Nature 2020 01 30 Part.01

Nature | Vol 577 | 30 January 2020 | 657

no γ-lactone or β-, γ-hydroxylated products were observed during the
reaction. The unique role of TBHP in favouring β-lactone formation
can be rationalized on the basis of studies on the oxidation of Pd(ii)
to Pd(iv) by benzoyl peroxide^25 and TBHP^4. Following the oxidation of
Pd(ii) to Pd(iv) by TBHP, tBuO− and HO− bound to a Pd(iv) centre are less
likely to undergo rapid reductive elimination due to the strong Pd–OtBu
(OH) bond. According to the principle of organometallic chemistry, the
steric hindrance of tBuO− could also enhance the reductive elimination
of the carboxylate from the substrate to generate β-lactone product.

In light of the recent advances in ligand-accelerated Pd(ii)-catalysed

C–H activation^26 , we next searched for ligands that could substantially

improve the reactivity of the catalyst. It is also possible that an appropri-

ate ligand could enhance the otherwise unfavoured β-lactonization.

Using the mono-N-protected α-amino acid (MPAA) ligand N-acetyl

glycine L1, the yield was improved to 36%. Modification of the backbone

of the α-amino acid ligand led only to minor improvements (L2 to L5).

Considering the challenging reductive elimination of a strained four-

membered ring from Pd(iv), we reasoned that switching the ligand

Nu = C(sp^3 ), C(sp^2 ), C(sp), CN,

F, Br, N 3 , NHNs, OH, SPh

Base, TBHP

HFIP, 60 °C, 12 h

Cat. Pd/L11 (≥1 mol%)

2

Up to 94% yield

a

OH

O

Nu

R^1

R^2

OH

O

H

R^1

R^2 O

R O

1

R^2

1

O

O

H

Cs+

R^1

R^2

b

Reductive

OH elimination

O

H

R^1

R^2 O

R^1 O

R^2

L

PdIV

O

R^2

R^1

L

OH

OtBu

O

Cs+

OH

O

OH

R^1

R^2

OH

O

OtBu

R^1

R^2

OH

O

Nu

R^1

R^2

PdII L

Pd(IV) intermediate

TBHP ++

Nu–

CO 2 H

NHAc L11

Me

PdIIL11

1

No column

+

Fig. 1 | β-C(sp^3 )–H functionalization. a, Lactonization as a general and scalable route to β-C(sp^3 )–H functionalization. b, Challenges: multiple reductive-
elimination pathways of Pd(iv) centres. Nu, nucleophile (acid, solvent); L, ligand.

OH

O

H

R^1

CsHCO 3 (0.5 equiv.)

TBHP (~5.5 M in decane) (2.0 equiv.)

HFIP, 60 °C, 12 h

Pd(CH 3 CN) 2 Cl 2 (10 mol%)

L11 (20 mol%)

1 2

O

O

Me

CF 3 ( )^4

O

Me O

O Me

O

Me

Me

O

O

Me O

O

Me

Me ( )^3

O

O

Me

Me

Me

2a, 73% 2b, 50% 2c, 71% 2d, 74% 2e, 73%

O

O

Me

F ( )^4

2g, 72%

O

O

Me

Me

O

2j, 74%

O

O

Me

BocN

O

O

Me

O

O

O

Me

O( )^3

Me

Me

O

O

Me

O

NO 2

O

O

Me

MeO( )^3

2v, 93%

from gemfibrozil

2n, 81%

n = 2, 2t, 86%

n = 3, 2u, 94%

2s, 41%

O

O

Me

MOMO

O

O

Et

Me

Me

2w, 62%

2z, 59%

O

O

Et

MeO( )^3

2y, 62%

O

O

Me

O

PhO( )n O

O

O

O

n = 3, 2ae, 69%

n = 4, 2af, 32%

2ac, 51%

O

O

Me

O

MeO( )^4 O

O

O

Me

BnO( )^4

Me

EtO P

O

OEt

2ad, 82%

2i, 67% 2k, 38%

2m, 71%

O

O

Me

( )^3

O

O

Me

( )^3

Cl

2f, 45%

2q, 60% 2r, 46%

2l, 51%

O

O

Me

PhO( )n

2o, 46% 2p, 56%

O

O( )^4 O

Br

O

O

Et

F ( )^4

O

O

Et

PhO( )n

O

O

Et

( )^3

O

O

Me

Cl ( )^5

2h, 47%

2x, 52%

n = 2, 2aa, 68%

n = 3, 2ab, 90%

2ag, 40%

O

R^1 O

R^2 R^2 CO^2 H

NHAc L11

Me

Fig. 2 | Aliphatic acid scope for β-C(sp^3 )–H lactonization. Conditions for 2a to
2s and 2w to 2z: 1 (0.1 mmol), Pd(CH 3 CN) 2 Cl 2 (10 mol%), L11 (20 mol%), CsHCO 3
(0.5 equiv.), TBHP (about 5.5 M in decane) (2.0 equiv.), HFIP (1.0 mL), 60 °C, 12 h.

Conditions for 2t to 2v and 2aa to 2ag: 1 (0.1 mmol), Pd(OAc) 2 (10 mol%), L11

(20 mol%), NaOAc (1.0 equiv.), TBHP (about 5.5 M in decane) (2.0 equiv.),

HFIP (1.0 mL), 60 °C, 12 h. See Supplementary Information for details.