40 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 40–41†
Intramolecular Nitrile Imide Cycloadditions leading to
Benzo[c]pyrazolo[1,5-e][1,5]-oxazonine and -oxazecine
Skeletons†
Giorgio Molteni
Dipartimento di Chimica Organica e Industriale dell’Universita`, via Golgi 19, 20133 Milano,
Italy
A synthetic route to the new title compounds 4, which involves an intramolecular nitrile imide cycloaddition to an
acetylenic moiety as the key step, is described.
Intramolecular 1,3-dipolar cycloadditions represent a valu-
able tool in the synthesis of a large variety of heterocyclic
systems containing a five-membered heterocycle fused or
bridged to another hetero- or carbo-cyclic ring.1 However,
despite copious literature on this methodology, examples
which involve the formation of a medium-sized ring are still
rare.2–5 A fruitful approach to the hitherto unreported ben-
zo[c]pyrazolo[1,5-e][1,5]oxazonine and benzo[c]pyrazolo-
[1,5-e][1,5]oxazecine skeletons is here reported, based on the
intramolecular cycloaddition of appropriately chosen nitrile
imides.
The hydrazonoyl chlorides 2, which we have devised as the
precursors for the in situ generation of the nitrile imides 3,
were obtained starting from isatoic anhydride and the appro-
priate alkynols (see Scheme 1). Treatment of 2 with silver
carbonate in refluxing acetonitrile gave the desired cycload-
ducts 4 in good yields (see Experimental section). It needs to
be added that, under the experimental conditions described
above, the nitrile imides 3 underwent, as a side-reaction, a
1,3-dipolar cycloaddition onto the solvent to give the triazole
derivatives 5.
of our previous works.6 However, in this case, the latter con-
ditions led to a lower yield of the cycloadduct 4a, since large
amounts of tarry material were formed.
In spite of the well known factors working against the
formation of nine- and ten-membered rings,7 the cycloaddi-
tive approach to compounds 4 has been proven to be success-
ful and the observed yields of cyclization are valuable on a
preparative scale.
Experimental
Analytical and spectroscopic instruments were as described in a
previous paper.8 J Values are given in Hz.
Preparation of Alkynyl Anthranilate Hydrochlorides 1. General
Procedure.sA solution of the appropriate alkynol (12.0 mmol) in
anhydrous toluene (13 ml) was treated with sodium hydride
(0.39 g, 16.4 mmol) and then refluxed for 1 h. Isotoic anhydride
(1.96 g, 12.0 mmol) in hot pyridine (7 ml) was added and the
solution was refluxed for 4 h. The mixture was poured onto crushed
ice (50 ml) and extracted with diethyl ether (50 ml). The organic
layer was washed with water, dried over sodium sulfate and evap-
orated. The oily residue was dissolved in anhydrous diethyl ether
(70 ml) and a solution of hydrogen chloride in diethyl ether (4 ;
M
12.0 ml) was added under stirring. The white precipitate was
filtered out and dried to give 1.
In order to prevent the formation of such by-products, the
hydrazonoyl chloride 2a was treated with silver carbonate in
dioxane at 80 °C. The choice of this solvent was determined
on the basis of the highly satisfactory results reported in some
Pent-4-yn-1-yl anthranilate hydrochloride (1a) (1.06 g, 37%) had
mp 167 °C; vmax/cmꢀ1 (Nujol) 3230, 2110, 1730; dH (CDCl3)
1.92–2.08 (3 H, m), 2.38 (2 H, dt, J 6.5, 2.4), 4.46 (2 H, t, J 6.5),
7.43–8.02 (4 H, m), 8.45 (3 H, br s); m/z 239 (Mǹ) (Found: C,
60.02; H, 5.92; Cl, 14.62; N, 5.77. C12H14ClNO2 requires C, 60.13; H,
5.89; Cl, 14.79; N, 5.84%).
H
NH3+Cl–
CO2Z
Hex-5-yn-1-yl anthranilate hydrochloride (1b) (0.91 g, 30%) had
mp 137 °C; vmax/cmꢀ1 (Nujol) 3240, 2110, 1730; dH (CDCl3)
1.58–1.91 (4 H, m), 1.95 (1 H, t, J 2.5), 2.39 (2 H, dt, J 6.5, 2.5), 4.36
(2 H, t, J 6.5), 7.39–8.06 (4 H, m), 8.50 (3 H, br s); m/z 253 (Mǹ)
(Found: C, 61.48; H, 6.30; Cl, 14.08; N, 5.60. C13H16ClNO2 requires
C, 61.54; H, 6.36; Cl, 13.97; N, 5.52%).
N
O
i
+
ZONa
O
ii
1
O
iii iv
Preparation of Hydrazonoyl Chlorides 2. General Procedure.sA
solution of 1 (3.5 mmol) in water (12 ml) and methanol (1.5 ml) was
H
CO2Me
Cl
–
N
+
N
CO2Me
N
N
treated with hydrochloric acid (12 ; 1.5 ml) and then cooled to
M
v
0 °C. Sodium nitrite (0.33 g, 4.7 mmol) in water (2.5 ml) was added
dropwise to the reaction mixture whilst it was cooled and stirred.
After 30 min, the cold mixture was adjusted to pH 5 with sodium
acetate and then methyl 2-chloroacetoacetate (0.53 g, 3.5 mmol) in
methanol (3 ml) was added under stirring. The mixture was stirred
at room temperature for 15 h and then extracted with diethyl ether
(60 ml). The organic layer was washed with sodium hydrogencarbo-
nate, dried (Na2SO4) and evaporated. Recrystallization from diiso-
propyl ether gave the pure hydrazonoyl chlorides 2.
CO2Z
CO2Z
3
2
CO2Me
CO2Me
N
N
N
N
Pent-4-yn-1-yl 2-[2-(1-chloro-2-methoxy-2-oxoethylidene)hydra-
zino]benzoate (2a) (0.85 g, 75%) had mp 90 °C; vmax/cmꢀ1 (Nujol)
3280, 3210, 2100, 1730, 1680; dH (CDCl3) 1.93–2.53 (5 H, m), 3.95
(3 H, s), 4.46 (2 H, t, J 6.3), 7.00–7.85 (4 H, m), 11.80 (1 H, br s);
m/z 322 (Mǹ) (Found: C, 55.71; H, 4.66; Cl, 11.07; N, 8.75.
C15H15ClN2O4 requires C, 55.82; H, 4.68; Cl, 10.98; N, 8.68%).
Z = [CH2]nC CH
N
a n = 3
b n = 4
[
]
n
Me
O
CO2Z
O
4
5
Hex-5-yn-1-yl
2-[2-(1-chloro-2-methoxy-2-oxoethylidene)hydra-
zino]benzoate (2b) (1.13 g, 96%) had mp 60 °C; vmax/cmꢀ1 (Nujol)
3280, 3200, 2105, 1730, 1680; dH (CDCl3) 1.50–1.93 (4 H, m), 1.95
(1 H, t, J 2.4), 2.27 (2 H, dt, J 6.2, 2.4), 3.90 (3 H, s), 4.35 (2 H, t, J
6.2), 6.97–7.95 (4 H, m), 11.80 (1 H, br s); m/z 336 (Mǹ) (Found:
C, 57.20; H, 5.13; Cl, 10.61; N, 8.44. C16H17ClN2O4 requires C,
57.06; H, 5.09; Cl, 10.53; N, 8.32%).
Scheme 1 Reagents and conditions: i, pyridine, heat; ii, HCl–
Et2O; iii, HCl–NaNO2; iv, MeCOCHClCO2Me; v, Ag2CO3–MeCN,
reflux
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Treatment of Hydrazonoyl Chlorides 2 with Silver Carbonate in
Acetonitrile. General Procedure.sA solution of 2 (2.5 mmol) in dry
acetonitrile (200 ml) was treated with silver carbonate (2.76 g, 10
Molteni, Giorgio
