Synthesis of β-Lactams by Palladium(0)-Catalyzed C(sp3)?H Carbamoylation

Article abstract of DOI:10.1002/anie.201703109

A general and user-friendly synthesis of β-lactams is reported that makes use of Pd⁰-catalyzed carbamoylation of C(sp³)?H bonds, and operates under stoichiometric carbon monoxide in a two-chamber reactor. This reaction is compatible with a range of primary, secondary and activated tertiary C?H bonds, in contrast to previous methods based on C(sp³)?H activation. In addition, the feasibility of an enantioselective version using a chiral phosphonite ligand is demonstrated. Finally, this method can be employed to synthesize valuable enantiopure free β-lactams and β-amino acids.

Full text of DOI:10.1002/anie.201703109

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201703109
German Edition: DOI: 10.1002/ange.201703109
ꢀ
C H Activation
3
ꢀ
Synthesis of b-Lactams by Palladium(0)-Catalyzed C(sp ) H
Carbamoylation
David Dailler, Ronan Rocaboy, and Olivier Baudoin*
Abstract: A general and user-friendly synthesis of b-lactams is
reported that makes use of Pd0-catalyzed carbamoylation of
3
ꢀ
C(sp ) H bonds, and operates under stoichiometric carbon
monoxide in a two-chamber reactor. This reaction is compat-
ible with a range of primary, secondary and activated tertiary
3
ꢀ
ꢀ
C H bonds, in contrast to previous methods based on C(sp )
H activation. In addition, the feasibility of an enantioselective
version using a chiral phosphonite ligand is demonstrated.
Finally, this method can be employed to synthesize valuable
enantiopure free b-lactams and b-amino acids.
b-Lactams are very important scaffolds for drug discovery,
as illustrated by the structure of numerous monocyclic (e.g.,
Aztreonam) and bicyclic (e.g., Sulbactam) antibiotics, as well
as the cholesterol-lowering drug Ezetinibe (Scheme 1,
bottom).[1] They are also valuable synthetic intermediates,
for instance in the synthesis of b-amino acids and their
derivatives upon ring-opening.[2] In the past few years,
3
ꢀ
methods based on C(sp ) H activation methods have been
introduced to access this motif in a straightforward manner.
On the one hand, methods employing PdII catalysis and
requiring stoichiometric oxidant have been reported. The
groups of Shi[3a] and Wu[3b,c] employed a pyridine- or
quinoline-based directing group (DG), respectively, to form
ꢀ
the N Cb bond of the b-lactam ring (Scheme 1a). The
reaction is operationally simple but requires the installation
and removal of a DG possessing a comparatively high
II
0
3
ꢀ
Scheme 1. Synthesis of b-lactams by Pd - and Pd -catalyzed C(sp ) H
activation: state-of-the-art and current work.
ꢀ
molecular weight. In addition, only secondary C H bonds
could be functionalized, and the bidentate nature of the DG
could hinder the development of an enantioselective version.
In parallel, Gaunt and co-workers described a carbonylative
ꢀ
monodentate ligands, from electron-poor phosphoramidites[7]
to electron-rich phosphines[8] and N-heterocyclic carbenes.[9]
This feature allows the modulation of reactivity and site
selectivity, as well as the development of enantioselective
reactions. In this context, Cramer and co-workers employed
C H activation method to synthesize b-lactams from simple
aliphatic secondary amines (Scheme 1b).[4] The reaction,
which requires CuII co-catalysis, benzoquinone (BQ) as the
terminal oxidant, and excess CO (balloon), shows impressive
ꢀ
a-chloroamides as precursors to construct the Ca Cb bond of
b-lactams (Scheme 1c).[10] Using a chiral phosphoramidite
ꢀ
scope, but was only reported with primary C H bonds. A
nitrogen ligand was found to be beneficial, which opens the
ligand, high enantioselectivity levels were achieved for the
ꢀ
desymmetrization of enantiotopic secondary C H bonds.
way for a future enantioselective version. On the other hand,
However, the reaction occurred only on activated methylenes
adjacent to a (hetero)aryl or ester group. Recently, we were
able to access highly strained a-alkylidene-b-lactams from
bromoalkenes, but this system, which was tailored for g-
lactams, lacked generality and efficiency.[11] Inspired by the
work of Takemoto and co-workers on the carbamoylation of
as initially shown by our group,[5,6] C(sp ) H activation
3
ꢀ
reactions operating through Pd0 catalysis allow the formation
of a wide variety of ring systems under oxidant-free con-
ditions and are compatible with the use of a range of
[12]
ꢀ
primary benzylic and cyclopropyl C H bonds,
we envi-
[*] D. Dailler, R. Rocaboy, Prof. Dr. O. Baudoin
University of Basel, Department of Chemistry
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: olivier.baudoin@unibas.ch
sioned that carbamoyl chlorides could constitute more
ꢀ
appropriate substrates to construct the C(O) Ca bond of b-
3
lactams through Pd0-catalyzed C(sp ) H activation
ꢀ
(Scheme 1d). Carbamoyl chlorides are easily accessed from
the corresponding secondary amines upon reaction with
triphosgene, and they can be engaged in the reaction without
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201703109.
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purification. We report herein the development of a conven-
we first conducted reactions under excess CO (balloon), as
reported by Takemoto and co-workers (Table 1). Optimiza-
tion studies were performed with TMB-protected[13] carba-
moyl chloride 1a. Initially, we employed Pd(PPh3)4 as the
catalyst and cesium pivalate as the active base,[11] which gave
rise to b-lactam 2a in modest yield (entry 1), together with
amine 3a. Variation of the Pd source, ligand, solvent, acid
additive, equivalents of carbonate, and temperature
(entries 2–10)[14] allowed the identification of PdCl2/PAd2(n-
Bu) as the optimal catalyst, in combination with cat. PivOH
(30 mol%)/Cs2CO3 (3 equiv) as the basic system in mesity-
lene at 1208C (entry 6). Employing the electron-rich PAd2(n-
Bu) phosphine (CataCXium A) was crucial, likely to avoid
catalyst deactivation by excess CO.[15] Well-defined PdII
(entry 11) and Pd0 (entry 12) complexes containing this
phosphine ligand[16] performed with comparable efficiency
to the in situ formed catalyst. This experiment with the Pd0L2
complex (entry 12) indicates that this reaction indeed pro-
ceeds through the Pd0!PdII!Pd0 catalytic cycle depicted in
Scheme 2. Further support for this mechanism was provided
by a control experiment performed with amine 3a instead of
carbamoyl chloride 1a, which failed to give any trace of the b-
lactam product (entry 13). Moreover, when the isolated
complex A (R = i-Pr, L = PPh3)[4b] was heated to 1208C with
PivOH and Cs2CO3 in mesitylene, the corresponding b-lactam
product was formed in comparable yield to the catalytic
3
ꢀ
ient method to synthesize b-lactams by C(sp ) H carbamoy-
lation, which is compatible with both primary and secondary
ꢀ
C H bonds and is adaptable to an enantioselective version.
At the outset of our work, we were aware that competitive
ꢀ
decarbonylation, occurring prior to the C H activation step
and leading to secondary amine 3, would likely impact the
reaction efficiency (Scheme 2).[12] To limit this side reaction,
Scheme 2. Mechanistic model.
Table 1: Optimization of reaction conditions.[a]
Entry
[Pd]
Ligand
n
Solvent
CO Source
COgen[b] (equiv)
T [8C]
Yield 2a [%][c]
balloon
p
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PAd2(n-Bu)-Pd-G3
Pd[PAd2(n-Bu)]2
PdCl2
PdCl2
PdCl2
–
PPh3
1.5
1.5
1.5
1.5
3
3
3
3
3
3
3
3
3
3
3
3
3
Xylene
Xylene
Xylene
Xylene
120
120
120
120
120
120
110
130
120
120
120
120
120
120
120
120
120
27%
10%
45%
76%
82%
92% (85%)
57%
58%
18%
28%
80%
88% (85%)
0%
70%
p
p
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2Bn
PCy3·HBF4
–
–
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
PAd2(n-Bu)·HI
p
p
Xylene
p
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
p
p
p
9
p
10
11
12
13[d]
14
15
16
17[e]
p
p
p
–
–
(1.5)
p
75%
p
PdCl2
PdCl2
(3)
(3)
94% (92%)
p
(95%) (75%)[f]
[a] Performed using 0.133 mmol of 1a unless otherwise stated. [b] 9-Methylfluorene-9-carbonyl chloride (COgen), Pd(OAc)2/P(t-Bu)3·HBF4 cat.,
Cy2NMe, mesitylene, two-chamber system (COware), both reaction chambers were placed at the same temperature. [c] Determined by NMR analysis
using trichloroethylene as internal standard. Yield of isolated product 2a is given within parentheses. [d] Using amine 3a instead of 1a. [e] Performed
using 1.33 mmol (400 mg) of 1a. [f] Performed using technical-grade mesitylene under non-inert conditions. TMB=2,4,6-trimethoxybenzyl.
2
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reaction performed with the carbamoyl chloride and Pd-
affect the yield (95%, entry 17). Moreover, the reaction was
(PPh3)4,[14] thereby indicating that complex A is a competent
intermediate. Therefore, this Pd0!PdII!Pd0 catalytic cycle
differs from the PdII!Pd0!PdII mechanism that operates in
the case of secondary amines (Scheme 1b).[4b] In the absence
of CO (entry 14), the reaction proceeded with reduced
(ꢀ22%) but yet acceptable yield (70%), in contrast to
observations of Takemoto and co-workers.[12a] In order to
develop a more convenient method that can be employed
without special safety equipment, we looked for an appro-
priate nongaseous source of stoichiometric CO. After unsuc-
cessful tries with various in situ CO sources,[14] we turned to
the use of the two-chamber (COware) system developed by
Skrydstrup and co-workers.[17] Gratifyingly, when using
3 equiv of COgen (entries 15–16), the yield of isolated 2a
increased to 92%, thereby surpassing the yield obtained with
excess CO (85%, entry 6). Of note, the same reaction
performed with 13COgen led to a very low (2.5%) incorpo-
ration of 13C into the b-lactam product,[14] which suggests that
the role of the added CO is mainly to saturate the reaction
solution to limit the decarbonylation of intermediate A
(Scheme 2). Finally, scaling up the reaction tenfold did not
performed successfully when technical-grade solvent was
employed and the experiment was set up under air (75%
yield), thereby demonstrating the robust and user-friendly
character of this method.
The scope of the reaction was next investigated, and for
comparison, both CO balloon and COgen conditions were
tested for each substrate (Scheme 3). In most cases, the
COgen conditions were found to be superior or equal to the
CO-balloon conditions. Moreover, in several instances, such
as for 2e, 2o,p, 2r, 2u, and 2ab–ad, the yield difference was
greater than 20%, thereby making the COgen-mediated
reaction an efficient b-lactam synthesis when the CO-balloon
ꢀ
method was sluggish. The carbamoylation of primary C H
bonds was first investigated with TMB-protected substrates
1a–i (Scheme 3a). Excellent yields were obtained with
reactants bearing a trisubstituted b position, including enan-
tiopure reactants (2e–h). In the case of substrate 1i, which
bears Me and Ph substituents on Cb, a competition between
3
2
ꢀ
ꢀ
C(sp ) H and C(sp ) H activation was observed, albeit in
favor of the former (2i/2j = 7:3), which is somewhat unusual
given the higher reactivity of the latter,[18] but likely reflects
Scheme 3. Scope and limitations of the b-lactam synthesis. Compounds 2e–j and 2v,w were obtained from enantiopure amines.
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the preferential formation of the kinetically favorable 5-
ꢀ
membered palladacycle intermediate in the C H activation
step. The reaction also occurred when the b position was
disubstituted (2b), albeit with markedly reduced efficiency.
3
ꢀ
Nevertheless, this is a rare case of C(sp ) H functionalization
of such an unfunctionalized substrate, which does not benefit
from favorable conformational effects. Surprisingly, b-tetra-
ꢀ
substituted substrates 1c,d failed to undergo C H carbamoy-
lation, likely due to excessive repulsion with the adjacent
TMB group. Fortunately, less-hindered
N substituents
restored reactivity for this interesting class of substrates
(Scheme 3c). Indeed the nature of the N substituent had
a marked effect on the reaction efficiency (Scheme 3b). For
instance a phenyl substituent was tolerated, but only when it
Scheme 4. Proof-of-concept enantioselective synthesis of b-lactams
through the desymmetrization of methyl groups.
was separated from the N atom by a sufficiently long carbon
2
ꢀ
chain (2o,p), presumably because competitive C(sp ) H
ꢀ
activation occurs when the chain is too short (2m,n). Other
functional groups such as an ester (2q) and a protected amine
(2r) could be employed, although the reaction occurred with
moderate yield. A range of carbamoyl chlorides bearing
a tetrasubstituted Cb also reacted successfully (Scheme 3c),
including those derived from more elaborate acyclic and
cyclic monoterpene precursors (1u–x). The reaction selectiv-
ity is especially noteworthy for 2v and 2w, wherein the alkene
Finally, this C H carbamoylation method was applied to
the synthesis of the enantiopure free b-lactam 4ac and b-
aminoacid 5ac. The latter, which was previously obtained by
enzymatic resolution, is of high interest for the synthesis of b-
peptides (Scheme 5).[23] Commercially available enantiopure
group did not undergo competitive carbopalladation or
2
ꢀ
C(sp ) H activation. The example of fused b-lactam 2x,
which is reminiscent of bicyclic antibiotics, is also worth
ꢀ
highlighting. In addition to primary C H bonds, activated
ꢀ
tertiary cyclopropyl C H bonds (2y–z) and benzylic secon-
ꢀ
dary C H bonds (2aa–ab) were found to be reactive, thus
affording original spirocyclic and fused b-lactams in high
yields (Scheme 3d). Moreover, we were pleased to find that
less-activated methylenes of both cyclic (2ac–ae) and acyclic
(2af) substrates also underwent carbamoylation (Scheme 3e),
albeit with variable efficiency. The latter was maximal for
product 2ac, which was obtained in quantitative yield using
the two-chamber system, whereas the CO-balloon conditions
were much less efficient (40%).
Scheme 5. Synthesis of an enantiopure b-amino acid. Reagents and
conditions: a) 2,4,6-trimethoxybenzaldehyde (1 equiv), NaBH(OAc)3
(2 equiv), AcOH (2 equiv), 1,2-dichloroethane, 208C, 100%; b) triphos-
gene (0.34 equiv), benzene, 608C, 86%; c) see Scheme 3, condi-
tions A; d) K2S2O8 (2 equiv), Na2HPO4·7H2O (2 equiv), MeCN/H2O
2:1, 808C, 91%; e) 6m HCl, reflux, quant.
0
3
ꢀ
Another attractive feature of Pd -catalyzed C(sp ) H
activation is the possibility to induce enantioselectivity by
using either a chiral ancillary ligand[19] or a chiral base.[20] We
pursued this possibility by examining the effect of various
chiral catalysts in the enantioselective desymmetrization of
carbamoyl chloride 1a (Scheme 4). Extensive screening,
followed by optimization of the best ligand lead structure,
converged towards the new TADDOL-derived phosphonite
L, which enabled the formation of b-lactam 2a in 76% yield
and good e.r. (92:8) under excess CO.[14] Using the COgen
conditions positively affected the yield (86%), but the
enantioselectivity slightly decreased (e.r. 86:14). Although
levels of enantioselectivity higher than 92:8 could not be
reached, this result constitutes a proof-of-concept enantiose-
lective synthesis of b-lactams through the desymmetrization
of unactivated methyl groups, which is to date unprece-
dented.[10] The cleavage of the TMB group was best per-
formed by employing potassium persulfate[21] to give the
known free lactam (R)-4a, which was previously synthesized
through the separation of diastereoisomeric precursors.[22]
tetrahydronaphthylamine 3ac was converted into carbamoyl
ꢀ
chloride 1ac, which underwent C H carbamoylation under
the optimal COgen conditions to give TMB-protected b-
lactam 2ac in 82% yield. Persulfate-mediated oxidative
cleavage provided b-lactam 4ac, which underwent acidic
hydrolysis to give (+)-5ac in very good overall yield (64% for
5 steps).
In conclusion, we report a new method to synthesize
0
3
ꢀ
valuable b-lactams through Pd -catalyzed C(sp ) H carba-
moylation from readily accessible carbamoyl chlorides. This
reaction is compatible with a range of primary, secondary and
ꢀ
activated tertiary C H bonds, in contrast to previous methods
3
ꢀ
based on C(sp ) H activation, and is adaptable to an
enantioselective version using a chiral ligand. Finally, its
applicability to the synthesis of valuable enantiopure free b-
lactams and b-aminoacids was demonstrated.
4
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Conflict of interest
[14] See the Supporting Information for comprehensive optimization
tables and additional experiments.
The authors declare no conflict of interest.
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ꢀ
ꢀ
Keywords: b-lactams · carbonylation · C C coupling · C
H activation · palladium
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Manuscript received: March 25, 2017
Revised: April 27, 2017
Final Article published: && &&, &&&&
[9] M. Nakanishi, D. Katayev, C. Besnard, E. P. Kꢂndig, Angew.
Chem. Int. Ed. 2011, 50, 7438; Angew. Chem. 2011, 123, 7576.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
ꢀ
C H Activation
D. Dailler, R. Rocaboy,
O. Baudoin*
&&&& — &&&&
Synthesis of b-Lactams by Palladium(0)-
3
ꢀ
Catalyzed C(sp ) H Carbamoylation
Fantastic four: A general and user-friendly
synthesis of b-lactams is reported that
a two-chamber reactor. This reaction is
compatible with a range of primary,
makes use of Pd0-catalyzed carbamoyla-
secondary, and activated tertiary C H
ꢀ
3
ꢀ
tion of C(sp ) H bonds, and operates
bonds, in contrast to previous methods
3
ꢀ
under stoichiometric carbon monoxide in
based on C(sp ) H activation.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!