Palladium Catalysis in the Intramolecular Carbene C–H Insertion of α-Diazo-α-(methoxycarbonyl)acetamides to Form β-Lactams

Article abstract of DOI:10.1002/ejoc.201800666

The intramolecular carbene C–H insertion of α-diazo-α-(methoxycarbonyl)acetamides leading to β-lactams is effectively catalyzed by palladium complexes. It is found that although Pd⁰ catalysts typically produce mixtures of β-lactams together wit

Full text of DOI:10.1002/ejoc.201800666

A Journal of
Accepted Article
Title: Palladium catalysis in the intramolecular carbene C-H insertion of
α-diazo-α-(methoxycarbonyl)acetamides to form β-lactams
Authors: Daniel Solé, Ferran Pérez-Janer, M.-Lluïsa Bennasar, and
Israel Fernández
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800666
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10.1002/ejoc.201800666
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Palladium Catalysis in the Intramolecular Carbene C–H Insertion
of α-Diazo-α-(methoxycarbonyl)acetamides to Form β-Lactams
Daniel Solé,*[a] Ferran Pérez-Janer,[a] M.-Lluïsa Bennasar,[a] and Israel Fernández*[b]
Abstract: The intramolecular carbene C–H insertion of α-diazo-α-
(methoxycarbonyl)acetamides leading to β-lactams is effectively
catalyzed by palladium complexes. It is found that whereas Pd(0)-
catalysts typically produce mixtures of β-lactams together with
Buchner-type reaction products, the use of Pd(II)-catalysts results in
highly chemoselective transformations. According to DFT
calculations, this insertion reaction occurs stepwise and involves an
unprecedented Pd(II)-promoted Mannich-type reaction through a
metallacarbene-induced zwitterionic intermediate.
palladium catalysts the C–H insertion of such amides occurs
selectively into the arylic Csp2–H to give the oxindole.[8]
The aim of the current work was to explore the palladium-
catalyzed intramolecular carbene insertion of α-diazo-α-
(methoxycarbonyl)acetamides for β-lactam elaboration. The β-
lactam system has attracted considerable attention due to its
ubiquitous presence in the molecular structure of natural
products and biologically active compounds.[9] We studied how
the selectivity of the process[10] is affected by the type of catalyst,
using two oxidation states of palladium, and the substituents on
the α-diazoacetamide (Scheme 1).
Introduction
The transition metal-catalyzed intramolecular carbene C–H
insertion by decomposition of diazo compounds is a well-
established powerful carbon-carbon bond-forming methodology
for the construction of carbocyclic and heterocyclic
frameworks.[1] Many transition metal complexes have been used
as effective catalysts to generate reactive metallacarbenes
starting from diazo derivatives.[2] Among them, rhodium(II),[3]
copper(I),[4] and more recently ruthenium(II) catalyst[5] have
proven especially useful for the development of highly selective
carbene C–H insertion methodologies via a variety of reaction
modes.
Scheme 1. Substituent and catalyst effects on Pd-catalyzed reactions of α-
diazoacetamides
Surprisingly, palladium, though one of the most commonly
employed metals in homogeneous catalysis, has been scarcely
applied to promote carbene C–H insertion processes.[6] In this
context, we recently reported that palladium catalysts are able to
promote Csp3–H insertion of carbenes derived from α-
diazoesters to form pyrrolidines through intramolecular Csp3–
Csp3 bond formation.[7] We also explored the palladium-
Results and Discussion
We commenced our investigation by studying the palladium-
catalyzed reactions of N,N-dibenzyl-α-diazoacetamide 1 (Table
1).[11]
Treatment of 1 with Pd2(dba)3 in 1,2-dichloroethane at
reflux for 24 h resulted in 76% conversion to give a 1:1 mixture
of cycloheptapyrrolone 2 and β-lactam trans-3, together with
some β-lactam cis-3 and the recovery of significant amounts of
unreacted starting material (Table 1, entry 1). When the reaction
was performed in the absence of the palladium catalyst, ca. 40%
of conversion was observed, giving a 1:0.1:1 mixture of 2, cis-3
and trans-3, together with the unreacted material (Table 1, entry
2). The complete consumption of the starting material was
achieved when reactions were run in refluxing toluene (Table 1,
entries 3-4).
On the other hand, the [(IMes)Pd(NQ)]2-catalyzed
decomposition of 1 in DCE at reflux gave cycloheptapyrrolone 2
as the major product (55%), together with small amounts of β-
lactams cis-3 and trans-3 (Table 1, entry 5). The complete
consumption of the starting material and the notably different
selectivity of the latter reaction compared to the thermal process
in DCE (Table 1, entry 2) clearly supports the role of
[(IMes)Pd(NQ)]2 as a catalyst in the decomposition of α-
diazoacetamide 1.
catalyzed
carbene
C–H
insertion
of
α-diazo-α-
(methoxycarbonyl)acetanilides. We found that when using
[a]
[b]
D. Solé, F. Pérez-Janer, M.-L. Bennasar
Laboratori de Química Orgànica, Facultat de Farmàcia i Ciències de
l’Alimentació,
Universitat de Barcelona
Av. Joan XXIII 27-31, 08028 Barcelona, Spain
E-mail: dsole@ub.edu
http://www.ub.edu/farmaco/ca/quimica/llistat_recerca
I. Fernández
Departamento de Química Orgánica and Centro de Innovación en
Química Avanzada (ORFEO−CINQA), Facultad de Ciencias
Químicas,
Universidad Complutense de Madrid
Ciudad Universitaria, 28040 Madrid, Spain
E-mail: israel@quim.ucm.es
http://www.ucm.es/info/computchem
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800666
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Pd(II)-catalysts were also able to promote the carbene
reactions of 1, which resulted in the major formation of β-lactams
cis-3 and trans-3 at the expense of the Buchner product 2.
Thus, the [Pd(allyl)Cl]2-catalyzed decomposition of 1 afforded a
1:1.4:0.5 mixture of cycloheptapyrrolone 2 and β-lactams cis-3
and trans-3 (Table 1, entry 7). However, after flash
chromatography, only 2 (20%) and trans-3 (23%) were isolated
because β-lactam cis-3 underwent isomerization to the more
stable trans isomer during the purification process. When using
(SIPr)Pd(allyl)Cl as the catalyst, products 2 and trans-3 were
isolated in comparable yields (Table 1, entry 8). Finally,
Pd(TFA)2 also led to the formation of the β-lactams as the main
products, although a longer reaction time was required and
trans-3 was still isolated in poor yield (Table 1, entry 10).
Table 1. Pd-catalyzed cyclisation reactions of α-diazoamide 1[a]
entry
catalyst (mol%)
Pd2(dba)3 (10)
---
solvent
DCE
1H NMR ratio[b]
yield [%][c]
1
2
3
4
5
6
7
8
9
10
1/2/cis-3/trans-3 (1:1.5:0.15:1.5)
1/2/cis-3/trans-3 (1:0.3:0.04:0.3)
2/cis-3/trans-3 (1:0.1:1)
2/cis-3/trans-3 (1:0.25:1)
2/cis-3/trans-3 (1:0.1:0.2)
1
---
DCE
---
Pd2(dba)3 (10)
---
toluene
toluene
DCE
2 (42), trans-3 (42)
2 (43), trans-3 (45)
2 (55), trans-3 (5)
---
[(IMes)Pd(NQ)]2 (2.5)
[(IMes)Pd(NQ)]2 (2.5)
[Pd(allyl)Cl]2 (5)
(SIPr)Pd(allyl)Cl (15)
(SIPr)Pd(allyl)Cl (10)
Pd(TFA)2 (10)
CH2Cl2
DCE
2/cis-3/trans-3 (1:1.4:0.5)
2/cis-3/trans-3 (1:0.25:1.1)
1/2/cis-3/trans-3 (1:1.1:0.3:1.4)
2/cis-3/trans-3 (1:1.2:1)
2 (20), trans-3 (23)[d]
2 (22), trans-3 (20)[d]
---
DCE[e]
DCE[e]
[e]
CHCl3
2 (15), trans-3 (24)[d]
[a] Reaction conditions: Catalyst (see table) in the indicated solvent at reflux for 24 h. [b] Ratio determined by 1H NMR (400 MHz) from the reaction mixture. [c]
Yields refer to products isolated by chromatography. [d] Small amounts (≤10%) of N,N-dibenzyl-α-chloro-α-(methoxycarbonyl)acetamide were also obtained. [e]
Reaction time: 48 h. Pd2(dba)3
= Tris(dibenzylideneacetone)dipalladium(0). [(IMes)Pd(NQ)]2 = 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (1,4-
naphthoquinone)palladium(0) dimer. (SIPr)Pd(allyl)Cl = Allyl-chloro-[1,3-bis-(2,6-diisopropylphenyl)-2-imidazolidinylidene]palladium(II).
The competition between Csp3–H insertion leading to β-
lactams and intramolecular aromatic cycloaddition to give the
corresponding cycloheptapyrrolone is also common in reactions
of α-diazoacetamides catalyzed by Rh(II)[11a] and Ru(II)-
catalysts.[11b,12] According to previous mechanistic studies on
related Rh(II)-catalyzed transformations, the competitive
formation of β-lactams and aromatic ring reaction products is
probably due to the stereoelectronic competition between the
two conformational isomers of the metallacarbene undergoing
the intramolecular reactions.[13] A strategy to improve site-
selectivity in the transition metal-catalyzed carbene reactions of
α-diazoacetamides involves replacing one of the N-substituents
at the amide moiety with a bulky group,[14] which sterically biases
the conformational preference around the amide N–C(O) bond
and makes the metallacarbene reaction at the remaining
substituent more feasible.
In search of higher site-selectivity in the palladium-
catalyzed insertion leading to β-lactams, we decided to replace
one of the benzyl groups in 1 with a tert-butyl substituent. Table
2 shows the results of the palladium-catalyzed reactions with N-
benzyl-N-tbutyl-α-diazoacetamide 4a.[15]
When α-diazoamide 4a was decomposed in the presence
of Pd2(dba)3 (Table 2, entry 1), cycloheptapyrrolone 5a (20%)
was isolated together with β-lactams cis-6a (9%) and trans-6a
(42%)[16] On changing the catalyst to [(IMes)Pd(NQ)]2, a slight
increase in the formation of the Buchner product was observed
(Table 2, entry 2). To our delight, the more electrophilic
[Pd(allyl)Cl]2 or (SIPr)Pd(allyl)Cl catalysts exclusively promoted
the Csp3–H insertion to give the β-lactams, which were isolated
in good overall yields (Table 2, entries 3-4).
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Table 2. Pd-catalyzed cyclisation reactions of α-diazoamide 4a[a]
Interestingly, when the reaction was catalyzed by
Pd2(dba)3, both 4a and 7 gave a ca. 1:3 Buchner/β-lactam ratio.
On the contrary, when the reaction of 7 was promoted by the
sterically
encumbered
[(IMes)Pd(NQ)]2
catalyst,
cycloheptapyrrolone 8 was obtained as the major product,
suggesting that the Pd(0)-catalyzed reaction is highly sensitive
to the steric hindrance on the reactive Csp3–H bond. At variance,
similar to the reactions of 4a, the use of Pd(II)-catalysts with 7
resulted in the chemoselective insertion into the Csp3–H bond
(Table 3, entries 3 and 4), [Pd(allyl)Cl]2 once again affording the
best result.
entry
1
catalyst (mol%)
Pd2(dba)3 (10)
5a/cis-6a/trans-
products (%)[d]
6a[b],[c]
26/46/28
35/40/25
5a (20)
cis-6a (9)
trans-6a (42)
[(IMes)Pd(NQ)]2 (2.5)
2
5a (28)
cis-6a (35)
trans-6a (23)
The studies with α-diazoacetamides 4a and 7 gave us two
experimental procedures for the insertion reaction based on the
use of either [Pd(allyl)Cl]2 (Method A) or (SIPr)Pd(allyl)Cl
(Method B) as the catalyst. To explore how the introduction of
substituents at the benzylic group might influence the insertion
process leading to β-lactams, these catalytic systems were
studied with α-diazoacetamides 4b-m (Scheme 2, see Table S1
in the SI for additional details).
3
4
[Pd(allyl)Cl]2 (5)
0/47/53
0/29/71
cis-6a (25)
trans-6a (65)
(SIPr)Pd(allyl)Cl (15)
cis-6a (17)
trans-6a (59)
[a] Reaction conditions: Catalyst in DCE at reflux for 24 h. [b] 1H NMR ratio. [c]
All reactions were performed twice. While the 5a/6a ratio was essentially the
same in the two runs, the cis/trans ratio was quite different due to the partial
isomerization of cis β-lactam to the more stable trans isomer during the work-
up. [d] Isolated yields.
The palladium-catalyzed carbene insertion was also
explored from α-diazoamide 7, which bears the α-methylbenzyl
substituent at the nitrogen (Table 3). Similarly to the reactions of
N-benzylamide 4a, when Pd(0)-catalysts were used to promote
the decomposition of 7 a significant amount of the Buchner
product 8 was obtained (Table 3, entries 1 and 2).
Table 3. Pd-catalyzed cyclisation reactions of α-diazoamide 7[a]
entry
1
catalyst (mol%)
Pd2(dba)3 (10)
8/9/10[b]
products (%)[c]
26/37/37
8[d] (15)
9 (18), 10 (24)
2
65/20/15
8[e] (42)
[(IMes)Pd(NQ)]2 (2.5)
9 (7), 10 (13)
3
4
[Pd(allyl)Cl]2 (5)
0/36/64
0/57/43
9 (23), 10 (47)
9 (24), 10 (18)
Scheme 2. Synthesis of β-lactams by Pd(II)-catalyzed cyclisation of α-
[a]
[b]
(SIPr)Pd(allyl)Cl (15)
diazoamides.
Method A: [Pd(allyl)Cl]2 or Method B: (SIPr)Pd(allyl)Cl.
(Method, Isolated yield (%), cis/trans ratio after chromatography).
[a] Reaction conditions: Catalyst in DCE at reflux for 24 h. [b] 1H NMR ratio. [c]
Isolated yields. [d] 1:1.2 mixture of stereoisomers. [e] 1:2.2 mixture of
stereoisomers.
The effect of the substituent varied according to its
electronic nature as well as its position on the aromatic ring. The
introduction of electron-releasing groups at the benzyl
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substituent led to an increased formation of the
cycloheptapyrrolone product, especially when using
(SIPr)Pd(allyl)Cl as the catalyst. The increase was lower when
the substituent was located at the ortho-position, probably due to
steric interactions. In contrast, electron-withdrawing groups
generally diverted the palladacarbene away from the Buchner
reaction in favor of the Csp3–H insertion. Similar electronic
effects have been observed in related Rh(II)-catalyzed
transformations.[11a]
Figure 1. Computed reaction profiles for the formation of β-lactams 6a. Relative free energies (∆G298, at 298 K) and bond distances are given in kcal/mol and
angstroms (Å), respectively
The examples in Tables 2 and 3, and Scheme 2 confirm
the generality and functional group tolerance of this novel Pd(II)-
catalyzed insertion. The resulting β-lactams were obtained in
moderate to good overall yields (44-90%), usually as mixtures of
cis and trans isomers, in transformations proceeding with high
site-selectivity. As an exception, the Pd(II)-catalyzed
decomposition of 4f gave trans-6f in poor yield together with
major amounts of 4-(dimethylamino)benzaldehyde. It is worth
noting that no product from the potentially competitive Pd-
catalyzed cross-coupling of the aryl halide with the α-diazoamide
moiety was observed in the reactions of 4k and 4l, which bear
an ortho-bromo and ortho-iodo substituent, respectively.
The above results also confirm the significant impact of the
electronic nature of the palladium catalyst and ensuing
electrophilicity of the carbene intermediate in the reaction
pathway. Thus, whereas benzylic Csp3–H insertion is strongly
favored over the Buchner reaction when using Pd(II)-catalysts,
an increased cycloheptapyrrolone product formation is usually
observed with the more electron-rich Pd(0)-catalysts.
Interestingly, Rh(II)-catalyzed transformations show opposite
reactivity trends, in which highly electrophilic Rh(II)-complexes
favor Buchner reactions over benzylic Csp3–H insertion.[10]
Our previous work has shown that the mechanism involved
in palladium-catalyzed insertion reactions[7,8] differs considerably
from that accepted for Rh(II)-catalyzed transformations.
Whereas Rh(II)-catalysts typically proceed in
a concerted
process that directly releases the insertion product and metal
catalyst in a single step,[17] palladium catalysts involve stepwise
reaction mechanisms initiated by a metal-mediated hydrogen
migration. To shed light on the reaction mechanism and the
influence of the Pd(II)-catalyst on the selectivity of the C–H
insertion described herein, density functional theory (DFT)
calculations were carried out.[18] To this end, the process
involving 4a in the presence of the [Pd(allyl)Cl]2 catalyst (see
Table 2, entry 3) was explored.
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To a solution of dibenzylamine (0.6 mL, 3.04 mmol) and Et3N (0.86 mL,
6.1 mmol) in CH2Cl2 (18 mL), cooled at 0 °C, was added slowly methyl
malonyl chloride (0.67 mL, 6.1 mmol). The mixture was stirred at room
temperature for 24 h. After the reaction was completed, the mixture was
poured into water and extracted with CH2Cl2. The organic extracts were
washed with saturated NaHCO3 aqueous solution, dried, filtered and
concentrated. The residue was purified by chromatography (SiO2, from
The data in Figure 1, which gathers the computed reaction
profile starting from the initial Pd(II)-carbene intermediate INT0,
indicate that the formation of the corresponding β-lactams 6a
occurs stepwise. Thus, INT0 is first transformed into the
zwitterionic intermediate INT1[19] in a highly exergonic process
via the transition state TS1. This step can be viewed as a 1,4-
hydrogen migration that is not directly assisted by the metal,
therefore resembling the mechanism involved in related Ru(II)-
C–H activation processes previously studied by us.[7b] The
transformation ends with the formation of the new C–C bond via
hexanes
to
hexanes/EtOAc
3:2)
to
give
N,N-dibenzyl-α-
(methoxycarbonyl)acetamide (0.88 g, 97%).
To a solution of N,N-dibenzyl-α-(methoxycarbonyl)acetamide (678 mg,
2.28 mmol) and DBU (0.52 mL, 3.43 mmol) in dry acetonitrile (16 mL)
was added dropwise a solution of p-ABSA (602 mg, 2.5 mmol) in dry
acetonitrile (6 mL). The mixture was stirred at room temperature
overnight. The solvent was removed in vacuo and the resulting residue
was partitioned between CH2Cl2 and 10% NaOH aqueous solution. The
organic extracts were dried, filtered and concentrated. The residue was
purified by chromatography (SiO2, from CH2Cl2 to CH2Cl2/MeOH 98:2) to
give N,N-dibenzyl-α-(methoxycarbonyl)-α-diazoacetamide (1, 554 mg;
75%).
the transition state TS2, again in
a strongly exergonic
transformation that releases the β-lactam with concomitant
regeneration of the active Pd(II)-catalyst. According to the rather
similar relative energies computed for the cis/trans transition
states TS1 and TS2, a ca. 50:50 mixture of cis-6a and trans-6a
can be expected, which is fully consistent with the experimental
findings (Table 2, entry 3).
Finally, we also investigated the reasons for the non-
formation of cycloheptapyrrolone 5a when using these reaction
conditions (i.e. 4a in the presence of [Pd(allyl)Cl]2). Our
calculations suggest that the first step of the alternative Buchner
N,N-Dibenzyl-α-(methoxycarbonyl)-α-diazoacetamide (1). Brown oil.
1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 4.51 (s, 4H), 7.15-7.19 (m, 4H),
7.25-7.36 (m, 6H). 13C NMR (CDCl3, 100.6 MHz) δ 50.5 (broad signal, 2
CH2), 52.5 (CH3), 67.0 (C), 127.8 (CH), 127.9 (2 CH), 128.8 (2 CH),
136.4 (C), 162.4 (C), 163.0 (C). HRMS (ESI-TOF) calcd. for C18H18N3O3:
324.1343 [M+H]+; found: 324.1347.
reaction, which involves
a palladium-promoted C–C bond
formation, is not competitive in view of the much higher
activation barrier required to reach the corresponding transition
state TS1’ as compared to TS1-trans (∆∆G≠= 8.5 kcal/mol) as
well as the endergonicity (∆∆G = +6.0 kcal/mol) associated with
this step. Therefore, no Buchner reaction product should be
expected, which agrees nicely with the complete selectivity
observed experimentally (Table 2, entry 3).
N-Benzyl-N-tert-butyl-α-(methoxycarbonyl)-α-diazoacetamide (4a).
4a was obtained as a yellow oil that solidified on refrigeration (433 mg)
following the procedures described above [(a) ClCOCH2CO2Me (1 equiv.),
Et3N (1 equiv.); (b) p-ABSA (1.1 equiv.), DBU (1.5 equiv.), 75% two
steps]. 1H NMR (CDCl3, 400 MHz) δ 1.39 (s, 9H), 3.77 (s, 3H), 4.62 (s,
2H), 7.18-7.35 (m, 5H). 13C NMR (CDCl3, 100.6 MHz) δ 28.9 (3 CH3),
51.7 (CH2), 52.3 (CH3), 59.1 (C), 68.2 (C), 126.9 (2 CH), 127.5 (CH),
128.8 (2 CH), 139.7 (C), 163.1 (C), 163.2 (C). HRMS (ESI-TOF) calcd.
for C15H19N3 NaO3: 312.1319 [M+H]+; found: 312.1327.
Conclusions
In summary, we have shown that palladium can be used to
promote the carbene Csp3–H insertion of α-diazoacetamides to
N-tert-Butyl-N-(4-methoxybenzyl)-α-(methoxycarbonyl)-α-
form
β-lactams,
Pd(II)-catalysts
giving
the
best
diazoacetamide (4b). 4b was obtained as a yellow oil that solidified on
refrigeration (600 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.2 equiv.), Et3N (1.2 equiv.), 61%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 98%]. 1H NMR (CDCl3, 400 MHz) δ 1.36 (s,
9H), 3.76 (s, 3H), 3.78 (s, 3H), 4.54 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H) 7.09
(d, J = 8.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.9 (3 CH3), 51.2
(CH2), 52.3 (CH3), 55.4 (CH3), 59.0 (C), 68.2 (C), 114.1 (2 CH), 128.1 (2
CH), 131.5 (C), 159.0 (C), 163.1 (C), 163.2 (C). HRMS (ESI-TOF) calcd.
for C16H21N3 NaO4: 342.1424 [M+H]+; found: 342.1423.
chemoselectivities. DFT calculations suggest that this
transformation involves an unprecedented Pd(II)-promoted
Mannich-type reaction through
zwitterionic intermediate.
a
metallacarbene-induced
Experimental Section
General Methods. All commercially available reagents were used
without further purification. 1H- and 13C NMR spectra were recorded
using Me4Si as the internal standard, with a Varian Mercury 400
instrument. Chemical shifts are reported in ppm downfield (δ) from Me4Si
N-tert-Butyl-N-[4-(methylthio)benzyl]-α-(methoxycarbonyl)-α-
diazoacetamide (4c). 4c was obtained as a yellow oil that solidified on
refrigeration (555 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.2 equiv.), Et3N (1.2 equiv.), 68%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 94%]. 1H NMR (CDCl3, 400 MHz) δ 1.37 (s,
9H), 2.47 (s, 3H), 3.76 (s, 3H), 4.56 (s, 2H), 7.10 (d, J = 8.0 Hz, 2H) 7.20
(d, J = 8.0 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 16.0 (CH3), 28.9 (3
CH3), 51.3 (CH2), 52.3 (CH3), 59.1 (C), 68.2 (C), 126.9 (2 CH), 127.4 (2
CH), 136.5 (C), 137.6 (C), 163.0 (C), 163.2 (C). HRMS (ESI-TOF) calcd.
for C16H22N3O3S: 336.1376 [M+H]+; found: 336.1378.
for 1H and 13C NMR. TLC was carried out on SiO2 (silica gel 60 F254
,
Merck), and the spots were located with UV light or 1% aqueous KMnO4.
Flash chromatography was carried out on SiO2 (silica gel 60, SDS, 230-
400 mesh ASTM). Drying of organic extracts during workup of reactions
was performed over anhydrous Na2SO4. Evaporation of solvents was
accomplished with a rotatory evaporator.
Representative Procedure for the Preparation of Diazoacetamides 1,
4a-m and 7.
N-tert-Butyl-N-[4-chlorobenzyl]-α-(methoxycarbonyl)-α-
diazoacetamide (4d). 4d was obtained as a yellow oil that solidified on
refrigeration (514 mg) following the procedures described above [(a)
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10.1002/ejoc.201800666
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ClCOCH2CO2Me (1.3 equiv.), Et3N (1.3 equiv.), 54%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 83%]. 1H NMR (CDCl3, 400 MHz) δ 1.38 (s,
9H), 3.77 (s, 3H), 4.58 (s, 2H), 7.14 (d, J = 8.4 Hz, 2H) 7.30 (d, J = 8.4
Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.9 (3 CH3), 51.1 (CH2), 52.4
(CH3), 59.2 (C), 68.4 (C), 128.3 (2 CH), 129.0 (2 CH), 133.2 (C), 138.3
(C), 163.0 (C), 163.4 (C). HRMS (ESI-TOF) calcd. for C15H18ClN3NaO3:
346.0929 [M+H]+; found: 346.0937.
N-tert-Butyl-N-(2-fluorobenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4j). 4j was obtained as a yellow oil that solidified on
refrigeration (563 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1 equiv.), Et3N (1 equiv.), 84%; (b) p-ABSA (1.1 equiv.),
DBU (1.5 equiv.), 56%]. 1H NMR (CDCl3, 400 MHz) δ 1.37 (s, 9H), 3.78
(s, 3H), 4.67 (s, 2H), 7.00-7.14 (m, 2H) 7.22-7.29 (m, 2H). 13C NMR
(CDCl3, 100.6 MHz) δ 28.8 (3 CH3), 46.2 (d, J = 3.4 Hz, CH2), 52.3 (CH3),
58.9 (C), 68.2 (C), 116.0 (d, J = 21.7 Hz, CH), 124.3 (d, J = 3.7 Hz, CH),
126.4 (d, J = 13.4 Hz, C), 129.3 (d, J = 8.2 Hz, CH), 129.5 (d, J = 4.3 Hz,
CH), 160.8 (d, J = 246.5 Hz, C), 163.1 (C), 163.6 (C). HRMS (ESI-TOF)
calcd. for C15H18FN3NaO3: 330.1224 [M+H]+; found: 330.1225.
N-tert-Butyl-N-(4-cyanobenzyl)-α-(methoxycarbonyl)-α-
diazoacetamide (4e). 4e was obtained as a red oil that solidified on
refrigeration (155 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.3 equiv.), Et3N (1.3 equiv.), 52%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 33%]. 1H NMR (CDCl3, 400 MHz) δ 1.38 (s,
9H), 3.77 (s, 3H), 4.67 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H) 7.63 (d, J = 8.0
Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 29.0 (3 CH3), 51.2 (CH2), 52.4
(CH3), 59.5 (C), 68.8 (C), 111.5 (C), 118.7 (C), 127.6 (2 CH), 132.6 (2
CH), 145.7 (C), 162.8 (C), 163.6 (C). HRMS (ESI-TOF) calcd. for
C16H18N4NaO3: 337.1271 [M+H]+; found: 337.1279.
N-(2-Bromobenzyl)-N-tert-butyl-α-(methoxycarbonyl)- α-
diazoacetamide (4k). 4k was obtained as a yellow oil that solidified on
refrigeration (417 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1 equiv.), Et3N (1 equiv.); (b) p-ABSA (1.1 equiv.),
1
DBU (1.5 equiv.), 83% two steps]. H NMR (CDCl3, 400 MHz) δ 1.42 (s,
9H), 3.76 (s, 3H), 4.72 (s, 2H), 7.13 (ddd, J = 8.0, 7.6 and 2.4 Hz, 1H),
7.26-7.34 (m, 2H), 7.54 (dd, J = 8.0 and 1.2 Hz, 1H). 13C NMR (CDCl3,
100.6 MHz) δ 28.9 (3 CH3), 51.6 (CH2), 52.4 (CH3), 59.4 (C), 67.6 (C),
122.1 (C), 127.5 (CH), 128.6 (CH), 128.9 (CH), 133.4 (CH), 138.5 (C),
163.2 (C), 163.6 (C). HRMS (ESI-TOF) calcd. for C15H18BrN3NaO3:
390.0424 [M+H]+; found: 390.0432.
N-tert-Butyl-N-[4-(dimethylamino)benzyl]-α-(methoxycarbonyl)-α-
diazoacetamide (4f). 4f was obtained as a yellow oil that solidified on
refrigeration (190 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.3 equiv.), Et3N (1.3 equiv.), 58%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 85%]. 1H NMR (CDCl3, 400 MHz) δ 1.38 (s,
9H), 2.93 (s, 6H), 3.77 (s, 3H), 4.52 (s, 2H), 6.68 (d, J = 8.8 Hz, 2H), 7.04
(d, J = 8.8 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.9 (3 CH3), 40.8 (2
CH3), 51.3 (CH2), 52.3 (CH3), 58.9 (C), 68.0 (C), 112.7 (2 CH), 126.9 (C),
127.9 (2 CH), 150.0 (C), 163.0 (C), 163.3 (C). HRMS (ESI-TOF) calcd.
for C17H25N4O3: 333.1921 [M+H]+; found: 333.1925.
N-tert-Butyl-N-(2-iodobenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4l). 4l was obtained as a yellow oil that solidified on
refrigeration (260 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.3 equiv.), Et3N (1.3 equiv.), 64%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 89%]. 1H NMR (CDCl3, 400 MHz) δ 1.42 (s,
9H), 3.76 (s, 3H), 4.63 (s, 2H), 6.97 (ddd, J = 8.0, 7.6 and 1.6 Hz, 1H),
7.24 (dd, J = 7.6 and 1.6 Hz, 1H), 7.35 (td, J = 7.6 and 1.6 Hz, 1H), 7.83
(dd, J = 8.0 and 1.6 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 29.0 (3
CH3), 52.4 (CH3), 56.7 (CH2), 59.6 (C), 67.6 (C), 97.1 (C), 127.9 (CH),
128.4 (CH), 129.1 (CH), 140.0 (CH), 141.2 (C), 163.2 (C), 163.5 (C).
HRMS (ESI-TOF) calcd. for C15H18IN3NaO3: 438.0258 [M+H]+; found:
438.0283.
N-tert-Butyl-N-(3-chlorobenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4g). 4g was obtained as a yellow oil that solidified on
refrigeration (505 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.2 equiv.), Et3N (1.2 equiv.), 82%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 85%]. 1H NMR (CDCl3, 400 MHz) δ 1.39 (s,
9H), 3.77 (s, 3H), 4.59 (s, 2H), 7.09 (d, J = 7.2 Hz, 1H), 7.18 (broad s,
1H), 7.22-7.29 (m, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 29.0 (3 CH3),
51.2 (CH2), 52.4 (CH3), 59.3 (C), 68.4 (C), 125.0 (CH), 127.1 (CH), 127.7
(CH), 130.1 (CH), 134.8 (C), 142.0 (C), 163.0 (C), 163.4 (C). HRMS
(ESI-TOF) calcd. for C15H18ClN3NaO3: 346.0929 [M+H]+; found: 346.0933.
N-tert-Butyl-N-(3,4-dimethoxybenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4m). 4m was obtained as a yellow oil that solidified on
refrigeration (570 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.2 equiv.), Et3N (1.2 equiv.), 68%; (b) p-ABSA (1.1
equiv.), DBU (1.5 equiv.), 80%]. 1H NMR (CDCl3, 400 MHz) δ 1.40 (s,
9H), 3.78 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 4.56 (s, 2H), 6.68 (d, J = 2.0
Hz, 1H), 6.74 (dd, J = 8.4 and 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H). 13C
NMR (CDCl3, 100.6 MHz) δ 28.9 (3 CH3), 51.3 (CH2), 52.3 (CH3), 56.0
(CH3), 56.1 (CH3), 59.1 (C), 67.9 (C), 110.0 (CH), 111.4 (CH), 119.0 (CH),
132.1 (C), 148.4 (C), 149.2 (C), 163.2 (2 C). HRMS (ESI-TOF) calcd. for
C17H24N3O5: 350.1710 [M+H]+; found: 350.1713.
N-tert-Butyl-N-(3-cyanobenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4h). 4h was obtained as a yellow oil that solidified on
refrigeration (330 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1.3 equiv.), Et3N (1.3 equiv.); (b) p-ABSA (1.1 equiv.),
1
DBU (1.5 equiv.), 63% two steps]. H NMR (CDCl3, 400 MHz) δ 1.38 (s,
9H), 3.78 (s, 3H), 4.65 (s, 2H), 7.45-7.51 (m, 3H), 7.55-7.59 (m, 1H). 13
C
NMR (CDCl3, 100.6 MHz) δ 29.0 (3 CH3), 51.0 (CH2), 52.4 (CH3), 59.4
(C), 68.8 (C), 113.0 (C), 118.6 (C), 129.7 (CH), 130.4 (CH), 131.3 (CH),
131.4 (CH), 141.7 (C), 162.8 (C), 163.6 (C). HRMS (ESI-TOF) calcd. for
C16H18N4NaO3: 337.1271 [M+H]+; found: 337.1278.
N-tert-Butyl-N-(1-phenylethyl)-α-(methoxycarbonyl)-α-
diazoacetamide (7). 7 was obtained as a yellow oil (210 mg) following
the procedures described above [(a) ClCOCH2CO2Me (1.3 equiv.), Et3N
(1.3 equiv.), 35%; (b) p-ABSA (1.1 equiv.), DBU (1.5 equiv.), 63%]. 1H
NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.80 (d, J = 7.2 Hz, 3H), 3.70 (s,
3H), 5.19 (q, J = 7.2 Hz, 1H), 7.22-7.28 (m, 1H), 7.32-7.37 (m, 4H). 13C
NMR (CDCl3, 100.6 MHz) δ 20.2 (CH3), 29.5 (3 CH3), 52.3 (CH3), 56.3
(CH), 60.1 (C), 66.8 (C), 126.9 (2 CH), 127.2 (CH), 128.6 (2 CH), 142.3
(C), 163.2 (C), 164.2 (C). HRMS (ESI-TOF) calcd. for C16H21N3NaO3:
326.1475 [M+H]+; found: 326.1471.
N-tert-Butyl-N-(2-methoxybenzyl)-α-(methoxycarbonyl)- α-
diazoacetamide (4i). 4i was obtained as a yellow oil that solidified on
refrigeration (384 mg) following the procedures described above [(a)
ClCOCH2CO2Me (1 equiv.), Et3N (1 equiv.); (b) p-ABSA (1.1 equiv.),
1
DBU (1.5 equiv.), 70% two steps]. H NMR (CDCl3, 400 MHz) δ 1.34 (s,
9H), 3.77 (s, 3H), 3.80 (s, 3H), 4.60 (s, 2H), 6.85 (dd, J = 8.0, and 1.2 Hz,
1H), 6.92 (td, J = 7.6 and 1.2 Hz, 1H), 7.18 (dd, J = 7.6 and 1.2 Hz, 1H),
7.25 (ddd, J = 8.0, 7.6 and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ
28.6 (3 CH3), 48.5 (CH2), 52.2 (CH3), 55.6 (CH3), 58.6 (C), 68.0 (C),
110.7 (CH), 120.5 (CH), 127.1 (C), 128.8 (CH), 129.3 (CH), 157.9 (C),
163.5 (C), 163.7 (C). HRMS (ESI-TOF) calcd. for C16H22N3O4: 320.1605
[M+H]+; found: 320.1601.
Representative Procedure for the Pd-Catalyzed Cyclisation
Reactions (Table 2, Entry 3). A mixture of diazoamide 4a (50 mg, 0.17
mmol), [Pd(allyl)Cl]2 (3 mg, 0.008 mmol) in dichloroethane (10 mL) was
stirred at reflux under Argon atmosphere for 24 h. The solvent was
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10.1002/ejoc.201800666
European Journal of Organic Chemistry
FULL PAPER
removed in vacuo, and the residue was purified by chromatography (SiO2,
from hexanes to hexanes-EtOAc 2:3) to give β-lactam trans-6a (29.5 mg,
65%) and β-lactam cis-6a (11 mg, 25%).
CH), 128.9 (CH), 129.2 (2 CH), 139.2 (C), 162.1 (C), 167.7 (C). HRMS
(ESI-TOF) calcd. for C15H20NO3: 262.1438 [M+H]+; found: 262.1439.
Methyl
2-tert-butyl-6-methoxy-3-oxo-1H-2,3-
Methyl
2-benzyl-3-oxo-1H-2,3-dihydrocyclohepta[c]pyrrole-3a-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (5b). 1H NMR (CDCl3,
400 MHz, signals from a 10:1 mixture of 5b and trans-6b) δ 1.45 (s, 9H),
3.60 (s, 3H), 3.61 (s, 3H), 4.18 (ddd, J = 14.4, 2.0 and 0.8 Hz, 1H), 4.42
(ddd, J = 14.4, 2.4 and 1.2 Hz, 1H), 5.63 (dd, J = 7.2 and 1.6 Hz, 1H),
5.73 (d, J = 10.8 Hz, 1H), 6.15 (dt, J = 7.2 and 2.0 Hz, 1H), 6.26 (dd, J =
10.8 and 2.4 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz, signals from a 10:1
mixture of 5b and trans-6b) δ 27.6 (3 CH3), 49.5 (CH2), 52.9 (CH3), 54.9
(C), 55.0 (CH3), 60.8 (C), 101.8 (CH), 118.8 (CH), 124.9 (CH), 125.1 (C),
126.2 (CH), 159.0 (C), 169.3 (C), 170.7 (C).
carboxylate (2). 25 mg (55%, Table 1, Entry 5). Brown oil. 1H NMR
(CDCl3, 400 MHz) δ 3.61 (s, 3H), 4.01 (dd, J = 14.8 and 1.6 Hz, 1H), 4.27
(dd, J = 14.8 and 2.4 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.69 (d, J = 14.8
Hz, 1H), 5.65 (d, J = 9.6 Hz, 1H), 6.24 (m, 1H), 6.42-6.54 (m, 3H), 7.23-
7.36 (m, 5H). 13C NMR (CDCl3, 100.6 MHz) δ 47.0 (CH2), 50.3 (CH2),
53.0 (CH3), 60.0 (C), 120.9 (CH), 122.4 (CH), 128.0 (CH), 128.1 (2 CH),
128.3 (CH), 128.7 (CH), 129.0 (2 CH), 130.0 (CH), 130.4 (C), 135.6 (C),
168.6 (C), 171.1 (C). HRMS (ESI-TOF) calcd. for C18H18NO3: 296.1281
[M+H]+; found: 296.1281.
Methyl
cis-1-tert-butyl-4-(4-methoxyphenyl)-2-oxoazetidine-3-
Methyl cis-1-benzyl-2-oxo-4-phenylazetidine-3-carboxylate (cis-3).
This compound could not be isolated and characterized. 1H NMR (CDCl3,
400 MHz, significant signals from the crude reaction mixture) δ 3.33 (s,
3H), 3.93 (d, J = 14.8 Hz, 1H), 4.34 (d, J = 6.0 Hz, 1H), 4.71 (dd, J = 6.0
and 1.2 Hz, 1H), 4.94 (d, J = 14.8 Hz, 1H).
carboxylate (cis-6b). 8 mg (18%, Table S1, Entry 1). Amorphous white
solid. 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 3.38 (s, 3H), 3.80 (s, 3H),
4.20 (d, J = 6.4 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 6.86 (d, J= 8.4 Hz, 2H),
7.29 (d, J= 8.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3),
52.0 (CH3), 55.1 (C), 55.4 (CH3), 56.4 (CH), 59.3 (CH), 113.9 (2 CH),
128.4 (2 CH), 128.5 (C), 160.0 (C), 163.1 (C), 166.8 (C). HRMS (ESI-
TOF) calcd. for C16H22NO4: 292.1543 [M+H]+; found: 292.1549.
Methyl trans-1-benzyl-2-oxo-4-phenylazetidine-3-carboxylate (trans-
3). 10.5 mg (23%, Table 1, Entry 7). Yellow gum. 1H NMR (CDCl3, 400
MHz) δ 3.79 (s, 3H), 3.84 (d, J = 15.2 Hz, 1H), 3.93 (dd, J = 2.0 and 0.8
Hz, 1H), 4.71 (d, J = 2.0 Hz, 1H), 4.85 (d, J = 15.2 Hz, 1H), 7.14-7.17 (m,
2H), 7.23-7.40 (m, 8H). 13C NMR (CDCl3, 100.6 MHz) δ 45.1 (CH2), 52.9
(CH3), 57.2 (CH), 63.4 (CH), 126.9 (2 CH), 128.0 (CH), 128.5 (2 CH),
129.0 (2 CH), 129.2 (CH), 129.3 (2 CH), 134.8 (C), 136.0 (C), 162.4 (C),
167.4 (C). HRMS (ESI-TOF) calcd. for C18H18NO3: 296.1281 [M+H]+;
found: 296.1275.
Methyl
trans-1-tert-butyl-4-(4-methoxyphenyl)-2-oxoazetidine-3-
carboxylate (trans-6b). 18 mg (39%, Table S1, Entry 1). Amorphous
yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 3.69 (d, J = 2.0
Hz, 1H), 3.77 (s, 3H), 3.82 (s, 3H), 4.81 (d, J = 2.0 Hz, 1H), 6.90 (d, J=
8.4 Hz, 2H), 7.30 (d, J= 8.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3
(3 CH3), 52.8 (CH3), 55.3 (C), 55.5 (CH3), 56.3 (CH), 62.5 (CH), 114.5 (2
CH), 128.1 (2 CH), 131.0 (C), 160.1 (C), 162.2 (C), 167.9 (C). HRMS
(ESI-TOF) calcd. for C16H22NO4: 292.1543 [M+H]+; found: 292.1547.
N,N-Dibenzyl-α-chloro-α-(methoxycarbonyl)acetamide. Amorphous
orange solid. 1H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H), 4.34 (d, J = 14.8
Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.62 (d, J = 17.2 Hz, 1H), 4.88 (d, J =
14.8 Hz, 1H), 5.13 (s, 1H), 7.18-7.23 (m, 4H), 7.28-7.43 (m, 5H). 13C
NMR (CDCl3, 100.6 MHz) δ 48.9 (CH2), 50.6 (CH2), 54.0 (CH), 54.5
(CH3), 126.7 (2 CH), 128.0 (CH), 128.3 (CH), 128.4 (2 CH), 129.0 (2 CH),
129.3 (2 CH), 132.3 (C), 136.2 (C), 165.5 (C), 165.6 (C). HRMS (ESI-
TOF) calcd. for C18H19ClNO3: 332.1048 [M+H]+; found: 332.1049.
Methyl
2-tert-butyl-6-(methylthio)-3-oxo-1H-2,3-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (5c). 1H NMR (CDCl3,
400 MHz, signals from a 3.3:1 mixture of trans-6c and 5c) δ 1.45 (s, 9H),
2.32 (s, 3H), 3.61 (s, 3H), 4.21 (d, J = 14.8 Hz, 1H), 4.43 (d, J = 14.8 Hz,
1H), 5.64 (d, J = 10.4 Hz, 1H), 6.14 (d, J = 6.8 Hz, 1H), 6.38 (d, J = 10.8
Hz, 1H), 6.39 (d, J = 6.8 Hz, 1H).
Methyl
cis-1-tert-butyl-4-[4-(methylthio)phenyl]-2-oxoazetidine-3-
Methyl
2-tert-butyl-3-oxo-1H-2,3-dihydrocyclohepta[c]pyrrole-3a-
carboxylate (cis-6c). 4.5 mg (10%, Table S1, Entry 3). Yellow gum. 1H
NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 2.48 (s, 3H), 3.37 (s, 3H), 4.22 (d,
J = 6.4 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 7.20 (d, J= 8.4 Hz, 2H), 7.29 (d,
J= 8.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 15.6 (CH3), 28.3 (3 CH3),
52.1 (CH3), 55.2 (C), 56.4 (CH), 59.2 (CH), 126.1 (2 CH), 127.7 (2 CH),
133.2 (C), 139.6 (C), 163.0 (C), 166.6 (C). HRMS (ESI-TOF) calcd. for
C16H22NO3S: 308.1315 [M+H]+; found: 308.1319.
carboxylate (5a). 1H NMR (CDCl3, 400 MHz, signals from a 8:1 mixture
of 5a and trans-6a) δ 1.46 (s, 9H), 3.59 (s, 3H), 4.24 (dd, J = 15.2 and
1.6 Hz, 1H), 4.47 (dd, J = 15.2 and 2.0 Hz, 1H), 5.59 (dd, J = 9.2 and 0.8
Hz, 1H), 6.28 (m, 1H), 6.38-6.46 (m, 3H). 13C NMR (CDCl3, 100.6 MHz,
signals from a 8:1 mixture of 5a and trans-6a) δ 27.6 (3 CH3), 49.6 (CH2),
52.8 (CH3), 55.0 (C), 61.3 (C), 120.5 (CH), 123.2 (CH), 127.8 (CH), 128.9
(CH), 129.9 (CH), 131.3 (C), 169.0 (C), 170.8 (C).
Methyl trans-1-tert-butyl-4-[4-(methylthio)phenyl]-2-oxoazetidine-3-
carboxylate (trans-6c). 22 mg (48%, Table S1, Entry 3). Colourless oil.
1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 2.49 (s, 3H), 3.68 (d, J = 2.0
Hz, 1H), 3.77 (s, 3H), 4.82 (d, J = 2.0 Hz, 1H), 7.24 (d, J= 8.0 Hz, 2H),
7.30 (d, J= 8.0 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 15.7 (CH3), 28.3
(3 CH3), 52.8 (CH3), 55.4 (C), 56.3 (CH), 62.4 (CH), 126.8 (2 CH), 127.3
(2 CH), 135.8 (C), 139.7 (C), 162.1 (C), 167.7 (C). HRMS (ESI-TOF)
calcd. for C16H22NO3S: 308.1315 [M+H]+; found: 308.1318.
Methyl cis-1-tert-butyl-2-oxo-4-phenylazetidine-3-carboxylate (cis-
6a). 11 mg (25%, Table 2, Entry 3). Yellow gum. 1H NMR (CDCl3, 400
MHz) δ 1.31 (s, 9H), 3.32 (s, 3H), 4.23 (d, J = 6.4 Hz, 1H), 4.91 (d, J =
6.4 Hz, 1H), 7.28-7.40 (m, 5H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3
CH3), 52.0 (CH3), 55.2 (C), 56.8 (CH), 59.3 (CH), 127.2 (CH), 128.6 (2
CH), 128.9 (2 CH), 136.7 (C), 163.0 (C), 166.6 (C). ). HRMS (ESI-TOF)
calcd. for C15H20NO3: 262.1438 [M+H]+; found: 262.1439.
Methyl
trans-1-tert-butyl-2-oxo-4-phenylazetidine-3-carboxylate
Methyl
cis-1-tert-butyl-4-(4-chlorophenyl)-2-oxoazetidine-3-
(trans-6a). 29 mg (65%, Table 2, Entry 3). Amorphous white solid. 1H
NMR (CDCl3, 400 MHz) δ 1.27 (s, 9H), 3.72 (d, J = 2.0 Hz, 1H), 3.78 (s,
3H), 4.86 (d, J = 2.0 Hz, 1H), 7.31-7.42 (m, 5H). 13C NMR (CDCl3, 100.6
MHz) δ 28.3 (3 CH3), 52.8 (CH3), 55.4 (C), 56.6 (CH), 62.5 (CH), 126.8 (2
carboxylate (cis-6d). 19 mg (42%, Table S1, Entry 5). Amorphous white
solid. 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 3.38 (s, 3H), 4.23 (d, J =
6.4 Hz, 1H), 4.89 (d, J = 6.4 Hz, 1H), 7.33 (s, 4H). 13C NMR (CDCl3,
100.6 MHz) δ 28.3 (3 CH3), 52.2 (CH3), 55.3 (C), 56.1 (CH), 59.2 (CH),
128.6 (2 CH), 128.8 (2 CH), 134.8 (C), 135.4 (C), 162.8 (C), 166.4 (C).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800666
European Journal of Organic Chemistry
FULL PAPER
HRMS (ESI-TOF) calcd. for C15H19ClNO3: 296.1048 [M+H]+; found:
296.1050.
(CH), 138.8 (C), 162.5 (C), 166.1 (C). HRMS (ESI-TOF) calcd. for
C16H19N2O3: 287.1390 [M+H]+; found: 287.1399.
Methyl
trans-1-tert-butyl-4-(4-chlorophenyl)-2-oxoazetidine-3-
Methyl
trans-1-tert-butyl-4-(3-cyanophenyl)-2-oxoazetidine-3-
carboxylate (trans-6d). 18 mg (40%, Table S1, Entry 5). Amorphous
white solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 3.67 (d, J = 2.0 Hz,
1H), 3.78 (s, 3H), 4.84 (d, J = 2.0 Hz, 1H), 7.32-7-38 (m, 4H). 13C NMR
(CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 52.9 (CH3), 55.5 (C), 55.9 (CH), 62.5
(CH), 128.1 (2 CH), 129.4 (2 CH), 134.8 (C), 137.9 (C), 162.0 (C), 167.4
(C). HRMS (ESI-TOF) calcd. for C15H19ClNO3: 296.1048 [M+H]+; found:
296.1051.
carboxylate (trans-6h). 19.5 mg (43%, Table S1, Entry 13). Amorphous
yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.28 (s, 9H), 3.68 (d, J = 2.4
Hz, 1H), 3.80 (s, 3H), 4.91 (d, J = 2.4 Hz, 1H), 7.54 (td, J= 7.6 and 0.4 Hz,
1H), 7.64-7.71 (m, 3H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3),
53.0 (CH3), 55.5 (CH), 55.7 (C), 62.5 (CH), 113.5 (C), 118.3 (C), 130.2
(CH), 130.4 (CH), 130.8 (CH), 132.6 (CH), 141.2 (C), 161.7 (C), 167.0
(C). HRMS (ESI-TOF) calcd. for C16H19N2O3: 287.1390 [M+H]+; found:
287.1387.
Methyl
cis-1-tert-butyl-4-(4-cyanophenyl)-2-oxoazetidine-3-
carboxylate (cis-6e). 12 mg (27%, Table S1, Entry 8). Yellow gum. 1H
NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 3.34 (s, 3H), 4.28 (d, J = 6.4 Hz,
1H), 4.94 (d, J = 6.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.65 (d, J= 8.4 Hz,
2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 52.2 (CH3), 55.5 (C),
56.0 (CH), 59.2 (CH), 112.9 (C), 118.4 (C), 128.0 (2 CH), 132.4 (2 CH),
142.5 (C), 162.5 (C), 166.0 (C). HRMS (ESI-TOF) calcd. for C16H19N2O3:
287.1390 [M+H]+; found: 287.1389.
Methyl
cis-1-tert-butyl-4-(2-methoxyphenyl)-2-oxoazetidine-3-
carboxylate (cis-6i). 5 mg (10%, Table S1, Entry 16). Yellow gum. 1H
NMR (CDCl3, 400 MHz) δ 1.33 (s, 9H), 3.29 (s, 3H), 3.85 (s, 3H), 4.22 (d,
J = 6.4 Hz, 1H), 5.43 (d, J = 6.4 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.94
(ddd, J= 8.0, 7.6 and 0.8 Hz, 1H), 7.26 (dd, J = 8.0 and 7.6 Hz, 1H), 7.44
(d, J = 8.8 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz, signals from a 1:8
mixture of 5i and cis-6i) δ 28.1 (3 CH3), 50.0 (CH), 51.8 (CH3), 54.9 (C),
55.8 (CH3), 58.7 (CH), 110.6 (CH), 120.2 (CH), 124.8 (C), 127.5 (CH),
129.6 (CH), 157.3 (C), 163.8 (C), 166.8 (C).
Methyl
trans-1-tert-butyl-4-(4-cyanophenyl)-2-oxoazetidine-3-
carboxylate (trans-6e). 23 mg (51%, Table S1, Entry 8). Amorphous
white solid. 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 9H), 3.67 (d, J = 2.4 Hz,
1H), 3.79 (s, 3H), 4.92 (d, J = 2.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.69
(d, J= 8.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 53.1
(CH3), 55.7 (C), 55.8 (CH), 62.5 (CH), 113.0 (C), 118.3 (C), 127.5 (2 CH),
133.1 (2 CH), 144.9 (C), 161.7 (C), 167.0 (C). HRMS (ESI-TOF) calcd.
for C16H19N2O3: 287.1390 [M+H]+; found: 287.1393.
Methyl
trans-1-tert-butyl-4-(2-methoxyphenyl)-2-oxoazetidine-3-
carboxylate (trans-6i). 29 mg (63%, Table S1, Entry 16). Amorphous
orange solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 3.78 (s, 3H),
3.84 (s, 3H), 3.86 (broad, 1H), 5.17 (d, J = 2.0 Hz, 1H), 6.89 (dd, J= 8.0
and 1.2 Hz, 1H), 6.96 (td, J= 7.6 and 1.2 Hz, 1H), 7.30 (ddd, J= 8.0, 7.6
and 2.0 Hz, 1H), 7.35 (dd, J= 7.6 and 2.0 Hz, 1H). 13C NMR (CDCl3,
100.6 MHz) δ 28.0 (3 CH3), 52.2 (broad, CH), 52.7 (CH3), 55.0 (C), 55.5
(CH3), 60.4 (CH), 111.0 (CH), 120.9 (CH), 126.5 (C), 128.5 (broad, CH),
129.9 (CH), 157.7 (C), 162.5 (C), 168.4 (C). HRMS (ESI-TOF) calcd. for
Methyl
trans-1-tert-butyl-4-[4-(dimethylamino)phenyl]-2-
oxoazetidine-3-carboxylate (trans-6f). 6 mg (14%, Table S1, Entry 9).
Orange oil. 1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 2.96 (s, 6H), 3.70
(d, J = 2.0 Hz, 1H), 3.76 (s, 3H), 4.77 (d, J = 2.0 Hz, 1H), 6.69 (d, J= 8.8
Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H). HRMS (ESI-TOF) calcd. for C17H25N2O3:
305.1860 [M+H]+; found: 305.1860.
C
16H22NO4: 292.1543 [M+H]+; found: 292.1539.
Methyl cis-1-tert-butyl-4-(2-fluorophenyl)-2-oxoazetidine-3-
carboxylate (cis-6j). 1H NMR (CDCl3, 400 MHz, signals from a 8:1
mixture of cis-6j and trans-6j) δ 1.32 (s, 9H), 3.36 (broad s, 3H), 4.28 (d,
J = 6.4 Hz, 1H), 5.30 (broad, 1H), 7.05 (ddd, J= 10.4, 8.0 and 1.2 Hz, 1H),
7.15 (td, J= 7.6 and 1.2 Hz, 1H), 7.27-7.33 (m, 1H), 7.49 (ddd, J= 8.0, 7.6
and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz, signals from a 8:1 mixture
of cis-6j and trans-6j) δ 28.1 (3 CH3), 52.1 (CH3), 55.2 (C), 58.5 (broad,
CH), 61.1 (broad, CH), 115.7 (d, J = 21.5 Hz, CH), 124.0 (d, J = 12.0 Hz,
CH), 124.0 (d, J= 3.6 Hz, CH), 128.0 (broad, C), 130.4 (d, J = 8.3 Hz,
CH), 163.0 (C), 166.4 (C). One C was not observed.
Methyl
cis-1-tert-butyl-4-(3-chlorophenyl)-2-oxoazetidine-3-
1
carboxylate (cis-6g). 20 mg (44%, Table S1, Entry 11). Yellow gum. H
NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 3.40 (s, 3H), 4.24 (d, J = 6.4 Hz,
1H), 4.87 (d, J = 6.4 Hz, 1H), 7.26-7.32 (m, 3H), 7.39 (d, J= 1.6 Hz, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 52.1 (CH3), 55.4 (C), 56.1
(CH), 59.3 (CH), 125.4 (broad CH), 127.4 (broad CH), 129.1 (CH), 129.9
(CH), 134.6 (C), 139.0 (C), 162.8 (C), 166.3 (C). HRMS (ESI-TOF) calcd.
for C15H19ClNO3: 296.1048 [M+H]+; found: 296.1057.
Methyl
trans-1-tert-butyl-4-(2-fluorophenyl)-2-oxoazetidine-3-
carboxylate (trans-6j). 30 mg (66%, Table S1, Entry 18). Amorphous
white solid. 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 9H), 3.79 (s, 3H), 3.84
(d, J = 2.4 Hz, 1H), 5.16 (d, J = 2.4 Hz, 1H), 7.08 (ddd, J= 10.4, 8.0 and
1.2 Hz, 1H), 7.18 (td, J= 7.6 and 1.2 Hz, 1H), 7.30-7.36 (m, 1H), 7.43 (td,
J= 7.6 and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 28.0 (3 CH3),
50.3 (d, J = 3.8 Hz, CH), 52.9 (CH3), 55.3 (C), 61.1 (d, J = 1.8 Hz, CH),
116.3 (d, J = 21.5 Hz, CH), 124.8 (d, J = 3.6 Hz, CH), 126.0 (d, J = 11.9
Hz, C), 128.5 (d, J= 3.6 Hz, CH), 130.6 (d, J = 8.4 Hz, CH), 160.9 (d, J =
248.7 Hz, C), 161.9 (C), 167.6 (C). HRMS (ESI-TOF) calcd. for
C15H19FNO3: 280.1343 [M+H]+; found: 280.1345.
Methyl
trans-1-tert-butyl-4-(3-chlorophenyl)-2-oxoazetidine-3-
carboxylate (trans-6g). 16.5 mg (36%, Table S1, Entry 11). Brown gum.
1H NMR (CDCl3, 400 MHz) δ 1.28 (s, 9H), 3.68 (d, J = 2.0 Hz, 1H), 3.78
(s, 3H), 4.83 (d, J = 2.0 Hz, 1H), 7.27-7.34 (m, 3H), 7.39 (broad singlet,
1H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 52.9 (CH3), 55.6 (C),
55.9 (CH), 62.5 (CH), 124.8 (CH), 127.0 (CH), 129.2 (CH), 130.5 (CH),
135.2 (C), 141.5 (C), 161.9 (C), 167.3 (C). HRMS (ESI-TOF) calcd. for
C15H19ClNO3: 296.1048 [M+H]+; found: 296.1050.
Methyl
cis-1-tert-butyl-4-(3-cyanophenyl)-2-oxoazetidine-3-
carboxylate (cis-6h). 10 mg (22%, Table S1, Entry 13). Colourless oil.
1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 3.38 (s, 3H), 4.28 (d, J = 6.4
Hz, 1H), 4.93 (d, J = 6.4 Hz, 1H), 7.50 (dd, J= 8.4 and 7.6 Hz, 1H), 7.64
(dt, J= 7.6 and 1.6 Hz, 1H), 7.65-7.70 (m, 2H). 13C NMR (CDCl3, 100.6
MHz) δ 28.3 (3 CH3), 52.3 (CH3), 55.5 (C), 55.7 (CH), 59.3 (CH), 112.9
(C), 118.4 (C), 129.5 (CH), 130.9 (broad, CH), 131.5 (broad, CH), 132.6
Methyl
2-tert-butyl-8-bromo-3-oxo-1H-2,3-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (5k). 1H NMR (CDCl3,
400 MHz, signals from a 1:2 mixture of 5k and trans-6k) δ 1.48 (s, 9H),
3.61 (s, 3H), 4.15 (d, J = 16.0 Hz, 1H), 4.28 (d, J = 16.0 Hz, 1H), 5.65-
5.69 (m, 1H), 6.36-6.43 (m, 2H), 6.50-6.57 (m, 1H).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800666
European Journal of Organic Chemistry
FULL PAPER
Methyl
cis-4-(2-bromophenyl)-1-tert-butyl-2-oxoazetidine-3-
NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 3.40 (s, 3H), 3.88 (s, 6H), 4.21 (d,
J = 6.4 Hz, 1H), 4.86 (d, J = 6.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.91-
6.93 (m, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (3 CH3), 52.2 (CH3),
55.1 (C), 56.0 (CH3), 56.1 (CH3), 56.8 (CH), 59.3 (CH), 109.8 (broad, CH),
110.9 (CH), 120.1 (broad, CH), 129.0 (C), 149.0 (C), 149.4 (C), 163.0 (C),
166.8 (C). HRMS (ESI-TOF) calcd. for C17H24NO5: 322.1654 [M+H]+;
found: 322.1656.
carboxylate (cis-6k). 16 mg (34%, Table S1, Entry 19). Amorphous
orange solid. 1H NMR (CDCl3, 400 MHz) δ 1.34 (s, 9H), 3.31 (s, 3H),
4.31 (d, J = 6.4 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 7.18 (ddd, J= 8.0, 7.2
and 1.6 Hz, 1H), 7.33 (ddd, J= 7.6, 7.2 and 1.2 Hz, 1H), 7.53-7.57 (m,
2H). 13C NMR (CDCl3, 100.6 MHz) δ 28.1 (3 CH3), 52.0 (CH3), 55.2 (C),
55.5 (CH), 58.4 (CH), 123.4 (C), 127.2 (CH), 128.5 (CH), 130.0 (CH),
133.0 (CH), 135.7 (C), 163.3 (C), 166.2 (C). HRMS (ESI-TOF) calcd. for
C15H19BrNO3: 340.0543 [M+H]+; found: 340.0542.
Methyl trans-1-tert-butyl-4-(3,4-dimethoxyphenyl)-2-oxoazetidine-3-
carboxylate (trans-6m). 17.5 mg (38%, Table S1, Entry 24). Amorphous
yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.28 (s, 9H), 3.71 (d, J = 2.4
Hz, 1H), 3.78 (s, 3H), 3.89 (s, 6H), 4.82 (d, J = 2.4 Hz, 1H), 6.85 (d, J=
8.0 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.0 and 2.4 Hz, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 28.2 (3 CH3), 52.8 (CH3), 55.3 (C), 56.1
(CH3), 56.2 (CH3), 56.6 (CH), 62.5 (CH), 109.1 (CH), 111.4 (CH), 119.6
(CH), 131.4 (C), 149.5 (C), 149.6 (C), 162.2 (C), 167.8 (C). HRMS (ESI-
TOF) calcd. for C17H24NO5: 322.1654 [M+H]+; found: 322.1655.
Methyl
trans-4-(2-bromophenyl)-1-tert-butyl-2-oxoazetidine-3-
carboxylate (trans-6k). 14 mg (31%, Table S1, Entry 19). Amorphous
yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 3.59 (broad, 1H),
3.80 (s, 3H), 5.38 (broad, 1H), 7.19 (ddd, J= 8.0, 7.6 and 1.2 Hz, 1H),
7.37 (ddd, J= 8.0, 7.6 and 1.2 Hz, 1H), 7.50 (dd, J = 8.0 and 1.2 Hz, 1H),
7.57 (dd, J = 8.0 and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 28.1 (3
CH3), 52.9 (CH3), 55.2 (broad, CH), 55.4 (C), 62.1 (broad, CH), 127.2
(broad, CH), 128.1 (CH), 128.5 (C), 130.1 (CH), 133.0 (C), 133.4 (broad,
CH), 162.5 (C), 167.4 (C). HRMS (ESI-TOF) calcd. for C15H19BrNO3:
340.0543 [M+H]+; found: 340.0552.
Methyl
2-tert-butyl-1-methyl-3-oxo-1H-2,3-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (8). 7 mg (15%, Table 3,
Entry 1). 1H NMR (CDCl3, 400 MHz, signals from a 1:1.2 mixture of
stereoisomers) δ 1.37 (d, J = 6.0 Hz, 3H minor isomer), 1.50 (s, 9H major
isomer), 1.51 (s, 9H minor isomer), 1.72 (d, J = 6.0 Hz, 3H major isomer),
3.55 (s, 3H minor isomer), 3.60 (s, 3H major isomer), 4.53 (qd, J = 6.0
and 1.6 Hz, 1H major isomer), 4.75 (qd, J = 6.0 and 1.6 Hz, 1H minor
isomer), 5.57 (d, J = 9.6 Hz, 1H major isomer), 5.65 (d, J = 9.6 Hz, 1H
minor isomer), 6.23-6.28 (m, 1H major and 1H minor isomer), 6.35-6.53
(m, 3H major and 3H minor isomer). 13C NMR (CDCl3, 100.6 MHz,
signals from a 1:1.2 mixture of stereoisomers) δ 25.7 (CH3), 28.3 (CH3),
28.4 (3 CH3), 29.4 (3 CH3), 52.8 (CH3), 52.9 (CH3), 55.3 (C), 55.4 (C),
57.5 (CH), 57.6 (CH), 60.7 (C), 61.0 (C), 118.8 (CH), 119.8 (CH), 122.8
(CH), 124.0 (CH), 127.7 (2 CH), 128.6 (CH), 128.9 (CH), 129.4 (CH),
130.0 (CH), 138.4 (C), 138.6 (C), 168.9 (C), 169.0 (C), 170.1 (C), 170.7
(C).
Methyl
2-tert-butyl-8-iodo-3-oxo-1H-2,3-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (5l). 1H NMR (CDCl3, 400
MHz, signals from a 1:3.3 mixture of 5l and trans-6l) δ 1.49 (s, 9H), 3.60
(s, 3H), 4.04 (d, J = 16.4 Hz, 1H), 4.22 (d, J = 16.4 Hz, 1H), 5.62 (d, J =
10.0 Hz, 1H), 6.23 (dd, J = 11.6 and 6.0 Hz, 1H), 6.43 (dd, J = 10.0 and
6.0 Hz, 1H), 6.72 (d, J = 11.6 Hz, 1H).
Methyl
cis-4-(2-iodophenyl)-1-tert-butyl-2-oxoazetidine-3-
carboxylate (cis-6l). 23 mg (49%, Table S1, Entry 21). Amorphous
yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 9H), 3.30 (s, 3H), 4.31
(d, J = 6.4 Hz, 1H), 5.22 (d, J = 6.4 Hz, 1H), 7.02 (ddd, J= 8.0, 7.2 and
1.6 Hz, 1H), 7.36 (ddd, J= 8.0, 7.2 and 1.6 Hz, 1H), 7.52 (dd, J = 8.0 and
1.6 Hz, 1H), 7.83 (dd, J = 8.0 and 1.6 Hz, 1H). 13C NMR (CDCl3, 100.6
MHz) δ 28.2 (3 CH3), 52.0 (CH3), 55.3 (C), 58.4 (CH), 60.6 (CH), 98.7 (C),
128.0 (CH), 128.2 (CH), 130.4 (CH), 138.5 (C), 139.7 (CH), 163.2 (C),
166.1 (C). HRMS (ESI-TOF) calcd. for C15H19INO3: 388.0404 [M+H]+;
found: 388.0405.
Methyl (2RS,3RS)-1-(tert-butyl)-2-methyl-4-oxo-2-phenylazetidine-3-
carboxylate (9). 10.5 mg (23%, Table 3, Entry 3). Yellow gum. 1H NMR
(CDCl3, 400 MHz) δ 1.38 (s, 9H), 2.11 (s, 3H), 3.23 (s, 3H), 3.84 (s, 1H),
7.29-7.38 (m, 3H), 7.46-7.50 (m, 2H). 13C NMR (CDCl3, 100.6 MHz) δ
26.2 (CH3), 28.6 (3 CH3), 51.8 (CH3), 55.8 (C), 64.9 (C), 66.8 (CH), 126.6
(2 CH), 128.3 (2 CH), 139.9 (C), 162.8 (C), 166.7 (C). One CH was not
observed. HRMS (ESI-TOF) calcd. for C16H22NO3: 276.1594 [M+H]+;
found: 276.1595.
Methyl
trans-4-(2-iodophenyl)-1-tert-butyl-2-oxoazetidine-3-
carboxylate (trans-6l). 18 mg (38%, Table S1, Entry 21). Yellow gum.
1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 3.55 (d, J = 2.0 Hz, 1H), 3.81
(s, 3H), 5.24 (d, J = 2.0 Hz, 1H), 7.03 (ddd, J= 8.0, 7.2 and 2.0 Hz, 1H),
7.40 (ddd, J= 8.0, 7.2 and 1.2 Hz, 1H), 7.46 (dd, J = 8.0 and 2.0 Hz, 1H),
7.85 (dd, J = 8.0 and 1.2 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 28.2 (3
CH3), 52.9 (CH3), 55.5 (C), 60.3 (CH), 62.4 (CH), 98.4 (C), 126.9 (broad,
CH), 128.9 (CH), 130.4 (CH), 140.0 (broad, CH), 141.4 (C), 162.5 (C),
167.4 (C). HRMS (ESI-TOF) calcd. for C15H19INO3: 388.0404 [M+H]+;
found: 388.0404.
Methyl (2RS,3SR)-1-(tert-butyl)-2-methyl-4-oxo-2-phenylazetidine-3-
carboxylate (10). 21 mg (47%, Table 3, Entry 3). Amorphous orange
solid. 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 1.96 (s, 3H), 3.75 (s, 3H),
3.86 (s, 1H), 7.32 (ddd, J = 7.2, 6.0 and 1.2 Hz, 1H), 7.37-7.42 (m, 2H),
7.47-7.51 (m, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 20.7 (CH3), 28.6 (3
CH3), 52.4 (CH3), 56.0 (C), 62.6 (C), 67.0 (CH), 125.5 (2 CH), 128.3 (CH),
128.9 (2 CH), 143.3 (C), 162.9 (C), 167.3 (C). HRMS (ESI-TOF) calcd.
for C16H22NO3: 276.1594 [M+H]+; found: 276.1596.
Methyl
2-tert-butyl-5,6-dimethoxy-3-oxo-1H-2,3-
dihydrocyclohepta[c]pyrrole-3a-carboxylate (5m). 1H NMR (CDCl3,
400 MHz, signals from a 1.5:1 mixture of 5m and trans-6m) δ 1.46 (s,
9H), 3.61 (s, 3H), 3.67 (s, 3H), 3.73 (s, 3H), 4.21 (ddd, J = 14.4, 1.6 and
0.8 Hz, 1H), 4.40 (ddd, J = 14.4, 2.4 and 1.2 Hz, 1H), 5.01 (s, 1H), 5.67
(d, J = 7.2 Hz, 1H), 6.00 (ddd, J = 7.2, 2.4 and 0.8 Hz, 1H). 13C NMR
(CDCl3, 100.6 MHz, signals from a 1.5:1 mixture of 5m and trans-6m) δ
27.6 (3 CH3), 49.2 (CH2), 52.9 (CH3), 55.0 (C), 55.9 (CH3), 56.2 (CH3),
57.9 (C), 99.8 (CH), 103.5 (CH), 117.3 (CH), 131.1 (C), 152.3 (C), 154.9
(C), 169.9 (C), 171.1 (C).
Computational Details. All the calculations reported in this paper were
performed with the Gaussian 09 suite of programs.[20] Electron correlation
was partially taken into account using the hybrid functional usually
denoted as B3LYP[21] in conjunction with the D3 dispersion correction
suggested by Grimme et al.[22] using the double-ζ quality plus polarization
def2-SVP[23] basis set for all atoms. Reactants and products were
characterized by frequency calculations,[24] and have positive definite
Hessian matrices. Transition structures (TS’s) show only one negative
eigenvalue in their diagonalized force constant matrices, and their
associated eigenvectors were confirmed to correspond to the motion
along the reaction coordinate under consideration using the Intrinsic
Methyl
cis-1-tert-butyl-4-(3,4-dimethoxyphenyl)-2-oxoazetidine-3-
carboxylate (cis-6m). 3 mg (6%, Table S1, Entry 24). Yellow gum. 1H
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800666
European Journal of Organic Chemistry
FULL PAPER
Reaction Coordinate (IRC) method.[25] Solvents effects were also taken
into account using the Polarizable Continuum Model (PCM)[26] during the
geometry optimizations. This level is denoted PCM-(dichloroethane)-
B3LYP-D3/def2-SVP. Single-point energy refinements were carried out
at the M06L[27]/def2-TZVPP[24] level of theory employing the PCM model
to account for solvation. This level is denoted PCM(dichloroethane)-
M06L/def2-TZVP//PCM-(dichloroethane)-B3LYP-D3/def2-SVP.
Tetrahedron 1996, 52, 2489-2514; b) Ruthenium: M. Grohmann, G.
Maas, Tetrahedron 2007, 63, 12172-12178; c) Cupper: J. Liu, J. Tu, Z.
Yang, C.-U. Pak, J. Xu, Tetrahedron 2017, 73, 4616-4626.
[12] V. K.-Y. Lo, Z. Guo, M. K.-W. Choi, W.-Y. Yu, J.-S. Huang, C.-M. Che, J.
Am. Chem. Soc. 2012, 134, 7588-7591.
[13] A. Padwa, D. J. Austin, A. T. Price, M. A. Semones, M. P. Doyle, M. N.
Protopopova, W. R. Winchester, A. Tran, J. Am. Chem. Soc. 1993, 115,
8669-8680.
[14] a) N. Watanabe, M. Anada, S.-H. Hashimoto, S. Ikegami, Synlett 1994,
1031-1033; b) M. P. Doyle, R. J. Pieters, J. Taunton, H. Q. Pho, A.
Padwa, D. L. Hertzog, L. Precedo, J. Org. Chem. 1991, 56, 820-829; c)
C. H. Yoon, A. Nagle, C. Chen, D. Gandhi, K. W. Jung, Org. Lett. 2003,
5, 2259-2262; d) Z. Chen, Z. Chen, Y. Jiang, W. Hu, Synlett 2004,
1763-1764; e) A. G. H. Wee, S. C. Duncan, J. Org. Chem. 2005, 70,
8372-8380.
Acknowledgements
We gratefully acknowledge financial support for this work from
MINECO-FEDER (Projects CTQ2015-64937-R, CTQ2016-
78205-P and CTQ2016-81797-REDC).
[15] For the use of other transition metals to promote the decomposition of
this amide, see: a) Rhodium: N. R. Candeias, C. Carias, L. F. R.
Gomes, V. André, M. T. Duarte, P. M. P. Gois, C. A. M. Afonso, Adv.
Synth. Catal. 2012, 354, 2921-2927; b) Ruthenium: T. Large, T. Müller,
H. Kunkel, S. Buck, G. Z. Maas, Naturforsch. B: J. Chem. Sci., 2012, 67,
347-353. See also ref. 11b.
Keywords: palladium-catalysis • carbene insertion • diazo
compounds • β-lactams • density functional theory calculations
[1]
For recent reviews, see: a) H. M. L. Davies, J. R. Manning, Nature 2008,
451, 417-424; b) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem.
Rev. 2010, 110, 704-724; c) A. Ford, H. Miel, A. Ring, C. N. Slattery, A.
R. Maguire, M. A. McKervey, Chem. Rev. 2015, 115, 9981-10080; d) F.
J. Lombard, M. J. Coster, Org. Biomol. Chem. 2015, 13, 6419-6431.
See, for example: a) Y. Cai, S.-F. Zhu, G.-P. Wang, Q.-L. Zhou, Adv.
Synth. Catal. 2011, 353, 2939-2944; b) T. Yao, K. Hirano, T. Satoh, M.
Miura, Angew. Chem. Int. Ed. 2012, 51, 775-779; c) Z. Yu, B. Ma, M.
Chen, H.-H. Wu, L. Liu, J. Zhang, J. Am. Chem. Soc. 2014, 136, 6904-
6907; d) M. R. Fructos, M. M. Díaz-Requejo, P. J. Pérez, Chem.
Commun. 2016, 52, 7326-7335; e) L. Liu, J. Zhang, Chem. Soc. Rev.
2016, 45, 506-516; f) A. Conde, G. Sabenya, M. Rodríguez, V. Postils,
J. M. Luis, M. M. Díaz-Requejo, M. Costas, P. J. Pérez, Angew. Chem.
Int. Ed. 2016, 55, 6530-6534.
[16] Following some literature precedents (see ref. 15a), the crude reaction
mixture was filtered over a basic alumina pad to induce complete
epimerization of β-lactam to the trans isomer before the
chromatographic purification. However, this process resulted in the
isolation of 5a and trans-6a in low yields.
[2]
[17] E. Nakamura, N. Yoshikai, M. Yamanaka, J. Am. Chem. Soc. 2002,
124, 7181-7192.
[18] All calculations were carried out at the PCM(dichloroethane)-
M06L/def2-TZVPP//PCM(dichloroethane)-B3LYP-D3/def2-SVP
See Computational Details.
level.
[19] The intermediacy of
a zwitterionic species in these Pd-catalyzed
insertions is experimentally supported by the isolation of 4-
(dimethylamino)benzaldehyde in the reactions of 4f. This aldehyde
would be formed by hydrolysis of the corresponding zwitterionic
intermediate.
[3]
[4]
H. M. L. Davies, B. T. Parr, in Contemporary Carbene Chemistry;
Wiley: Hoboken, NJ, 2013, pp 363-403.
[20] Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery,
Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.
M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A.
D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D.
J. Fox, Gaussian, Inc., Wallingford CT, 2009.
a) M. M. Díaz-Requejo, P. J. Pérez, Chem. Rev. 2008, 108, 3379-3394;
b) X. Zhao, Y. Zhang, J. Wang, Chem. Commun. 2012, 48, 10162-
10173.
[5]
[6]
[7]
a) M. K-W. Choi, W.-Y. Yu, C.-M. Che, Org. Lett. 2005, 7, 1081-1084;
b) M. K-W. Choi, W.-Y. Yu, M.-H. So, C.-Y. Zhou, Q.-H. Deng, C.-M.
Che, Chem. Asian J. 2008, 3, 1256-1265; c) C. Y. Zhou, J. S. Huang,
C.-M. Che, Synlett 2010, 2681-2700; d) A. R. Reddy, C.-Y. Zhou, Z.
Guo, J. Wei, C.-M. Che, Angew. Chem. Int. Ed. 2014, 53, 14175-14180.
See, for example: a) D. F. Taber, J. C. Amedio Jr., R. G. Sherill, J. Org.
Chem. 1986, 51, 3382-3384; b) M. Matsumoto, N. Watanabe, H.
Kobayashi, Heterocycles 1987, 26, 1479-1482; c) M. L. Rosenberg, J.
H. F. Aasheim, M. Trebbin, E. Uggerud, T. Hansen, Tetrahedron Lett.
2009, 50, 6506-6509.
a) D. Solé, F. Mariani, M.-L. Bennasar, I. Fernández, Angew. Chem. Int.
Ed. 2016, 55, 6467-6470; b) D. Solé, A. Amenta, F. Mariani, M.-L.
Bennasar, I. Fernández, Adv. Synth. Catal. 2017, 359, 3654-3664.
D. Solé, F. Pérez-Janer, I. Fernández, Chem. Commun. 2017, 53,
3110-3113.
[21] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648-5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1998, 37, 785-789; c) S. H. Vosko, L.
Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200-1211.
[8]
[9]
[22] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132,
154104-154119.
For some reviews on the transition metal-catalyzed synthesis of β-
lactams, see: a) P. M. P. Gois, C. A. M. Afonso, Eur. J. Org. Chem.
2004, 3773-3788; b) A. Ring, A. Ford, A. R. Maguire, Tetrahedron Lett.
2016, 57, 5399-5406.
[23] a) A. Schäfer, H. Horn, R. Ahlrichs, J. Chem. Phys. 1992, 97, 2571-
2577; b) F. Weigend, R. Alhrichs, Phys. Chem. Chem. Phys. 2005, 7,
3297-3305.
[10] a) C. A. Merlic, A. L. Zechman, Synthesis 2003, 1137-1156; b) H. M. L.
Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857-1869; c) A.
DeAngelis, R. Panish, J. M. Fox, Acc. Chem. Res. 2016, 49, 115-127.
[11] For the use of other transition metals to promote the decomposition of
this amide, see: a) Rhodium: S. Miah, A. M. Z. Slawin, C. J. Moody, S.
M. Sheedan, J. P. Marino, M. A. Semones, A. Padwa, I. C. Richards,
[24] J. W. McIver, A. K. Komornicki, J. Am. Chem. Soc. 1972, 94, 2625-
2633.
[25] C. González, H. B. Schlegel, J. Phys. Chem. 1990, 94, 5523-5527.
[26] a) S. Miertuš, E. Scrocco, J. Tomasi, Chem. Phys. 1981, 55, 117-129;
b) J. L. Pascual-Ahuir, E. Silla, I. Tuñón, J. Comp. Chem. 1994, 15,
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10.1002/ejoc.201800666
European Journal of Organic Chemistry
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1127-1138; c) V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995-
[27] Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157-167.
2001.
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10.1002/ejoc.201800666
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
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The intramolecular carbene C–H
insertion of α-diazo-α-
(methoxycarbonyl)acetamides leading
to β-lactams is effectively catalyzed by
Pd(II)-complexes. According to DFT
calculations, this insertion reaction
C-H activation*
Daniel Solé,* Ferran Pérez-Janer, M.-
Lluïsa Bennasar, and Israel Fernández*
Page No. – Page No.
tBu
O
O
Palladium Catalysis in the
Intramolecular Carbene C–H Insertion
of α-Diazo-α-
(methoxycarbonyl)acetamides to
Form β-Lactams
occurs stepwise through a
tBu
R
CO2Me
N
[Pd(II)] cat.
DCE reflux
H
N
metallacarbene-induced zwitterionic
intermediate
N2
CO2Me
H
.
C-H carbene insertion
R
chemoselective Csp3-H insertion
stepwise mechanism through a
zwitterionic intermediate
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.