Palladium(II)-Catalyzed C(sp 3)-H Activation of N,O-Ketals towards a Method for the β-Functionalization of Ketones

Article abstract of DOI:10.1055/s-0037-1611664

A method for the formal β-functionalization of aliphatic ketones via a palladium-catalyzed sp ³ C-H activation pathway is reported. An N,O-ketal directs an aliphatic C-H carbonylation to form γ-lactams which upon hydrolysis generate γ-keto carb

Full text of DOI:10.1055/s-0037-1611664

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
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D. K. Ho et al.
Letter
Synlett
Palladium(II)-Catalyzed C(sp3)–H Activation of N,O-Ketals towards
a Method for the β-Functionalization of Ketones
Danny K. H. Ho
R
O
Jonas Calleja
R
O
O
Pd(II) cat.
hydrolysis
R
N
Matthew J. Gaunt*
0
0
0
0-0
0
0
2-7
2
1
4-
6
0
8
X
R
OH
N
H
CO, oxidant
O
O
Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge, CB2 1EW, UK
mjg32@cam.ac.uk
H
15 examples
19–80% yield
from simple
dialkyl ketones
functionalized
pyrrolidinone
1,4-dicarbonyl
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 23.11.2018
Accepted after revision: 07.01.2019
Published online: 05.02.2019
dicarbonyl compounds,7 a class of molecules used exten-
sively as precursors to pharmaceuticals and other value-
added products.8 The development of a broadly applicable
method for accessing β-functionalised ketones would
therefore be of interest to the synthetic community.
We recently reported the application of hindered ali-
phatic amines as directing groups in a palladium-catalyzed
C–H activation reaction proceeding through a previously
unknown 4-membered ring cyclopalladation pathway
(Scheme 1).9 This strategy used the steric properties of the
amine to favour the formation of a catalytically active mo-
no(amine)-Pd(II) complex necessary for C–H activation
(Scheme 1, a).
DOI: 10.1055/s-0037-1611664; Art ID: st-2018-b0762-l
License terms:
Abstract A method for the formal β-functionalization of aliphatic ke-
tones via a palladium-catalyzed sp3 C–H activation pathway is reported.
An N,O-ketal directs an aliphatic C–H carbonylation to form γ-lactams
which upon hydrolysis generate γ-keto carboxylic acids. This C–C bond-
forming reaction is tolerant of a range of functional groups, enabling
the synthesis of a range of synthetically important building blocks. Fur-
thermore, the concepts underlying this transformation have also en-
abled the development of a related C–H alkenylation process to highly
functionalised heterocycles.
More recently, we utilised the concepts underlying this
sterically promoted C–H activation protocol to enable the
functionalization of primary amino alcohols, through their
transient conversion into hindered N,O-ketals (Scheme 1,
b).10 This catalytic strategy led to the development of a
number of useful reactions, providing a means by which
simple, readily accessible amines could be converted into
structurally complex products.
Inspired by these discoveries, we questioned whether
this sterically controlled, amine-directed C–H activation
methodology could be extended to encompass other func-
tional groups of synthetic importance. In particular, we
questioned whether we could exploit the structural fea-
tures of the N,O-ketal functionality to develop a strategy for
the functionalization of ketones. Analysis of the molecular
constitution of the N,O-ketal scaffold revealed that simply
switching the position of the oxygen atom in the oxazoli-
dine ring would enable the C–H activation to occur on the
ketone component of the heterocycle, which upon hydroly-
sis would reveal a β-functionalised ketone (Scheme 1, c).
Key words oxazolidine, palladium, carbonylation, lactam, ketone,
C–H activation
Methods for directly functionalizing C–H bonds repre-
sent ideal reactions for synthetic chemists, with the appeal
of such transformations lying in their ability to enable the
rapid build-up of molecular complexity from simple and
readily accessible building blocks.1 Despite recent advances
in the field of palladium-catalyzed aromatic C–H function-
alization, the development of methods for the selective
functionalization of unactivated sp3 C–H bonds remains an
ongoing challenge.2 In this regard, the functionalization of
aliphatic C–H bonds in the β-position to a carbonyl group
has been the subject of sustained interest.3 Seminal contri-
butions from the group of Yu have led to the development
of a variety of palladium-catalyzed reactions for the func-
tionalization of sp3 C–H bonds at the β-position of carbox-
ylic acids4 and their derivatives,5 however, the development
of palladium-catalysed C–H activation processes involving
the analogous ketones remains a challenge.6 In particular,
the development of methodology for the β-carbonylation of
ketones would provide access to structurally important 1,4-
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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D. K. Ho et al.
Letter
Synlett
methylene C–H bonds of the cyclohexyl group would be
less likely to undergo activation than the terminal C–H
bonds on the ketone component.
a) Sterically driven C–H activation of aliphatic amines
Me
Me
O
O
H
H
N
H
O
O
Pd(OAc)2
N
Upon treatment of N,O-ketal 1 with Pd(OAc)2 (1.5
equiv.) at room temperature, the trinuclear cyclopalladation
complex 2 was isolated in 72% yield. Structural analysis by
single-crystal X-ray diffraction confirmed that the C–H ac-
tivation had occurred on the methyl group of the ketone
component. The reactivity of the C–Pd bond was subse-
quently demonstrated through carbonylation of the cy-
clopalladated intermediate (CO, PhMe, 50 °C) which fur-
nished the desired lactam 3 in 57% yield (Scheme 2).11
Pd
O
Pd
O
N
N
H
O
H
H
Me
O
H
H
Me
simple
amine
mono-amine
Pd(II) complex
bis-amine
Pd(II) complex
essential for C–H activation
stability affected by sterics
b) C–H Activation of amino alcohol derivatives
O
O
5 mol% Pd(OAc)2
PhI(OAc)2
N
N
H
H
O
Ac
PhMe/Ac2O, 60 ºC
Me
Ac
O
O
H
H
OAc
Pd
H
N
Me
1.5 equiv Pd(OAc)2
N
O
N,O-ketal of
amino alcohol
functionalized amino
alcohol derivative
N
O
H
O
Me
Ac
O
CHCl3, rt
72% yield
Ac
H
c) Constitutional isomers give complementary C–H activation scaffolds
1
2
O
R
O
R
constitutional
isomers
O
R
N
R
N
H
H
H
CO (1 atm.)
PhMe, 50 °C
57% yield
H
H
C–H activation on amino
alcohol fragment
C–H activation on
ketone fragment
O
d) C–H Carbonylation of N,O-ketals towards protected 1,4-dicarbonyls
N
Me
R
O
R
O
O
pyrrolidinone 3
O
Pd(II) cat.
hydrolysis
R
N
R
OH
N
2 (X-ray)
H
CO, oxidant
O
O
Scheme 2 Cyclopalladation and carbonylation of 1
H
dervied from
simple ketones
functionalized
pyrrolidinone
1,4-dicarbonyl
Encouraged by these initial results, we sought to devel-
op a catalytic variant of this transformation. Evaluation of
the critical reaction parameters revealed that treatment of
N,O-ketal 1 with Pd(OAc)2 (10 mol%), AgOAc (2.0 equiv.) as
the oxidant in toluene at 120 °C under an atmosphere of CO
gave lactam 3 in an optimal 77% yield. Increasing the load-
ing of AgOAc, changing the oxidant, or the addition of a
weak base were found to have a deleterious effect on the re-
action efficiency (Table 1, entries 6–11). Pleasingly, modifi-
cations to the N,O-ketal core were tolerated; upon replace-
ment of the cyclohexyl ring with a gem-dimethyl group, the
desired carbonylation product was obtained in 76% isolated
yield (Table 1, entry 14). Notably, no evidence of carbonyla-
tion on the oxazolidine methyl groups via a competitive 4-
membered ring cyclopalladation pathway nor via β-C–H
methylene carbonylation were observed.11
Scheme 1 Sterically promoted C–H activation of amines
Herein, we report a palladium-catalyzed C–H carbonyla-
tion of N,O-ketal-protected ketones, enabling the synthesis
of substituted pyrrolidinones which are readily trans-
formed into 1,4-dicarbonyl compounds upon hydrolysis
(Scheme 1, d). Furthermore, we demonstrate that this for-
mal β-functionalization of ketones is not limited to C–H
carbonylation; a related sp3 C–H alkenylation protocol is
also reported.
To commence our investigations, we chose to prepare
N,O-ketal 1, formed via condensation of 3-pentanone with
the corresponding amino alcohol (see Supporting Informa-
tion for details). We reasoned that the cyclohexyl substitu-
ent would provide the steric bulk required to favour the for-
mation of a mono-(amine)-Pd(II) complex, a pre-requisite
for C–H activation. Furthermore, we speculated that the
With optimised reaction conditions in hand, we set out
to explore the scope of the reaction for the cyclohexyl N,O-
ketal analogues (Scheme 3). A range of substituted 2,2-ox-
azolidines were carbonylated to give the corresponding γ-
lactams in good yield. Pleasingly, gem-dimethyl N,O-ketals
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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D. K. Ho et al.
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Table 1 Optimization of the Pd(II)-Catalyzed Carbonylation
O
O
N
10 mol% Pd(OAc)2
CO (1 atm.)
N
O
10 mol% Pd(OAc)2
Me
O
H
AgOAc, PhMe
120 °C, 16 h
CO source
N
O
N
Me
H
H
oxidant, additive
solvent, 120 °C, 16 h
4
5
O
H
1
3
O
O
O
Me
Me
Me
Me
N
N
N
Entry CO sourcea
Oxidant (equiv.) Additive Solvent
Yield 3 (%)b
O
O
O
1
2
6.25% CO
AgOAc (2)
AgOAc (2)
Cu(OAc)2(2)
BQ (2)
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
PhCF3
22
5a, 72%
5b, 73%
5c, 78% (d.r. 2.8 : 1)
6.25% CO
NaOAc
59
3
6.25% CO
–
39
O
O
N
O
4
6.25% CO
–
13
3
Ph
N
O
N
O
5
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
CO balloon
AgOAc (2)
AgOAc (2)
AgOAc (2) / O2
Cu(OAc)2(2)
AgOAc (2.5)
AgOAc (3.5)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
–
84 (77)c
63
Me
O
6
NaOAc
7
–
–
–
–
–
–
–
–
48
5d, 78%
5e, 74%
5f, 69%
8
18
OH
O
9
70
O
N
O
CF3
Me
CO2Me
10
11
12
13
14
68
N
N
Me
32
O
O
O
N
50
5g, 0%
5h, 19%
5i, 77%
n-PrOH
toluene
0
O
76d
O
N
a Reaction with 6.25% CO was conducted at 2 bar pressure.
O
N
NPhth
b Yield determined by 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane
as the internal standard.
O
OBn
O
c Yield of isolated product.
N
O
d Oxazolidine cyclohexyl substituent replaced with a gem-dimethyl group.
Ts
5k, 80%
5l, 79%
5j, 79%
were also found to give similar yields under the standard
reaction conditions (see Supporting Information for de-
tails). In all cases, exclusive activation of the terminal ethyl
sp3 C–H bonds was observed with no evidence of activation
on the amino alcohol component of the N,O-ketal or the β-
methylene C–H bonds.
Scheme 3 Substrate scope
Pleasingly, other oxygen and nitrogen-containing groups
were readily tolerated giving the desired γ-lactams in good
yield (5i–l).
A range of simple aliphatic ketones were tolerated under
the standard reaction conditions (Scheme 3, 5a–d). A reac-
tion employing an isopropyl-substituted oxazolidine pro-
ceeded in good yield with moderate levels of diastereoselec-
tivity (5c, dr = 2.8:1). In addition, olefins and aryl rings
could also be incorporated into the ketone component with
no deleterious effects on the reaction efficiency (5e and 5f).
Disappointingly, a substrate with a strongly electron-with-
drawing trifluoromethyl group in close proximity to the ni-
trogen atom gave only recovered starting material even af-
ter prolonged heating at 120 °C (5g). Importantly, heteroat-
om-containing ketones could also be employed in the
transformation. A low yield was observed for a substrate
containing an unprotected tertiary alcohol (5h), which was
attributed to an undesired bidentate coordination of the
substrate to the palladium forming a coordinatively saturat-
ed palladium complex precluding the C–H activation event.
We next sought to apply the methodology to substrates
containing multiple sites for C–H activation in order to in-
vestigate the regioselectivity of the transformation (Scheme
4). Unsurprisingly, when an aromatic ketone was used to
prepare the oxazolidine (i.e., a phenyl group was incorpo-
rated at the 2-position), the inherently more facile aryl sp2
C–H activation pathway predominated to give exclusively
the isoindolinone product 7 in excellent yield. In contrast,
when the cyclopropyl-substituted oxazolidine 8 was sub-
jected to the reaction conditions, a mixture of two products
was obtained: The major product, spirocyclic oxindole 9
(57% yield), formed through activation of the cyclopropyl
methine C–H bond, and the expected γ-lactam 10 (28%
yield). Whilst methine C–H functionalization is known un-
der palladium catalysis, it remains relatively uncommon
compared to methyl and methylene activation.12 This meth-
odology represents a rare example of a methine C–H bond
being activated in preference to a methyl C–H bond. Nota-
bly, only products arising from a 5-membered ring pallada-
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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D. K. Ho et al.
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Synlett
cycle intermediate were obtained; in no instances were
products arising from competitive β- or δ-membered ring
cyclopalladation pathways observed.13
Finally, in order to highlight the broader scope of this
methodology, we set out to explore other transformations
involving N,O-ketal-protected ketones. Pleasingly, initial re-
sults have shown that N,O-ketal 1 participates in a C–H
alkenylation reaction using a modified set of reaction con-
ditions.14 The product was isolated as the corresponding
substituted pyrrolidine 13, formed via a conjugate addition
of the oxazolidine nitrogen into the newly incorporated ac-
rylate (Scheme 6).
(a) Competition between sp2 and sp3 C–H bonds
Me
O
O
10 mol% Pd(OAc)2
CO (1 atm.)
Me
N
N
H
AgOAc, PhMe
120 °C, 16 h
O
6
7, 90%
Me
Pd(OAc)2 (10 mol%)
AgOAc (3 equiv)
O
O
Me
H
(b) Competition between cyclopropyl C–H bonds and standard sp3 C–H bonds
N
N
KH2PO4, K2HPO4, DCE, 120 °C
CO2CH(CF3)2
H
(F3C)2HCO2C
Me
O
H
10 mol% Pd(OAc)2
CO (1 atm.)
O
O
1
13, 80% (d.r. > 20 : 1)
Me
N
N
+
N
AgOAc, PhMe
120 °C, 16 h
H
O
Me
O
O
8
9, 57%
10, 28%
N
H
(F3C)2HCO2C
Pd(II)-catalyzed
alkenylation
conjugate
addition
Me
O
N
Pd
Scheme 6 Pd(II)-catalyzed alkenylation
Scheme 4 Pd(II)-catalyzed carbonylation of a) aryl C–H and b) methine
C–H
In summary, we have developed a palladium(II)-cata-
lysed sp3 C–H carbonylation of N,O-ketal-masked ketones.
This transformation, which represents a formal β-function-
alization of ketones, demonstrates a broad substrate scope
and good functional group tolerance. The products ob-
tained undergo facile hydrolysis to reveal the γ-keto car-
boxylic acids in excellent yields. Finally, the transformation
is not limited to carbonylation as demonstrated through a
palladium-catalysed C–H alkenylation process.
Having demonstrated the scope of the transformation,
we next sought to demonstrate the practicality of this
methodology for accessing β-functionalised ketones. A se-
lection of the γ-lactams products was subjected to acid-me-
diated ring opening to obtain the desired γ-keto carboxylic
acids in excellent yields (Scheme 5, a). We also found that
the bicyclic lactam core underwent diastereoselective al-
kylation to 12, further functionalizing this heterocyclic
framework (Scheme 5, b).
Funding Information
We acknowledge the EPRSC (EP/I00548X/1 & EP/N031792/1) for
(a) hydrolysis of lactams
funding to (D.K.H.H., J.C. and M.J.G.) for funding.
E
n
g
i
n
e
eri
n
g
a
n
d
P
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ysi
c
a
lS
c
i
e
n
c
es
R
esearc
h
C
o
u
n
c
i
l(EP/I
0
0
5
4
8
X/1)E
n
g
i
n
e
eri
n
g
a
n
d
P
h
ysi
c
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C
o
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n
c
i
l(EP/N
0
3
1
7
9
2/1)
O
O
3 N HCl : THF/dioxane
reflux
OH
N
Acknowledgment
O
O
Mass spectrometry data was acquired at the EPSRC UK National Mass
Spectrometry Facility at Swansea University. We are grateful to Dr
James Cuthbertson and Dr Hiroki Azuma for assistance with the
preparation of this manuscript.
5
11
O
O
Me
OH
OH
O
O
11a, 93%
(b) alkylation of lactams
Me
11b, 91%
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611664.
Me
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
O
O
LiHMDS then MeI
78% yield, 8:1 d.r.
N
N
O
O
Me
3
12
Scheme 5 Ring opening of γ-lactams to reveal γ-keto carboxylic acids
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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D. K. Ho et al.
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Synlett
References and Notes
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(13) General Experimental Procedure for a Representative C–H
Carbonylation to 5l
To a flame-dried round-bottom flask, equipped with a stir bar,
was charged the oxazolidine (0.20 mmol), palladium(II) acetate
(0.02 mmol, 0.1 equiv), silver(I) acetate (0.40 mmol, 2.0 equiv),
and toluene (0.05 M). The reaction flask was evacuated and
back-filled with carbon monoxide (3 times, balloon). A balloon
filled with carbon monoxide was fitted, and then the flask was
placed in a pre-heated oil bath at 120 °C and heated at this tem-
perature for 16 h under vigorous stirring. The reaction mixture
was then cooled to room temperature and filtered through a
small pad of Celite®. The filtrate was concentrated in vacuo and
purified by flash chromatography (eluting with 0–20% ethyl
acetate in petroleum ether) provided the desired lactam 5l (54
mg, 79%). Rf (ethyl acetate in petroleum ether, 25%): 0.23. IR
(film): νmax = 2976, 2952, 1773, 1704, 1466, 1396, 1366, 1273,
(6) For an example of sp3 C–H functionalization at the β-position of
an oxime-masked ketone, see: (a) Desai, L. V.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (b) Gao, P.; Guo,
W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. J. Am. Chem. Soc.
2015, 137, 12231.
(7) For a seminal example of a palladium-catalysed β-carbonylation
of amides, see: (a) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 17378. For examples of C(sp3)–H carbonylation of
alklyamine derivatives, see: (b) Hernando, H.; Villalva, J.;
Martínez, Á. M.; Alonso, I.; Rodríguez, N.; Gómez Arrayás, R.;
Carretero, J. C. ACS Catal. 2016, 6, 6868. (c) Wang, P.-L.; Li, Y.;
Wu, Y.; Li, C.; Lan, Q.; Wang, X.-S. Org. Lett. 2015, 17, 3698.
(d) Wang, C.; Zhang, L.; Chen, C.; Han, J.; Yao, Y.; Zhao, Y. Chem.
Sci. 2015, 6, 4610.
1124, 1058, 1002, 882, 721, 667 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.85 (dd, J = 5.5, 3.0 Hz, 2 H), 7.73 (dd, J = 5.5, 3.0 Hz,
2 H), 4.00 (d, J = 9.2 Hz, 1 H), 3.94 (d, J = 8.9 Hz, 1 H), 3.81–3.64
(m, 2 H), 2.63 (ddd, J = 17.0, 12.3, 8.0 Hz, 1 H), 2.56–2.40 (m, 1
H), 2.20 (ddd, J = 12.3, 8.0, 0.8 Hz, 1 H), 2.02–1.66 (m, 5 H), 1.55
(s, 3 H), 1.40 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 173.5,
168.3, 134.1, 132.0, 123.3, 102.6, 81.6, 58.1, 37.9, 35.4, 33.0,
32.5, 26.7, 24.5, 23.5. HRMS (ESI): m/z calcd for C19H23N2O4:
343.1652; found [M + H]+: 343.1656.
(8) (a) Manzer, L. E. Appl. Catal., A 2004, 272, 249. (b) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277.
(c) Lange, J.-P.; Vestering, J. Z.; Haan, R. J. Chem. Commun. 2007,
(14) He, C.; Gaunt, M. J. Chem. Sci. 2017, 8, 3586.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E