Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of catalysts and substrate substitution in the synthesis of oxindoles and β-lactams

Article abstract of DOI:10.3390/molecules24193551

The Pd-catalyzed intramolecular carbene C–H insertion of α-diazo-α(methoxycarbonyl)acetamides to prepare oxindoles as well as β-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))₂ can be used as an alternative to Pd₂(dba)₃ to catalyze the carbene C_Arsp²–H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp³–H insertion leading to β-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations.

Full text of DOI:10.3390/molecules24193551

molecules
Article
Site Selectivity in Pd-Catalyzed Reactions of
α-Diazo-α-(methoxycarbonyl)acetamides: Effects of
Catalysts and Substrate Substitution in the Synthesis
of Oxindoles and β-Lactams
Daniel Solé 1,
*
, Ferran Pérez-Janer 1, Arianna Amenta 1, M.-Lluïsa Bennasar 1 and
Israel Fernández 2,
*
1
Laboratori de Química Orgànica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona,
Av. Joan XXIII 27-31, 08028 Barcelona, Spain; ferranperez1@hotmail.com (F.P.-J.);
amenta.arianna@gmail.com (A.A.); bennasar@ub.edu (M.-L.B.)
Departamento de Química Orgánica I and Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
Correspondence: dsole@ub.edu (D.S.); israel@quim.ucm.es (I.F.); Tel.: +34-934024540 (D.S.)
2
*
Academic Editor: Renata Riva
Received: 19 September 2019; Accepted: 27 September 2019; Published: 30 September 2019
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract:
The Pd-catalyzed intramolecular carbene C–H insertion of
α-diazo-α-
(methoxycarbonyl)acetamides to prepare oxindoles as well as
β-lactams was studied. In order to
identify what factors influence the selectivity of the processes, we explored how the reactions are
affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found
that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to
catalyze the carbene CArsp2–H insertion, although it was less versatile. On the other hand, it was
demonstrated that the Csp3–H insertion leading to
β-lactams can be effectively promoted by both
Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms
involved in these transformations was provided by DFT calculations.
Keywords: palladium; diazo compounds; carbenes; oxindoles;
β-Lactams; density functional
calculations
1. Introduction
In recent years, the development of new methodologies for the selective functionalization of
unactivated C–H bonds has become a very active area of research [ ]. As part of this exciting field, the
transition metal-catalyzed intramolecular carbene C–H insertion by decomposition of -diazocarbonyl
compounds has emerged as a powerful methodology for the construction of carbocyclic and heterocyclic
frameworks [ ]. A number of transition metal complexes have been used as effective catalysts
to generate reactive metallacarbenes starting from -diazocarbonyl compounds [ 16]. Among
them, rhodium(II) [17 18], copper(I) [19 20], and more recently ruthenium(II) catalysts [21 27] have
1,2
α
3–8
α
9–
,
,
–
been proven to be especially useful for the development of highly selective carbene C–H insertion
methodologies via a variety of reaction modes. Interestingly, palladium, one of the most commonly
employed metals in homogeneous catalysis, remains underexploited in this type of carbene C–H
insertion processes. Thus, while the effectiveness of palladium complexes in catalyzing carbene C–H
insertion reactions from
use has been restricted to a couple of examples of insertion into CArsp2–H bonds [29
highly surprising if we take into account the great success of palladium catalysis in cross-coupling
reactions of diazo compounds with organic halides, pseudohalides, or arylboronic acids [32 35] and
α
-diazo carbonyl compounds was demonstrated some time ago [28], their
–31]. This fact is
–
Molecules 2019, 24, 3551; doi:10.3390/molecules24193551
www.mdpi.com/journal/molecules

Molecules 2019, 24, 3551
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that the palladium-catalyzed cyclopropanation of olefins with diazomethane is a widely used synthetic
methodology [36].
The longstanding research on transition metal-catalyzed carbene C–H insertion has generated an
extensive literature on the use of dirhodium(II) catalysts to promote the intramolecular C–H insertion of
α
-diazoacetamides [37
common scaffolds found in numerous natural products. In recent years, some ruthenium(II) catalysts
have also been applied to promote this kind of C–H insertion process [21 22 25 39 43]. It has been shown
that the site selectivity of these reactions not only depends on the type of diazocarbonyl compound
but also is governed by conformational, steric, as well as electronic factors [44 46]. Moreover,
,38], as the insertion products, namely β- and γ-lactams as well as 2-oxindoles, are
,
,
,
–
–
some dramatic ligand effects have also been observed. For example, the use of carboxylate and,
in particular, carboxamide ligands in dirhodium(II) catalysts has resulted in highly chemo-, regio- and
stereoselective transformations [47,48] despite a variety of potentially competitive carbene-mediated
processes (Scheme 1).
Scheme 1. Typical Rh(II)-catalyzed reactions of α-diazoamides.
As part of our research program on the synthesis of nitrogen heterocycles, we have been
exploring different ways to increase the versatility of palladium catalysis in C–C bond-forming
reactions [49–51], for example, by controlling the ambiphilic character of the organopalladium
intermediates in the intramolecular coupling reactions with carbonyl derivatives [52]. Continuing our
search for methodologies to enhance the synthetic potential of organopalladium chemistry, we have
also investigated the versatility of palladium as a catalyst for the carbene C–H insertion. In this context,
we 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 [53,54].
We have also demonstrated that the carbene CArsp2–H functionalization of
α
-diazo-α-(methoxycarbonyl)acetanilides to give oxindoles can also be promoted by using
Pd2(dba)3 as the catalyst [55]. This allowed us to develop a one-pot methodology to prepare
3-(chloroethyl)oxindoles by means of a sequential C–H insertion/alkylation process (Equation (a) in
Scheme 2). More recently, we have described the synthesis of
β-lactams by Pd(II)-catalyzed carbene
Csp3–H insertion of α-diazo-α-(methoxycarbonyl)acetamides (Equation (b) in Scheme 2) [56].

Molecules 2019, 24, 3551
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Scheme 2. Pd catalysts in C–H insertion reactions of α-diazo-α-(methoxycarbonyl)acetamides.
The aim of the current work was to gain more insight into the Pd-catalyzed carbene insertion
reactions of -diazo- -(methoxycarbonyl)acetamides leading to oxindoles and -lactams. In order to
ascertain the factors governing the selectivity of the processes, we explored how the reactions are affected
by the substituents on -diazoacetamide and the type of catalyst, using complexes with two oxidation
states of Pd and a variety of ligands (Scheme 3). Herein, we present a full account of our experimental
and computational studies on the intramolecular insertion of -diazo- -(methoxycarbonyl)acetamides
α
α
β
α
α
α
using Pd(0) and Pd(II) complexes, focused on identifying differences in the catalyst reactivities
and selectivities.
Scheme 3.
Catalyst and substituent effects in Pd-catalyzed C–H insertion reactions of
α-diazo-α-(methoxycarbonyl)acetamides.
2. Results and Discussion
The oxindole system is a common structural motif in pharmaceuticals and natural products, and the
development of efficient procedures for their preparation is, therefore, of considerable interest [57
–60].
Our previous studies on the carbene reactions of -diazo- -(methoxycarbonyl)acetanilides showed
α
α
that, when using palladium catalysts, the C–H insertion giving the oxindole occurs selectively in the
CArsp2–H rather than the Csp3–H bonds (Equation (a) of Scheme 2) [55]. The optimization process
with α
-diazoacetanilide 1a revealed that the carbene CArsp2–H insertion can be selectively promoted
by both Pd(0) and Pd(II), the best result being obtained when using Pd2(dba)3 in the presence of
Cs2CO3 in dichloroethane at reflux for 96 h, which afforded oxindole 2a in 66% yield (Table 1, entry 1).
However, this reaction required a high catalyst loading and long reaction time. All attempts to increase
the efficiency of the Pd(0)-catalyzed reaction by adding different phosphine ligands failed, always
resulting in a slower reaction rate.
In order to improve the efficiency of the carbene insertion of α-diazoacetanilide 1a, in the present
study, we tested some palladium catalysts bearing non-phosphine ligands. (Pd(allyl)Cl)2 was first
explored for the insertion/alkylation sequential process (Table 1, entries 2–3), but significant amounts of
the starting material were recovered even after 60 h. In contrast, the use of ((IMes)Pd(NQ))2 required a
notably shorter reaction time and lower catalyst loading (Table 1, entry 4).

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Table 1. Palladium-catalyzed reactions of α-diazoamide 1a 1.
Entry
Catalyst (mol%)
Time
Products (Yield (%)) 2
96 h 3
24 h
60 h
24 h
1
2
3
4
Pd2(dba)3 (10)
(Pd(allyl)Cl)2 (5)
(Pd(allyl)Cl)2 (5)
((IMes)Pd(NQ))2 (4)
2a (66)
1a/2a (1:2.2) 4
1a/2a (1:5.5) 4
2a (65)
1
All reactions were conducted with 1a (0.2 mmol), catalyst (see table), and Cs2CO3 (1 equiv.) in
dichloroethane (0.2 M) at reflux. Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0). ((IMes)Pd(NQ))2
2
= 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (1,4-naphthoquinone) palladium(0) dimer. Isolated yield.
3
Cs2CO3 (2 equiv.). 4 1H-NMR ratio; yields were not quantified.
With these data in hand, we then explored the generality of the NHC-Pd(0) catalyst in the sequential
C–H insertion/alkylation process, leading to 3-(chloroethyl)-3-(methoxycarbonyl)oxindoles. Table 2
gathers the results of the reactions of different α-diazoacetanilides (1b–1j) when using ((IMes)Pd(NQ))2
as the catalyst and compares them with those previously obtained with Pd2(dba)3 [55].
Table 2. Palladium-catalyzed cyclization reactions of α-diazoamides 1b–1j.
Entry
Substance 1
Catalyst 1,2
Product (Yield (%)) 3
1
1b (R:Me)
Pd2(dba)3
2b (71)
2
3
4
5
6
7
8
9
1b (R:Me)
1c (R:Et)
1c (R:Et)
1d (R:i-Pr)
1d (R:i-Pr)
1e (R:Ph)
1e (R:Ph)
((IMes)Pd(NQ))2
Pd2(dba)3
((IMes)Pd(NQ))2
Pd2(dba)3
2b (79)
2c (54)
2c (78)
2d (61)
2d (64)
2e (55) 5
2e (35)
2f (23) 6
2f (0) 7
2g (36)
2g (76)
((IMes)Pd(NQ))2
4
Pd2(dba)3
((IMes)Pd(NQ))2
1f
Pd2(dba)3
10
11
12
1f
((IMes)Pd(NQ))2
Pd2(dba)3
1g (R1:OMe)
1g (R1:OMe)
((IMes)Pd(NQ))2
13
14
15
16
1h (R1F)
1h (R1:F)
1i (R1:CO2Me)
Pd2(dba)3
2h (64)
2h (39) 8
2i (22)
2i (0) 9
((IMes)Pd(NQ))2
4
Pd2(dba)3
1i (R1:CO2Me)
((IMes)Pd(NQ))2
17
18
4
1j
1j
2j (27)
Pd2(dba)3
2j (23) 10
((IMes)Pd(NQ))2
1
Reactions were conducted with
1
(0.2 mmol), Pd2(dba)3 (10 mol%), and Cs2CO3 (1 equiv.) in dichloroethane
(0.2 mmol), ((IMes)Pd(NQ))2 (4 mol%), and Cs2CO3
2
(0.2 M) at reflux for 96 h. Reactions were conducted with
1
3
4
5
(1 equiv.) in dichloroethane (0.2 M) at reflux for 48 h. Isolated yield. Catalyst loading: 15%. 20% of unreacted
1e was recovered. 6 1H-NMR analysis of the reaction mixture showed a 1:1 mixture of 1f and 2f
.
1f was recovered.
7
8 1H-NMR analysis of the reaction mixture showed a 1:4.8 mixture of 1h and 2h
10 1H-NMR analysis of the reaction mixture showed a 1:1.5 mixture of 1j and 2j.
.
Complex reaction mixture.
9

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As can be seen in Table 2, like Pd2(dba)3, ((IMes)Pd(NQ))2 also selectively promoted the carbene
insertion into the arylic C–H bond in substrates having substituents at the nitrogen atom with primary,
secondary, as well as tertiary Csp3–H bonds. Notably, ((IMes)Pd(NQ))2 was more efficient than
Pd2(dba)3 in promoting the insertion of N-alkylacetanilides lacking substituents on the arylic ring
(1b–1d) (Table 2, entries 1–6) or bearing an electron-donating substituent (1g) (Table 2, entries 11–12).
In contrast, the introduction of electron-withdrawing groups dramatically diminished the catalytic
efficiency of ((IMes)Pd(NQ))2. Thus, for example, acetanilide 1f, bearing an ortho-bromo substituent,
was recovered unchanged when using ((IMes)Pd(NQ))2, whereas in the presence of Pd2(dba)3, it
afforded oxindole 2f in 23% yield (Table 2, entries 9 and 10). Oxindole 2h, with a fluoro group,
was isolated in a modest 39% yield when using ((IMes)Pd(NQ))2 but obtained in an acceptable 64%
yield in the presence of Pd2(dba)3 (Table 2, entries 13–14). No insertion product was formed in the
((IMes)Pd(NQ))2-catalyzed reaction of acetanilide 1i, which bears a methoxycarbonyl substituent, while
oxindole 2i was isolated in 22% yield when using Pd2(dba)3 (Table 2, entries 15–16). ((IMes)Pd(NQ))2
also gave worse results in the sequential insertion/alkylation sequence from N,N-diphenylacetamide
1e (Table 2, entries 7 and 8) and N-naphthylacetamide 1j (Table 2, entries 17–18).
At this point, we studied the decomposition of
treatment with a catalytic amount of ((IMes)Pd(NQ))2 under the optimized reaction conditions,
afforded mesoionic compound (77%), resulting from the interception of the transient metallacarbene
α-diazo-N-pyridinylacetamide 3, which, upon
4
by the pyridine nitrogen (Scheme 4). This kind of mesoionic imidazopyridines have been previously
prepared [61] and show interesting insecticidal activity [62].
Scheme 4. Pd-catalyzed cyclization of α-diazoamide 3.
Regarding the palladium-catalyzed reactions shown in Tables 1 and 2, it should be noted that the
formation of β
-lactam products, resulting from the possible competitive carbene Csp3–H insertion,
was not observed. This sharply contrasts with the competition between the carbene CArsp2–H and
Csp3–H insertions observed in Rh(II)-promoted processes (see, for instance, Scheme 1(a)) [48].
Our previously reported DFT calculations suggested that the Pd(0)-catalyzed CArsp2–H insertion of
α
-diazo-α-(methoxycarbonyl)acetanilides to give oxindoles proceeds via a genuine stepwise mechanism
involving a Pd-mediated 1,5-hydrogen migration from the initially generated pallada(0)carbene
complex, followed by a reductive elimination [55]. It was also shown that the complete chemoselectivity
of the process, which exclusively produces oxindoles over β-lactams, takes place mainly under kinetic
control. We now decided to check the generality of this unprecedented Pd(0)-mediated mechanism
using the model Pd(NHC) (NHC = 1,3-bis(phenyl)-imidazil-2-ylidene) catalyst.
Figure 1 shows the computed reaction profile for the formation of oxindole 2b’, precursor of the
experimentally observed oxindole 2b (see Table 2). As expected, based on our previous report [55],
the process begins from pallada(0)carbene INT0, formed upon reaction of
active catalyst species Pd(NHC). This species evolves into intermediate INT1 in a highly exergonic
process ( GR = –25.3 kcal/mol) through the transition state TS1 with a computed activation barrier of
α-diazoamide 1b and the
∆
16.2 kcal/mol, which is fully compatible with the reaction conditions used in the experiment. Closer
inspection of TS1 indicates that this reaction step can be viewed as a Pd-mediated 1,5-hydrogen
migration, which involves the formal oxidation of the transition metal. The alternative Csp3–H
activation reaction via TS1’, which would involve an analogous Pd-mediated 1,4-hydrogen migration,
is not competitive in view of the much higher activation barrier (∆
G, = 8.2 kcal/mol) computed for this
alternative transformation. Therefore, it is once again found that the complete selectivity of the process
takes place under kinetic control. The transformation ends with an exergonic (∆GR = –6.8 kcal/mol)

Molecules 2019, 24, 3551
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reductive elimination reaction that directly transforms INT1 into oxindole 2b’ with the concomitant
release of the active catalytic species Pd(NHC) through the transition state TS2 (with a feasible
activation barrier of 18.7 kcal/mol).
Figure 1.
INT0 into oxindole 2b’
in kcal/mol and angstroms, respectively.
Computed reaction profile for the transformation of pallada(0)carbene
Relative free energies and bond distances are given
All data have been computed at the
:
PCM(dichloroethane)-B3LYP-D3/def2-TZVPP//PCM(dichloroethane)-B3LYP-D3/def2-SVP level.
On the other hand, we have also reported that the intramolecular carbene C–H insertion of
α
-diazo-
complexes (Scheme 2b) [56]. Due to its ubiquitous presence in the molecular structure of natural
products and biologically active compounds, -lactam synthesis has attracted considerable attention
over the years [63 65]. To further understand the impact of the electronic nature of the catalyst in
the aforementioned insertion reaction, we decided to explore the use of some Pd(0)-precatalysts.
Table 3 shows the results of the reactions of diversely substituted N-benzyl-N-tbutyl-
-diazoacetamides
5a 5m) when using either Pd2(dba)3 or ((IMes)Pd(NQ))2 as the catalyst and compares them with
those previously obtained in the Pd(II)-catalyzed reactions [56].
α-(methoxycarbonyl)acetamides to form β-lactams can be effectively catalyzed by Pd(II)
β
–
α
(
–

Molecules 2019, 24, 3551
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Table 3. Palladium-catalyzed cyclization reactions of α-diazoamides 5a–5m 1.
Entry
5 (X)
5a (H)
5a (H)
Catalyst (mol%)
6/7/8 2,3
26/74/0
35/65/0
cis-7/trans-7 2,3
46/28
Products (Yield (%)) 4
6a (20)
cis-7a (9), trans-7a (42)
6a (28)
cis-7a (35), trans-7a (23)
cis-7a (25), trans-7a (65)
cis-7a (17), trans-7a (59)
6b (24)
cis-7b (9), trans-7b (20)
6b (22)
cis-7b (21), trans-7b (24)
6b (8)
cis-7b (18), trans-7b (39)
6b (10)
cis-7b (8), trans-7b (52)
6c (6)
cis-7c (4), trans-7c (30)
6c (7)
1
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
(Pd(allyl)Cl)2 (5)
2
40/25
3
4
5a (H)
5a (H)
0/100/0
0/100/0
47/53
29/71
(SIPr)Pd(allyl)Cl (15)
5
6
7
8
9
5b (4-MeO)
5b (4-MeO)
5b (4-MeO)
5b (4-MeO)
5c (4-MeS)
Pd2(dba)3 (10)
50/50/0
34/66/0
14/86/0
16/84/0
18/82/0
21/29
46/20
29/57
42/42
36/46
((IMes)Pd(NQ))2
(2.5)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
(Pd(allyl)Cl)2 (5)
10
11
12
5c (4-MeS)
5c (4-MeS)
5c (4-MeS)
11/89/0
5/95/0
68/21
42/53
48/40
cis-7c (30), trans-7c (50)
cis-7c (10), trans-7c (48)
6c (7)
cis-7c (4), trans-7c (60)
6d (9)
(SIPr)Pd(allyl)Cl (15)
12/88/0
13
14
5d (4-Cl)
5d (4-Cl)
Pd2(dba)3 (10)
15/85/0
5/95/0
8/77
cis-7d (5), trans-7d (50)
6d (5)
((IMes)Pd(NQ))2
(2.5)
69/26
cis-7d (53), trans-7d (19)
cis-7d (42), trans-7d (40)
cis-7d (27), trans-7d (42)
cis-7e (22), trans-7e (38)
cis-7e (15), trans-7e (33)
8e (15)
15
16
17
5d (4-Cl)
5d (4-Cl)
5e (4-CN)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
0/100/0
0/100/0
3/97/0
52/48
62/38
67/30
18
5e (4-CN)
5/75/20
25/50
19
20
21
5e (4-CN)
5e (4-CN)
5f (4-NMe2)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
0/100/0
0/100/0
CM
71/29
38/62
—
cis-7e (34), trans-7e (36)
cis-7e (27), trans-7e (51)
—
cis-7f (9), trans-7f (10)
22
5f (4-NMe2)
CM
—
10 (15) 5
23
24
5f (4-NMe2)
5f (4-NMe2)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
CM
CM
—
—
trans-7f (14), 10 (36)
trans-7f (10), 10 (45)
6g 6 (7)
25
5g (3-Cl)
Pd2(dba)3 (10)
8/92/0
54/38
cis-7g (30), trans-7g (43)
6g6 (5)
((IMes)Pd(NQ))2
(2.5)
26
5g (3-Cl)
6/94/0
73/21
cis-7g (50), trans-7g (20)
cis-7g (44), trans-7g (36)
cis-7g (30), trans-7g (31)
cis-7h (25), trans-7h (48)
cis-7h (15), trans-7h (37)
8h (6)
27
28
29
5g (3-Cl)
5g (3-Cl)
5h (3-CN)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
0/100/0
0/100/0
0/100/0
64/36
50/50
33/67
30
5h (3-CN)
4/74/22
30/44
31
32
5h (3-CN)
5h (3-CN)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
0/100/0
0/100/0
47/53
29/71
cis-7h (22), trans-7h (43)
cis-7h (15), trans-7h (55)
6i (8)
33
5i (2-MeO)
Pd2(dba)3 (10)
14/86/0
43/43
cis-7i (12), trans-7i (19)

Molecules 2019, 24, 3551
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Table 3. Cont.
Entry
5 (X)
Catalyst (mol%)
6/7/8 2,3
20/80/0
cis-7/trans-7 2,3
57/23
Products (Yield (%)) 4
((IMes)Pd(NQ))2
(2.5)
6i (10)
cis-7i (45), trans-7i (24)
cis-7i (23), trans-7i (31)
cis-7i (10), trans-7i (63)
cis-7j (5), trans-7j (66)
cis-7j (10), trans-7j (62)
8j (11)
34
5i (2-MeO)
35
36
37
5i (2-MeO)
5i (2-MeO)
5j (2-F)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
5/95/0
6/94/0
8/92/0
42/53
39/55
8/84
38
5j (2-F)
5/83/12
24/59
39
40
5j (2-F)
5j (2-F)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
0/100/0
0/100/0
69/31
0/100
cis-7j (26), trans-7j (56)
trans-7j (66)
6k (6)
41
42
43
5k (2-Br)
5k (2-Br)
5k (2-Br)
Pd2(dba)3 (10)
7/93/0
0/85/15
14/86/0
70/23
66/19
52/34
cis-7k (46), trans-7k (15)
cis-7k (43), trans-7k (20)
8k (12)
((IMes)Pd(NQ))2
(2.5)
6k (9)
(Pd(allyl)Cl)2 (5)
cis-7k (34), trans-7k (31)
6k (4)
cis-7k (8), trans-7k (42)
cis-7l (5), trans-7l (45)
cis-7l (64), trans-7l (12)
8l (15)
44
45
46
5k (2-Br)
5l (2-I)
(SIPr)Pd(allyl)Cl (15)
8/92/0
0/100/0
0/78/22
21/71
9/91
Pd2(dba)3 (10)
((IMes)Pd(NQ))2
(2.5)
5l (2-I)
66/12
6l (9)
47
48
49
5l (2-I)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
Pd2(dba)3 (10)
8/92/0
0/100/0
50/50/0
50/42
77/23
21/29
cis-7l (49), trans-7l (38)
cis-7l (53), trans-7l (15)
6m (25)
cis-7m (11), trans-7m (20)
6m (13)
cis-7m (23), trans-7m (30)
6m (6)
trans-7m (39)
6m (9)
cis-7m (6), trans-7m (38)
5l (2-I)
5m (3-MeO,
4-MeO)
5m (3-MeO,
4-MeO)
5m (3-MeO,
4-MeO)
5m (3-MeO,
((IMes)Pd(NQ))2
(2.5)
50
51
52
32/68/0
15/85/0
24/76/0
44/24
8/77
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
43/33
4-MeO)
1
2
Reaction conditions: Catalyst (see table) in DCE at reflux for 24 h.
Ratios determined by integration of
characteristic 1H-NMR absorptions from the spectrum of the reaction mixture. The majority of reactions were
performed twice, while the Buchner: -lactam: -lactam ratio ( ) was essentially the same in the two runs and
the cis:trans ratio was quite different due to the partial isomerization of cis -lactams to the more stable trans
isomers during the work-up or even when recording the 1H-NMR spectra. Yields refer to products isolated by
3
β
γ
6/7/8
β
4
5
6
chromatography. 4-(Dimethylamino)benzaldehyde (10). Mixture of regioisomers.
The examples in Table 3 confirm the generality and functional group tolerance of Pd2(dba)3 and
((IMes)Pd(NQ))2 as catalysts for these insertion processes. Although both Pd(0) and Pd(II) catalysts
can be used to promote Csp3–H insertion, some significant differences were identified. On the whole,
the Pd(II) complexes proved to be more versatile for
β-lactam formation despite not always giving the
highest yield. In general, the resulting -lactams were obtained in moderate to good overall yields
β
(53–90%), usually as mixtures of cis and trans isomers, in transformations proceeding with high site
selectivity, except when using 5f. In this particular case, the use of Pd(II) catalysts to promote its
decomposition resulted in the formation of trans-7f (10–14%), together with major amounts of aldehyde
10. On the other hand, when ((IMes)Pd(NQ))2 was used, a complex reaction mixture was obtained,
from which cis-7f (9%), trans-7f (10%), and aldehyde 10 (15%) were isolated, while no cyclization
product was obtained in the presence of Pd2(dba)3.

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Notably, partial or complete isomerization of the cis
β-lactam to the more stable trans isomer took
place during the chromatographic purification of the reaction mixtures, which explains the observed
differences in cis/trans ratios before and after purification.
The effect of adding phosphine ligands to the Pd(0) catalyst was also explored. However, similarly
to the oxindole-forming reactions, the use of Pd2(dba)3 in the presence of phosphine ligands resulted
in slower reaction rates. Thus, for example, treatment of 5a with Pd2(dba)3 (10 mol%) in the presence
of (o-tolyl)3P (20 mol%) under otherwise the same reaction conditions gave a mixture of
6
(12%), cis-
7
(22%), and trans-7 (26%) together with some unreacted α-diazoamide (10%) (result not included in
the table).
Interestingly, no product from the potentially competitive palladium-catalyzed cross-coupling
of the aryl halide with the -diazoamide moiety [32 35] was observed in the reactions of 5k (Table 3,
α
–
entries 41–42) and 5l (Table 3, entries 45–46) when using Pd(0) catalysts.
As can be seen in Table 3, the effect of the substituent at the benzyl group on the outcome
of the process varied according to its electronic nature as well as its position on the aromatic ring.
The introduction of electron-donor groups led to an increased formation of the cycloheptapyrrolone
product, especially when using Pd(0) catalysts. The increase was lower when the substituent was
located at the ortho-position, probably due to steric interactions. In contrast, the 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 [48].
On the other hand, the use of ((IMes)Pd(NQ))2 as the catalyst in the reaction of those substrates
bearing electron-withdrawing groups resulted in the formation of minor amounts of the corresponding
γ
-lactam (
8 γ-lactams were not observed
), which arises from the tbutyl Csp3–H insertion. Notably, the
when using Pd(II) catalysts.
The above results also confirm the significant impact of the electronic nature of the Pd catalyst
and ensue 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), an
increased cycloheptapyrrolone product formation is usually observed with the more electron-rich Pd(0)
complexes. Interestingly, Rh(II)-catalyzed transformations show opposite reactivity trends, in which
highly electrophilic Rh(II) complexes favor Buchner reactions over benzylic Csp3–H insertion [44
Finally, we explored the transition metal-catalyzed decomposition of -diazoacetamide 11, which
–46].
α
bears a (4-pyridinyl)methyl group instead of the N-benzyl substituent (Table 4). Treatment of 11
with a catalytic amount of ((IMes)Pd(NQ))2 under the optimized reaction conditions resulted in the
complete decomposition of the material (Table 4, entry 1). When the reaction was performed at lower
temperatures (refluxing dichloromethane), 11 was recovered unchanged (Table 4, entry 2). In contrast,
the use of Pd(II) catalysts (Table 4, entries 3 and 4) resulted in the formation of
β-lactam 12 (cis/trans
mixture), with (SIPr)Pd(allyl)Cl affording the highest yield. Interestingly, -diazoacetamide 11 was
α
recovered unchanged when using the well-known (Rh(OAc)2)2 catalyst (Table 4, entry 5).
Table 4. Transition metal-catalyzed reactions of α-diazoamide 11 1.
Entry
Catalyst (mol%)
Solvent
Temp.
Time
Products (Yield (%)) 2
1
2
3
4
5
((IMes)Pd(NQ))2 (2.5)
((IMes)Pd(NQ))2 (2.5)
(Pd(allyl)Cl)2 (5)
(SIPr)Pd(allyl)Cl (15)
(Rh(OAc)2)2 (3)
DCE
CH2Cl2
DCE
DCE
CH2Cl2
reflux
reflux
reflux
reflux
r.t.
24 h
24 h
24 h
48 h
24 h
—
11
cis-12/trans-12 (1:10, 30%)
cis-12/trans-12 (1:2.2, 54%)
11
1
2
All reactions were conducted with 11 (0.2 mmol). Isolated yield.

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In our previous work on the synthesis of
β-lactams, we studied computationally the
Pd(II)-catalyzed insertion reaction of -diazo-α-(methoxycarbonyl)acetamides [56]. According to
α
our DFT calculations, this insertion reaction also occurs stepwise and involves an unprecedented
Pd(II)-promoted Mannich-type reaction through a pallada(II)carbene-induced zwitterionic intermediate.
To shed light on the reaction mechanism and the influence of the Pd(0) catalyst on the selectivity of
the C–H insertion described above, DFT calculations were also carried out. To this end, the process
involving 5a in the presence of the model Pd(NHC) (NHC = 1,3-bis(phenyl)-imidazil-2-ylidene) catalyst
was explored.
Figure 2 shows the computed reaction profile for the transformation of the initially formed
pallada(0)carbene intermediate INT0 into the observed β-lactams cis-7a and trans-7a. Similar to the
reaction profile computed for the formation of oxindoles discussed above (Figure 1), the initial INT0
readily evolves into the corresponding five-membered pallada(II)cycle INT1 via the transition state
TS1 in a highly exergonic transformation (
associated with a 1,4-hydrogen migration reaction mediated by the transition metal fragment, thus
∆
GR
≈
–40 kcal/mol). Once again, this saddle point is
confirming the generality of this type of C–H insertion reaction. Then, species INT1 is transformed
into the final
catalyst able to enter into a new catalytic cycle. Interestingly, the computed cis/trans activation barrier
differences for either the initial 1,4-H migration (
G, = 1.3 kcal/mol) or for the subsequent elimination
reaction (
G, = 0.2 kcal/mol) indicates that the formation of the cis-7a β-lactam should be only slightly
β–lactam through a reductive elimination reaction via TS2, which releases the active
∆
∆
favored over the formation of its trans counterpart, which nicely matches the experimental findings
(see Table 3, entry 2).
Figure 2.
into -lactams cis-7a and trans-7a
given in kcal/mol and angstroms, respectively.
PCM(dichloroethane)-B3LYP-D3/def2-TZVPP//PCM(dichloroethane)-B3LYP-D3/def2-SVP level.
Computed reaction profile for the transformation of pallada(0)carbene INT0
Relative free energies and bond distances are
All data have been computed at the
β
:

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3. Materials and Methods
3.1. General Information
1
All commercially available reagents were used without further purification. H- and 13C-NMR
spectra were recorded using Me4Si as the internal standard with a Varian Mercury 400 instrument
(Oxford, United Kingdom). Chemical shifts are reported in ppm downfield (δ
) from Me4Si 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). Organic extracts were dried over anhydrous Na2SO4 during workup of reactions.
Evaporation of solvents was accomplished with a rotatory evaporator (Büchi, Flavill, Switzerland).
α
-Diazoacetamides 1a–1j and oxindoles 2a–2j are known compounds previously prepared by us [55],
as are α-diazoacetamides 5a–5m and β-lactams 7a–7m [56].
3.2. Synthesis of N-Benzyl-N-(2-pyridinyl)-α-(ethoxycarbonyl)-α-diazoacetamide (3).
To a solution of 2-benzylaminopyridine (0.5 g, 2.71 mmol) and Et3N (0.39 mL, 2.71 mmol) in CH2Cl2
(10 mL), cooled at 0 ◦C, ethyl malonyl chloride (0.38 mL, 2.71 mmol) was added slowly. 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 CH2Cl2 to CH2Cl2/MeOH 97:3) to give N-benzyl-N-(2-pyridinyl)-α-(ethoxycarbonyl) acetamide
(0.77 g, 95%).
To a solution of N-benzyl-N-(2-pyridinyl)-α-(ethoxycarbonyl)acetamide (0.25 g, 0.84 mmol) and
Et3N (0.14 mL, 1.0 mmol) in dry acetonitrile (15 mL), p-toluenesulfonylazide (2.6 mL of a 11% solution
in toluene, 1.45 mmol) was added dropwise. The mixture was stirred at room temperature for 90
h. 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 99:1) to give
N-benzyl-N-(2-pyridinyl)-
α
-(ethoxycarbonyl)-
α-diazoacetamide (3, 150 mg; 55%) as a brown oil.
1H-NMR (CDCl3, 400 MHz)
δ
1.07 (t, J = 7.2 Hz, 3H), 3.92 (q, J = 7.2 Hz, 2H), 5.22 (s, 2H), 7.04 (ddd,
J = 7.4, 4.8, and 0.8 Hz, 1H), 7.10 (dt, J = 8.4 and 0.8 Hz, 1H), 7.20 (tt, J = 7.2 and 1.2 Hz, 1H), 7.23–7.29
(m, 2H), 7.32–7.36 (m, 2H), 7.60 (ddd, J = 8.4, 7.4 and 2.0 Hz, 1H), and 8.40 (ddd, J = 4.8, 2.0 and 0.8 Hz,
1H). 13C-NMR (CDCl3, 100.6 MHz)
δ 14.3 (CH3), 52.3 (CH2), 61.4 (CH2), 70.2 (C), 118.3 (CH), 120.8
(CH), 127.4 (CH), 127.9 (2 CH), 128.6 (2 CH), 137.5 (C), 138.0 (CH), 148.6 (CH), 156.1 (C), 161.4 (C),
and 162.3 (C).
3.3. Synthesis of N-tert-Butyl-N-(4-pyridinylmethyl)-α-(methoxycarbonyl)-α-diazoacetamide (11).
To a solution of N-tert-butyl-N-(4-pyrid◦inylmethyl)amine (0.67 g, 4.1 mmol) and Et3N (0.58 mL,
4.1 mmol) in CH2Cl2 (20 mL), cooled at 0 C, methyl malonyl chloride (0.57 mL, 5.3 mmol) was
added slowly. 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 to give
N-tert-butyl-N-(4-pyridinylmethyl)-α-(methoxycarbonyl)acetamide as an orange oil (0.98 g, 90%),
which was used in the next reaction without purification.
To a solution of N-tert-butyl-N-(4-pyridinylmethyl)-α-(methoxycarbonyl)acetamide (0.5 g,
1.89 mmol) and DBU (0.45 mL, 2.85 mmol) in dry acetonitrile (6 mL), a solution of p-ABSA (515 mg,
2.1 mmol) in dry acetonitrile (2 mL) was added dropwise. 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-tert-butyl-N-(4-pyridinylmethyl)-α-(methoxycarbonyl)-α-diazoacetamide (11, 145 mg; 26%) as an

Molecules 2019, 24, 3551
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orange oil. 1H-NMR (CDCl3, 400 MHz)
δ
1.40 (s, 9H), 3.77 (s, 3H), 4.63 (s, 2H), 7.15 (d, J = 6.0 Hz,
2H), and 7.57 (d, J = 6.0 Hz, 2H). 13C-NMR (CDCl3, 100.6 MHz)
δ 29.0 (3 CH3), 50.6 (CH2), 52.4 (CH3),
59.5 (C), 68.7 (C), 121.9 (2 CH), 149.3 (C), 150.2 (2 CH), 162.8 (C), and 163.5 (C).
3.4. Characterization Data for New Compounds of Scheme 4 and Tables 3 and 4
1-Benzyl-3-(ethoxycarbonyl)-2-oxo-2,3-dihydro-1H-imidazo (1,2-a)pyridin-4-ium-3-ylide (
4
). Amorphous
1
orange solid. H-NMR (CDCl3, 400 MHz)
δ 1.45(t, J = 7.2 Hz, 3H), 4.43 (q, J = 7.2 Hz, 2H), 5.20 (s, 2H),
6.99 (ddd, J = 8.8, 1.6, and 0.8 Hz, 1H), 7.08 (ddd, J = 7.6, 6.8, and 1.2 Hz, 1H), 7.25–7.37 (m, 5H), 7.40
(ddd, J = 8.8, 7.6, and 1.2 Hz, 1H), 9.65 (d, J = 6.8 Hz, 1H). 13C-NMR (CDCl3, 100.6 MHz)
δ
14.9 (CH3),
43.3 (CH2), 60.0 (CH2), 94.0 (C), 106.4 (CH), 115.7 (CH), 127.8 (2 CH), 128.2 (CH), 129.0 (CH), 129.1
(2 CH), 129.9 (CH), 135.4 (C), 135.6 (C), 157.0 (C), and 162.6 (C).
1
Methyl 2-tert-butyl-6-chloro-3-oxo-1H-2,3-dihydrocyclohepta(c)pyrrole-3a-carboxylate (6d). H-NMR (CDCl3,
400 MHz, signals from a 4.5:1 mixture of trans-7d and 6d) δ 1.45 (s, 9H), 3.64 (s, 3H), 4.21 (dd, J = 14.8
and 1.2 Hz, 1H), 4.44 (d, J = 14.8 Hz, 1H), 5.63 (d, J = 10.2 Hz, 1H), 6.17 (d, J = 6.8 Hz, 1H), 6.39 (d,
J = 10.2 Hz, 1H), and 6.62 (d, J = 6.8 Hz, 1H).
Methyl 1-(4-cyanobenzyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (8e). Amorphous orange solid.
1H-NMR (CDCl3, 400 MHz)
δ
1.16 (s, 3H), 1.22 (s, 3H), 2.19 (dd, J = 13.2 and 9.2 Hz, 1H), 2.33 (dd,
J = 13.2 and 9.2 Hz, 1H), 3.62 (t, J = 9.2 Hz, 1H), 3.82 (s, 3H), 4.33 (d, J = 16.0 Hz, 1H), 4.60 (d, J = 16.0
Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H). 13C-NMR (CDCl3, 100.6 MHz)
27.1 (CH3),
δ
28.1 (s, CH3), 38.3 (CH2), 43.2 (CH2), 47.4 (CH), 53.0 (CH3), 60.0 (C), 111.5 (C), 118.8 (C), 128.3 (2 CH),
132.6 (2 CH), 143.9 (C), 170.2 (C), and 170.9 (C).
Methyl cis-1-tert-butyl-4-[4-(dimethylamino)phenyl]-2-oxoazetidine-3-carboxylate (cis-7f). Amorphous
1
orange solid. H-NMR (CDCl3, 400 MHz)
δ
1.30 (s, 9H), 2.95 (s, 6H), 3.40 (s, 3H), 4.18 (d, J = 6.0 Hz,
1H), 4.83 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 8.8 Hz, 2H), and 7.21 (d, J = 8.8 Hz, 2H).
Methyl 2-tert-butyl-7-chloro-3-oxo-1H-2,3-dihydrocyclohepta[c]pyrrole-3a-carboxylate (6g). H-NMR
(CDCl3, 400 MHz, signals from a 11:1 mixture of trans-7g and 6g 1.45 (s, 9H), 3.64 (s, 3H), 4.22 (dd,
1
)
δ
J = 15.6 and 2.0 Hz, 1H), 4.47 (dd, J = 15.6 and 2.4 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 6.27–6.30 (m, 1H),
6.32 (dd, J = 9.6 and 7.2 Hz, 1H), and 6.61 (dd, J = 7.2 and 1.2 Hz, 1H).
1
Methyl 2-tert-butyl-5-chloro-3-oxo-1H-2,3-dihydrocyclohepta[c]pyrrole-3a-carboxylate (6g’). H-NMR (CDCl3,
400 MHz, signals from a 12:4:1 mixture of trans-7g, 6g, and 6g’) δ 1.46 (s, 9H), 3.64 (s, 3H), 4.23 (dd,
J = 15.2 and 2.0 Hz, 1H), 4.42 (dd, J = 15.2 and 2.4 Hz, 1H), 5.76 (t, J = 1.2 Hz, 1H), 6.18–6.21 (m, 1H),
and 6.38–6.40 (m, 2H).
1
Methyl 1-(3-cyanobenzyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (8h). H-NMR (CDCl3, 400 MHz,
significant signals from a 2:1 mixture of 8h and cis-7h) δ 1.16 (s, 3H), 1.24 (s, 3H), 2.19 (dd, J = 12.8 and
9.2 Hz, 1H), 2.33 (dd, J = 12.8 and 9.2 Hz, 1H), 3.62 (t, J = 9.2 Hz, 1H), 3.80 (s, 3H), 4.33 (d, J = 16.0 Hz,
1H), and 4.55 (d, J = 16.0 Hz, 1H).
Methyl 2-tert-butyl-8-methoxy-3-oxo-1H-2,3-dihydrocyclohepta[c]pyrrole-3a-carboxylate (6i). 1H-NMR
(CDCl3, 400 MHz, signals from a 1.5:1 mixture of 6i and cis-7i) δ 1.47 (s, 9H), 3.55 (s, 3H), 3.69
(s, 3H), 4.23 (dd, J = 14.4 and 1.6 Hz, 1H), 4.48 (dd, J = 14.4 and 1.6 Hz, 1H), 5.65 (d, J = 7.2 Hz,
1H), 6.29–6.33 (m, 1H), 6.31 (d, J = 7.6 Hz, 1H), and 6.38–6.45 (m, 1H). 13C-NMR (CDCl3, 100.6 MHz,
significant signals from a 1:8 mixture of 6i and cis-7i
) δ 27.6 (3 CH3), 49.4 (CH2), 52.8 (CH3), 55.1 (C),
57.5 (CH3), 99.8 (CH), 120.6 (CH), 122.5 (CH), and 126.9 (CH).
1
Methyl 1-(2-fluorobenzyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (8j). H-NMR (CDCl3, 400 MHz,
signals from a 8:1 mixture of 8j and cis-7j 1.14 (s, 3H), 1.25 (s, 3H), 2.15 (dd, J = 12.8 and 9.2 Hz, 1H),
)
δ
2.31 (dd, J = 12.8 and 9.2 Hz, 1H), 3.61 (t, J = 9.2 Hz, 1H), 3.82 (s, 3H), 4.46 (d, J = 16.0 Hz, 1H), 4.55 (d, J
= 16.0 Hz, 1H), 7.00 (ddd, J = 10.4, 8.4, and 1.2 Hz, 1H), 7.09 (td, J = 7.6 and 1.2 Hz, 1H), 7.19–7.25 (m,
1H), and 7.39 (td, J = 7.6 and 1.2 Hz, 1H).

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Methyl 1-(2-bromobenzyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (8k). Amorphous orange solid.
1H-NMR (CDCl3, 400 MHz)
1.18 (s, 3H), 1.23 (s, 3H), 2.20 (dd, J = 12.8 and 9.2 Hz, 1H), 2.35 (dd,
δ
J = 12.8 and 9.2 Hz, 1H), 3.65 (t, J = 9.2 Hz, 1H), 3.83 (s, 3H), 4.45 (d, J = 16.4 Hz, 1H), 4.64 (d, J = 16.4
Hz, 1H), 7.10 (ddd, J = 8.0, 6.8 and 2.4 Hz, 1H), 7.24–7.30 (m, 2H), 7.51 (dd, J = 7.6 and 1.2 Hz, 1H).
13C-NMR (CDCl3, 100.6 MHz)
δ 26.9 (s, CH3), 27.8 (s, CH3), 38.3 (CH2), 43.1 (CH2), 47.6 (CH), 52.9
(CH3), 60.0 (C), 122.6 (C), 128.0 (CH), 128.9 (CH), 129.2 (CH), 132.7 (CH), 137.1 (C), 170.1 (C), and
171.1 (C).
Methyl 1-(2-iodobenzyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (8l). Amorphous orange solid.
1H-NMR (CDCl3, 400 MHz)
δ 1.20 (s, 3H), 1.22 (s, 3H), 2.20 (dd, J = 13.2 and 9.2 Hz, 1H), 2.35
(dd, J = 13.2 and 9.2 Hz, 1H), 3.65 (t, J = 9.2 Hz, 1H), 3.83 (s, 3H), 4.35 (d, J = 16.4 Hz, 1H), 4.59 (d,
J = 16.4 Hz, 1H), 6.93 (td, J = 8.0 and 1.6 Hz, 1H), 7.23 (dd, J = 8.0 and 1.6 Hz, 1H), 7.30 (td, J = 8.0 and
1.2 Hz, 1H), and 7.79 (dd, J = 8.0 and 1.2 Hz, 1H).
1
Methyl cis-1-tert-butyl-2-oxo-4-(pyridin-4-yl)azetidine-3-carboxylate (cis-12). H-NMR (CDCl3, 400 MHz,
signals from a 2.6:1 mixture of trans-12 and cis-12
4.88 (d, J = 6.4 Hz, 1H), 7.32-7.35 (m, 2H), and 8.61–8.65 (m, 2H). 13C-NMR (CDCl3, 100.6 MHz, signals
from a 2.6:1 mixture of trans-12 and cis-12 28.2 (3 CH3), 52.2 (CH3), 55.4 (CH), 55.5 (C), 59.0 (CH),
121.1 (2 CH), 146.2 (C), 150.2 (2 CH), 162.5 (C), and 165.9 (C).
) δ 1.32 (s, 9H), 3.36 (s, 3H), 4.28 (d, J = 6.4 Hz, 1H),
)
δ
1
Methyl trans-1-tert-butyl-2-oxo-4-(pyridin-4-yl)azetidine-3-carboxylate (trans-12). H-NMR (CDCl3, 400
MHz) 1.27 (s, 9H), 3.67 (d, J = 2.4 Hz, 1H), 3.78 (s, 3H), 4.84 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 4.4 and
1.6 Hz, 2H), and 8.64 (dd, J = 4.4 and 1.6 Hz, 2H). 13C-NMR (CDCl3, 100.6 MHz)
28.2 (3 CH3), 53.0
δ
δ
(CH3), 55.2 (CH), 55.7 (C), 62.1 (CH), 121.6 (2 CH), 148.5 (C), 150.7 (2 CH), 161.7 (C), and 167.0 (C).
4. Computational Details
All the calculations reported in this paper were performed with the Gaussian 09 suite of
programs [66]. Electron correlation was partially taken into account using the hybrid functional usually
denoted as B3LYP [67
al. [70] using the standard double-
Continuum Model (PCM) [73 75] was used to model the effects of the solvent. This level is denoted
–69] in conjunction with the D3 dispersion correction suggested by Grimme et
ζ
quality def2-SVP [71 72] basis set for all atoms. The Polarizable
,
–
PCM(solvent)-B3LYP-D3/def2-SVP. Geometries were fully optimized in solution without any geometry
or symmetry constraints. Reactants, intermediates, and products were characterized by frequency
calculations and have positive definite Hessian matrices. Transition structures (TSs) 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 Reaction Coordinate (IRC) method [76]. Frequency calculations were also used
to determine the difference between the potential (E) and Gibbs (G) energies, G
the zero-point, thermal, and entropy energies. Potential energies were refined, Esol, by means of
single point (SP) calculations at the same level with a larger basis set, def2-TZVPP [71 72], where
all elements were described with a triple- plus polarization quality basis set. This level is denoted
PCM(solvent)-B3LYP-D3/def2-TZVPP//PCM(solvent)-B3LYP-D3/def2-SVP. The G and
G, values
given in the text were obtained from the Gibbs energy in solution, Gsol, which was calculated by
−
E, which contains
,
ζ
∆
∆
adding the thermochemistry corrections, G
See Supplementary Materials.
−
E, to the refined SP energies, Esol, i.e., Gsol = Esol + G
−
E.
5. Conclusions
In summary, in the present paper, we report a full account of our experimental
and computational studies on the Pd-catalyzed intramolecular carbene C–H insertion of
α
-diazo-
α
-(methoxycarbonyl)acetamides to prepare oxindoles and
β-lactams. We have explored
how the reactions are affected by the substituents on the
α-diazoamide moiety and by the catalyst type,
exploring the use of both Pd(0) and Pd(II) catalysts.

Molecules 2019, 24, 3551
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The chemoselectivity of the Pd-catalyzed C–H insertion reactions of
α
-diazo acetamides is mainly
governed by the nature of the substrates. Thus, while N-aryl acetamides selectively afforded oxindoles,
starting from N,N-dialkyl acetamides, the corresponding β-lactams were obtained.
The results obtained in the annulation reactions to form oxindoles show that Pd(0) catalysts were
much more efficient than Pd(II) catalysts and that ((IMes)Pd(NQ))2 can be used as an alternative to
Pd2(dba)3 to catalyze the carbene CArsp2–H insertion.
On the other hand, both Pd(0) and Pd(II) catalysts can be used to promote Csp3–H insertion
leading to β-lactams. However, the Pd(II) complexes proved to be more versatile for β-lactam formation
since the use of Pd(0) catalysts resulted in increased amounts of Buchner products and, in some cases,
of the corresponding γ-lactams.
Our computational studies show that when using ((IMes)Pd(NQ))2 as the catalyst, both CArsp2–H
and Csp3–H insertions involve similar stepwise reaction mechanisms, in which a palladium-mediated
hydrogen migration is followed by a reductive elimination.
Supplementary Materials: The following are available online, Copies of 1H and 13C-NMR spectra of new
compounds and Cartesian coordinates and total energies of all species described in the manuscript.
Author Contributions: D.S. designed and planned the research; D.S. and M.-L.B. supervised the experimental
work; F.P.-J. and A.A. performed the experimental work and characterized the compounds; I.F. carried out the
computational studies; D.S. and I.F. prepared the manuscript for publication.
Funding: This research was funded by MINECO/FEDER, Spain (Projects CTQ2015-64937-R, CTQ2016-78205-P,
CTQ2016-81797-REDC, and RTI2018-09394-B-I00).
Conflicts of Interest: The authors declare no conflict of interest.
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