A simple approach to azirines containing an aldehyde functionality and their stabilization as palladium(II) complexes

Article abstract of DOI:10.1016/j.tetlet.2005.07.086

A simple and useful method for the synthesis of azirines containing an aldehyde functionality, from open chain bromo/chloro-aldehydes at room temperature and their stabilization as palladium(II) complexes are reported.

Full text of DOI:10.1016/j.tetlet.2005.07.086

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6575–6578
A simple approach to azirines containing an aldehyde
functionality and their stabilization as palladium(II) complexes
Sulagna Brahma and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 25 April 2005; revised 1 July 2005; accepted 14 July 2005
Available online 3 August 2005
Abstract—A simple and useful method for the synthesis of azirines containing an aldehyde functionality, from open chain bromo/
chloro-aldehydes at room temperature and their stabilization as palladium(II) complexes are reported.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The most common and efficient route for the prepara-
tion of azirines involves the photolysis or thermolysis
of vinyl azides, through a vinyl nitrene intermediate.14
In this paper, we describe a simple route to 3-substi-
tuted-2-formyl-azirines 3 and 7 from acyclic vinyl bro-
mo/chloro-aldehydes 1 and 5. Padwa et al. synthesized
azirines such as 3 by the addition of iodine azide to
the dimethyl acetal of cinnamaldehyde followed by
dehydrohalogenation, thermolysis and hydrolysis.15
Nitrogen-containing heterocycles are versatile struc-
tures, which often occur in natural products1–3 and fre-
quently show biological activity.4,5 Among them,
azirines are highly reactive three-membered unsaturated
strained heterocycles.6,7 Each of the three bonds of the
azirine can be cleaved depending on the experimental
conditions used and hence azirines have been used for
the preparation of a wide range of polyfunctional acyclic
and cyclic nitrogen-containing compounds.8,9 This small
ring can act as a dienophile or as a dipolarophile and
can also function as an electrophile or nucleophile.4,6
Azirines are thermally unstable10 and decompose even
at ambient temperature.11 They are stabilized by form-
ing complexes with transition metals.12 It was reported
that, compared to free azirines, their palladium com-
plexes exhibit an unusually high stability towards air,
moisture and UV light.13
In our synthesis, the acyclic bromo/chloro-aldehydes
116 were reacted with sodium azide in DMSO at
10 °C to give the corresponding non-isolable 3-azido-
aldehydes 2, which at room temperature underwent
spontaneous denitrogenation and ring closure to 2-for-
myl-azirines 3 as the major products presumably via the
corresponding vinyl nitrenes17 (Scheme 1 and Table 1).
We also obtained isoxazoles 4 although in very low
yields.
R1
R1
X/
N3
R1
R2
R1
R2
N
rt, 5 min
NaN3/DMSO
10 oC, 15 min
+
N
O
R2
CHO
CHO
R2
CHO
4
3
1
2
Scheme 1.
Keywords: Bromo/chloro-aldehyde; Vinyl nitrene; Azirines; Palladium complex.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222 282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.086

6576
S. Brahma, J. K. Ray / Tetrahedron Letters 46 (2005) 6575–6578
Table 1. Reaction of bromo/chloro-aldehydes 1a–f with NaN3 in DMSO
Entry
Substrates
Products
Yield (%) (azirine, isoxazole)
1
2
3
4
5
6
1a (R1 = Ph, R2 = H, X0 = Cl)
1b (R1 = naphthyl, R2 = H, X0 = Cl)
1c (R1 = Ph, R2 = Ph, X0 = Cl)
1d (R1 = Ph, R2 = H, X0 = Br)
1e (R1 = naphthyl, R2 = H, X0 = Br)
1f (R1 = Ph, R2 = Ph, X0 = Br)
3a, 4a
3b, 4b
3c, 4c
3a, 4a
3b, 4b
3c, 4c
65, 8
63, 7
60, 6
68, 8
64, 6
61, 7
X
X
X/
X/
NaN3/DMSO
10 oC, 15 min
N3
N3
OHC
CHO
CHO
OHC
6
5
rt, 5 min
X
X
N
O
+
N
H
H
O
CHO
N
N
OHC
8
7
Scheme 2.
Table 2. Reaction of bis-bromo/chloro-aldehydes 5a–f with NaN3 in
DMSO
H
Ph
H
O
H
Entry Substrates
Products Yield (%)
(azirine, isoxazole)
N
Pd
N
1
2
3
4
5
6
5a (X = CH2, X0 = Cl) 7a, 8a
60, 8
57, 7
58, 6
47, 8
42, 7
44, 6
5b (X = O, X0 = Cl)
5c (X = S, X0 = Cl)
7b, 8b
7c, 8c
Ph
O
H
5d (X = CH2, X0 = Br) 7a, 8a
5e (X = O, X0 = Br)
5f (X = S, X0 = Br)
7b, 8b
7c, 8c
Figure 1. Palladium complex of 3a.
rine–palladium complex with a trans configuration.13
However, our azirines 3 formed complexes with palla-
dium in a 2:1 ratio, which were different from the usual
Pd–azirine complexes. Here, the lone pairs of both the
azirine nitrogens and aldehyde oxygens were involved
in the coordination (Fig. 1).
Bis-bromo/chloro-aldehydes 518 also underwent reac-
tion in analogous fashion, that is, giving mainly 2H-azi-
rines 7 with minor amounts of isoxazoles 8 (Scheme 2
and Table 2).
For the detection of unstable azido-aldehydes 2 and 6
we performed the reaction of chloroaldehyde 1 and 5
with sodium azide in an NMR tube using DMSO-d6
as solvent.19 A UV study showed a prominent isosbestic
point, which indicated that the reaction proceeds
through intermediate, presumably an azide or a vinyl
nitrene. There are several reports about photolyses and
pyrolyses of vinyl azides where the nitrene intermediate
could not be detected.20,21
A most exciting result was obtained when bis-azirines 7
were reacted with Pd(PhCN)2Cl2. In this case, both azi-
rine nitrogens and an aldehyde oxygen from either ring
were involved in the coordination forming a 1:1 complex
(Fig. 2) in order to attain trans geometry. To the best of
our knowledge this is the first example of a 1:1 azirine–
1
Pd complex. The H NMR and mass spectra were con-
sistent with the assigned structures (Figs. 1 and 2).22
Since azirines are very unstable, we tried to stabilize our
products by forming complexes with Pd(PhCN)2Cl2. It
had been reported that the lone pair of an azirine nitro-
gen coordinates with palladium resulting in a 2:1 azi-
Typical experimental procedure for syntheses of 2-for-
myl-azirines: To an ice-cold solution of sodium azide
(2.5 mmol) in DMSO (15 ml), a solution of bromo- or
chloroaldehyde 1 (1 mmol) dissolved in DMSO was

S. Brahma, J. K. Ray / Tetrahedron Letters 46 (2005) 6575–6578
6577
X
An EPR study of this complex revealed that it was a
diamagnetic species and so it should adopt a square
planner structure. If we consider the geometry of the
complex as cis then the two aldehyde groups should be
identical and should appear as a doublet in the NMR
spectra. However as we observed two sets of resonances
for the aldehyde protons, the complex must adopt a
trans geometry.
Cl
N
Pd
N
CHO
H
H
O
H
X = CH2, O
Figure 2. Palladium complexes of 7a and 7b.
Physical and spectral data for the palladium complex of
added dropwise. The mixture was stirred for 15 min at
10 °C and then for 5 min at rt (25–30 °C). Then, the
reaction mixture was decomposed with water and the
aqueous portion was extracted with DCM. Removal
of the solvent under reduced pressure followed by puri-
fication by preparative TLC [silica gel GF-254, hexane–
ethyl acetate (7:1) as eluent] gave 2-formyl-azirines 3
(60–68%) and the isoxazoles 4 (6–8%) as the only isola-
ble products. 2H-azirines 7 were prepared in a similar
manner.
7a: Brownish yellow powdery solid, mp: darkened at
185 °C , IR (KBr) mmax: 1770, 1740, 1620 cmꢀ1 1H
;
NMR (200 MHz, CDCl3): d 8.97 (d, 1H, J = 6.2 Hz),
8.95 (d, 1H, 6.6 Hz), 7.94 (d, 2H, J = 8.6 Hz), 7.70 (d,
2H, J = 8.6), 7.43–7.07 (m, 6H), 2.89 (d, 1H,
J = 6.2 Hz), 2.87 (d, 1H, J = 6.5); MS (ES+): m/z
441.84, 443.84, 445.84 [M++PdCl]; Elemental analysis
calcd for C19H14N2O2ClPd: C 51.36, H 3.15, N 6.31;
found C 51.31, H 3.20, N 6.28.
Physical and spectral data for 3b: Yellow viscous liquid,
2. Conclusion
1
IR (KBr) mmax: 1771, 1706, 1279, 1110, 819 cmꢀ1; H
NMR (200 MHz, CDCl3): d 8.92 (d, 1H, J = 6.6 Hz
CH@O), 7.86–7.97 (m, 4H), 7.53–7.63 (m, 3H), 2.89
(d, 1H, J = 2.6 Hz for azirine-H); MS (ES+): m/z 196
[M++H], 167 [M+ꢀCO]; Elemental analysis calcd for
C13H9NO: C 80.07, H 4.65, N 7.18, found C 79.98, H
4.65, N 7.0. For 4b: H NMR (200 MHz, CDCl3): d
8.50 (d, 1H, J = 1.5 Hz), 8.27 (1H, s), 7.87–7.97 (4H,
m), 7.51–7.59 (2H, m), 6.80 (d, 1H, J = 1.5 Hz).
This work reports that 3-substituted 2-formyl-azirines
can be obtained in moderate yields from open chain
vinyl bromo/chloro-aldehydes at room temperature
and consequently forming complexes with palladium
can stabilize these products. To the best of our knowl-
edge, compounds 7a and 7b constitute the first examples
of 1:1 complexes of bis-2-formyl azirines with palla-
dium(II) salts.
1
Physical and spectral data for 7a: Pale yellow viscous
liquid, IR (KBr) mmax: 1738, 1618 cmꢀ1
;
1H NMR
Acknowledgements
(200 MHz, CDCl3): d 8.95 (d, 2H, J = 6.4 Hz CH@O),
7.88 (d, 4H, J = 8.1 Hz), 7.44 (d, 4H, J = 8.1 Hz), 4.21
(s, 2H), 2.87 (d, 2H, J = 6.4 Hz azirine-H); 13C NMR
(50 MHz, CDCl3): d = 200.00, 158.93, 146.70, 130.63,
129.34, 42.19, 38.95, 29.67; MS (FAB): m/z 303
[M++H]; Elemental analysis calcd for C19H14N2O2: C
75.48, H 4.67, N 9.27; found C 75.35, H 4.71, N 9.17.
We thank the DRDO and the CSIR (New Delhi) for
financial assistance.
References and notes
1
For 8a: H NMR (200 MHz, CDCl3): d 8.43 (d, 2H,
J = 1.5 Hz), 7.75 (d, 4H, J = 10.3 Hz), 6.62 (d, 2H,
1. Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. K.
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J = 1.5 Hz), 4.07 (s, 2H).
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Typical procedure for the formation of azirine–palla-
dium complexes: Two equivalents of azirine 3a or one
equivalent of azirine 7a was added to a suspension of
Pd(PhCN)2Cl2 (1.0 mmol) in benzene (10 ml), the mix-
ture was stirred for 10 min, then ether (20 ml) was
added. The product was collected by filtration and
washed with ether to give the pure corresponding palla-
dium complex.
4. Padwa, A.; Woolhouse, A. D. In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
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Pharmaceutical Substances: Synthesis, Patents, Applica-
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8. Gilchrist, T. L. Aldrichim. Acta 2001, 34, 51.
9. Hassner, A. Adv. Strained Interesting Org. Mol. 2000, 8,
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Physical and spectral data for the palladium complex of
3a: Yellow powdered solid, mp: darkened at 165 °C , IR
(KBr) mmax: 1780, 1690 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 8.86 (d, 1H, J = 2.9 Hz), 8.83 (d, 1H,
2.7 Hz), 7.91 (d, 4H, J = 7.2 Hz), 6.42–7.14 (m, 6H),
2.55 (d, 2H, J = 6.0 Hz); MS (ES+): m/z 395.28,
396.01, 398.28 [2M++Pd]; Elemental analysis calcd for
C18H14N2O2Pd: C 54.49, H 3.56, N 7.06; found C
54.42, H 3.61, N 6.98.
10. Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483.
11. Alves, M. J.; Gilchrist, T. L. Tetrahedron Lett. 1998, 39,
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S. Brahma, J. K. Ray / Tetrahedron Letters 46 (2005) 6575–6578
12. Cyclobutadiene, another 4-p anti-aromatic system, is well
known to be stabilized in p-coordinated complexes.
Maitlis, P. M. Adv. Organomet. Chem. 1966, 4, 95.
13. Hassner, A.; Bunnell, C. A.; Haltiwanger, K. J. Org.
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1988, Vol. 6, 893.
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447.
19. Data for the NMR experiment of compound 5a: Initially
the 1H NMR spectrum of chloroaldehyde 5a showed a
signal for the aldehyde proton at 10.10 ppm and for
C@CH–CHO at 6.94 ppm. Immediately after the addition
of NaN3, these two peaks were shifted upfield (10.10 ppm
to 9.97 ppm and 6.94 ppm to 5.76 ppm), which clearly
supported the formation of azido-aldehyde 6a. Due to the
formation of NaCl, we could not take further clear NMR
spectra. So after work-up, followed by separation using
preparative TLC, azirine 7a (60%) and isoxazole 8a (8%)
were obtained.
20. Smolinsky, G. J. Org. Chem. 1962, 27, 3557.
21. Lwowski, W.; Mattingly, T. W., Jr. J. Am. Chem. Soc.
1965, 87, 1947.
22. We performed the complexation reaction of compounds
3a and 7a with Pd(PhCN)2Cl2. In the case of 3a, after the
addition of the Pd-salt into a solution in benzene-d6, the
doublet for the aldehyde proton at d 8.70 ppm split into
two sets of signals with a downfield shift of 0.16 ppm and
in its mass spectrum (ES+), the appearance of peaks at m/z
395.28, 396.01, 398.28, that is, for [2M++Pd] clearly
showed that both azirine-ring nitrogens and the oxygens
of both aldehydes were taking part in complexation.
Whereas for 7a, after similar treatment we obtained two
types of signals for the aldehyde, one shifted downfield
and other remained unchanged. In the mass spectrum
(ES+), peaks at m/z 441.84, 443.84, 445.84, that is, for
[M++PdCl] clearly demonstrated that both nitrogen
atoms from both azirine-rings and one carbonyl oxygen
atom were involved in the coordination.