Experimental and theoretical investigation of benzyl-N-pyrrolylketene, one- step procedure for preparing of new β-lactams by [2 +2] cycloaddition reaction

Article abstract of DOI:10.1007/s12039-015-1007-7

3-Phenyl-2-(1-H-pyrrol-1-yl) propanoic acid has been used as a ketene source in synthesizing of monocyclic-2-azetidinones. Hindrance in ketene and imines successfully controlled the diastereoselectivity of the reaction. For example, in some cases only one isomer was achieved. By using Mukaiyama reagent, the leaving group in acid was activated and the by-products were separated by simple aqueous work-up. DFT calculation indicated that the benzyl-N-pyrrolylketene has nonconjugated structure and the pyrrolyl ring is perpendicular to the ketene plane in both the twisted and planar structures.

Full text of DOI:10.1007/s12039-015-1007-7

c
J. Chem. Sci. Vol. 128, No. 1, January 2016, pp. 111–117. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-1007-7
Experimental and theoretical investigation of benzyl-N-pyrrolylketene,
one- step procedure for preparing of new β-lactams by [2+2]
cycloaddition reaction
MASOUMEH BEHZADI, KAZEM SAIDI∗, MOHAMMAD REZA ISLAMI and
HOJATOLLAH KHABAZZADEH
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169-14111, Iran
e-mail: saidik@uk.ac.ir
MS received 11 August 2015; revised 20 October 2015; accepted 26 October 2015
Abstract. 3-Phenyl-2-(1-H-pyrrol-1-yl) propanoic acid has been used as a ketene source in synthesizing of
monocyclic-2-azetidinones. Hindrance in ketene and imines successfully controlled the diastereoselectivity of
the reaction. For example, in some cases only one isomer was achieved. By using Mukaiyama reagent, the
leaving group in acid was activated and the by-products were separated by simple aqueous work-up. DFT
calculation indicated that the benzyl-N-pyrrolylketene has nonconjugated structure and the pyrrolyl ring is
perpendicular to the ketene plane in both the twisted and planar structures.
Keywords. β-Lactam; [2+2] Cycloaddition; Benzyl-N-pyrrolylketene; NMR; NOE; Diasteroselectivity.
1. Introduction
be cis-, trans-, or a mixture of cis- and trans-β-lactam
derivatives.
2-Azetidinones, commonly known as β-lactams, are
found to be associated with various antibacterial
drugs and medicinal activities. Ezetimibe (a choles-
terol absorbing inhibitor),1 Taxol and taxorate (anti-
tumor drugs),2 monobactams such as aztreonam and
carumonam3 (figure 1) and norcardicins1 (displaying
antibacterial activities) have β-lactam skeleton in their
structures.
Besides the utility of β-lactams as biologically active
agents, they are used as intermediates in the synthe-
sis of organic compounds having functionalized group,
for example, α- and β-amino acid synthesis4 and in
particular, natural products (alkaloids and medicines),5
aminosugars,6 different peptidomimetics7 and chiral
catalysts.8 The general procedure for the synthesis of
amino acids is known as the β-lactam synthon method.9
Consequently, the biological activities of β-lactam ele-
ments depend on the stereo structure of them.10 Thus,
it is more important to synthesize such derivatives with
special stereostructures.11
Both experimental and theoretical investigations
explain the relative stereoisomers. The reaction condi-
tions such as temperature,12 solvent,13 and base,14 may
affect the stereo chemical outcomes. In the Staudinger
reaction, ketenes are generated in situ and the reaction is
stepwise. The mechanism is involving the nucleophilic
attack of an imine to a ketene that generates a zwitteri-
onic intermediate and subsequently closure of the ring
occurs and therefore β-lactam has been produced. If
cyclization step is faster than zwitterion production, the
final product is cis. Otherwise the trans isomer would
be the outcome of the reaction when formation
of intermediate is faster.15 The relative (cis/trans) stere-
oselectivity is a result of the competition between the
direct ring closure and the imine moiety in the zwit-
terionic intermediate.12a The polar solvent is suitable
for trans−β-lactam formation because this condition
affects the stability and half-time of the zwitterionic
intermediate.13
The investigations on 2-azetidinones revealed that
the electron-donating ketene substituents, electron-
withdrawing and more bulky imines are convenient for
cis-β-lactam formation. Imines with less steric hin-
drance give trans stereoisomer.12a,16
On the basis of the first previous report with
pyrrolylketene in Tidwell laboratories by Islami
et al.,17 we now wish to report the synthesis of
β-lactam by using benzyl-N-pyrrolylketene. On the
One of the most powerful methods for the prepa-
ration of these compounds is the [2+2] cycloaddition
reaction of ketenes to imines (the Staudinger reaction).
This reaction usually generates two new stereocenters
(C3 and C4 in the β-lactam ring). So the product might
∗For correspondence
111

112
Masoumeh Behzadi et al.
was dried over MgSO4. The organic layer phase was
H2N
O
O
SO3H
CH3
SO3H
H2N
O
O
N
N
N
O
O
N
concentrated and the oil was collected that crystalized
with n-heptane and a white solid was obtained. M.p.:
94-98◦C. IR (KBr) cm−1: 1715.70 (CO).1H NMR δ
3.20-3.50 (CH2, qq, 2H), 4.73-4.83 (CH, dd, 1H), 6.13
(H-pyrrolyl, t, 2H, J=2.26), 6.73 (H-pyrrol, t, 2H,
J=2.29), 7.03-7.28 (Ar-H, m, 5H).
S
S
NH2
N
H
O
N
H
N
N
O
H3C
H3C
CO2H
CO2H
Aztreonam
Carumonam
Figure 1. Clinically used monobactams.
2.3 Synthesis of Schiff basses (5)
other hand, computation by B3LYP/6-31G+D) showed
that benzyl-N-pyrrolylketene has twisted structure such
that pyrrolyl plane is perpendicular to the ketene and
as a result, there is no interaction between the ketenyl
group and the pyrrolyl π-system and this structure is
more stable for benzyl-N-pyrrolylketene.
Imines from aldehydes, corresponding amines and
CaCl2 as a Lewis acid were prepared in dry toluene for
7 h.22
2.4 General procedure for the synthesis
of 2-azetidinones 6(a-j)
3-phenyl-2-(1-H-pyrrol-1-yl) propanoic acid 2 (0.22 g,
1.0 mmol) was mixed with 2-chloro-N-methylpyridi-
nium iodide 4 (0.30 g, 1.2 mmol) and dry Et3N (5.0
mL, 3.6 mmol) in anhydrous CH2Cl2 (15 mL) under
an argon atmosphere at room temperature. The suspen-
sion was stirred for 5 min and then a solution of imines
(1.1 mmol) in dry CH2Cl2 (5 mL) was added, and the
reaction mixture was stirred overnight. The red solu-
tion was washed with 8% aq. HCl and then with water.
The organic layer was dried over Na2SO4 and the sol-
vent was removed under reduced pressure to give the
crude products. β-Lactams were purified first, by col-
umn chromatography for separation of cis/trans mix-
ture from other by-products and then plate chromatog-
raphy gave cis- and trans-isomer which were identi-
fied with experimental analysis. Column chromatogra-
phy 6a-b (hexane/EtOAc 30:1 v/v), 6c (hexan/EtOAc
19:1 v/v), 6d-e (hexane/EtOAc 35:1 v/v),6f-g (hex-
ane/EtOAc 38:1 v/v) and 6h-i (hexane/EtOAc 42:1v/v),
6h (hexane/EtOAc 15:1 v/v).
2. Experimental
2.1 Chemical reagents
All required chemicals were purchased from Merck and
Fluka chemical companies. All the known compounds
were identified by comparison of their spectral data and
physical properties with those of the authentic sam-
1
ples. H NMR and 13C NMR spectra were recorded
on a BRUKER DRX-300 AVANCE NMR spectrometer
using CDCl3 as a solvent and using tetramethylsilane
(TMS) as an internal standard. Chemical shifts were
reported in parts per million (δ) downfield from TMS.
All of the coupling constants (J) are in hertz. IR spec-
tra were recorded on Bruker Tensor-27 FTIR spectrom-
eter using KBr pellets. Melting points were recorded
on an Electrothermal-9100 melting point apparatus and
were uncorrected. Mass spectrometer operating at an
ionization potential of 70 eV. Elemental analyses were
run on a Perkin-Elmer USA-2400 series. Column chro-
matography was performed on silica gel 40 (Merck,
70-230 mesh).Thin-layer chromatography plate was
carried out on silica gel 60 Gf-254 analytical sheets. UV
light (λ =254) was used.
2.4a (3R,4R)-3-benzyl-1,4-diphenyl-3-(1H-pyrrol-1-yl)
azetidin-2-one (6a-trans): White yellow solid; Yield:
(15.87%); M.p.: 54-57◦C; IR (KBr, cm−1): 1731
1
(C=O, β-lactam). H-NMR (400 MHz, CDCl3): δ
2.81-3.13 (dd, 2H, CH2), 5.42 (s, 1H, H-4), 6.19 (t,
2H, J = 2.12 Hz, H-pyrrolyl), 6.53 (d, 2H, Ar-H), 6.90
2.2 Preparation benzyl-N-pyrrolylacetic acid (2)
A mixture of S(-)-phenyl alanine 1 (4.48 g, 27.2 (t, 2H, J = 2.12 Hz, H-pyrrol), 7.05-7.57 (m, 13H, Ar-
mmol,), sodium acetate anhydrous (2 g, 27.2 mmol) and H,). 13C-NMR (400 MHz, CDCl3): δ 39.8 (CH2), 67.8
300 mL glacial acetic acid was stirred under reflux for (C-4 β-lactam), 76.1 (C-3 β-lactam), 108.9, 117.7,
1 h. Then, 2,5-dimethoxy tetrahydrofuran 10 mL was 119.1, 124.6, 126.8, 127.4, 127.7, 128.8, 129.1, 129.3,
added dropwise for 30 min. The mixture was stirred 129.7, 133.2, 133.6, 136.8 (aromatic carbons), 163.2
for 1 h. Then the additional acetic acid was distillated (C=O, β-lactam); MS: m/z 378 (100) (M+), 311 (7.69)
(250 mL). The resultant solution was extracted with (M+-[Ph]), 258 (35.89), 197 (92.30), 181 (79.48)
5x50 mL ethyl acetate. Afterwards, the solution was ([PhCH=NPh]+), 167 (79.48), 91 (46.15) ([PhCH2]+),
washed with water (5x50 mL) and the organic layer 77 (41.02) ([Ph]+). Anal.Calcd. for C26H22N2O: C,

Preparing new β-lactams by [2+2] cycloaddition
113
([PhCH2]+). Anal.Calcd. for C26H21N2OCl: C, 75.63;
H, 5.13; N, 6.78%; Found: C, 75.97; H, 5.33; N, 6.60%.
82.51; H, 5.86; N 7.40%; Found: C, 82.36; H, 5.77; N,
6.98%.
2.4b (3R,4S)-3-benzyl-1,4-diphenyl-3-(1H-pyrrol-1-yl)
azetidin-2-one (6b-cis): 1H-NMR (400 MHz, CDCl3):
δ 3.41-3.62 (dd, 2H, CH2), 5.07 (s, 1H, H-4), 5.73 (t,
2H, J = 1.50 Hz, H-pyrrolyl), 6.43 (t, 2H, J = 1.50 Hz,
H-pyrrol), 6.99-7.17 (m, 15H, Ar-H). 13C-NMR (400
MHz, CDCl3): δ 42.9 (CH2), 65.5 (C-4 β-lactam),
76.7 (C-3 β-lactam), 103.3, 117.3, 119.2, 124.6, 126.8,
127.4, 128.4, 128.5, 128.8, 129.0, 130.2, 133.2, 134.0,
135.5 (aromatic carbons), 163.2 (C=O, β-lactam);
MS: m/z 378 (100) (M+), 311 (7.69) (M+-[Ph]), 258
(35.89), 197 (92.30), 181 (79.48) ([PhCH=NPh]+),
167 (79.48), 91 (46.15) ([PhCH2]+), 77 (41.02)
([Ph]+). Anal.Calcd. for C26H22N2O: C, 82.51; H, 5.86;
N 7.40%; Found: C, 82.36; H, 5.77; N, 6.98%.
2.4e (3R,4S)-3-benzyl-1-(4-chlorophenyl)-4-phenyl-
3-(1H-pyrrol-1-yl)azetidin-2-one (6e-cis): White solid;
Yield (4.85%); IR (KBr, cm−1): 1749 (C=O, β-
1
lactam); H-NMR (400 MHz, CDCl3): δ 3.49-3.79
(dd, 2H, CH2), 5.12 (s, 1H, H-4), 5.88 (t, 2H, J = 2.16
Hz, H-pyrrolyl), 6.52 (t, 2H, J = 2.16 Hz, H-pyrrol),
7.03-7.80 (m, 14H, Ar-H); 13C-NMR (400 MHz,
CDCl3): δ 42.9 (CH2), 68.1 (C-4 β-lactam), 76.5 (C-3
β-lactam), 108.4, 119.1, 126.7, 127.6, 128.5, 128.8,
129.1, 129.7, 130.1, 130.8, 132.4, 132.8, 133.8, 135.0
(aromatic carbons), 163.1 (C=O, β-lactam); MS:
m/z 414 (7.93) (M+237Cl), 412 (23.80) (M+35Cl),
215 (35.71) ([PhCH=NPhCl]+), 197 (50.00) (M+-
[PhCH=NPhCl]), 167 (92.85), 149 (100), 91 (26.19)
([PhCH2]+). Anal.Calcd. for C26H21N2OCl: C, 75.63;
H, 5.13; N, 6.78%; Found: C, 75.97; H, 5.33; N, 6.60%.
2.4c (3R,4S)-3-benzyl-1-(4-methoxyphenyl)-4-phenyl-
3-(1H-pyrrol-1-yl)azetidin-2-one
(6c-cis): White
solid; Yield: (41.66%); M.p.: 132-133◦C; IR (KBr,
1
2.4f (3R,4R)-3-benzyl-4-(4-chlorophenyl)-1-phenyl-3-
(1H-pyrrol-1-yl)azetidin-2-one (6f-trans): White solid;
Yield (48.54%); M.p.: 164-168◦C; IR (KBr, cm−1):
1760 (C=O, β-lactam); H-NMR (400 MHz, CDCl3):
cm−1): 1739 (C=O, β-lactam); H-NMR (400 MHz,
CDCl3): δ 3.49-3.73 (dd, 2H, CH2), 3.73 (s, 3H, OMe),
5.11 (s, 1H, H-4), 5.88 (t, 2H, J = 2.17 Hz, H-pyrrolyl),
6.53 (t, 2H, J = 2.16 Hz, H-pyrrol), 6.72-7.28 (m,
14H, Ar-H); 13C-NMR (400 MHz, CDCl3): δ 42.9
(CH2), 55.0 (OMe), 65.5 (C-4 β-lactam), 76.5 (C-3
β-lactam), 108.2, 114.2, 119.0, 119.2, 126.8, 127.4,
128.3, 128.4, 128.7, 129.9, 130.2, 133.4, 134.1, 156.2
(aromatic carbons), 164.0 (C=O, β-lactam); MS: m/z
408 (78.05) (M+), 317 (9.76) (M+-[PhCH2]), 258
(17.07), 211 (100) ([PhCH=NPhOMe]+), 196 (56.09)
(M+-[PhCH=NPhOMe]), 167 (34.15), 91 (36.58)
([PhCH2]+). Anal.Calcd. for C27H24N2O2: C, 79.39; H,
5.92; N 6.86%; Found: C, 78.96; H, 5.85; N, 6.71%.
1
δ 2.80-3.10 (dd, 2H, CH2), 5.38 (s, 1H, H-4), 6.20 (t,
2H, J = 2.09 Hz, H-pyrrolyl), 6.58 (d, 2H, Ar-H), 6.88
(t, 2H, J = 2.10 Hz, H-pyrrol), 7.07-7.50 (m, 14H, Ar-
H). 13C-NMR (400 MHz, CDCl3): δ 39.9 (CH2), 67.2
(C-4 β-lactam), 76.1 (C-3 β-lactam), 109.1, 117.7,
119.0, 124.8, 126.9, 127.8, 128.7, 129.2, 129.6, 129.7,
131.8, 133.4, 135.1, 136.5 (aromatic carbons), 162.9
(C=O, β-lactam); MS: m/z 414 (7.93) (M+237Cl), 412
(23.80) (M+35Cl), 215 (35.71) ([PhCH=NPhCl]+), 197
(50.00) (M+-[PhCH=NPhCl]), 167 (92.85), 149 (100),
91 (26.19) ([PhCH2]+). Anal.Calcd. for C26H21N2OCl:
C, 75.63; H, 5.13; N, 6.78%; Found: C, 75.97; H, 5.33;
N, 6.60%.
2.4d (3R,4R)-3-benzyl-1-(4-chlorophenyl)-4-phenyl-
3-(1H-pyrrol-1-yl)azetidin-2-one (6d-trans): White
solid; Yield (14.56%); M.p.: 164-165◦C; IR (KBr,
cm−1): 1756 (C=O, β-lactam); H-NMR (400 MHz, 2.4g (3R,4S)-3-benzyl-4-(4-chlorophenyl)-1-phenyl-
CDCl3): δ 2.79-3.10 (dd, 2H, CH2), 5.40 (s, 1H, 3-(1H-pyrrol-1-yl)azetidin-2-one (6g-cis): White solid;
H-4), 6.20 (t, 2H, J = 2.16 Hz, H-pyrrolyl), 6.50 Yield (12.13%); M.p.: 139-145◦C; IR (KBr, cm−1):
1
1
(d, 2H, Ar-H), 6.88 (t, 2H, J = 2.17 Hz, H-pyrrol), 1749 (C=O, β-lactam); H-NMR (400 MHz, CDCl3):
7.04-7.58 (m, 14H, Ar-H); 13C-NMR (400 MHz, δ 3.48-3.72 (dd, 2H, CH2), 5.12 (s, 1H, H-4), 5.91 (t,
CDCl3): δ 39.8 (CH2), 67.9 (C-4 β-lactam), 76.4 (C-3 2H, J = 2.21 Hz, H-pyrrolyl), 6.52 (t, 2H, J = 2.19
β-lactam), 109.0, 119.0, 119.1, 126.8, 127.4, 127.7, Hz, H-pyrrol), 7.02-7.30 (m, 14H, Ar-H); 13C-NMR
128.8, 129.2, 129.4, 130.9, 132.4, 132.8, 133.4, 135.3 (400 MHz, CDCl3): δ 42.8(CH2), 64.8 (C-4 β-lactam),
(aromatic carbons), 167.7 (C=O, β-lactam); MS: 76.5 (C-3 β-lactam), 108.7, 117.5, 119.1, 124.8, 127.5,
m/z 414 (7.93) (M+237Cl), 412 (23.80) (M+35Cl), 128.1, 128.5, 128.7, 129.0, 130.1, 131.9, 133.8, 135.0,
215 (35.71) ([PhCH=NPhCl]+), 197 (50.00) (M+- 136.0 (aromatic carbons), 162.0 (C=O β–lactam);
[PhCH=NPhCl]), 167 (92.85), 149 (100), 91 (26.19) MS: m/z 414 (7.93) (M+237Cl), 412 (23.80) (M+35Cl),

114
Masoumeh Behzadi et al.
215 (35.71) ([PhCH=NPhCl]+), 197 (50.00) (M+-
[PhCH=NPhCl]), 167 (92.85), 149 (100), 91 (26.19)
([PhCH2]+). Anal.Calcd. for C26H21N2OCl: C, 75.63;
H, 5.13; N, 6.78% Found: C, 75.97; H, 5.33; N, 6.60%.
2.4j (3R,4S)-3-benzyl-4-ethoxy-1-phenyl-3-(1H-pyrrol-
1-yl)azetidin-2-one (6j-cis): White solid; Yield (17.34%);
M.p.: 177◦C (decomposed); IR (KBr, cm−1): 1766
(C=O, β-lactam); 1H-NMR (400 MHz, CDCl3)δ
1.11 (t, 3H, CH3), 3.20-3.45 (dd, 2H, CH2), 5.55 (s,
1H, H-4), 5.93 (t, 2H, J = 1.19 Hz, H-pyrrolyl), 6.46
(t, 2H, J = 0.99 Hz, H-pyrrol), 7.08-7.31 (m, 10H,
Ar-H). 13C-NMR (400 MHz, CDCl3): δ 15.2 (Me),
36.1(CH2), 62.8 (OMe), 67.1 (C-4 β-lactam), 76.6
(C-3 β-lactam), 108.7, 121.6, 122.7, 124.4, 126.1,
128.2, 128.9, 129.0, 138.1 (aromatic carbons), 168.0
(C=O, β-lactam); MS: m/z 316 (15.38) (M+-[Et,H],
197 (25.64) ([PhCH2C4H4NC=C=O]+, 168 (28.20)
([PhC=CC4H4]+, 150 (48.71), 91 (84.61) ([PhCH2]+,
58 (100), 57 (100). Anal.Calcd. for C26H20N2OCl2: C,
76.28; H, 6.40; N, 8.09%; Found: C, 76.65; H, 6.44; N,
7.82%.
2.4h (3R,4R)-3-benzyl-4-(2,4-dichlorophenyl)-1-phe-
nyl-3-(1H-pyrrol-1-yl)azetidin-2-one (6h-trans): White
solid; Yield (11.12%); IR (KBr, cm−1): 1762 (C=O,
β-lactam); 1H-NMR (400 MHz, CDCl3): δ 2.92-
3.16 (dd, 2H, CH2), 5.73 (s, 1H, H-4), 6.19 (t, 2H,
J = 2.21 Hz, H-pyrrolyl), 6.51 (t, 2H, J = 2.20 Hz,
H-pyrrol), 7.08-7.58 (m, 13H, Ar-H); 13C-NMR (400
MHz, CDCl3): δ 39.0 (CH2), 63.9 (C-4 β-lactam),
76.6 (C-3 β-lactam), 108.9, 117.6, 119.9, 125.0,
126.9, 127.8, 129.3, 129.5, 129.8, 129.9, 130.4, 133.1,
134.6, 135.7, 136.0 (aromatic carbons), 163.0 (C=O,
β-lactam); MS: m/z 450 (2.92) (M+4 37Cl37Cl), 448
(9.75) (M+237Cl), 446 (29.26) (M+), 411 (9.75) (M+-
[Cl]), 249 (21.95) ([Cl2PhCH=NPh]+), 214 (12.19),
197 (100) ([PhCH2C4H4NC=C=O]+), 168 (97.56)
([PhC=CC4H4]+), 149 (97.56), 91 (53.65) ([PhCH2]+.
Anal.Calcd. for C26H20N2OCl2: C, 69.81; H, 4.51%;
Found: C, 69.53; H, 4.70%.
3. Results and Discussion
According to the model published by Tidwell and co-
workers,17 we decided to use synthesis of 3-phenyl-2-
(1-H-pyrrol-1-yl) propanoic acid 2 from S(-)-phenyl
alanine 1, as the source of benzyl-n-pyrrolylketene
3. Reaction of 3-phenyl-2-(1-H-pyrrol-1-yl) propionic
acid 2 with Mukaiyama’s reagent (4)18 and Et3N in
CH2Cl2 in the presence of imines 5 gave azetidinones
6 as cis/trans mixtures (scheme 1). In some cases,cis-
β-lactam was obtained. The results summarized in
table 1.
2.4i (3R,4S)-3-benzyl-4-(2,4-dichlorophenyl)-1-phenyl-
3-(1H-pyrrol-1-yl)azetidin-2-one (6i-cis): White solid;
Yield (2.24%); M.p.: 63-67◦C; IR (KBr, cm−1): 1763
1
(C=O, β-lactam); H-NMR (400 MHz, CDCl3): δ
Both experimental and theoretical investigations at the
3.68-3.80 (dd, 2H, CH2), 5.55 (s, 1H, H-4), 5.92 (t,
2H, J = 2.15 Hz, H-pyrrolyl), 6.73 (t, 2H, J = 2.13 Hz,
H-pyrrol), 6.80-7.34 (m, 13H, Ar-H); 13C-NMR (400
MHz, CDCl3): δ 41.8 (CH2), 61.1 (C-4 β-lactam),
76.6 (C-3 β-lactam), 109.1, 117.3, 118.8, 124.9, 127.1,
127.6, 128.5, 129.1, 129.6, 130.2, 133.5, 133.6, 134.8,
135.8, 136.0 (aromatic carbons), 163.0 (C=O, β -
lactam). MS: m/z 450 (2.92) (M+4 37Cl37Cl), 448
(9.75) (M+237Cl), 446 (29.26) (M+), 411 (9.75) (M+-
[Cl]), 249 (21.95) ([Cl2PhCH=NPh]+), 214 (12.19),
197 (100) ([PhCH2C4H4NC=C=O]+), 168 (97.56)
([PhC=CC4H4]+), 149 (97.56), 91 (53.65) ([PhCH2]+.
Anal.Calcd. for C26H20N2OCl2: C, 69.81; H, 4.51%;
Found: C, 69.53; H, 4.70%.
B3LYP/6-31G∗ indicate that for various combinations
Table 1. β-lactams 6 from Benzyl-N-pyrrolylketene and
imines 5.
Entry
R1
R2
Product Cis/Trans Yield Yield
No.
Trans Cis
(%) (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
4-MeOPh
4-ClPh
Ph
6a,b
6c
6d,e
6f,g
6h,i
6j
40:60 16.00 11.00
100:0
–
42.00
24:76 15.00 5.00
20:80 49.00 12.00
83:17 11.00 3.00
4-ClPh
2,4-ClPh
OEt
Ph
Ph
100:0
–
18.00
N
O
N
Cl
N
O
N
R1
I
O
PhCH2
PhCH2
Me
4
+
N
N
N
OH
PhCH2
+
R2
Et3N, CH2Cl2
R1
R2
R1
R2
2
5
rt, N2, overnight
Trans-6
Cis
-
6
Scheme 1. Synthesis of cis/trans-β-lactams 6 and derivatives.

Preparing new β-lactams by [2+2] cycloaddition
115
R
O
R2
H
R
H
N
N
R2
R1
k3
O
R1
R
R2
R2
R
H
7b
H
Trans-9
k1
k-1
+
H
C
N
N
R1
O
O
R1
k3
R
O
7a
r
i
n
g
-
c
l
o
s
e
r
N
R1
R2
Cis-8
Scheme 2. Model for the relative stereoselectivity in the Staudinger reaction.
Table 2. Calculated ꢀG for ketene 10 compound with
groups R in RC4H4C=C=O (B3LYP/6-31G*).
N
N
N
C
O
C
O
Planar
(a.u)
Twisted
(a.u)
C
O
Entry
R
ꢀG(kcal/mol)
1
2
3
4
H
Me
Ph
–3.91
–4.73
–
–400.891 –400.898
(planar)
(twisted)
(twisted)
–
–592.636
–631.93
PhCH2 –631.922
–5.27
Figure 2. The stable structures for the substituted N-
pyrrolylketene.
R
Me
Me
R
N
DE=SE
kcal/mol
of substituents, ketene gives stepwise reaction with
imines with formation of zwitterions 7a followed by
conrotatory ring closure giving cis-product 8 and iso-
merization to less crowded intermediates 7b and ring
closure to trans-β-lactam 9 (scheme 2).
C
O
+
C
O
+
CH2
CH2
N
Scheme 3. Calculated substituent effects on ketene
stability.
To assist in understanding the chemistry of benzyl-
N-pyrrolylketene, the structure was calculated with phenyl-N-pyrrolylketene 11. There is no evidence in
the B3LYP/6-31G+d method, which predicts that the 10a for any bonding interaction between the ketenyl
twisted structure 10a, with the pyrrolyl plane per- group and the pyrrolyl πsystem, as shown by the elec-
pendicular to the ketene plane, is more stable by tronic contour depicted in figure 2. Higher reaction
5.27 kcal/mol than the planar structure 10b. For more temperature results in the predominant formation of
comparision, we calculated various R groups based trans-β-lactams.
on stable structure for N-pyrrolylketene having 4.89
Diastereoselectivity and the ratio of cis/trans-
(MP2/6-31G*) and 3.91 (B3LYB/6-31G*)17 with sta- products for cycloaddition reaction involving monosub-
1
ble twisted structure. Methyl-N-pyrrolylketene twisted stituted ketenes determined by H NMR analysis of
structure with 4.73 kcal/mol is more stable than the the reaction mixture from the signals of the 3- and 4-
planar structure. Phenyl-N-pyrrolylketene 11 has only ring protons by their characteristic of coupling con-
twisted structure such that Ph group is coplanar with stants. Thus, cis stereoisomer has J3,4 ≥ 4.0 Hz and for
ketene face and the hindrance phenyl branch induces trans-β-lactams J3,4 ≤ 3.0 Hz.17
the pyrrole ring to be nonconjugated (figure 2). Com-
Since the ketene 3 which has been used contains two
pared with phenyl-N-pyrrolylketene and methyl-N- substituents on the ketene functionality, there is no pro-
pyrrolylketene, our ketene was more stable in the ton in C-4 of 2-azetidinones 6 which is present in mono
twisted form. ꢀG are given in table 2.
substituted ketene.
For rotation around the ketenyl-pyrrolyl bond, calcu-
Therefore, we had no J3,4 for indication of stere-
lated substituent effects on ketene stability evaluated as ochemistry and the ratio of cis/trans products. We
stabilization free energies (SE) from isodesmic energy resorted to NOE experiments. Irradiation of the methy-
comparisons by scheme 3 19 are summarized in table 3. lene signal at δ = 3.606 ppm in the 1H NMR of cis-6e
For R= benzyl, value of 0.032 kcal/mol (B3LYP) caused the intensity of the H signal at δ = 5.13 ppm to
was found as compared to 0.340 (B3LYP) for Ph. increase by 4.62%, whereas, when the methylene sig-
1
Thus, 10 is remarkably destabilized, in comparison with nal δ = 2.945 ppm in the H NMR of trans-6d was

116
Masoumeh Behzadi et al.
Table 3. Ketene stabilization energy (SE, kcal/mol), Eq 1, for R groups in RC4H4C=C=O (B3LYP/6-31G*).
Entry
R
12 (a.u)
13(a.u)
14 (a.u)
15 (a.u)
ꢀE (kcal/mol)
1
2
3
Me
Ph
PhCH2
–400.856
–592.585
–631.875
–117.862
–117.862
–117.862
–117.86227
–309.59134
–348.88203
–400.856
–400.856
–400.856
0
0.34
0.03
O
H2N
O
H3C
OH
-MeOH
+
MeO
O
OMe
OH
O
OMe
MeO
O
PhH2C
O
OMe
O
H
ONa
16
H3C
1
ONa
H3C
HN
PhH2C
O
PhH2C
O
O
PhH2C
OH
OH
OH
-MeOH
H2N
HN
O
O
O
OMe
OMe
H
H
H
PhH2C
O
O
PhH2C
HN
O
PhH2C
OH
OH
-H2O
OH
N
H
N
O
OH
2
Scheme 4. A proposed mechanism for preparation of ketene precursor 2.
Table 4. Effect of reaction temperature on the product
distribution of 6h-i.
2-azetidinones 6a-b, 6c-d, 6e-f and 6g-h were obtained
as a cis–trans mixture with low cis-selectivity. Because
the RFs for cis-trans products were very low, all these
products were easily separated by column and plate
chromatography. Also the yields were higher at room
temperature than 0◦C.
At higher temperatures, ketene 3 was polymerized
and the yields for 2-azetidinones 6 decreased. Benzyl-n-
pyrrolylketene 3 had two electron-donating substituents
and therefore steric hindrance was more. So, with
Entry
T(◦C)
Time (h)
Yield 6h
(%)
Yield 6i
(%)
1
25
0
17
17
11.12
<5
2.24
0
saturated, decrease by 3.75% was observed (all of the
data analysis are shown in Supplementary Information).
For the preparation of β-lactams 6, 2-chloro-N- imines which had methoxy substituent 6j resulted in
methyl pyridinium iodide (Mukaiyama reagent) was cis-β-lactam as the sole product. Also, the steric effect
used as the condensating agent, compounds 6c, 6j at the nitrogen substituent in imines PhCH=NR gave
were obtained as single cis-diastereomers. In contrast, cis-isomer 6c.
PhH2C
N
O
PhH2C
O
PhH2C
N
N
Cl
OH
O
I
O
N
O
N
Dry Et3N
4
Me
I
Me
-
Et3NHCl
2
Activating leaving group
N
O
PhH2C
N
O
O
N
PhH2C
R1
C
O
PhH2C
R1
Trans-6
-
N
, -Et3NHI
N
Me
+
N
NR2
+
R1CH
R2
R2
NEt3
3
Cis-6
Scheme 5. A possible mechanism for the Staudinger reaction.

Preparing new β-lactams by [2+2] cycloaddition
117
2. (a) Ge H, Spletstoser J T, Yang Y, Kayser M and Georg
G I 2007 J. Org. Chem. 72 756; (b) Paik Y, Yang C,
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3. Ternansky R J and Morin J M 1993 In Organic Chem-
istry G I Georg (Ed.) (New York: VCH) p. 257
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Palomo C, Aizpurua J M, Ganboa I and Oiarbide M
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For preparation of 3-phenyl-2-(1-H-pyrrol-1-yl)
propanoic acid S(-)-phenyl alanine 1 reacts with sodium
acetate and 2,5-dimethoxy dihydrofuran 16 to gener-
ate this compound 2, and the plausible mechanism is
depicted in scheme 4.
To improve this particular procedure, the effect of
the reaction temperature in the product distribution was
analyzed at 25◦C and 0◦C. Experiments conducted at
0◦C afforded much lower yields of product 6d (table 4).
Based on the previous experiments on solvent effects,
dry CH2Cl2 was chosen as a solvent in this report and
our reaction was also done in dry solvent and under our
argon atmosphere for 17-20 h.
A plausible mechanism has been suggested in
scheme 5, which is in accordance with the proposed
mechanism for Staudinger reaction.21
6. Bose A K, Mathur C, Wagle D R, Naqvi R and Manhas
M S 1994 Heterocycles 39 491
7. Martinek T A and Fülöp F 2012 Chem. Soc. Rev. 41 687
8. Kiss L and Fülöp F 2010 Synlett. 1302
9. Ojima I and Delaloge F 1997 Chem. Soc. Rev. 26 377
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Biology of β-Lactam Antibiotics Vol. 1–3 (New York:
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2 G Luckacs (ed.) (Berlin: Springer) p. 621
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Chem. Res. 41 925; (b) Xu J X 2009 Arkivoc 21
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128 6060; (b) Hegedus L S 1997 Tetrahedron 53 4105
13. (a) Arrieta A, Lecea B and Cossio F P 1998 J. Org.
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J W, Domalski M, Dugar S, Pushpavanam P, Sher R,
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4. Conclusions
Summarizing, benzyl-N-pyrrolylketene proved to be
adequate material for the synthesis of new and bulky 2-
azetidinone ring from Staudinger reaction. The driving
force for this reaction is the novelty of providing steric
ketene with two substituents. Moreover, Mukaiyama
reagent is as a versatile and available acid activator
and its work-up procedure is simple. The methodology
worked well with electron-donating substituent on N
atom in imines. With electron-withdrawing substituent,
for example, PhCH=N-4-O2NPh, the yield was very
low. We could distinguish between cis- and trans-
products by two different methods: First, chemical shift
of pyrrol ring hydrogens and CH2 diastereotopic on
C-3 β-lactam. Second, NOE-experiment that identified
trans- product for 6d and cis-isomer for 6e.
16. Wang Z X, Chen N and Xu J X 2011 Tetrahedron 67
9690
17. Islam i M R, Allen A D, Vukovic S and Tidwell T T
2011 Org. Lett. 13 494
18. (a) Mukaiyama T 1979 Angew. Chem. Int. Ed. Engl. 18
707; (b) Funk R L, Abelman M M and Jellison K M
1989 Synlett. 36; (c) Amin S G, Glazer R D and Manhas
M S 1979 Synthesis 210
Supplementary Information
Copies of IR,1H NMR, 13C NMR and Mass spectra
for a representative set of compounds 6a-j and NOE-
difference experiments for 6d-e, are available at www.
ias.ac.in/chemsci.
19. (a) Gong L, McAllister M A and Tidwell T T 1991 J.
Am. Chem. Soc. 113 6021; (b) Tidwell T T 2006 In
Ketenes 2nd ed. (New Jersey: John Wiley); (c) Aguilar-
Aguilar A, Allen A D, Penã-Cabrera E, Fedorov A, Fu
N, Henry-Riyad H, Kobayashi S, Leuninger J, Schmid
U, Tidwell R and Verma T T 2005 J. Org. Chem. 70 9556
20. Li B N, Wang Y K, Jiao L, Du D M and Xu J X 2007 J.
Org. Chem. 72 990
Acknowledgements
This work was supported by grants from the Research
Council of Shahid Bahonar University of Kerman.
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