One-pot synthesis of trans-β-lactams from ferrocenylketene generated by thermal Wolff rearrangement

Article abstract of DOI:10.1080/00397911.2017.1378358

A series of β-lactams containing the ferrocene moiety were synthesized through the Staudinger reaction between ferrocenylketene generated by the thermal Wolff rearrangement of the corresponding diazo ketone and various imines. The stereochemical outcome h

Full text of DOI:10.1080/00397911.2017.1378358

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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One-pot synthesis of trans-β-lactams from
ferrocenylketene generated by thermal wolff
rearrangement
Mingshun Liu, Jian’an Wang, Xiaoxi Yuan, Rong Jiang & Nanyan Fu
To cite this article: Mingshun Liu, Jian’an Wang, Xiaoxi Yuan, Rong Jiang & Nanyan Fu
(2017): One-pot synthesis of trans-β-lactams from ferrocenylketene generated by thermal wolff
rearrangement, Synthetic Communications, DOI: 10.1080/00397911.2017.1378358
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Date: 16 September 2017, At: 03:23

One-pot synthesis of trans-β-lactams from ferrocenylketene
generated by thermal wolff rearrangement
Mingshun Liu
College of Chemistry, Fuzhou University, Fuzhou, Fujian, P.R. China
Jian’an Wang
College of Chemistry, Fuzhou University, Fuzhou, Fujian, P.R. China
Xiaoxi Yuan
College of Chemistry, Fuzhou University, Fuzhou, Fujian, P.R. China
Rong Jiang
College of Chemistry, Fuzhou University, Fuzhou, Fujian, P.R. China
Nanyan Fu
College of Chemistry, Fuzhou University, Fuzhou, Fujian, P.R. China
Address correspondence to Nanyan Fu. E-mail: nanyan_fu@fzu.edu.cn
Provide short biographical notes on all contributors here if the journal requires them.
ABSTRACT
1

A series of β-lactams containing the ferrocene moiety were synthesized via the
Staudinger reaction between ferrocenylketene generated by the thermal Wolff rearrangement of
the corresponding diazo ketone and various imines. The stereochemical outcome has been
investigated and the trans-products were isolated as the main products, opposite to the reported
results by Bonini and co-workers. The absolute configuration of (±)-trans-1,4-diphenyl-3-
ferrocenylazetidin-2-one (3c) was determined by X-ray analysis. The stereoselectivity is
discussed from the viewpoint of the reaction mechanism.
Graphical Abstract
KEYWORDS: ferrocenylketene, β-lactams, stereoselectivity, thermal Wolff rearrangement
Subject classification codes: include these here if the journal requires them
Introduction
The β-lactam antibiotic penicillin was discovered by Fleming in 1928.[1] Once the
therapeutic value of this substance became known on the eve of World War II, a great effort was
made not only to prepare this in large quantities, but also to elucidate the structure in order to
obtain new generations of antibiotics by structural modification. Staudinger had reported in 1907
the reaction of diphenylketene and N-phenyl benzylidenenamine yielding 1,3,3,4-
tetraphenylazetidin-2-one, marking not only the beginning of cycloaddition chemistry, but also
that of the chemistry of β-lactams.[2] After more than one hundred years this versatile reaction
yielding β-lactams is still one of the best choices for the synthesis of these strained
2

heterocycles.[3] For this reason, the reaction has been extensively investigated experimentally and
theoretically during recent decades.[4] The accepted reaction mechanism[5] is a stepwise process,
initiated by nucleophilic attack of an imine to a ketene, affording a zwitterionic intermediate,
followed by a ring-closure process to give the final β-lactam product. The formation of such
zwitterionic intermediates was first observed by Kagan and Luche in 1968.[6] Two new
stereogenic centers at the C3 and C4 positions of the 2-azetidinone ring are generated during this
process when a monosubstituted ketene and an acyclic imine are involved, so that the product
may be cis-, trans-, or a mixture of cis- and trans-β-lactam derivatives, and the stereochemistry
of β-lactams will strongly affect their biological activities. Usually the penicillin and
cephalosporin antibiotics possess cis-β-lactam units,[7] whereas the cholesterol absorption
inhibition activity is mainly associated with trans-β-lactam moieties.[8] Therefore the
stereochemistry of the Staudinger reaction continues to attract considerable attention.[5]
Ferrocenyl as an aryl group in organic synthesis is useful when a bulky and stable three-
dimensional metal-containing substituent with low toxicity is desired,[9] and ferrocenyl
derivatives have recently found many applications in biological and medical systems.[10]
Conjugates of ferrocene with antibiotics such as penicillins and cephalosporins have been
reported.[11] Almost all of the ferrocenyl-penicillins and -cephalosporins exhibit antibiotic
activity, some being highly active, while others proved to be potent β-lactamase inhibitors.[11d]
In 2001, Bonini and co-workers reported a one-pot Staudinger reactions to synthesize
ferrocene substituted β-lactams from ferrocenylacetic acid or the corresponding carbonyl
chloride and imines.[12] Ferrocenyl ketene was generated by treatment of the acid with
PhOP(O)Cl2 and Et3N or from the acyl chloride and Et3N, and the unobserved intermediate was
captured in[2+2]-cycloadditions with imines such as PhCH = NPh giving a cis-β-lactam.[12] The
3

first direct observation of ferrocenylketene was reported in 2005, and calculations showed that
ferrocenylketene is destabilized by 1.6 kcal/mol relative to phenylketene by B3LYP isodesmic
comparison to the corresponding alkenes.[13a] Ferrocenylketene was generated by Wolff
rearrangement in CH3CN and was directly observed by UV and IR spectroscopy as a short-lived
and reactive intermediate in solution.[13]
However, it is not always convenient to generate short-lived ketenes by photochemical
Wolff rearrangement when the imine has a strong absorption at 300–350 nm bands or is not
stable upon irradiation. Herein, we report a new way to generate ferrocenylketene from the
corresponding diazo ketone by thermal Wolff rearrangement and the synthesis of ferrocenyl
substituted β-lactams by reaction with imines. The stereochemical outcome of Staudinger
reactions under these conditions is found to differ from those found previously for
ferrocenylketene.[12]
Results and Discussion
As noted above there are two ways reported to generate ferrocenylketene, from
ferrocenyl diazomethyl ketone by the photochemical Wolff rearrangement, in which the ketene
was observed directly,[13] or from ferrocenylacetic acid by the acid activator PhOP(O)Cl2 and
Et3N, or from the acetyl chloride and Et3N,[12] where the ketene was not observed but the [2 + 2]-
ketene-imine cycloaddition product was isolated. Because the reaction conditions, such as
temperature,[14a] solvent,[14b] base,[14c] the chloride anion,[14d] and the metal[14d,e] may affect the
stereochemical outcome, a clean ketene-imine reaction system should be applied to help
understanding the influence of the reaction conditions on the stereoselectivity. The
photochemical Wolff rearrangement is a clean way to generate ketenes, releasing only nitrogen
4

gas. However, it is not convenient to generate short-lived ketenes under irradiation when the
imines or the β-lactam products have strong absorptions or are not stable during excitation.
Thermal Wolff rearrangement is a more convenient choice. To the best of our knowledge, this is
the first report of the thermal generation of ferrocenylketene from the corresponding diazo
ketone.
Several reaction conditions were surveyed to generate ferrocenylketene leading to β-
lactams, as shown in the Table 1. Compared with phenylketene, the formation of
ferrocenylketene needs higher temperatures. Diazoacetylbenzene undergoes thermal Wolff
rearrangement at 110oC effectively, while thermal Wolff rearrangement of diazoacetylferrocene
requires 140oC. Higher temperature such as 170oC in sealed tube has also been tested, and the
results show that the thermal stability of ferrocenyl derivatives is not good and no desired
product has been isolated. Because ferrocenylketene is highly reactive, adding
diazoacetylferrocene, the precursor of the ketene, slowly to the reaction mixture at the desired
temperature improves the yield of the [2 + 2]-cycloaddition product.
To investigate the stereochemical outcome of the [2 + 2]-cycloaddition of
ferrocenylketene, the ketene was generated by the thermal Wolff rearrangement of
diazoacetylferrocene in the presence of various imines under the optimized reaction conditions.
The cis- or trans-stereochemistry of the products β-lactams was established on the basis of their
1H NMR spectra. The coupling constant values for the signals corresponding to the C3 and C4
protons (5.6–6.4 Hz) for the cis-isomers and (2.0–2.8 Hz) for the trans-isomers are in agreement
with the previously reported values.[15] Furthermore X-ray analysis of (±)-trans-1,4-diphenyl-3-
ferrocenylazetidin-2-one (3c) confirmed the trans-configuration (Figure 1). In this way, the ratio
of the cis/trans isomers were determined by 1H NMR analysis of the product mixture, and then
5

both isomers were separated by column chromatography for yield calculation and structure
characterization.
The electron donating power of the ferrocenyl group as measured by σ values[16] and
carbocation forming reactions[17] is similar to that of methoxy, and much greater than that of 4-
methoxyphenyl. Ferrocenyl ketene generated by photochemical Wolff rearrangement in CH3CN
has a rate constant for reaction with n-BuNH2 less than that for the phenyl ketene by only a
factor of 5.[3a] Rate constants of thermal ring closure of diferrocenylbisketene, diphenylbisketene
and dimethoxybisketene have been reported, and show that the reactivity of the ferrocenyl
substituted bisketene is quite similar to the phenyl substituted bisketene, and much lower than
that of the bismethoxy substituted ketene.[13a] [18]
These results reflect the tendency of aryl groups
,
to stabilize ketenes, while methoxy destabilizes ketenes and stabilizes the elcctron deficient
cyclobutenedione ring.
For comparison we also studied the [2 + 2]-cycloadditions of p-methoxyphenylketene, as
well as some other substituted phenylketenes, under similar conditions as the controlled
reactions. The results are shown in Table 2.
As shown in Table 2 (Entries 1–5), trans-products are isolated as the main products of
the Staudinger reaction between ferrocenylketene and various substituted imines. With the
increase of the electronic withdrawing ability of the substituent on the imines the cis/trans
products ratio increased from only trans to 0.64:1. Similar trends were observed in the
Staudinger reaction of substituted phenylketenes. However, the steric and electronic effect of the
ketene substituent on the stereoselectivity is not strong, as shown comparing entries 3, 9, 17 and
21 (0.16:1, 0.10:1, 0.08:1, 0.10:1 respectively). Most interestingly, the trans-products are favored
6

in all the cases that we studied using thermal Wolff rearrangement, which is opposite to the
reported results by Bonini and co-workers,[12] noted above for synthesis of β-lactams by using
ferrocenylacetic acid with PhOP(O)Cl2 activation, or the corresponding carbonyl chloride in the
presence of triethylamine and imines with conventional heating (30 – 70oC) or microwave
irradiation. Thus we find that the stereoselectivity of the Staudinger reaction of ferrocenylketene
can be controlled by the reaction conditions, and in particular by the temperature.
Now it is widely accepted that the Staudinger reaction is a two-step process instead of a
concerted [2 + 2]-cycloaddition.[5] On the basis of systematic studies of the uncatalyzed
formation of β-lactams, Xu and co-workers[5a,b] proposed the stepwise mechanism of the
Staudinger reaction involving mono-substituted ketenes. The reaction starts with nucleophilic
attack of the imine to a ketene, giving a zwitterionic intermediate. The zwitterionic intermediate
undergoes either conrotatory electrocyclic ring closure to produce a cis-β-lactam product, or it
undergoes isomerization of the imine moiety to form a sterically more favorable intermediate,
which produces the final trans-β-lactam product via contoratory electrocyclic ring closure. It was
proposed that the diastereoselectivity is results from competition between direct ring closure and
isomerization of the imine moiety in the zwitterionic intermediate. Since the electron
withdrawing substituent on the imine could accelerate the direct ring-closure process the ratio of
the cis-product could increase. Our experimental results support this explanation quite well.
It was reported previously[5a,b] that for reaction of PhSCH = C = O generated by thermal
Wolff rearrangement with 4-RC6H4CH = N(i-Pr) that there is a correlation of log (cis/trans) with
σ constants with a slope ρ of 1.62. Similarly in our study, a good linear correlation of log
(cis/trans) with σ parameters for the aryl substituents with a slope ρ = 0.84 (r2 = 0.99) is
observed (entries 7, 9, 10, 11 and 13, Figure 2). The increase of cis/trans ratio with electron-
7

withdrawing aryl substituents on C of imines we observe is also consistent with the acceleration
of the direct ring closure of intermediate to cis-β-lactam.
In order to predict the stereochemical outcome of β-lactam formation, an empirical
classification of the stereochemical preference of different ketenes was devised by Georg and co-
workers, grouped as “Bose-Evans ketenes” with strong electron-donating substituents (such as
O-alkyl, O-aryl, and N-alkylaryl) and having a distinct preference for cis-β-lactams formation,
“Sheehan ketenes” with medium sized substituents producing complex stereochemical outcomes,
and “Moore ketenes” with moderately electron-donating substituents (such as S-alkyl, S-aryl,
alkyl, and aryl) and favoring the trans-β-lactams formation.[19] Our experimental results fit this
rule quite well since ferrocenylketene, as well as other substituted phenylketenes belong to
“Moore ketenes”. However, as found by Xu and co-workers,[5b] and in our study the ketene
reactivity is temperature dependent, and thus the Georg classification varies according to
temperature. The trans selectivity often increases with temperature, and this explains the
opposite results obtained by Bonini and us.
Conclusion
In conclusion, thermal Wolff rearrangement was applied to generate ferrocenylketene at
140oC and the Staudinger reaction with various imines was carried out in situ with the formation
of β-lactams containing the ferrocenyl moiety. trans-Products were favored under this reaction
condition. Electron withdrawing groups on the imine increase the cis/trans products ratio.
Compared to the results reported by Bonini, the product stereochemistry changes from cis to
trans at higher temperature of the thermal Wolff rearrangement. This provides a way to control
the stereoselectivity of the Staudinger reaction of ferrocenylketene.
8

Experimental
General procedures
Infrared spectra were recorded on a Perkin–Elmer 2000 series Fourier Transform IR
spectrometer. Melting points were determined with an Electrothermal X-4 series digital mp
apparatus without corrections. The NMR spectra were recorded on Bruker Avance 400 MHz/500
MHz or Varian Inova 500 MHz spectrometer; chemical shifts are reported in ppm in δ-values
against tetramethylsilane (TMS) as an internal standard and the coupling constants in Hertz. Low
and high resolution mass spectra were determined using an Applied Biosystems (Sciex) QStar or
API300LC/MS/MS spectrometer. Elemental analyses were carried out using a Vario Micro
elemental analyzer.
General procedure for synthesis of α-diazo ketones 1a-1d
The carbonyl chloride (5 mmol) in ether (5 mL) was added dropwise to a stirred pre-
cooled solution of freshly prepared diazomethane (20 mmol) in ether (40 mL), and then the
mixture was stirred on an ice-water bath overnight. The solvent was evaporated under reduced
pressure. Purification of the residue by column chromatography on neutral alumina or silica gel
(elution with petroleum ether/ethyl acetate = 4:1 v/v) gave the diazo ketone.
2-Diazo-1-ferrocenylethanone (1a) 0.79 g, 62% yield; red solid; mp 77–78oC; IR (KBr):
3086, 2925, 2107, 1597, 1455, 1379, 1347, 1249, 1152, 1107, 1064, 1026, 1004, 918, 826, 814,
743, 525, 500 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.23 (s, 5H), 4.46 (t, J = 2.0 Hz, 2H), 4.69 (t,
J = 2.0 Hz, 2H), 5.50 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 53.35, 68.42, 70.04, 71.69, 79.30,
9

189.32. Elem. Anal. Calcd for C12H10FeN2O: C, 56.73; H, 3.97; N, 11.03. Found: C, 56.55; H,
3.82; N, 11.13.[13a]
General procedure for synthesis of imines 2a-2i
A mixture of amine (2 mmol) and aromatic aldehyde (2 mmol) was dissolved in
anhydrous EtOH (10 mL) at room temperature, and left to stir on an ice-water bath. The
precipitate formed was collected by filtration, and the filtrate was washed with cold anhydrous
EtOH. The product was recrystallized from anhydrous EtOH,[20] with yields of 77–92%.
Preparation of β-lactams 3
General procedure
A flamed-dried three-neck flask was charged with a solution of imine (0.20 mmol) in 10
mL of dry xylenes (or toluene). The flask was immersed in an oil bath and heated to desired
temperature. A solution of diazo ketone (0.26 mmol) in 5 mL of dry xylenes was then added
dropwise through dropping funnel. After the addition, the resulting solution was stirred for
another 12 h at the same temperature. After removal of the solvent, the residue was purified by
flash chromatography to remove highly polar impurities. The product mixture was submitted to
1H NMR analysis to determine the cis/trans ratio. Column chromatography of the crude mixture
on neutral alumina or silica gel afforded the corresponding cis- and trans-β-lactam products.[5a]
(±)-trans-1-Phenyl-4-(4-methoxyphenyl)-3-ferrocenylazetidin-2-one (3a) The reaction
mixture was chromatographed on a neutral alumina using 10:1 petroleum ether/EtOAc (v/v) to
afford the indicated compound as a yellow solid: 61 mg, 70% yield; mp 163oC; IR (KBr): 2959,
2920, 2832, 1742, 1615, 1598, 1512, 1500, 1463, 1383, 1371, 1307, 1244, 1177, 1154, 1108,
10

1038, 1002, 826, 814, 753, 692, 487 cm−1; 1H NMR (400 MHz, CDCl3): δ 3.81 (s, 3H), 3.94 (d, J
= 2.8 Hz, 1H), 4.19 (s, 8H), 4.27 (s, 1H), 4.84 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.04
(t, J = 7.2 Hz, 1H), 7.24–7.28 (m, 2H), 7.32–7.36 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 55.5,
60.5, 62.9, 67.1, 67.6, 68.3, 68.5, 69.1, 81.9, 114.8, 117.3, 124.0, 127.4, 129.3, 129.9, 137.9,
+
+
160.0, 165.7; EI-MS: m/z 437.1 (M ); HRMS (EI): Calcd for C26H23FeNO2 (M ): 437.1078,
Found: 437.1074. Anal. Calcd for C26H23FeNO2: C, 71.41; H, 5.30; N, 3.20. Found: C, 71.63; H,
5.24; N, 3.11.
X-ray crystallographic investigations
The diffraction data were measured on a Rigaku Saturn 724 CCD diffractometer with Mo
Ka radiation (0.778) by ω scan mode at 293(2) K. All data were corrected by semi-empirical
method using SADABS program. The program SAINT14 was used for integration of the
diffraction profiles. The structure was solved by the direct methods using SHELXS program of
the SHELXL-97 package and refined with SHELXL. The final refinement was performed by full
matrix least-squares methods with anisotropic thermal parameters for all non-hydrogen atoms on
F2. The hydrogen atoms were placed in the geometrically calculated positions. All hydrogen
atoms were included in the final refinement in the riding model approximation with displacement
parameters derived from the parent atoms to which they were bonded.
X-ray crystallography data for 3c: C25H21FeNO, Mr = 407.28, yellow block crystal,
orthorhombic, space group Pca2 (1), T = 293(2) K, a = 9.865 (2), b = 20.857 (4), c = 9.4829 (19)
Å, α = β = γ = 90.00 °, V = 1951.1 (7) Å3, Z = 4, μ(Mo-Kα) = 0.778 mm-1, 15791 reflections
collected, 4343 unique (Rint = 0.0487), R1 = 0.0844 (I > 2σI), wR2 = 0.2148 for all data.[21]
Supporting information
11

Full synthetic details (1, 2, and 3), their FT-IR, 1H NMR, 13C NMR and MS spectral data
1
(1 and 3), and copies of FT-IR, H NMR, 13C NMR and MS spectra of 1 and 3 have been
included in supplementary data. Supplementary data associated with this article can be found
through the supplementary content section of this article’s web page.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No.
20702005), the Scientific Research Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry (No. LXKQ0802) and Fujian Provincial Natural Science Foundation of
China (No. 2017J01577).
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[21] Further crystallographic data have been deposited with the Cambridge Crystallographic
Data Centre. Copies of the data (CCDC 735635) can be obtained free of charge from
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Tel: +44 1223 762910; fax:+44 1223
336 033; e-mail: deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk/deposit).
13

Table 1. [2 + 2]-Cycloaddition of diazoketone 1a and imine 2c under different reaction
conditions
Entry
Temp (oC)
80
Time (h)
2 h
Solvent
Toluene
Toluene
Toluene
Toluene
Xylenes
Xylenes
Yield (%)a
cis/trans
Only trans
0.14:1
1
2
3
4
5
6
Trace
5
12 h
2 h
110
140
27
12 h
2 h
40
54
12 h
74
0.16:1
Note: a The isolated yield of trans-3c.
14

Table 2. [2 + 2]-Cycloaddition of diazo ketones 1 and imines 2 with different substituents
Entry
1
R
R1
CH3O
H
R2
H
cis/trans
Only trans
Only trans
0.16:1
Yield(%)a
70
1
2
a
b
c
d
e
f
3
a
b
c
d
e
f
a
Fc
2
OCH3
H
82
3
H
74
4
O2N
O2N
OCH3
H
0.40:1
40
5
0.64:1
50
6
b
p-CH3O-Ph (CH3)2N
H
Only trans
0.05:1
52
7
a
b
c
g
h
d
e
CH3O
H
H
g
h
i
78
8
OCH3
H
0.07:1
77
9
H
0.10:1
70
10
11
12
13
Cl
H
j
0.13:1
63
Br
H
k
l
0.15:1
74
O2N
O2N
OCH3
H
0.30:1
45
m
0.40:1
46
15

14
15
16
17
18
19
20
21
22
c
i
Ph
CH3O
CH3O
H
OCH3
H
n
o
p
q
r
0.02:1
0.03:1
0.02:1
0.08:1
0.30:1
0.25:1
0.08:1
0.10:1
0.25:1
76
71
77
83
49
37
57
36
43
a
b
c
d
e
a
c
e
OCH3
H
H
O2N
O2N
CH3O
H
OCH3
H
s
d
p-O2N-Ph
H
t
H
u
v
O2N
H
Note: a The isolated yield of trans-3.
16

Figure 1. X-ray structure of (±)-trans-1,4-diphenyl-3-ferrocenylazetidin-2-one (3c).
17

Figure 2. Correlation of log (cis/trans) with σ (entries 7, 9, 10, 11 and 13).
18