reaction temperature and the reac-
tion time using ketimine 1a and tosylisocyanate.‡ This reaction
proceeded smoothly at 135 ◦C for 10 min, and the 4H-pyrido[1,2-
a]pyrimidin-4-one derivative 3a was obtained in quantitative yield
(Table 1, entry 1). The yield of 3a decreased to 24% when the
reaction was conducted at 80 ◦C for 10 min (Table 1, entry 2).
In order to increase the yield of 3a derived from 7a, the lone pair
of a nitrogen atom on the pyridyl group should work effectively
for the deprotonation followed by dissociation of the amine,
as shown in Scheme 1. Therefore, we choose a picolyl group
instead of the pyridyl one. The corresponding 4H-pyrido[1,2-
a]p◦yrimidin-4-one derivative 3b was obtained quantitatively at
80 C for 10 min (Table 1, entry 3).11 The reaction did not proceed
with a ketimine bearing ortho-tolyl group. These results indicate
that deprotonation by a nitrogen atom on the picolyl group is
important.
In the next stage, we examined the reaction of several ketimines
with tosylisocyanate (Table 1). All aromatic ketimines having an
electron-withdrawing or an electon-donating group at the para-
position of the imine moiety afforded the corresponding 4H-
pyrido[1,2-a]pyrimidin-4-one derivatives 3c–f in excellent yields
(Table 1, entries 4–7). Acyclic and cyclic alkyl ketimines also gave
the corresponding 4H-pyrido[1,2-a]pyrimidin-4-one derivatives
3g–i in good to excellent yields (Table 1, entries 8–10). By the reac-
tion of◦cyclohexylidene(pyridin-2-yl)-amine with tosylisocyanate
at 135 C for 1 h, the corresponding 4H-pyrido[1,2-a]pyrimidin-
Notes and references
‡ 3,9-Dimethyl-2-phenyl-pyrido[1,2-a]pyrimidin-4-one (3b). The mix-
ture of (3-methyl-pyridin-2-yl)-(1-phenyl-propylidene)amine (112 mg,
0.500 mmol) and tosylisocyanate (197 mg, 1.00 mmol) in toluene (1.0 mL)
was heated at 80 ◦C for 10 min. After the solvent was removed in vacuo, the
product was isolated by silica gel column chromatography. Yield: 116 mg
(93% yield). 1H NMR (400 MHz, CDCl3) d 2.34 (s, 3H), 2.59 (s, 3H), 7.00
204 | Org. Biomol. Chem., 2006, 4, 203–205
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(t, J = 6.9 Hz, 1H), 7.45–7.51 (m, 4H), 7.70 (d, J = 8.1 Hz, 2H), 8.94 (d,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 13.96 (1C), 17.96 (1C),
111.16 (1C), 114.36 (1C), 124.75 (1C), 127.94 (2C), 128.74 (1C), 129.23
(2C), 132.95 (1C), 134.90 (1C), 139.46 (1C), 147.75 (1C), 159.66 (1C),
159.98 (1C); IR (nujol, m / cm−1) 2039 (m), 1978 (m), 1965 (m), 1941 (w),
1671 (s), 1634 (m), 1600 (w), 1540 (w), 1419 (w), 1240 (m), 1191 (w), 1169
(m), 1142 (w), 1076 (m), 1030 (w), 909 (w), 804 (w), 775 (w), 759 (s), 728
(w), 689 (m), 666 (w), 651 (w); HR-MS ([M + H]+) calcd for C16H14N2O:
251.1184; found: 251.1186.
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10 A referee suggested another possible mechanism for the formation of
4b as follows: 1) the interaction between a ketimine with an isocyanate
at the nitrogen atom on the pyridyl group; 2) the formation of a
pyridinium salt; 3) the formation of an enamine; 4) the interaction of
the enamine with the substituent, which is derived from the isocyanate,
on the nitrogen atom of the pyridyl group.
11 At 50 ◦C, unsaturated b-lactam derivative 3b and amide 4b were
obtained in 31 and 68% yields, respectively.
12 The structure of 3j was determined by comparison with the data
reported in ref 7e.
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