1.2 BACKGROUND TO DIASTEREO-, ENANTIO-, AND REGIOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION WITH REGIOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION WITH
1.2.1 IRIDIUM CATALYST-CONTROLLED PROCESSES .1 Acyclic Nucleophiles .1 Acyclic Nucleophiles
1.2.1.2 Cyclic Nucleophiles
In 2013, Hartwig published the first example of a diastereoselective iridium- catalyzed allylic alkylation of cyclic, prochiral nucleophiles (Scheme 1.4).8a In this report, vicinal tertiary and tetra-substituted stereodyads are created via the allylic alkylation of azlactones 18 with aryl- and alkenyl-substituted allylic carbonates 11 in the
R3 OCO2Me + Ar
O OR2
15 (2 mol %) LiHMDS (200 mol %)
CuBr (200 mol %) THF, 5 °C 23 examples 71–99% yield 6:1–20:1 dr 88–99% ee
16 R1
Ar O
R1 R3
OR2 13
R1 = aryl, heteroaryl R2 = Me, MOM, MEM, PMB
14 R3 = aryl, heteroaryl,
alkenyl, methyl
Ir N Ar
P
Ar Me O O
15 Ar = 2-Napthyl Ph
BF4
*
presence of catalytic amounts of achiral silver phosphate 17, 3 Å molecular sieves, and an iridium catalyst generated in situ from [Ir(cod)Cl]2 and ligand L3. Through a series of control experiments, the authors were able to determine that both the phosphate and methyl carbonate anions, but not the silver cation, are key to the high reaction diastereoselectivity (up to >20:1 dr). The counteranions are presumed to deprotonate and control the facial attack of the nucleophile while the silver cation is believed to sequester chloride and promote the formation of the active metallacyclic iridium catalyst.
Scheme 1.4 Counterion-assisted iridium-catalyzed allylic alkylation of azlactones by Hartwig
This counterion strategy did not prove fruitful in the iridium-catalyzed allylic alkylation of substituted 5H-oxazol-4-ones 20 or 5H-thiazol-4-ones 24 (Scheme 1.5).8b Application of the previously developed conditions to the reaction of 5H-oxazol-4-ones 20 with cinnamyl carbonates failed to yield desired allylic alkylation products 23 (Scheme 1.5a). The yields were improved by examining a number of organic and inorganic bases in combination with silver phosphate 17. However, it was not until a substoichiometric amount of diethyl zinc, allylic acetate 21, and preformed catalyst 22
18 R1 = 1° or 2° alkyl, Bn
[Ir(cod)Cl]2 (2 mol %) (R,R,Ra)-L3 (4 mol %)
17 (8 mol %) toluene, 23 °C
R2 OCO2Me
15 examples 68–96% yield 7:1–20:1 dr
80–99% ee +
19
N O
Ph R1
O
11 R2 = aryl, heteroaryl,
alkenyl
N O
Ph R1 O R2 N
Ar Ar
(R,R,Ra)-L3 Ar = 2-MeO-C6H4
t-Bu t-Bu
t-Bu t-Bu
17 O
P
O O
O OAg P O
were used in place of the silver phosphate that good diastereoselectivities were achieved (up to 18:1 dr). The authors propose that the addition of diethyl zinc leads to the formation of zinc enolate aggregates ranging from dimers to tetramers, which in turn impart facial selectivity to the prochiral nucleophile.
Scheme 1.5 Cation control of diastereoselectivity in iridium-catalyzed allylic alkylation of a) 5H- oxazol-4-ones 20 and b) 5H-thiazol-4-ones 24 by Hartwig
Application of the optimal conditions developed for 5H-oxazol-4-ones 20 using diethyl zinc does not afford a diastereoselective reaction (1.3:1 dr) with substituted 5H- thiazol-4-ones 24 (Scheme 1.5b). Instead, the authors achieved diastereoselectivity using a magnesium enolate formed from magnesium bis(diisopropyl)amide. The aggregation states of magnesium enolates, which are generally thought to be higher order aggregates than that of the corresponding zinc enolates, are believed to be responsible for the difference in diastereoselectivity. The authors also found that tert-butyl carbonate electrophiles 25 further improve the diastereoselectivities (up to 13:1 dr) for this nucleophile class.
20 R1 = 1° or 2° alkyl
22 (2 mol %) Et2Zn (60 mol %)
CPME, 23 °C
R2 OAc
15 examples 80–94% yield 6:1–18:1 dr 98–99% ee +
23
O N
PMP R1
O
21 R2 = aryl, heteroaryl
O N
PMP R1 O R2 a)
b)
24 R3 = 1° alkyl, Bn
22 (2 mol %) Mg(Ni-Pr2)2 (60 mol %)
dioxane, 23 °C
R4 OBoc
14 examples 75–96% yield 6:1–13:1 dr 98–99% ee +
26
S N
Ph R3
O
25 R4 = aryl, heteroaryl
S N
Ph R3 O R4
Ir N Ar
P
Ar Me O O
22 Ar = 2-MeO-C6H4
*
In 2013, our group pioneered the discovery of diastereo- and enantioselective iridium-catalyzed allylic alkylation chemistry of cyclic enolates for the formation of vicinal tertiary and all-carbon quaternary stereocenters (Scheme 1.6).6b Initial investigations involving tetralone 27 revealed that a wide variety of aryl- and heteroaryl- substituted allylic carbonates 28 react to provide products 29 with high yields and stereoselectivities (Scheme 1.6a). The use of Me-THQphos (L2) as the chiral ligand and LiBr as a stoichiometric additive were found to be critical in attaining high selectivity.
We postulate that LiBr results in lithium enolate aggregates, similar to those proposed by Hartwig.8b In further investigations, we found that reactions involving various monocyclic substrates 30 afford the corresponding products 31 with similarly high yields and selectivities to those of the tetralone-based nucleophiles (Scheme 1.6b). Of note, the use of electron-deficient aryl-substituted electrophiles leads to an erosion in regioselectivity (50:50 to 71:29 branched/linear) in reactions of bicyclic nucleophiles.
Scheme 1.6 Allylic alkylation of a) bicyclic β-ketoesters 27 and b) monocyclic β-ketoesters 30 by Stoltz
O
[Ir(cod)Cl]2 (2 mol %) (R,Ra)-L2 (4 mol %)
TBD (10 mol %) LiBr (100 mol %)
THF, 20 °C
R OCO2Me
OMe +
O O R
CO2Me
29
27 90–99% yield9 examples
50:50–95:5 branched/linear 8:1–20:1 dr 90–99% ee 28
R = aryl, heteroaryl, alkenyl
X O
[Ir(cod)Cl]2 (2 mol %) (R,Ra)-L2 (4 mol %)
TBD (10 mol %) LiBr (100 mol %) THF, 20 °C
Ph OCO2Me
OR O
X
O Ph
CO2R
32 31
30 X = CH2, O, NBn
R = alkyl n = 0 or 1
n n
6 examples 85–99% yield 85:15–93:7 branched/linear
8:1–20:1 dr 97–99% ee +
a)
b)
Studies toward substrate scope expansion of this reaction led to the successful allylic alkylation of extended enolates derived from unsaturated β-ketoester 33 (Scheme 1.7).6e Though the yields and selectivities were generally found to be lower than the corresponding saturated analogs (vide supra), allylic alkylation at the α-carbon atom of the extended enolate was achieved to provide products 35 bearing an additional olefin for further functionalization of the molecule.
Scheme 1.7 Allylic alkylation of extended enolates by Stoltz
In 2013, Hartwig found that non-stabilized enolates 36 undergo selective iridium- catalyzed allylic alkylation reactions to form vicinal tertiary and all-carbon quaternary stereocenters using preformed iridium complex 22 and BaOt-Bu (Scheme 1.8).6d In all cases, products 37 are afforded with excellent enantioenrichment (>98% ee), and even simple cyclohexanone derivatives provide good selectivity for allylic alkylation of the corresponding thermodynamic enolate. This protocol is currently the only reported set of conditions for cyclic nucleophiles that is not limited to softer enolate equivalents (e.g., malonates and β-ketoesters).
X O
OR O
33 X = CH2, NBn
n = 0 or 1 n
[Ir(cod)Cl]2 (2 mol %) (S,Sa)-L2 (4 mol %)
TBD (10 mol %) THF, 20 °C
Ar OCO2Me
34
8 examples 40–99% yield 11:1–20:1 branched/linear
1.2:1–5:1 dr 79–98% ee (major diastereomer)
62–91% ee (minor diasteromer)
+ X
O Ar
CO2R 35 n
Scheme 1.8 Allylic alkylation of non-stabilized enolates by Hartwig