The first aza-Wittig reaction of the β-lactam carbonyl group

Article abstract of DOI:10.1055/s-1998-1920

The imination of the β-lactam carbonyl group by the aza-Wittig reaction is described. The process is only amenable when carried out intramolecularly.

Full text of DOI:10.1055/s-1998-1920

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The First Aza-Wittig Reaction of the β-Lactam Carbonyl Group
Mateo Alajarín,* Pedro Molina, Ángel Vidal and Fulgencio Tovar
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, E-30071 Murcia, Spain
Fax: Int code + 968 364149; E-mail alajarin@fcu.um.es
Received 24 July 1998
Abstract: The imination of the β-lactam carbonyl group by the aza-
Wittig reaction is described. The process is only amenable when carried
out intramolecularly.
R1
R3
HN
H
R2
O
The reaction of λ5-phosphazenes (iminophosphoranes, phosphine
Route B
b
imines) with carbonyl compounds affording the corresponding
imination products is known as the aza-Wittig reaction, and its synthetic
relevance has been summarized in several review articles.1 The
intramolecular version of this reaction has drawn considerable attention
because of its high potential in heterocyclic synthesis.1b,e
R1
H
X
R2
R3
H
N
O
a
N
R1
The reactivity towards cyclization of the intramolecular aza-Wittig
reaction is controlled by several factors: chain length (product ring size
and ring strain), the substituents at the P and N atoms of the
phosphazene function, and the chemical nature of the carbonyl group.
Concerning the last one, whereas participation of imide carbonyl groups
in such reactions is now well established,2 only a few examples of
intramolecular aza-Wittig reactions involving less reactive amide
carbonyl groups are known,3 usually suffering of low yields.
Route A
N3
N3
1 (X = H2; O)
c
R1
X
H
X
R1
R3
R2
R3
N
d
To our knowledge there are no reported examples of successful aza-
Wittig reactions involving the carbonyl group of a β-lactam ring.
Moreover, two literature reports4 dealing with intermolecular attempts
to carry out such process were disappointing.
N
H
R2
O
N
N
PMe3
2
Herein we report that the imination of a β-lactam carbonyl group by the
aza-Wittig reaction is synthetically amenable when carried out
intramolecularly, provided that reactive P,P,P-trimethyl-λ5-
phosphazenes are used as the imination reagents.
Reagents and conditions: (a) R2R3C=C=O, toluene, r.t., 1h; (b)
2-N3-C6H4-CH2I , K2CO3, cat. n-Bu4NBr, acetonitrile, reflux, 20 h or
2-N3-C6H4-COCl, Et3N, CH2Cl2, 0°C, 1 h, then r.t., 12 h; (c) PMe3,
toluene, r.t., 10 min; (d) toluene, reflux, 12-24 h.
Scheme 1
N
N
+
OPMe3
Due to the extreme hydrolytic susceptibility of the
trimethylphosphazene group, strict anhydrous conditions were required
for the success of these reactions. In some cases the chromatographic
purification of the reaction products caused the oxidation of azeto[2,1-
b]quinazolines 2 (X = H2) to quinazolin-8-ones 2 (X = O), which
occasionally render difficult the isolation of pure 2 (X = H2). This
spontaneous oxidation is not unprecedented5b and was particularly
notable in product 2e, where flash column chromatography and
exclusion of sunlight were unable to suppress this phenomenon.
N
N
O
Me3P
In the course of our research on the intramolecular [2 + 2] cycloaddition
of ketenimines with imines,5 an easy access to N-(2-azidobenzyl)-β-
lactams 1 (X = H2; R2 = R3 = C6H5) was accomplished by the reaction
of N-(2-azidobenzyl) aldimines with diphenylketene.5a In that way,
azido-β-lactams 1a-c have been prepared (Route A, Scheme 1). For the
preparation of compounds 1d-l the more convenient N-alkylation6 or
acylation7 of commercially available or easily synthesized N-
unsubstituted β-lactams with 2-azidobenzyl iodide8 or 2-azidobenzoyl
chloride9 respectively, was the method of choice (Route B).10
Initial attempts to achieve the conversion of compounds 1 to the
corresponding azeto[2,1-b]quinazolines 2 (X = H2) or quinazolin-8-
ones 2 (X = O) by treatment with PPh3 or PBu3 under different reaction
conditions (solvent, temperature) were unsuccessful, leading to complex
mixtures in which the desired products could not be detected by tlc.11
More satisfactorily, when a 1 M toluene solution of PMe3 was used to
effect the conversion of the azido group in 1 to the non-isolated N-aryl-
P,P,P-trimethyl-λ5-phosphazene (nitrogen evolution was clearly
observed) and the resulting toluene solution was refluxed under nitrogen
for 12-24 h, the corresponding benzo-fused bicyclic amidines 2 were
obtained in variable yields (40-90%) (Scheme 1, Table).12

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1289
Spectroscopic identification of compounds 2 was accomplished by the
usual techniques (IR, 1H and 13C NMR, MS).13 The course of the
conversion 1 → 2 could be monitored by the decreasing intensity of the
IR absorption due to the carbonyl group of 1 at 1760-1810 cm-1 and the
subsequent increasing of the C=N band of 2 at 1660-1680 cm-1.
Proced. Int. 1992, 24, 209; d) Barluenga J.; Palacios, F. Org.
Prep. Proced. Int. 1991, 23, 1; e) Gusar, N. I. Russ. Chem. Rev.
(Engl. Transl.) 1991, 60, 146.
(3) Kurita, J.; Iwata, T.; Yasuike, S.; Tsuchiya, T. J. Chem. Soc.,
Chem. Commun. 1992, 81; Molina, P.; Alajarín, M.; López-
Leonardo, C.; Madrid, I.; Foces-Foces, C.; Cano, F. H.
Tetrahedron 1989, 45, 1823; Molina, P.; Alajarín, M.; Vidal, A.;
Elguero, J.; Claramunt, R. M. Tetrahedron 1988, 44, 2249;
Gololobov, Y. G.; Gusar, N. I.; Chaus, M. P. Tetrahedron 1985,
41, 793; Flitsch, W.; Mukidjam, E. Chem. Ber. 1979, 112, 3577.
14
Detection of O=PMe3 in the final reaction mixtures corroborated the
aza-Wittig nature of these reactions.
The examples reported so far involved achiral or racemic azido-β-
lactams 1. The present method was also applicable to the preparation of
azeto[2,1-b]quinazolin-8-one 4 in 47% yield,15 starting from the
commercially available, enantioenriched β-lactam 3 (Scheme 2).
(4) L'abbé, G.; Sorgeloos, D.; Toppet, S. Tetrahedron Lett. 1982, 23,
2909; Marchand-Brynaert, J.; Ghosez, L. In Recent Progress in
the Chemical Synthesis of Antibiotics, Lukacs, G. and Ohno, M.,
Eds.; Springer-Verlag: Berlin, 1990, p 733.
O
H
H
HN
OAc
H
a, b
N
OAc
H
(5) a) Alajarín, M.; Molina, P.; Vidal, A. Tetrahedron Lett. 1996, 37,
8945; b) Alajarín, M.; Molina, P.; Vidal, A.; Tovar, F.
Tetrahedron 1997, 53, 13449.
O
N
TBDMSO
CH3
TBDMSO
CH3
(6) Chmielewski, M.; Kaluza, Z.; Abramski, W.; Belzecki, C.
3
4
Tetrahedron Lett. 1987, 28, 3035.
(7) See for instance: Sakurai, O.; Ogiku, T.; Takahashi, M.; Hayashi,
M.; Yamanaka, T.; Horikawa, H.; Iwasaki, T. J. Org. Chem. 1996,
61, 7889.
Reagents and conditions: (a) 2-N3-C6H4-COCl, Et3N, CH2Cl2, 0°C,
1 h, then r.t., 12 h; (b) PMe3, toluene, r.t., 10 min, then reflux, 12 h.
Scheme 2
(8) Alajarín, M.; López-Lázaro, A.; Vidal, A.; Berná, J. Chem. Eur.
J., in press.
Attempts to carry out reactions similar to the ones summarized in the
Table but intermolecularly, by the employment of several N-substituted
(alkyl, acyl) β-lactams and the phosphazenes PhCH2N=PMe3 and
PhCON=PMe3 (generated in situ from the azides and PMe3), failed.
Other intramolecular attempts, starting from alkyl azides 5 and 6, or
aryl azide 7, also resulted in failure.
(9) Porter, T. C.; Smalley, R. K.; Teguiche, M.; Purwono, B.
Synthesis 1997, 773.
Typical Experimental Procedure for the Alkylation of N-
Unsubstituted β-Lactams. Tetrabutylammonium bromide (0.26
g, 0.8 mmol) and K2CO3 (4.42 g, 32 mmol) were added to a
solution of 2-azidobenzyl iodide (1.24 g, 4 mmol) and the
corresponding 2-azetidinone (4 mmol) in dry acetonitrile (40 ml).
The mixture was stirred at reflux temperature for 24 h. After
cooling the mixture was poured into water (100 ml) and extracted
with CH2Cl2 (3 x 40 ml). The combined organic layer was washed
with water (100 ml) and brine (100 ml), dried over MgSO4 and
evaporated. The residue was purified by column chromatography
(silica gel; elution with n-hexane: EtOAc).
Data for 1e: mp 148°C, 1H NMR (300 MHz, CDCl3) δ 2.85 (dd, J
= 2.4, 14.7 Hz, 1H), 3.36 (dd, J = 5.1, 14.7 Hz, 1H), 3.96 (d, J =
14.9 Hz, 1H), 4.42 (dd, J = 2.4, 5.1 Hz, 1H), 4.59 (d, J = 14.9 Hz,
1H), 7.03-7.09 (m, 2H), 7.17-7.37 (m, 7H); 13C NMR (75.4 MHz,
CDCl3) δ 40.37, 47.05, 54.46, 118.16, 124.98, 126.45, 126.74,
128.45, 128.86, 129.37, 131.03, 128.28, 138.44, 167.34; IR
(Nujol) 2122, 1754, 1406, 1305, 755, 701 cm-1; MS (EI) m/z (%)
278 (M+, 24), 103 (100); Anal. Calcd. for C16H14N4O: C, 69.05;
H, 5.07; N, 20.13. Found: C, 68.83; H, 5.21; N, 20.01.
Typical Experimental Procedure for the Acylation of N-
Unsubstituted β-Lactams. To a solution of the corresponding 2-
azetidinone (3 mmol) and 2-azidobenzoyl chloride (1.63 g, 9
mmol) in dry CH2Cl2 (30 ml), with ice cooling, was added
dropwise a solution of Et3N (3.03 g, 30 mmol) in dry CH2Cl2 (15
ml), and the mixture was stirred overnight. Then the mixture was
poured into water (100 ml), and extracted with CH2Cl2 (2 x 25
ml). The combined organic layer was washed with saturated
NaHCO3 aqueous solution (2 x 100 ml), water and brine, dried
over MgSO4, and evaporated. The residue was purified by column
chromatography (silica gel, elution with n-hexane/ EtOAc).
Data for 1i: mp 130°C, 1H NMR (300 MHz, CDCl3) δ 3.02 (dd, J
= 3.7, 16.5 Hz, 1H), 3.53 (dd, J = 6.5, 16.5 Hz, 1H), 5.22 (dd, J =
3.7, 6.5 Hz, 1H), 7.18-7.26 (m, 2H), 7.32-7.56 (m, 7H); 13C NMR
(75.4 MHz, CDCl3) δ 45.81, 52.98, 118.68, 124.67, 125.95,
C6H4-NO2-4
N3
N
H
C6H4-NO2-4
n
Ph
N
H
Ph
O
Ph
N3
O
Ph
5
6
n = 2
n = 3
7
These last results were relevant in order to quote the scope and
applicability of the method: reactions involving aliphatic azide
fragments or leading to five-membered rings did not work properly.
In conclusion, the aza-Wittig imination of β-lactam carbonyl groups by
the action of λ5-phosphazenes has been achieved, for the first time, in an
intramolecular manner to yield azeto[2,1-b]quinazolines or quinazolin-
8-ones. The method requires the intermediacy of highly reactive N-aryl-
P,P,P-trimethyl-λ5-phospha-zenes, and it has only proven useful when
it results in the formation of a six-membered ring.
Acknowledgements: The authors wish to thank the Dirección General
de Investigación Científica y Técnica (DGICYT) for financial support
(project number PB95-1019). One of us (F.T.) also thanks the MEC for
a fellowship.
References and notes
(1) a) Wamhoff, H.; Rechardt, G.; Stölben, S. Adv. Heterocycl. Chem.
1995, 64, 159; b) Molina, P.; Vilaplana, M. J. Synthesis 1994,
1197; c) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.

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126.07, 128.43, 128.92, 129.82, 132.63, 137.81, 138.68, 163.21,
163.76; IR (Nujol) 2134, 1811, 1679 cm-1; MS (EI) m/z (%) 292
(M+, 11), 104 (100); Anal. Calcd. for C16H12N4O2: C, 65.75; H,
4.14; N, 19.17. Found: C, 65.87; H, 4.03; N, 19.34.
second diastereoisomer. The mixture could not be
chromatographically resolved into its two components. The trans
configuration of both diastereoisomers was unambiguously
deduced from the values of the coupling constant between the
protons at the sp3 carbon atoms of the azetidine ring: 1.7 and 1.3
Hz for the major and minor diastereoisomer respectively. The
same ratio of diastereoisomers (4:1) was also present in the
acylation product resulting from the first step of the sequence
depicted in Scheme 2. It is reasonable to assume, albeit
speculatively, the (1R,2R,1’R ) and (1S,2S,1’R) configurations for
the major and minor diastereoisomers of 4, the minor one arising
from partial racemization at the sp3 carbon atoms of the β-lactam
ring during the base-catalysed N-acylation step, probably through
the intermediacy of the azetone A.
(11) Compound 2c has been previously prepared by us through a
different methodology, see ref. 5b.
(12) Typical Experimental Procedure for the Preparation of
Azeto[2,1-b]quinazolines and Azeto[2,1-b]quinazolin-8-ones 2.
To a solution of the 2-azetidinone 1 (1 mmol) in dry toluene (15
ml) trimethylphosphane was added (1.0 ml of a 1 M toluene
solution), and the mixture was stirred at room temperature until
the evolution of nitrogen ceased (5-10 min). Then the solution was
heated at reflux temperature for 12-24 h. After cooling, the solvent
was removed under reduced pressure and the resulting material
was chromatographed (silica gel; elution with n-hexane/EtOAc).
(13) Data for 2j: mp 125°C, 1H NMR (300 MHz, CDCl3) δ 2.21 (s,
3H), 3.51 (dd, J = 1.9, 16.2 Hz, 1H), 3.93 (dd, J = 4.3, 16.2 Hz,
1H), 6.90 (dd, J = 1.9, 4.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.65
(d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 8.26 (d, J = 7.8 Hz,
1H); 13C NMR (75.4 MHz, CDCl3) δ 20.59, 41.72, 78.59, 123.32,
126.55, 126.84, 127.24, 134.34, 149.87, 154.57, 157.33, 168.93;
IR (Nujol) 1759, 1684, 1659, 1221, 775 cm-1; MS (EI) m/z (%)
230 (M+, 34), 43 (100); Anal. Calcd. for C12H10N2O3: C, 62.60;
H, 4.38; N, 12.17. Found: C, 62.74; H, 4.23; N, 12.23.
O
H
N
2-N3-C6H4
CH3
O
TBDMSO
A
(14) O=PMe3: 1H NMR (300 MHz, CDCl3, TMS) δ 1.52 (d, 2JHP 12.9
It is well known that 4-acyloxy-β-lactams are configurationally
unstable under basic conditions (Kametani, T.; Honda, T.;
Nakayama, A.; Sasaki, Y.; Mochizuki, T.; Fukumoto, K. J. Chem.
Soc., Perkin Trans. 1 1981, 2228 and references therein).
Hz); 31P NMR (121.4 MHz, CDCl3, 85% H3PO4) δ 36.0.
(15) Compound 4 thus obtained was impurified by a minor amount
(approximately 20%, as revealed by 1H NMR analysis) of a