Mechanistic investigation of the ring opening in the Staudinger cycloaddition involving ketenes with electron-withdrawing substituents

Article abstract of DOI:10.1002/hlca.201100483

The cycloaddition of ketenes and imines (Staudinger cycloaddition) is a general method for the synthesis of various β-lactams. However, reactions of imines and ketenes with electron-withdrawing substituents produce α,β-unsaturated alkenamides, ring-opening products of the intermediates generated from imines and the ketenes, even as sole products, besides the desired β-lactams. The mechanism of the formation of α,β-unsaturated alkenamides was investigated. The results indicate that the α,β-unsaturated alkenamides are generated via a base-induced C=C bond isomerization followed by electrocyclic ring opening of the formed azacyclobutenes (=1,2-dihydroazetes; cf. Scheme 3). Copyright

Full text of DOI:10.1002/hlca.201100483

Helvetica Chimica Acta – Vol. 95 (2012)
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Mechanistic Investigation of the Ring Opening in the Staudinger
Cycloaddition Involving Ketenes with Electron-Withdrawing Substituents
by Shanyan Mo and Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of
Science, Beijing University of Chemical Technology, Beijing 100029, P. R. China
(phone/fax: þ86-10-64435565; e-mail: jxxu@mail.buct.edu.cn)
The cycloaddition of ketenes and imines (Staudinger cycloaddition) is a general method for the
synthesis of various b-lactams. However, reactions of imines and ketenes with electron-withdrawing
substituents produce a,b-unsaturated alkenamides, ring-opening products of the intermediates generated
from imines and the ketenes, even as sole products, besides the desired b-lactams. The mechanism of the
formation of a,b-unsaturated alkenamides was investigated. The results indicate that the a,b-unsaturated
alkenamides are generated via a base-induced C¼C bond isomerization followed by electrocyclic ring
opening of the formed azacyclobutenes (¼1,2-dihydroazetes; cf. Scheme 3).
Introduction. – The b-lactam structure is the fundamental structural skeleton of the
important and widely used b-lactam antibiotics [1] and key intermediates in organic
and pharmaceutical synthetic chemistry [2]. To date, numerous methods have been
developed for the synthesis of b-lactams due to their important role in pharmaceutical
chemistry [2]. Among them, the Staudinger cycloaddition, i.e., the formation of
azetidin-2-ones from ketenes and imines, is one of the most versatile methods for the
synthesis of b-lactam derivatives with a clear configuration control [3]. However, the
method has been seldom applied to the synthesis of b-lactams with electron-
withdrawing substituents, such as acyl [4], COOH or derivative thereof [5], and CN
[6], especially to the synthesis of 3-monosubstituted b-lactams with electron-with-
drawing substituents. Indeed, a,b-unsaturated alkenamides, i.e., ring-opening products
of the intermediates were obtained from imines and ketenes with electron-withdrawing
substituents, even as sole products, besides the desired b-lactams in most cases [7].
Although the mechanism of the formation of a,b-unsaturated alkenamides has been
discussed previously [7d][7e][8], it is still unclear. This limits the application of the
Staudinger cycloaddition for the preparation of b-lactams with electron-withdrawing
substituents. The latter are key intermediates or precursors for the synthesis of b-lactam
antibiotics and their analogs for drug production or discovering. To understand and
thereby avoid the side reaction generating alkenamides, with the aim to utilize the
Staudinger cycloaddition efficiently in the synthesis of b-lactams with electron-
withdrawing substitutents, we report below on the mechanism of the formation of a,b-
unsaturated alkenamides.
Results and Discussion. – Analyzing the structural features of a,b-unsaturated
alkenamides, it might be assumed that they are formed from certain enolic isomers of
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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the b-lactams generated from imines and the ketenes with electron-withdrawing
substituents by a conrotatory 4e electrocyclic ring opening. Thus, to verify this
assumption, we hoped to prepare model b-lactams with p-acceptor substituents at C(3)
and to investigate their reactions in the presence of different bases.
Therefore, the 3-substituted b-lactams 3-acetylazetidin-2-one 1a, ethyl 2-oxazeti-
dine-3-carboxylate 1b, and 2-oxazetidine-3-carbonitrile 1c were prepared by reported
procedures (Scheme 1). trans-3-Acetylazetidin-2-one (ꢀ)-1a was obtained from the
reaction of diketene and N-benzylideneaniline (¼ N-(phenylmethylene)benzenamine)
in the presence of 1H-imidazole in CH2Cl2 [9]. Ethyl carboxylate (ꢀ)-1b was
synthesized from the reaction of the ethyl half ester of malonic acid and N-
benzylideneaniline in the presence of di(1H-imidazol-1-yl)methanone (CDI) in
CH2Cl2 [10]. The cis-carbonitrile (ꢀ)-cis-1c was prepared by referring to Mooreꢂs
method [6e]. Mucobromic acid (¼ (2Z)-2,3-dibromo-4-oxobut-2-enoic acid) was first
treated with boron trifluoride etherate solution in MeOH to convert it to 3,4-dibromo-
5-methoxyfuran-2(5H)-one (2) [11], which further reacted with sodium azide to afford
4-azido-3-bromo-5-methoxyfuran-2(5H)-one (3). The latter and N-(4-nitrobenzylide-
ne)propan-1-amine were refluxed in benzene to give rise to the 3-bromo-2-oxoazeti-
dine-3-carbonitrile 4. Although it was reported that 3-chloro-2-oxoazetidine-3-carbo-
nitriles were smoothly reduced to 2-oxoazetidine-3-carbonitriles with Zn/AcOH as
reductant [6c][12], 3-bromo-2-oxoazetidine-3-carbonitrile 4 produced a messy product
mixture under the same reduction conditions. Fortunately, the Br-substituent could be
removed successfully from 4 with sodium borohydride in MeOH to yield b-lactam (ꢀ)-
Scheme 1. Synthesis of b-Lactams with p-Electron-Withdrawing Substituents at C(3)

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cis-1c. Its relative configutation was determined on the basis of its vicinal H,H-coupling
constant. Moore and co-workers confirmed previously that cis-2-oxoazetidine-3-
carbonitriles are major products in the reduction of 3-halo-2-oxoazetidine-3-carbo-
nitriles with Zn/AcOH as reductant [6c][12].
To investigate the electrocyclic ring-opening reactions, all synthetic model b-
lactams were dissolved in different solvents, e.g., in toluene, CH2Cl2, and THF, which
are usually used in Staudinger cycloadditions, and the resulting solutions were heated
under reflux and stirring in the presence of bases, such as Et3N, pyridine, and even
strong bases such as NaH. In all cases, no a,b-unsaturated alkenamide derivative was
observed, and most of the b-lactams remained unchanged, except for (ꢀ)-cis-1c, which
was converted to the more stable (ꢀ)-trans-1c under reflux in the presence of base
(Scheme 2). The results (Table) indicate that if b-lactams with p-electron-withdrawing
substituents at C(3) are generated in the reactions, they cannot undergo the
electrocyclic ring-opening reaction to produce the corresponding a,b-unsaturated
alkenamides under basic reaction conditions.
Scheme 2. Conversion of (ꢀ)-cis-1c to (ꢀ)-trans-1c in the Presence of Et3N
Table. Reaction of b-Lactams with p-Acceptor Substituents at C(3) in the Presence of Base
b-Lactam
Base
Solvent
Temp. [8]
Time [d]
Product(s)
Ratio (cis/trans)
(ꢀ)-1a
Et3N
NaH
Et3N
Et3N
Et3N
NaH
toluene
THF
toluene
toluene
CH2Cl2
THF
110
66
110
110
25
2
1.5
2
1
0.5
1
(ꢀ)-1a
(ꢀ)-1a
(ꢀ)-1a
(ꢀ)-1b
(ꢀ)-1b
(ꢀ)-cis-1c
(ꢀ)-cis-1c
(ꢀ)-cis-1c
(ꢀ)-cis-1c
(ꢀ)-cis/trans-1c
(ꢀ)-cis/trans-1c
(ꢀ)-cis/trans-1c
(ꢀ)-cis/trans-1c
45 : 55
40 : 60
0 : 100
70 : 30
66
110
pyridine
toluene
6
A survey of the literature showed that several acetylketene precursors, including
2,2,6-trimethyl-4H-1,3-dioxin-4-one [7e], diketene [7c], acetoacetyl chloride [5b], and
AcCl [7b], reacted with some imines to give rise to 2,3-dihydro-6-methyl-4H-1,3-
oxazin-4-ones 5, 2-alkylideneacetoacetamides 6, and 3-acetylazetidin-2-ones 1, or their
mixtures (cf. Scheme 3). Cyanoacetyl chloride reacted with linear imines in the
presence of Et3N to afford 2-cyanoalk-2-enamides [7a]. However, with cyclic imines,
cyanoacetylchloride yielded b-lactam products [3c]. Futhermore, 2-cyanoalkanoyl
chlorides (except for cyanoacetyl chloride) gave rise to b-lactam products when they
reacted with linear imines [13].
On the basis of the above results, we are inclined to consider that the mechanism of
the formation of a,b-unsaturated alkenamides is as follows (Scheme 3). An (E)-imine
attacks the generated ketene with an electron-withdrawing substituent (EWG) from its
less hindered exo-side in the reaction system to yield zwitterionic intermediate A,

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Scheme 3. Proposed Reaction Mechanism of the Reaction of Imines and Ketenes with Electron-
Withdrawing Substituents
which isomerizes to form the more stable zwitterion B because ring closure of
intermediate A to afford the cis-b-lactam directly is unfavorable due to the electron-
withdrawing substituent [3a]. There exists another possibility to generate intermediate
B via N-inversionꢁisomerization of the (E)-imine to the (Z)-imine, which attacks the
ketene with an electron-withdrawing substituent from its exo-side. The intermediate B
undergoes conrotatory ring closure to form the azaenolate C of the trans-b-lactam,
which converts to the enolate D by base-induced deprotonation at the a-position of C.
Intermediate D undergoes a conrotatory electrocyclic ring opening to produce amide
enolate E which, on protonation by the conjugated acid HB, gives 6, possibly via F, or
which tautomerizes to amide anion G and following protonation by the conjugated acid
HB gives 6. On the other hand, the intermediate C tautomerizes directly to the trans-b-
lactams (ꢀ)-1. The rate constants ka (the rate constant of the acid-base reaction) and kt
(the rate constant of the tautomerization from C to trans-b-lactam (ꢀ)-1) control the
ratio of the products 6 and (ꢀ)-1. For an enolate C with a strong electron-withdrawing
substituent, the H-atom at C(3) is more acidic. Thus, the intermediate C is

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1083
predominantly converted to D in the presence of base (ka >> kt), resulting in the
formation of a,b-unsaturated alkenamide 6. The azaenolate C with an electron-
withdrawing substituent can produce both the a,b-unsaturated alkenamide 6 and the
trans-b-lactam (ꢀ)-1 if ka is close to kt. However, the HꢁC(3) of b-lactams without an
eletron-withdrawing substituents is less acidic. Intermediate A predominantly converts
to b-lactams (ꢀ)-1 if ka << kt. Once the b-lactam is generated, it cannot convert to the
a,b-unsaturated alkenamide 6, even by carbanion formation at C(3) because this
carbanion H is more stable than the enolate D.
Furthermore, 3-nitro-b-lactams are prepared by nitration of lithiated b-lactams at
C(3) with propyl nitrate. In these preparations, no ring-opening reaction was observed,
revealing that 3-nitro-b-lactam carbanions cannot convert to the corresponding a,b-
unsaturated nitroalkenamides [14][15].
Acetylketene and imines can also undergo a DielsꢁAlder cycloaddition to afford
2,3-dihydro-6-methyl-4H-1,3-oxazin-4-ones 5, which can undergo, on heating, a retro-
DielsꢁAlder reaction to regenerate acetylketene and imines. They can react to form
intermediates C, which further convert to a,b-unsaturated alkenamides 6 and trans-b-
lactams (ꢀ)-1 as final products (Scheme 3). This provides a rational explanation for the
reported experimental results [7].
Mooreꢂs group reported that 2,5-diazidobenzo-1,4-quinone derivatives can serve as
cyanoketene precursors and thus undergo cycloadditions with imines under thermal
conditions in the absence of base [6a – 6e]. To verify our proposed mechanism, we
hoped to realize the synthesis of 2-oxoazetidine-3-carbonitrile (ꢀ)-trans-1c via thermal
cycloaddition of N-(nitrobenzylidene)propan-1-amine and cyanoketene, generated
from 2,5-diazido-1,4-benzoquinone under heating (Scheme 4); under the conditions of
thermal cycloaddition, no base exists, hence the 3-carbonitrile was assumed to be
generated. Thus, 2,5-diazido-1,4-benzoquinone was prepared from 2,5-dichloro-1,4-
benzoquinone with sodium azide [16] and treated with N-(nitrobenzylidene)propan-1-
amine in refluxing toluene (Scheme 4). However, no cycloaddition was observed
although 2,5-diazido-1,4-benzoquinone decomposed completely.
Scheme 4. Reaction of 2,5-Diazido-1,4-benzoquinone and N-(Nitrobenzylidene)propan-1-anime
Conclusions. – The mechanism of the formation of a,b-unsaturated alkenamides in
the Staudinger cycloaddition of imines and ketenes with electron-withdrawing
substituents was investigated. The results indicate that the a,b-unsaturated alken-
amides were generated via the base-promoted C¼C bond isomerization and electro-
cyclic ring-opening reaction of formed azacyclobutenes (¼1,2-dihydroazetes) from the
intermediates generated from imines and ketenes with electron-withdrawing substitu-
ents.

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The project was supported by the National Natural Science Foundation of China (Nos. 20972013 and
20772005) and the Beijing Natural Science Foundation (No. 2092022).
Experimental Part
General. Column chromatography (CC): silica gel (SiO2, 200 – 300 mesh); petroleum ether (60 – 908)
and AcOEt as eluents. M.p.: uncorrected. 1H- and 13C-NMR Spectra: at 400 MHz in CDCl3; d in ppm rel.
to Me4Si as internal standard, J in Hz. IR Spectra: in KBr. HR-MS: LC/MSD TOF mass spectrometer; in
m/z.
(ꢀ)-trans-3-Acetyl-1,4-diphenylazetidin-2-one ((ꢀ)-1a). Diketene (2.1 g, 25 mmol) in CH2Cl2,
(10 ml) was added dropwise to a soln. of N-(benzylidene)aniline (906 mg, 5 mmol) and 1H-imidazole
(525 mg, 7.5 mmol) in CH2Cl2, (10 ml) at ꢁ 158. The resulting soln. was stirred overnight. After
evaporation, the residue was purified by CC ( SiO2, petroleum ether AcOEt 6 :1 ! 1:1): 790 mg (59.5%
of (ꢀ)-1a). Colorless crystals. M.p. 74 – 768. IR: 1754 (C¼O), 1717 (C¼O). 1H-NMR: 2.38 (s, Me); 4.13
(d, J ¼ 2.4, CH); 5.47 (d, J ¼ 2.4, CH); 7.04 – 7.07 (m, 1 arom. H); 7.22 – 7.27 (m, 4 arom. H); 7.33 – 7.38 (m,
5 arom. H). 13C-NMR: 29.8; 55.5; 71.8; 117.0; 124.2; 126.0; 127.3; 128.0; 129.0; 129.2; 136.5; 137.1; 160.2;
198.7. HR-ESI-MS: 266.1177 ([M þ H]þ, C17H16NO2þ ; calc. 266.1176).
(ꢀ)-Ethyl trans-2-Oxo-1,4-diphenylazetidine-3-carboxylate ((ꢀ)-1b). A soln. of 3-ethoxy-3-oxopro-
panoic acid (15.4 g, 20 mmol) and di(1H-imidazol-1-yl)methanone (2.64 g, 60 mmol) in CH2Cl2, (100 ml)
was stirred at r.t. for 1 h. To the soln. was added N-(benzylidene)aniline (3.62 g, 20 mmol) in CH2Cl2,
(40 ml) while stirring. The resulting mixture was stirred for another 1 h. After evaporation, the residue
was purified by CC (SiO2, with petroleum ether/AcOEt 30 :1 ! 20 :1): 1.8 g (30.5%) of (ꢀ)-1b. Colorless
crystals. M.p. 92 – 938 ([10]: m.p. 87 – 898). IR: 1767 (C¼O), 1713 (C¼O). 1H-NMR (200 MHz): 1.33 (t,
J ¼ 7.2, MeCH2); 3.98 (d, J ¼ 2.7, CHCO); 4.30 (q, J ¼ 7.2, MeCH2); 5.34 (d, J ¼ 2.7, CHN); 7.05 – 7.42 (m,
10 arom. H). 13C-NMR (75.5 MHz): 14.1; 57.5; 62.1; 63.5; 117.1; 124.3; 126.1; 128.96; 129.03; 129.2; 136.2;
137.1; 159.2; 166.2.
3,4-Dibromo-5-methoxyfuran-2(5H)-one (2). Et2O · BF3 (1.26 ml, 10.2 mmol) was added to a soln. of
mucobromic acid (2.58 g, 10 mmol) in MeOH (40 ml), and the resulting soln. was stirred at r.t. for 2 d.
After evaporation, the residue was dissolved in CH2Cl2, (20 ml), the resulting soln. washed with sat. aq.
Na2CO3 soln. (3 ꢂ 20 ml), and the org. phase dried (Na2SO4) and concentrated: 2.43 g (90%) of 2. White
solid. M.p. 49 – 508 ([11]: m.p. 528).
4-Azido-3-bromo-5-methoxyfuran-2(5H)-one (3). To a soln. of 2 (2.43 g, 8.94 mmol) in MeOH
(20 ml), NaN3 (581 mg, 8.94 mmol) was slowly added under stirring at 08, and the resulting soln. was
stirred for 1 h. Addition of H2O and filtration gave 1.65 g (78.9%) of 3. White solid. M.p. 74 – 758.
3-Bromo-2-(4-nitrophenyl)-4-oxo-1-propylazetidin-3-carbonitrile (4). A soln. of 3 (468 mg, 2 mmol)
and N-(4-nitrobenzylidene)propan-1-amine (294 mg, 1.53 mol) in anh. benzene (10 ml) was stirred
overnight at 808. After evaporation, the residue was purified by CC (SiO2, petroleum ether/AcOEt
10 :1 ! 5 :1): 469 mg (90%) of 4. Colorless crystals. M.p. 120 – 1218. IR: 2235 (CN), 1790 (C¼O).
1H-NMR: 0.97 (t, J ¼ 7.6, Me); 1.53 – 1.72 (m, MeCH2); 2.97 (ddd, J ¼ 5.6, 7.6, 14.0, 1 H, CH2N); 3.57
(ddd, J ¼ 7.6, 7.6, 14.0, 1 H, CH2N); 5.06 (s, CH); 7.62 (d, J ¼ 8.4, 2 arom. H), 8.38 (d, J ¼ 8.4, 2 arom. H).
13C-NMR: 11.2; 20.5; 44.1; 45.3; 68.8; 111.7; 124.7; 128.4; 138.1; 149.3; 156.6. HR-ESI-MS: 338.0140
([M þ H]þ, C13H13BrN3Oþ3 ; calc. 338.0135).
(ꢀ)-cis-2-(4-Nitrophenyl)-4-oxo-1-propylazetidin-3-carbonitrile ((ꢀ)-cis-1c). To a soln. of 4 (338 mg,
1 mmol) in MeOH (10 ml), H2O (5 ml) was added, and the resulting soln. was cooled to 08. NaBH4
(46 mg, 1.2 mmol) was portionwise added, and the resulting soln. was stirred for 2 h. After evaporation,
the residue was purified by CC (SiO2, petroleum ether/AcOEt 3 :1 ! 1:1): 181 mg (70%) of (ꢀ)-cis-1c.
Colorless crystals. M.p. 136 – 1388. IR: 2247 (CN), 1774 (C¼O). 1H-NMR: 0.92 (t, J ¼ 7.6, Me); 1.47 – 1.65
(m, CH2); 2.95 (ddd, J ¼ 6.0, 8.0, 14.0, 1 H CH2N); 3.57 (ddd, J ¼ 7.6, 7.6, 14.0, 1 H, CH2N); 4.47 (d, J ¼
5.4, CHN); 4.99 (d, J ¼ 5.4, CHCO); 7.58 – 7.60 (m, 2 arom. H); 8.34 – 8.37 (m, 2 arom. H). 13C-NMR:
11.4; 20.7; 43.9; 46.0; 56.0; 112.3; 124.5; 128.3; 140.0; 148.9; 157.7. HR-ESI-MS: 260.1027 ([M þ H]þ,
C13H14N3Oþ3 ; calc. 260.1030).
Reaction of b-Lactams with p-Acceptor Substituents at C(3) in the Presence of Base: General
Procedure. The b-lactam (0.1 mmol) was added to the desired solvent (see Table). The selected base

Helvetica Chimica Acta – Vol. 95 (2012)
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(1.5 mmol) was added and the resulting soln. was refluxed for a period of time (TLC monitoring). If
reaction occurred, the ratio of products was determined by 1H-NMR analysis of the crude reaction
mixture.
(ꢀ)-trans-2-(4-Nitrophenyl)-4-oxo-1-propylazetidin-3-carbonitrile ((ꢀ)-trans-1c). To a soln. of (ꢀ)-
cis-1c (104 mg, 0.4 mmol) in CH2Cl2, (5 ml) was added Et3N (80 mg, 0.79 mmol). The resulting soln. was
stirred for 1 h. After evaporation, the residue was purified by CC (SiO2, petroleum ether/AcOEt 3 :1 !
1:1): (ꢀ)-trans-1c (52 mg, 50%), besides recovered (ꢀ)-cis-1c (30 mg). (ꢀ)-trans-1c: Colorless crystals.
M.p. 97 – 988. IR: 2247 (CN), 1771 (C¼O). 1H-NMR: 0.94 (t, J ¼ 7.4, Me); 1.50 – 1.61 (m, CH2); 2.91 (ddd,
J ¼ 7.0, 7.0, 14.2, 1 H, CH2N); 3.46 (ddd, J ¼ 7.6, 7.6, 14.2, 1 H CH2N); 3.81 (d, J ¼ 2.6, CHN); 4.90 (d, J ¼
2.6, CHCO); 7.59 (d, J ¼ 8.6, 2 arom. H), 8.38 (d, J ¼ 8.6, 2 arom. H). 13C-NMR: 11.4; 20.8; 43.9; 46.8;
58.0; 113.3; 124.8; 127.5; 141.7; 148.9; 157.4. HR-ESI-MS: 260.1029 ([M þ H]þ, C13H14N3O3þ ; calc.
260.1030).
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Received December 2, 2011