Pd-Catalyzed Acyl C-O Bond Activation for Selective Ring-Opening of α-Methylene-β-lactones with Amines

Article abstract of DOI:10.1021/acs.orglett.7b00494

A Pd-catalyzed ring-opening of β-lactones with various types of amines (primary, secondary, and aryl) to provide β-hydroxy amides with excellent selectivity toward acyl C-O bond cleavage is reported. The utility of this protocol is demonstrated in an asym

Full text of DOI:10.1021/acs.orglett.7b00494

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Acyl C−O Bond Activation for Selective Ring-Opening
of α‑Methylene-β‑lactones with Amines
Christian A. Malapit, Donald R. Caldwell, Nicole Sassu, Samuel Milbin, and Amy R. Howell*
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States
S
* Supporting Information
ABSTRACT: A Pd-catalyzed ring-opening of β-lactones with various types of amines (primary, secondary, and aryl) to provide
β-hydroxy amides with excellent selectivity toward acyl C−O bond cleavage is reported. The utility of this protocol is
demonstrated in an asymmetric kinetic resolution providing enantioenriched α-methylene-β-lactones.
β-Lactones are important intermediates in organic synthesis.1
They can be readily accessed in high enantiomeric purity, and
they undergo a broad range of transformations, providing
highly functionalized products. As part of our interest in the
utility of β-lactones or β-lactone-derived strained heterocycles
in organic synthesis, we have reported several of their reactions
in the presence of transition-metal (TM) catalysts.2 In
particular, we reported that α-methylene-β-lactones 1 readily
undergo cross-metathesis reactions2e and recently used this to
access a focused library of 3,4-disubstituted β-lactones for
proteomic profiling.2c,d A current interest is to develop further
useful methods employing 1, especially applications involving
ring-opening reactions.
The ring-opening of β-lactones with different nucleophiles
has been utilized in the synthesis of biologically important
synthetic and natural products. Nevertheless, a major problem
in opening β-lactones can be the formation of two isomeric
Figure 1. Alkyl vs acyl C−O bond cleavage in β-lactones.
products due to competing alkyl C−O and acyl C−O bond
cleavages (Figure 1A).1a In particular, the selective opening of
lactones. Puddephatt reported the oxidative addition of oxetan-
β-lactones with amines has proven to be challenging.3 We
2-one with a stoichiometric amount of a Pt complex via alkyl
C−O cleavage (Figure 2).6 Noels described a Pd-catalyzed
hypothesized that α-methylene-β-lactones 1 could undergo
selective ring opening with amine nucleophiles under Pd
catalysis (Figure 1B). These unsaturated β-lactones could be
expected to undergo allyl C−O bond activation with Pd to
provide palladacycle A4 (Figure 1B, path a). Alternatively, the
olefin could act as a directing group5 to facilitate the oxidative
addition of Pd into the acyl C−O bond to form palladacycle B
(Figure 1B, path b). Herein, the development of a Pd-catalyzed
activation of α-methylene-β-lactones to provide solely β-
hydroxy-α-methyleneamides in good to excellent yields is
reported. The broad scope of the transformation using various
β-lactones and amines is described.
opening of vinyl-substituted β-lactones to form butadiene
acids.7 This transformation was proposed to involve allyl C−O
bond activation to form a palladalactone, which then undergoes
β-hydride elimination. This mode of activation was utilized by
Hattori with vinyl β-lactones generated in situ from the reaction
of ketene with α,β-unsaturated aldehydes.8 These allylic
systems would appear to be especially relevant to an
expectation that Pd catalysis might be used for allyl C−O
bond cleavage in α-methylene-β-lactones.
There are, to our knowledge, no reports of TM-catalyzed
ring opening of β-lactones at the acyl C−O bond.
Consequently we looked into TM-catalyzed coupling of esters
As mentioned above, we postulated that selective opening of
α-methylene-β-lactones might be promoted by oxidative
addition of a TM into either the alkyl or acyl C−O bond.
There is direct precedent for alkyl C−O bond activation of β-
Received: February 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00494
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Organic Letters
Letter
3a. After optimization of the concentration and of the molar
ratio of benzylamine, 3a was isolated in 92% yield (entry 2). At
45 °C, complete conversion was achieved after 12 h, providing
3a in nearly quantitative yield. Other solvents, such as THF and
CHCl3, as well as biphosphine ligands (BINAP and
SEGPHOS), gave outcomes similar to that of entry 2. Other
Pd sources (entries 4−6) also promoted the transformation.
Notably, the use of catalytic Pd(PPh3)4 without exogenous
phosphine ligand provided an efficient conversion, but 3a and
3a′ were formed in a 10:1 ratio. When the reaction was carried
out in the absence of Pd catalyst or phosphine ligand (entries
7−9), no significant conversion was observed. It is also worth
noting that the other possible product, β-amino acid 2 (Figure
1B, path a) was never observed. Consistent with our alternate
hypothesis (Figure 1B, path b), these results indicate that the
reaction is promoted by initial oxidative addition of Pd(0) to
the acyl C−O bond of β-lactone 1.
Figure 2. Transition-metal activation of alkyl C−O bonds in β-
lactones.
with amines. Certain types of esters, activated with α-aromatic/
heteroaromatic or CF3 substituents or certain alkoxy moieties,
have been shown to undergo TM-catalyzed acyl C−O bond
activation. The intermediates can be cross-coupled to form
ketones9 or undergo decarbonylation10 before reductive
coupling. Of potential direct relevance, Bao and co-workers
recently developed a Pd-catalyzed amidation of activated esters
that was believed to involve an acyl C−O insertion with a Pd
catalyst.11 Also, the Garg group utilized a nickel catalyst for the
activation of aromatic methyl esters for amide formation.12 We
surmised that the α-methylene could play the role of an
activating group for C−O insertion.
The optimized conditions shown in the reaction scheme in
Table 1 were utilized for the ring-opening of several α-
methylene-β-lactones with various types of amines. As
highlighted in Scheme 1, primary, secondary, and allyl amines
Scheme 1. Scope of Pd-Catalyzed Amidation of α-
a
b
Methylene-β-lactones with Various Amines
We initially probed the ring-opening of α-methylene-β-
lactone 1a with benzylamine in the presence of a catalytic
amount of Pd(OAc)2 and PPh3 in DCM at rt (Table 1). The
use of 2 equiv of benzylamine provided a 4:1 mixture of β-
hydroxy amides 3a and 3a′ (entry 1). The latter was believed to
arise from aza-Michael addition of the excess amine to product
Table 1. Initial Studies on the Pd-Catalyzed Amidation of β-
a
Lactone 1a with Benzylamine
c
ratio
3a:3a′
yield of 3a
b
entry
variation from general conditions
(%)
a
For the syntheses of the α-methylene-β-lactones, see the Supporting
b
1
2
3
4
2 equiv of BnNH2, 0.5 M
none
4:1
>20:1
>20:1
>20:1
80
92
98
Information. General conditions: 0.1−0.2 mmol of 1 (1 equiv),
amine (1.1 equiv), Pd(OAc)2 (5 mol %), PPh3 (15 mol %) in DCM
(0.2 M) at rt or 45 °C for 24 h. For aryl amines: 2−4 equiv of aryl
amine was used in DCM (0.5 M) at 45 °C. 1.0 mmol scale.
45 °C, 12 h
2 mol % [Pd(allyl)Cl]2; 12 mol %
PPh3
c
d
90
d
5
6
7
8
9
2 mol % Pd2(dba)3; 12 mol % PPh3
5 mol % Pd(PPh3)4; no PPh3
5 mol % Pd2(dba3); no PPh3
no Pd(OAc)2
>20:1
10:1
95
d
85
provided β-hydroxy amides 3a−f in good to excellent yields.
The outcome observed with morpholine (3e) is noteworthy.
Adam and co-workers found that cyclic, secondary amines
(such as piperidine and pyrrolidine) reacted with α-methylene-
β-lactones in the absence of a Pd catalyst to give conjugate
addition products.13
Aryl amines were also successfully coupled to give exclusively
the corresponding amides. When these amines were used in
excess (2−4 equiv) and the reaction was conducted at 45 °C, β-
hydroxy-α-methylene arylamides 3g−j were obtained in high
yields.
e
nr
b
<5 conv
b
no PPh3
∼10 conv
a
General conditions: 0.1 mmol of 1a, benzylamine (1.1 equiv), Pd
catalyst (5 mol % Pd(OAc)2), 15 mol % of PPh3 in DCM (0.2 M) at rt
b
for 24 h. Ratios and conversions were estimated by 1H NMR analysis
c
d
of the crude reaction mixture. Isolated yields except where noted. 1H
e
NMR yields using 1,3,5-trimethoxybenzene as internal standard. The
starting material was recovered; Pd black was observed on the wall of
the reaction tube.
B
DOI: 10.1021/acs.orglett.7b00494
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To extend the generality of this method, we next explored
whether the Pd-catalyzed ring-opening can be used for simple
β-lactones. As shown in Scheme 2, α-phenyl-β-lactone 4
Scheme 3. Pd-Catalyzed Asymmetric Kinetic Resolution of
β-Lactones
a
Scheme 2. Scope of Pd-Catalyzed Amidation of Various
a
Types of β-Lactones
a
General conditions: 0.1 to 0.2 mmol 1 (1 equiv), amine (1 equiv),
Pd(OAc)2 (2 mol %), chiral ligand (5 mol %) in CDCl3 (0.2 M) at rt
for 16−20 h.
a
For the syntheses of the β-lactones, see the Supporting Information.
General conditions: 0.2 mmol of 1 (1 equiv), amine (1.1 equiv),
Pd(OAc)2 (5 mol %), PPh3 (15 mol %) in DCM (0.2 M) at rt or 45
°C for 24 h.
(such as the use of various Pd sources, solvents, type and
amounts of amine, reaction concentration, and temperature)
did not improve the enantioselectivities. The conditions
developed above for Pd-catalyzed asymmetric kinetic resolution
were utilized for other β-lactones. With the exception of α-
phenyl-β-lactone 4, good yields and moderate enantioselectiv-
ities were obtained.
In conclusion, we have developed a highly selective Pd-
catalyzed ring opening of α-methylene-β-lactones and β-
lactones with various types of amines (primary, secondary,
and aryl) to give amides via acyl C−O activation. The complete
chemoselectivity and efficiency of the transformation are
remarkable. Moreover, enantioenriched α-methylene-β-lactones
can be obtained through kinetic resolution by using chiral
phosphine ligands. The kinetic resolution of α-methylene-β-
lactones has previously only been achieved by an enzymatic
process.
underwent facile ring-opening with benzylamine, providing the
ring-opened product in excellent yield at rt. Racemic trans-
disubstituted β-lactone 5 also gave the desired product with
complete selectivity, albeit in slightly lower yield. Notably,
when β-lactone 4 or 5 was reacted with benzylamine in the
absence of a Pd catalyst, the reaction was messier (based on 1H
NMRs of crude reaction mixtures), and the isolated yield for 3k
(65%) or 3l (52%) was lower. Homochiral β-lactone (R)-1a
(99% ee) also underwent ring opening to yield β-hydroxy
amide (R)-3a (99% ee) without erosion of the stereochemical
integrity. Likewise, α-alkylidene-β-lactone 6, prepared by the
Ru-catalyzed cross-metathesis of its corresponding α-methyl-
ene-β-lactone,2e provided α-alkylidene-β-hydroxy amide with
complete retention of olefin geometry.
ASSOCIATED CONTENT
* Supporting Information
To date, enantioenriched α-methylene-β-lactones 1 have
only been accessed via enzymatic kinetic resolution.14 Our
interest in α-methylene-β-lactones 1 as privileged intermediates
in organic synthesis led us to explore the Pd-catalyzed
amidation for potential resolution of racemic β-lactones. Several
chiral phosphine ligands typically used in asymmetric Pd-
catalyzed C−N bond coupling reactions were evaluated
(Scheme 3). Racemic β-lactone 1a underwent efficient
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00494.
Detailed experimental procedures, analytical and spectral
data for all new compounds, and HPLC traces for kinetic
resolution experiments (PDF)
1
amidation. Reactions were monitored by H NMR analysis
and were quenched after obtaining ∼50−55% conversions,
typically after 16−20 h. (R)-BINAP and (R)-SEGPhos (not
shown) did not provide any selectivity. When chiral Trost
ligands15 L2 and L3 were utilized, 5−38% ee’s were obtained.
The use of chiral spiroketal phosphine (SKP) ligands, recently
developed by Ding and co-workers,16 provided improved
resolution, up to 68% ee (using SKP-L4). Further optimization
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: amy.howell@uconn.edu.
ORCID
Amy R. Howell: 0000-0003-1958-6411
C
DOI: 10.1021/acs.orglett.7b00494
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) (a) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem.
Soc. 1992, 114, 9327. (b) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.;
Calkins, T. L. J. Am. Chem. Soc. 2000, 122, 5968.
Notes
The authors declare no competing financial interest.
(16) (a) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Ding, K. J. Am. Chem.
Soc. 2014, 136, 405. (b) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen,
Y.; Liu, L.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 9276.
ACKNOWLEDGMENTS
■
This paper is based upon work partially supported by the
National Institutes of Health (NIH) under Grant No. R01
CA193994. Boehringer Ingelheim (BI Fellowship for C.A.M.)
is acknowledged for financial support. S.M. acknowledges
support from the University of Connecticut McNair Scholars
program.
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DOI: 10.1021/acs.orglett.7b00494
Org. Lett. XXXX, XXX, XXX−XXX