Thermal behavior of dipolarophile-containing 2-azidocarbonylpyrroles and -indoles

Article abstract of DOI:10.3987/COM-04-10079

The thermal reaction of N-allyl- or N-propargyl-2-azidocarbonylpyrroles (2) or -indoles (9) involves competition between intramolecular azide cycloaddition and Curtius rearrangement.

Full text of DOI:10.3987/COM-04-10079

HETEROCYCLES, Vol. 63, No. 7, 2004, pp. 1645 - 1650
Received, 19th March, 2004, Accepted, 13th May, 2004, Published online, 14th May, 2004
THERMAL
BEHAVIOR
OF
DIPOLAROPHILE-CONTAINING
2-AZIDOCARBONYLPYRROLES AND -INDOLES
Giorgio Molteni*
University of Milan, Dipartimento di Chimica Organica e Industriale, via Golgi
19, 20133 Milano, Italy
Abstract – The thermal reaction of N-allyl- or N-propargyl-2-azidocarbonyl-
pyrroles (2) or -indoles (9) involves competition between intramolecular azide
cycloaddition and Curtius rearrangement.
INTRODUCTION
Azide cycloadditons were the object of recent investigations as the ideal representative of the “click”
chemistry concept.1 As a consequence, an intense research was developed upon the azide cycloadditions
from both the synthetic2,3 and the theoretical4 point of view. The thermal behavior of acyl azides
associated with the Curtius reaction have been investigated being traditionally well-known.5 Among the
rare examples available, the intramolecular version of acylazide 1,3-dipolar cycloadditions has been
applied to the synthesis of some thieno[1,2,3]triazolo[5,1-c][1,4]diazepines6 and as the key step in the
enantioselective synthesis of (+)-biotine.7 Here it is presented a study onto N-propargyl- or
N-allyl-2-azidocarbonylpyrroles (2) or -indoles (6) in order to establish the degree of competition between
intramolecular cycloaddition and Curtius rearrangement. The resulting pyrrolo[1,2-d][1,2,3]triazolo-
[5,1-a]pyrazine skeleton is an aza-analogue of potent hypotensive drugs8 as well as inhibitor of the
serotonine contractile factor,9 thus representing a valuable target in medicinal chemistry.
RESULTS AND DISCUSSION
1-Substituted 2-azidocarbonylpyrroles or -indoles (2) and (9) were readily synthesised from the
corresponding carboxylic acids (1) or (5), respectively (see Scheme). Subsequent heat treatment of (2) or
(6) was carried out in boiling toluene. Reaction times, products and product yields are summarised in
Table 1. Structural assignements are unequivocal and rely upon analytical and spectral data (see
1
EXPERIMENTAL). In particular, the H NMR spectra of cycloadducts (4) are perfectly consistent with
literature data concerning 5-substituted 1H-1,2,3-triazoles.10

Scheme
O
Y
Y
N
H
N
H
N
N
O
O
3
+
Y
Y
1) EtOCOCl/Et3N
2) NaN3
∆
toluene
N
N
O
OH
N3
N
N
N
N
1
2
Y
4
O
O
O
Y
Y
Y
Y
1) EtOCOCl/Et3N
2) NaN3
∆
N
H
N
H
toluene
N
N
N
N
OH
N3
7
+
5
6
O
O
N
N
N
N
-N2
N
N
Y
Y
a: Y = H, H; b: Y = (CH CH)2
9
8
Table 1. Thermal behavior of acylazides (2) and (6).
__________________________________________________________________
Compd
Timea
(h)
Products and Yields (%)b
_______________________________
3 or 7
4 or 9
__________________________________________________________________
2a
2b
6a
6b
8
7
31
40
53
59
49
48
16
19
12
13
__________________________________________________________________
aIn refluxing toluene. bIsolated yields.

As it may be argued from the Scheme, sym-ureas (3) and (7) were isolated as a consequence of the
Curtius rearrangement of starting acylazieds (2) and (6), respectively. On the other hand, the
intramolecular cycloaddition products (4) were obtained only from substrates (2) bearing an acetylenic
dipolarophile. In fact, in the case of ethylenic acylazides (6) further evolution of the first-formed
cycloadducts (8) was operative with the extrusion of molecular nitrogen, reflecting a well-known
behaviour pattern of 1,2,3-triazolines.11
The results listed in Table 1 show that the intramolecular cycloaddition pattern is more effective in the
case of acetylenic acylazides (2). This behaviour matches with the reduced degree of rotational freedom
of the latter substrates (2) with respect to the ethylenic acylazides (6), thus facilitating the approach of the
reactive π systems as required for concerted cycloadditions.12 On the other hand, the Curtius
rearrangement can overwhelm the intramolecular azide cycloaddition pathway due to the powerful
driving force exerted by the loss of molecular nitrogen from both acylazides (2) and (6).
EXPERIMENTAL
Melting points were determined with a Büchi apparatus in open tubes and are uncorrected. IR spectra
were recorded with a Perkin-Elmer 1725 X spectrophotometer. MS spectra were determined with a
1
VG-70EQ apparatus. H NMR (300 MHz) spectra were taken with a Bruker AMX 300 instrument (in
CDCl3 solutions at room temperature). Chemical shifts are given as ppm from tetramethylsilane and J
values are given in Hz.
Compounds (1a),13 (1b),15 (6a),14 and (6b)16 are known in the literature.
Synthesis of acylazides (2) and (6). A solution of the appropriate N-substituted 2-carboxy-pyrrole or
-indole (1) or (5) (6.0 mmol) in dry acetone (20 mL) was cooled to 0°C. Triethylamine (0.61 g, 6.0 mmol)
and ethyl chloroformate (0.65 g, 6.0 mmol) were added and the mixture was stirred at 0°C for 45 min.
Sodium azide (0.63 g, 9.7 mmol) was added portionwise under cooling and vigorous stirring. After 2 h
the mixture was evaporated, taken up with water (10 mL) and extracted with dichloromethane (2 x 30
mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure affording
crude (2) or (6). The oily residue was chromatographed on a silica gel column with ethyl acetate-hexane
(3:1) giving analytically pure acylazides (2) or (6).
1-Propargyl-2-azidocarbonylpyrrole (2a) (0.81 g, 77%) as undistillable yellow oil; IR (nujol): 2130, 1670
(cm-1); 1H-NMR: 2.48 (1H, t, J=2.5 Hz), 5.20 (2H, d, J=2.5 Hz), 6.24 (1H, dd, J=2.7, 1.4 Hz), 6.91 (1H,
dd, J=3.7, 1.4 Hz), 7.13 (1H, dd, J=3.7, 2.7 Hz); MS: 174 m/z (M+). Anal. Calcd for C8H6N4O: C, 55.17;
H, 3.47; N, 32.17. Found: C, 55.23; H, 3.53; N, 32.10.

1-Propargyl-2-azidocarbonylindole (2b) (1.13 g, 84%) as undistillable pale yellow oil; IR (nujol): 2140,
1
1670 (cm-1); H-NMR: 2.27 (1H, t, J=2.5 Hz), 5.48 (2H, d, J=2.5 Hz), 6.95 (1H, s), 7.18-7.60 (4H, m);
MS: 224 m/z (M+). Anal. Calcd for C12H8N4O: C, 64.28; H, 3.60; N, 24.99. Found: C, 64.33; H, 3.64; N,
25.07.
1-Allyl-2-azidocarbonylpyrrole (6a) (0.71 g, 67%) as undistillable yellow oil; IR (nujol): 2130, 1680
1
(cm-1); H-NMR: 4.94-5.05 (2H, m), 5.07 (1H, dd, J=10.9, 1.8 Hz), 5.18 (1H, dd, J=7.9, 1.8 Hz),
5.90-6.10 (1H, m), 6.20 (1H, dd, J=3.0, 1.5 Hz), 6.98 (1H, dd, J=3.8, 1.5 Hz), 7.06 (1H, dd, J=3.8, 3.0
Hz); MS: 176 m/z (M+). Anal. Calcd for C14H13N3O: C, 54.54; H, 4.58; N, 31.80. Found: C, 54.60; H,
5.03; N, 31.86.
1-Allyl-2-azidocarbonylindole (6b) (1.08 g, 80%) as undistillable pale yellow oil; IR (nujol): 2120, 1680
(cm-1); 1H-NMR: 5.08 (2H, m), 5.26 (1H, dd, J=10.8, 1.8 Hz), 5.31 (1H, dd, J=7.7, 1.8 Hz), 6.05 (1H, m),
6.91 (1H, s), 7.15-7.57 (4H, m); MS: 226 m/z (M+). Anal. Calcd for C12H10N4O: C, 63.71; H, 4.46; N,
24.76. Found: C, 63.66; H, 4.50; N, 24.82.
Thermal behavior of acylazides (2) and (6). A solution of the appropriate acylazide (2) or (6) (4.5
mmol) in dry toluene (225 mL) was refluxed for the time indicated in Table 1. The solvent was removed
under reduced pressure and the residue was chromatographed on a silica gel column with ethyl
acetate-hexane (6:1). Cycloadducts (4) was eluted first, followed by pyrrolo- or indolo[1,2-a]pyrazine (9).
Further elution gave urea derivatives (3) or (7).
N,N’-bis-(1-Propargyl-2-pyrrolyl)urea (3a) (0.19 g, 31%) as white amorphous powder having mp 194°C
(from acetone-chloroform); IR (nujol): 1670 (cm-1); 1H-NMR: 2.53 (2H, t, J=2.7 Hz), 5.35 (4H, d, J=2.7
Hz), 6.15-6.95 (6H, m), 8.78 (2H, br s); MS: 266 m/z (M+). Anal. Calcd for C15H14N4O: C, 67.65; H,
5.30; N, 21.04. Found: C, 67.70; H, 5.33; N, 20.08.
N,N’-bis-(1-Propargyl-2-indolyl)urea (3b) (0.33 g, 40%) as white amorphous powder having mp 185°C
(from acetone-chloroform); IR (nujol): 3280, 1720 (cm-1); 1H-NMR: 2.54 (2H, t, J=2.4 Hz), 5.02 (4H, d,
J=2.4 Hz), 6.52 (2H, s), 7.05-7.82 (8H, m), 8.92 (2H, br s); MS: 366 m/z (M+). Anal. Calcd for
C23H18N4O: C, 75.39; H, 4.95; N, 15.29. Found: C, 75.44; H, 4.99; N, 15.36.
8-Oxo-pyrrolo[1,2-d][1,2,3]triazolo[5,1-a]pyrazine (4a) (0.31 g, 39%) as white amorphous powder
1
having mp 166°C (from methanol); IR (nujol): 1680 (cm-1); H-NMR: 5.35 (2H, s), 6.20 (1H, dd, J=2.8,
1.5 Hz), 6.96 (1H, dd, J=3.7, 1.5 Hz), 7.05 (1H, dd, J=3.7, 2.8 Hz), 7.66 (1H, s); MS: 174 m/z (M+). Anal.
Calcd for C8H6N4O: C, 55.17; H, 3.47; N, 32.17. Found: C, 55.24; H, 3.51; N, 32.24.
10-Oxo-indolo[1,2-d][1,2,3]triazolo[5,1-a]pyrazine (4b) (0.43 g, 43%) as pale yellow amorphous powder
1
having mp 98°C (from diisopropyl ether); IR (nujol): 1650 (cm-1); H-NMR: 5.02 (2H, s), 6.82 (1H, s),
7.05-7.40 (4H, m), 7.81 (1H, s); MS: 224 m/z (M+). Anal. Calcd for C12H8N4O: C, 64.28; H, 3.60; N,
24.99. Found: C, 64.33; H, 3.63; N, 25.07.

N,N’-bis-(1-Allyl-2-pyrrolyl)urea (7a) (0.32 g, 53%) as white amorphous powder having mp 172°C (from
1
acetone-chloroform); IR (nujol): 3285, 1640 (cm-1); H-NMR: 4.90-4.97 (4H, m), 5.18 (4H, dd, J=11.0,
1.7 Hz), 6.06 (2H, ddd, J=11.0, 7.4, 5.2 Hz), 6.20-6.90 (6H, m), 8.85 (2H, br s); MS: 270 m/z (M+). Anal.
Calcd for C15H18N4O: C, 66.64; H, 6.71; N, 20.73. Found: C, 66.60; H, 6.67; N, 20.80.
N,N’-bis-(1-Propargyl-2-indolyl)urea (7b) (0.49 g, 59%) as white amorphous powder having mp 179°C
1
(from acetone-chloroform); IR (nujol): 3280, 1685 (cm-1); H-NMR: 5.02-5.12 (4H, m), 5.20 (2H, dd,
J=10.9, 1.8 Hz), 5.28 (2H, dd, J=7.8, 1.8 Hz), 6.2-6.12 (2H, m), 6.84 (2H, s), 7.0-7.4 (8H, m), 8.85 (2H,
br s); MS: 370 m/z (M+). Anal. Calcd for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.62; H,
6.03; N, 15.20.
2-Methyl-7-oxo-pyrrolo[1,2-a]pyrazine (9a) (0.11 g, 16%) as pale yellow undistillable oil; IR (nujol):
1
1670 (cm-1); H-NMR: 2.89 (3H, s), 5.06 (2H, s), 6.18 (1H, dd, J=2.8, 1.5 Hz), 6.89 (1H, dd, J=3.7, 1.5
Hz), 6.97 (1H, dd, J=3.7, 2.8 Hz); MS: 148 m/z (M+). Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N,
18.91. Found: C, 64.89; H, 5.40; N, 18.97.
2-Methyl-10-oxo-indolo[1,2-a]pyrazine (9b) (0.17 g, 19%) as pale yellow undistillable oil; IR (nujol):
1680 (cm-1); 1H-NMR: 2.90 (3H, s), 5.11 (2H, s), 6.82 (1H, s), 6.9-7.4 (4H, m); MS: 198 m/z (M+). Anal.
Calcd for C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C, 72.75; H, 5.12; N, 14.20.
ACKNOWLEDGEMENTS
Thanks are due to MURST and CNR for financial support.
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