1 1 Negishi Coupling Substrate Study With Pd-PEPPSI-IPent - - PowerPoint PPT Presentation

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Guest Lecturer: Michael G. Organ

January 31, 2017

Designing Catalysts For Cross-Coupling CHM-4328 Tactics and Strategies for the Construction

• f Complex Natural Products

2

Designing a Catalyst for Cross-Coupling

(electrophile)

R1 - X PdoLn R1 - PdllLn X

(nucleophile)

R2 - M R1 - PdllLn R2 R1 - R2 Oxidative Addition Transmetallation Reductive Elimination

• What are the ideal catalyst properties for this cycle?

electron rich sterically small electron poor sterically small electron poor sterically large

• Ligand (L) properties are key to facilitate suitable properties of Pd
• Properties that promote one step are apt to disfavour another
• Problems become exacerbated when some form of selectivity is required
• For activity, it is important to maintain ‘reasonable’ TS barriers for all steps

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Designing a Catalyst for Cross-Coupling

• Phosphanes
• Phosphanes have moderate σ-donating ability
• The most reactive phosphanes are hindered and quite inflexible
• N-heterocyclic carbenes (NHC)
• NHCs have strong σ-donating ability (Tolman analysis, Nolan)
• NHCs project their bulk toward the metal (buried bulk, Nolan)

N N Pd R R R R

• Most reactive NHCs have ‘flexible steric bulk’ (Glorius)

Pd P P R R R R R R P Cy R R Pd Cy

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• Compare Pd-PEPPSI-IPr with Pd-PEPPSI-IPent:

Is Bigger Bigger?

N N Pd Cl Cl N Cl

Pd-PEPPSI-IPr

N N Pd Cl Cl N Cl

Pd-PEPPSI-IPent

2 2

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Suzuki-Miyaura Coupling Substrate Study With Pd-PEPPSI-IPent

Organ, M. G.; Çalimsiz, S; Sayah, M.; Hoi, K. H. Angew. Chem. Int. Ed. 2009, 48, 2383-2387.

• Pd-PEPPSI-IPent is more reactive than Pd-PEPPSI-IPr

+ R - Cl R1 - B(OH)2 R - R1 IPent: 70 % IPr: <2 % (2 equiv) Pd-PEPPSI (2 mol %) KOtBu, tBuOH, 65 oC, 24 h

O O

IPent: 61 % IPr: 0 % IPent: 65 % IPr: 0 % IPent: 78 % IPr: 32 % IPent: 49 % IPr: 34 % IPent: 95 % IPr: 47 % IPent: 95 % IPr: 0 % IPent: 88 % IPr: 0 % IPent: 80 % IPr: 0 % IPent: 89 %

N OH O F

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Negishi Coupling Substrate Study With Pd-PEPPSI-IPent

• Hindered biaryls accessible at room temperature - and even lower!

(equiv)

BrMgAr NMP, 2.5h, Temp, Time O

ArMgBr (1.2 equiv) ZnCl2 (1.4 equiv) 40 oC, 24h IPent: 73 %, 0 oC, 8h IPent: 90 %

XnZnAr Ar-Br

ZnX2 (equiv) THF, RT, 20 min.

Ar - Ar

ArMgBr (1.2 equiv) ZnCl2 (1.4 equiv) RT, 16h IPent: 99 %

Si

ArMgBr (1.2 equiv) ZnCl2 (1.4 equiv) RT, 4h IPent: 85 % ArMgBr (1.6 equiv) ZnBr2 (1.6 equiv) 50 oC, 8h IPr: 34 % IPent: 94 %, 0 oC, 8h IPent: 80 % ArMgBr (1.6 equiv) ZnBr2 (1.6 equiv) 50 oC, 24h IPr: 13 %, IPent: 80 %

O Pd-PEPPSI (2 mol %) O

ArMgBr (1.6 equiv) ZnCl2 (1.6 equiv), 50 oC, 16h, IPr: 43 %, IPent: 80 %

O HO

ArMgBr (1.2 equiv) ZnCl2 (1.4 equiv), NaH (1.0 equiv) 50 oC, 24h, IPr: 43 %, IPent: 80 %

H2N

ArMgBr (2.6 equiv) ZnBr2 (3.0 equiv) 50 oC, 24h IPr: 1 %, IPent: 57 %

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• Top 100 Drugs by 2011 US Retail Sales:
• Molecules with higher sp3 content are gaining in interest in drug discovery
• Fraction of sp3 C: at discovery stage: 0.36;
• f successful drugs: 0.47 (a 31% increase!)
• Greater binding specificity and improved bioavailability relative to biaryls

Cross-Coupling With Secondary Alkylzincs

N PhHN O CO2H OH OH F Lipitor (Pfizer) N N SO2Me N CO2H OH OH Crestor (AstraZeneca) N O OH Effexor (Pfizer)

Problem: there are few ways to quickly and reliably install alkyl groups onto aromatic systems, especially when the desired substituent is secondary. Solution: Cross-coupling of secondary alkyls?

Lovering, F. et al J. Med. Chem. 2009, 52, 6752; Med. Chem. Commun. 2013, 4, 515

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R1 Pd H L R β-hydride elimination R2

• Catalyst must be designed to favour RE over BHE

H R1 PdllLn R2 R migratory insertion PdoLn R PdllLn X R-X R1 ZnX ZnX2 R PdllLn R1 R2 H R2 R1 R2 R

• xidative

addition transmetallation

If R2 << R1 (H) this is the lower energy Pd-alkyl and thermodynamic sink

R1 R2 R reductive elimination

• What about catalyst size? A larger ligand should favour RE

Cross-Coupling With Secondary Alkylzincs

3 3

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• Test Reactions with Isopropylzinc Bromide and Aromatic Halides:

2-OCH3 2-CN 3-OCH3 Ar-Br IPent IPr IPent IPr IPent IPr Cat 46 99 80 99 57 31 Yield 2 : 1 1 : 9 2.4 : 1 1 : 8 34 : 1 3.5 : 1 B:L 11 : 1 84 IPent 1 : 1.4 77 IPr 3-CN 33 : 1 95 IPent 2.5 : 1 89 IPr 4-OCH3 40 : 1 98 IPent 6 : 1 99 IPr 4-CO2CH3 B:L Yield Cat Ar-Br

Br BrZn

+ Pd-PEPPSI cat. (1 mol%)

R R R

+ branched (B) (normal) linear (L) (rearranged) THF / Toluene, RT, 30 min.

• Pd-PEPPSI-IPent resists β-hydride elimination / migratory insertion

Cross-Coupling With Secondary Alkylzincs

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• What about electronic effects?

N N Pd Cl Cl N Cl

Pd-PEPPSI-IPent

N N Pd Cl Cl N Cl

Pd-PEPPSI-IPr

N N Pd Cl Cl N Cl

Pd-PEPPSI-IPrCl

Cl Cl N N Pd Cl Cl N Cl

Pd-PEPPSI-IPrQuino

O O N N Pd Cl Cl N Cl

Pd-PEPPSI-IPentCl

Cl Cl

• An electron poor Pd centre should favour reductive elimination

Cross-Coupling With Secondary Alkylzincs

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2-CN Ar-Br 8.5 : 1 70 IPrQuino 13.4 : 1 78 IPrQuino IPentCl IPent IPrCl IPr Cat 56 80 66 58 Yield 27.1 : 1 2.4 : 1 4.3 : 1 1 : 6.6 B:L 56 : 1 81 IPentCl 10.5 : 1 66 IPent 14.7 : 1 81 IPrCl 1 : 1.4 82 IPr 3-CN B:L Yield Cat Ar-Br

Br BrZn

+ Pd-PEPPSI cat. (1 mol%)

R R R

+ branched (B) (normal) linear (L) (rearranged) THF / Toluene, RT, 30 min.

• The installation of electron-withdrawing substituents on the imidazolium

core dramatically impacts β-hydride elimination / migratory insertion

• What about electronic effects?

Cross-Coupling With Secondary Alkylzincs

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• Are the causative effects actually electronic in origin?

56 : 1 10.5 : 1 15 : 1 13.4 : 1 14.7 : 1 1 : 1.4 Selectivity 2049.3 2021.3 2064.5, 1978.2 IPrMe 4 2053.0 2049.6 2057.1 2054.0[b] 2051.5[b] TEP (cm-)[a] 2030.5 2073.7, 1987.3 IPrQuino 3 2025.8 2069.3, 1982.2 IPentCl 6 2021.7 2064.7, 1978.6 IPent 5 2028.3 2071.4, 1985.1 IPrCl 2 2023.9 2066.8, 1981.0 IPr 1 νCO (avg) νCO (CH2Cl2, cm- 1) NHC Entry

[a] TEP = TEP computed using the linear regression: TEP (cm-1) = 0.8475*(νCO(avg)) + 336.2; [b] Organometallics 2008, 27, 202-210. N N R R R R R R R R X X (+) N N R R R R R R R R X X Ir CO Cl CO

• 1. KOtBu (1.2 equiv.)

THF, RT, 2h

• 2. [(COD)IrCl)]2 (0.5 equiv.)

RT, 24 h

• 3. CO(g), CH2Cl2, RT, 1h

Cross-Coupling With Secondary Alkylzincs

• Tolman Electronic Parameter Analysis (Schrock, Nolan)

4 4

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• OK, if it is not electronic (entirely at least), then what is it?

N N Pd Cl Cl N Cl R R N N Pd R R Ph

Reductive Elimination TS

N N Pd R R Ph

Beta-Hydride Elimination TS

H

• Two critical transition states (TS)

Cross-Coupling With Secondary Alkylzincs

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• Increasing the steric bulk around Pd has the greatest impact on BHE

Cross-Coupling With Secondary Alkylzincs

• OK, if it is not electronic (entirely at least), then what is it?

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• Reaction scope

+ Ar - X secAlkyl - ZnX Ar - secAlkyl (1.2 equiv) Pd-PEPPSI-IPentCl (2 mol %)

N N N Boc N S X = Br, (94 %) N : R, > 99 : 1 X = Cl, 5 h, (99%) N : R, >99 : 1 H O X = Cl, 24 h, (67%) N : R, 56 : 1 N Boc N OCH3 X = Br, 4 h, (84 %) N : R, > 99 : 1 X = Br, (98 %) N : R, > 99 : 1 H O N Boc N N X = Cl, (99 %) N : R, > 99 : 1 X = Cl, 4 h, (84 %) N : R, > 99 : 1 (2.2 equiv. RZnBr) X = Cl, 16h (88 %) N : R, >99 : 1 N OH O F

THF / Toluene, RT, 30 min

Pompeo, M.; Hadei, N.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 11354 –11357.

Cross-Coupling With Secondary Alkylzincs

• All single isomers - zero isomerization!

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• Limitation: 5-membered ring heterocycles

Cross-Coupling With Secondary Alkylzincs

• What is different with these systems that drives migratory insertion?
• Due to bond angles, steric effects have been reduced

+ (1.2 equiv) Pd-PEPPSI-IPentCl (2 mol %) THF / Toluene, RT, 30 min

Br ZnBr C3 only isomer (95 %)

1 2 3

+ Ar - X secAlkyl - ZnX Ar - secAlkyl (1.2 equiv) Pd-PEPPSI-IPentCl (2 mol %)

X = Br, (86 %) C3 : C2, > 2.4 : 1 X = Br, (88 %) C3 : C2 : C1, > 0.2 : 0.7 : 1 X = Br, (56 %) C3 : C2, > 1.2 : 1 X = Br, (88 %) C3 : C2 : C1, > 0.5 : 1 : 0.2

THF / Toluene, RT, 30 min

O S N S O O Ph S O

1 2 3 3 3 3 2 2 2 1 1 1

• Effect appears not to be steric in origin

5 5

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• Evaluating new catalysts

Cross-Coupling With Secondary Alkylzincs

N N Pd Cl Cl N Cl

Pd-PEPPSI-IHeptCl

Cl Cl N N Pd Cl Cl N Cl

Pd-PEPPSI-IHept

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• Evaluating new catalysts in test couplings

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar

1 : 3 5 : 1 1.1 : 1 Only 2 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl No Rxn 1 : 2 (22%) Trace 1.3 : 1 (17%) Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl Ratio 2 : 1 Catalyst Product

N S O O Ph N S O O Ph

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• Evaluating new catalysts in test couplings

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar

2.7 : 1 20.7 : 1 9 : 1 Only 2 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl 1.6 : 1 23 : 1 7.2 : 1 Only 2 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl Ratio 2 : 1 Catalyst Product

N N

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• Evaluating new catalysts in test couplings

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar

1 : 1 24 : 1 3 : 1 Only 2 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl 1 : 18 1 : 1 1 : 8 2 : 1 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl Ratio 2 : 1 Catalyst Product

S S

6 6

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• Evaluating new catalysts in test couplings

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar

5.5 : 1 1 : 1.5 9 : 1 Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl 1 : 9 3 : 1 1 : 3 6 : 1 Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl Pd-PEPPSI-IHept Pd-PEPPSI-IHeptCl Ratio 2 : 1 Catalyst Product

O O

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• Some applications:

Cross-Coupling With Secondary Alkylzincs

Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G.

• Angew. Chem. Int. Ed. 2015, 54, 9502 –9506.

Pd-PEPPSI-IHeptCl (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h N N SO2Ph N S N S S MeO O S OMe O N N Boc O N Boc S N Boc MeO2C 85% yield, 50 oC 13 : 1, N: R + N R R Ar R1 R1 Ar R (normal) (rearranged) + (1.2 equiv.) R ZnBr Ar - Br R1 90 % yield Only N 99 % yield 21 : 1, N: R 99 % yield Only N 89 % yield 8 : 1, N: R 77 % yield 1.2 : 1, N: R 93 % yield Only N 86 % yield 22 : 1, N: R

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• Revisit 6-membered ring examples:

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar OMe OMe CN IPent: 1 : 1 IPentCl: 29 : 1 IHept: 3 : 1 IHeptCl: 40 : 1 IPent: 14 : 1 IPentCl: 22 : 1 IHept: 13 : 1 IHeptCl: only 2 IPent: 10 : 1 IPentCl: 55 : 1 IHept: 27 : 1 IHeptCl: only 2 IPent: 2 : 1 IPentCl: 18 : 1 IHept: 5 : 1 IHeptCl: only 2 CN

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• Revisit 6-membered ring examples:

Cross-Coupling With Secondary Alkylzincs

1 2

+ Ar - X Cat (2 mol %) THF / Toluene, 0oC for 5 min., to RT over 1h (1.2 equiv)

ZnBr Ar

• Again Pd-PEPPSI-IHeptCl demonstrates dramatic selectivity over all
• ther catalysts in the series

OMe IPent: 4 : 1 IPentCl: 14 : 1 IHept: 7 : 1 IHeptCl: only 2 OMe IPent: 14 : 1 IPentCl: only 2 IHept: only 2 IHeptCl: only 2 IPent: 2 : 1 IPentCl: 10 : 1 IHept: 7 : 1 IHeptCl: only 2

7 7

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• Selective alkylation of amines is an old problem

Alkylating and Arylating Amines

N H H H N R H H R-X R N R R H N R R R R-X R-X N R R R R-X (+) X (-)

• Metal-catalysed arylation of amines also is problematic
• Selective Pd-catalysed mono-arylation has been investigated:
• Buchwald
• Hartwig
• Stradiotto

N R H H N R Ar H Ar-X Cat. N R Ar Ar Ar-X N Ar Ar Ar Ar-X where R = H

• Basicity vs.nucleophilicity

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• All chlorides, all done at rt
• Requires strong base (e.g., alkoxide)

Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C.; Organ, M. G. Chem. Eur. J. 2008, 14, 2443-2452

Amination with Alkyl Amines

N O

(87 %)

CH3O N O N N F3C

(59 %) (99 %)

N N H O

+ 2 mol % Pd-PEPPSI-IPr DME, KOtBu, 24h, RT R - Cl R - NR1R2

N R1 R2 H N O

(92 %)

F3C S O N N N N

(83 %)

N CH3O N H

(78 %) (60 %) (46 %)

N N

(87 %)

O

(90 %)

N H N N Pd Cl Cl N Cl

Pd-PEPPSI-IPr 27

• Key observations with Pd-PEPPSI-IPr:
• Simple aromatics work poorly while hetero aromatics work well
• Aromatics that perform poorly in amination work well in other couplings
• Which step is rate-limiting?
• Deprotonation is controlled by the extent of amine coordination and pKa

PdoLn Ar-X Pd llLn Ar X H N R1 R2 Pd llLn Ar X N R1 H R2 Base M Base-H Pd llLn Ar X N R1 R2 M Pd llLn Ar N R1 R2 MX Ar N R1 R2

• xidative

addition reductive elimination amine coordination deprotonation

Amination Reactions With Mild Bases (e.g., carbonate)?

• Amine coordination and deprotonation is favoured by an e-poor metal centre
• Hammett Analysis Prediction: Reaction will be favoured by e-poor halides

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Reassess Hammett Analysis of Amination with Pd-PEPPSI-IPent

• Pd-PEPPSI-IPr
• Pd-PEPPSI-IPent

vary N O H R Cl + Pd-PEPPSI (4 %) Cs2CO3 (3 equiv) DME, 80 oC, 24 h R N O

8 8

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• Pd-PEPPSI-IPent appears to be somewhat insensitive to electronics of the OA

partner meaning that the electronic properties at Pd dominate the substrate

Reassess Hammett Analysis of Amination with Pd-PEPPSI-IPent

• Pd-PEPPSI-IPr
• Pd-PEPPSI-IPent

vary N O H R Cl + Pd-PEPPSI (4 %) Cs2CO3 (3 equiv) DME, 80 oC, 24 h R N O

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Determining the Order of the Reactants

• Inverse order in halide

N O H CN Cl + Pd PEPPSI-IPr (4 %) Cs2CO3 (3 equiv) DME, 80 oC, 9 h CN N O

• Chloride
• Morpholine
• Doubling amine concentration

increases rate ~ 20%

• Neither oxidative addition or amine coordination is rate limiting

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• What About the Base?
• (CH3)3COK (3 equiv.)

100 % conversion < 15 sec at room temperature!

N O H CN Cl + Pd PEPPSI-IPr (4 %) Base (X equiv) DME, 80 oC, 9 h CN N O

• Cs2CO3

Determining the Order of the Reactants

• First order in base

Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086-3090 32

What About the Amine?

• Pd-PEPPSI-IPr
• Pd-PEPPSI-IPent
• Compared with alkyl amines, aniline is:
• Less nucleophilic
• Its protons are more acidic

vary R Cl + Pd PEPPSI (4 %) NH2 N H R Cs2CO3 (3 equiv) DME, 80 oC, 9 h

Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145-151.

9 9

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• Aniline
• Chloride
• Base
• Zero order in chloride

+ Pd PEPPSI-IPr (4 %) NH2 N H CH3O Cs2CO3, DME, 80 oC CH3O Cl

Determining the Order of the Reactants With Aniline

• First order in aniline
• First order in base

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Effects of Varying the Electronics of the Aniline?

• Pd-PEPPSI-IPr
• Pd-PEPPSI-IPent
• IPent shows higher general reactivity, but also show sensitivity to EWGs
• With a ‘neutral’ oxidative addition partner, EWGs cripple the reaction with IPr

+ Pd PEPPSI (4 %) N H Cs2CO3, DME, 80 oC R H2N R Cl H fixed vary

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Putting all the Pieces Together

• EWGs on the aryl chloride enhance all steps
• Morpholine: First order in base, Pseudo-zero order in chloride and amine
• Aniline: First order in base, First order in amine, Zero order in chloride
• Alkylamines are likely to be strongly coordinated to Pd(II), thus is
• perating under saturation kinetics accounting for the reaction being

zero order in amine

• Any aniline only requires weak coordination for deprotonation to occur,

thus the TS for deprotonation is early and the rate would be first order in amine

Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086-3090 Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145-151. 36

Addressing the Over-Arylation Problem

• How do these properties impact on selectivity with primary amines?
• Starting amine is much more basic/nucleophilic than product aniline
• Metal anilinium salt is much more acidic than metal ammonium salt
• The selectivity-determining process in mono arylation of amines is very

different than typical catalytic processes, such enantioselective reactions

Pd llNHC Ar X N H R H late TS for deprotonation Pd llNHC Ar X N H R R1 early TS for deprotonation A cat [cat-A or cat-A*] B k k' C C' + cat + cat

• Rigorous understanding of the reactive intermediate’s structure is necessary
• A general knowledge of k and k’ will allow an accurate prediction of C/C’
• If ΔΔG‡ at -78 ºC is ~1 Kcal/mol, k = 10 X k’, C/C’ ~ 10 : 1

10 10

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• Catalyst requirements: extremely high reactivity, yet retain selectivity!

Addressing the Over-Arylation Problem

• k1 / k2 must be much greater than preceding example for a similar result
• Concentration now plays a very critical role
• Selectivity is determined by the competitive rates of two different processes
• The product of the first reaction is the substrate for the second one
• k1 / k2 (hence ΔΔG‡) must be vastly greater to obtain absolute selectivity

3.5 385 1000 : 1 0.5 : 1 5.1 3636 (202x 10 : 1) 1000 : 1 1 : 1 6.4 50,000 1000 : 1 1.5 : 1 3.5 370 (20x 10 : 1) 100 : 1 1 : 1 1.7 17.9 10 : 1 1 : 1 ΔΔG‡ (kcal/mol at 25 ºC) k1 / k2 RNHAr / RNAr2 Ar-X / RNH2

N R H H N R Ar H Ar-X Cat. N R Ar Ar Ar-X k1 k2 K = k[A]x[B]y

38

Addressing the Over-Arylation Problem

• Effect of catalyst concentration
• Mono animination using tbutoxide base

+ Pd PEPPSI-IPentCl (X %) N H CH3O NaOtBu (1.1 equiv.) Toluene, 80 oC, 24h CH3O Cl NH2 ( )7 N CH3O ( )7 O + Mono Di (1.0 equiv.) (1.1 equiv.)

90 66 : 1 92 0.5 4 87 33 : 1 89 1 3 93 22 : 1 93 2 2 90 18 : 1 90 3 1 % Yield Mono Mono : di % Conversion Mol % Cat. Entry

• Catalytic efficiency is retained below 1 mol % load

39

Addressing the Over-Arylation Problem

• Mono animination using tbutoxide base - Scope Study
• Generally applicable, highly selective for mono arylation

+ Pd PEPPSI-IPentCl (1 %) Ar R N H NaOtBu (1.1 equiv.) Toluene, 60 or 80 oC, time + Mono Di (1.0 equiv.) (0.25 M) (1.1 equiv.) N N H ( )7 60 oC, 4h yield: ND Mono : Di, 50 : 1 N N H ( )7 60 oC, 3h yield: 88 %

• nly Mono

60 oC, 2h yield: 95%

• nly Mono

N N H ( )7 60 oC, 4h yield: 96 Mono : Di, 50 : 1 N N H ( )7 60 oC, 2h yield: ND Mono : Di, 25 : 1 Ar - X R-NH2 Ar R N Ar N N H ( )7 N N N H ( )7 60 oC, 3h yield: ND Mono : Di, 10 : 1 N N N H ( )7 60 oC, 3h yield: ND Mono : Di, 1 : 1 N N H ( )7 80 oC, 2h yield: 98% Mono : Di, 50 : 1 N N H ( )7 60 oC, 2h yield: 99%

• nly Mono

O 40

Addressing the Over-Arylation Problem

• Carbonate enjoys very high substrate functional group tolerance
• With non-deactivated substrates
• Mono animination using carbonate base - Scope Study
• Electron-poor substrates improve conversion, with high selectivity

+ Pd PEPPSI-IPentCl (1 %) N H R Cs2CO3 (3 equiv.) Toluene, 60 or 80 oC, 24h R Cl NH2 ( )7 N R ( )7 R + Mono Di (1.0 equiv.) (0.25M) (1.5 equiv.) N H ( )7 60 oC 93 % conv.

• nly Mono

O N H ( )7 60 oC 90 % conv.

• nly Mono

O O 80 oC 98 % conv.

• nly Mono

N H ( )7 80 oC 100 % conv. 50 : 1, Mono : Di O2N N N H ( )7 80 oC 100 % conv. 22 : 1, Mono : Di

11 11

41

Addressing the Over-Arylation Problem

• Impact of using 2,6-di-tButylphenoxide

81 29 : 1 100 1.5 Na (isolated) 5 69 20 : 1 100 1.5 K (in situ) 2 1.5 1.25 1.25

• Equiv. BHT

95 25 : 1 100 Na (in situ) 4 85 22 : 1 100 Na (in situ) 3 66 15 : 1 100 K (in situ) 1 % Yield Mono Mono : di % Conversion BHT-M Entry

+ Pd PEPPSI-IPentCl (1 %) N H CH3O BHT salt (1.25 equiv.) Toluene, 60 oC, 24h CH3O Cl NH2 ( )7 N CH3O ( )7 O + Mono Di (1.0 equiv.) (1.25 equiv.) OM BHT

• Sodium BHT salt leads to better selectivity than potassium

42

Addressing the Over-Arylation Problem

• Mono animination using NaBHT base - Aromatic Scope Study
• Nicely functional group tolerant

+ Pd PEPPSI-IPentCl (1 %) Ar Oct N H NaBHT (1.0 equiv.) Toluene, 60 oC, time + Mono Di (1.0 equiv.) (0.25 M) (1.1 equiv.) N H ( )7 24h yield: 90% Mono : Di, 22 : 1 N H ( )7 2h yield: 92 %

• nly Mono

20h yield: 90 %

• nly Mono

Ar - Cl Oct-NH2 Ar Oct N Ar N H ( )7 4h yield: 57 %

• nly Mono

O O O N H ( )7 24h yield: 84 % Mono : Di, 32 : 1 O N H ( )7 24h yield: 85 %

• nly Mono

F3C N H ( )7 24h yield: 92% Mono : Di, 12 : 1 NC 20h yield: 80 %

• nly Mono

N H ( )7 O2N N H ( )7 CF3

43

Addressing the Over-Arylation Problem

• Mono animination using NaBHT base - Heteroaromatic Scope Study

+ Pd PEPPSI-IPentCl (1 %) ArHet R N H NaBHT (1.0 equiv.) Toluene, 50 oC, time + Mono Di (1.0 equiv.) (0.25 M) (1.1 equiv.) HetAr - Cl R-NH2 ArHet R N HetAr N H N Me Me N H N N N N H MeO N H N N H N N H N N H N N O N H N N H N N H N OMe ( )6 ( )6 ( )6 2h, yield: 86% Mono : Di, 20 : 1 3h, yield: 89% Mono : Di, 40 : 1 3h yield: 87% Mono : Di, 45 : 1 2h yield: 84% Only Mono 4h yield: 86% Only Mono 16h, 60 oC yield: 90% Only Mono 16h yield: 87% Mono : Di, 14 : 1 8h yield: 97% Mono : Di, 40 : 1 2h yield: 94% Only Mono 16h yield: 90% Only Mono

44

12h yield: 93 Only Mono N H S S N

Addressing the Over-Arylation Problem

• Mono animination using NaBHT base - Exotic amines and aryl partners

+ Pd PEPPSI-IPentCl (1 %) Ar R N H NaBHT (1.0 equiv.) Toluene, 50 oC, time + Mono Di (1.0 equiv.) (0.25 M) (1.1 equiv.) 2h, 60 oC yield: 90% Only Mono 16h, 60 oC yield: 71 % Only Mono Ar - Cl R-NH2 Ar R N Ar N H S N H O O 2h, Ar-Br yield: 84 % Only Mono 2h yield: 90 % Only Mono 16h yield: 80 % Only Mono N H N N N H N N N N N H OMe N H N3 N H N3 12h, Ar-Br yield: 59 Only Mono 12h, Ar-Br yield: 61 Only Mono

12 12

45

Increased Catalytic Performance

• Acidic groups can be tolerated with a modification of reaction conditions

Sharif, S.; Rucker; R. P.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9507-9511.

+ Pd PEPPSI-IPentCl (1 %) Ar R N H LiHMDS (2.0 equiv.) Toluene, 60 oC, 24h + Mono Di (1.0 equiv.) (0.25 M) (1.1 equiv.) Ar - Cl R-NH2 Ar R N Ar yield: 71% Mono : Di, 18 : 1 Ar-Br, yield: 61% Mono : Di, 20 : 1 yield: 92% Only Mono yield: 77% Mono : Di, 15 : 1 yield: 81% Only Mono N H MeO OH OH N H NH yield: 73% Mono : Di, 10 : 1 N H O OH O OH OH O N H N H N H

46

• The new threshold for amination has been reached: carbonate at RT

N N Pd Cl Cl N Cl Cl CH3 N O F F F (75%) N O CF3 (86%) N CO2Me (98%) O O (75 %) N N (98%) F O N OH N (70 %, 45°C: 91%) CF3 F3C Cl Pd-PEPPSI-IPentCl-o-picoline (3 mol%) H N (1.0 equiv.) (1.5 equiv.) NH2 R' R' R' R' N O O O N (96 %) CF3 H H H H H H Cs2CO3 (3 equiv.) DME, RT, 24 h Pd-PEPPSI-IPentCl

• o-picoline

O N F F F H O

Increased Catalytic Performance

• How have these ligand modifications affected overall reactivity?

47

• Racemization of existing stereocentre is problematic

Increased Catalytic Performance

• Can very high reactivity actually improve selectivity?
• Process is sensitive to sterics

N N Pd Cl Cl N Cl Cl CH3 N Cl Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

(1.0 equiv.) (1.3 equiv.) Cs2CO3 (3 equiv.) DME, 80 oC, 24 h Pd-PEPPSI-IPentCl

• o-picoline

Ph O OR NH2 Ph O OR N N H ee > 98% HCl

58 83 100 methyl 1 75 93 100 ethyl 2 98 95 100 t-butyl 3 % ee % Yield % Conv. R Entry

48

Increased Catalytic Performance

• Temperature?
• Catalyst?
• Base?
• Normal Reaction Conditions
• Source of isomerization control experiments: starting material

Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

Cs2CO3 (3 equiv.) DME, 80 oC, 24 h Ph O OEt NH2 ee > 98% Ph O OEt NH2 ee > 98% DME, 80 oC, 24 h Ph O OEt NH2 ee > 98% Ph O OEt NH2 ee > 98% Cs2CO3 (3 equiv.) DME, 80 oC, 24 h Ph O OEt NH2 ee > 98% Ph O OEt NH2 ee > 98% Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

DME, 80 oC, 24 h Ph O OEt NH2 ee > 98% Ph O OEt NH2 ee > 98%

13 13

49

Increased Catalytic Performance

• Source of isomerization control experiments: product
• Normal Reaction Conditions?
• Temperature?
• Catalyst?

Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

Cs2CO3 (3 equiv.) DME, 80 oC, 24 h ee > 84% ee > 8% N O OEt N H Bn N O OEt N H Bn DME, 80 oC, 24 h ee > 84% ee > 84% Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

N O OEt N H Bn N O OEt N H Bn DME, 80 oC, 24 h ee > 84% ee > 84% N O OEt N H Bn N O OEt N H Bn

Remember: little (or no) β-hydide elimination in alkyl couplings with bulky NHCs

50

Increased Catalytic Performance

• Source of isomerization control experiments: product
• Normal Reaction Conditions?
• Temperature?
• Catalyst?
• Base?

Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

Cs2CO3 (3 equiv.) DME, 80 oC, 24 h ee > 84% ee > 8% N O OEt N H Bn N O OEt N H Bn DME, 80 oC, 24 h ee > 84% ee > 8% Cs2CO3 (3 equiv.) N O OEt N H Bn N O OEt N H Bn DME, 80 oC, 24 h ee > 84% ee > 84% Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

N O OEt N H Bn N O OEt N H Bn DME, 80 oC, 24 h ee > 84% ee > 84% N O OEt N H Bn N O OEt N H Bn

**Isomerization

• ccurs with the

most mild of heterogeneous bases - problem

51

Increased Catalytic Performance

• Substrate scope

92%, 98% ee N O OtBu N H 95%, 98% ee N O OtBu N H Leucine 91%, 98% ee N O OtBu N H Isoleucine 76%, 98% ee O OtBu N N 87%, 98% ee O OtBu N O Proline

• Coupling is excellent and no sign of erosion of optical purity
• High rate of catalyst turnover is essential for selectivity (base is consumed)

Pd-PEPPSI-IPentCl-

• -picoline (3 mol%)

(1.0 equiv.) (1.3 equiv.) Cs2CO3 (1.5 equiv.) DME, 60 - 80 oC, 24 h R O O NH2 ee > 98% Ar Cl R O O N Ar H 92%, 98% ee N O OtBu N H 95%, 98% ee N O OtBu N N H O Alanine 88%, 98% ee N O OtBu H Bn 89%, 98% ee N O OtBu N H Bn O 93%, 98% ee N O OtBu N N H Bn O O Phenyl alanine

52

What About Ammonia?

• The metal amide of ammonia is especially difficult to reductively eliminate

making selective mono arylation more challenging than with 1o amines

• Sterics of the ligand will be pivotal
• Substrate structure will have a much greater impact on selectivity

Cl Cl O > 50 : 1 > 50 : 1 Cl O Cl > 50 : 1 40 : 1 Cl O Cl F F F Cl 5 : 1 3 : 1 1.4 : 1 N N Pd Cl Cl N Cl Cl Cl Pd-PEPPSI-IPentCl (3 mol%) H N (10 equiv.) NH3 R' R' R' NaOtBu (1.5 equiv.) dioxane, 100 oC, 24 h Pd-PEPPSI-IPentCl Cl NH2 R' Mono Di +

• Mono : Di arylated product

14 14

53

What About Ammonia?

• Catalyst screen

Cl Pd-PEPPSI (1 mol%) (10 equiv.) NH3 NaOtBu (1.5 equiv.) dioxane, 100 oC, 24 h Mono + NH2 Di H N

• Mono : Di arylated product

N N Pd Cl Cl N H H Cl 1 : 33 N N Pd Cl Cl N Cl Cl Cl 2.7 : 1 N N Pd Cl Cl Cl Cl N Cl 4.6 : 1

• Poor electronics and a lack of steric footprint in substrate can be overcome

by overwhelming bulk of the catalyst, yet retain high reactivity

N N Pd Cl Cl Cl Cl N Cl 43 : 1

54

What About Ammonia?

• Substrate electronics screen:

Cl (10 equiv.) NH3 O O Pd-PEPPSI-IHept Branched (1 mol%) NaOtBu (1.4 equiv.) dioxane, 100 oC, 24 h + + NH2 O O H N O O O O Mono : Di, 80 : 1 (68%) Cl Pd-PEPPSI-IHept Branched (1 mol%) (10 equiv.) NH3 NaOtBu (1.4 equiv.) dioxane, 100 oC, 24 h O Mono : Di, 10 : 1 (80%) H N O O NH2 O + + N N Pd Cl Cl Cl Cl N Cl Pd-PEPPSI-IHept Branched Cl (10 equiv.) NH3 + NH2 H N Mono : Di, 43 : 1 (92%) Pd-PEPPSI-IHept Branched (1 mol%) NaOtBu (1.4 equiv.) dioxane, 100 oC, 24 h +

55 (10 equiv.) NH3 Mono : Di Pd-PEPPSI-IHept Branched (1 mol%) NaOtBu (1.4 equiv.) dioxane, 100 oC, 24 h + Ar X Ar NH2 + Ar NH Ar 74:1, 93% (2 h) NH2 O 43:1, 92% (6 h) NH2 But O NH2 NH2 CN 24:1, 88% (4 h) NC NH2 26:1, 92% (2 h) 13:1, 85% (4 h) NH2 O NH2 O2N 41:1, 89% (6 h) 36:1, 84% (2 h) >99:1, 51% (2h) NH2 O O 23:1, 91% (8 h) NH2

tBuO

N NH2 40:1, 88% (16 h) N N NH2 11:1, 76% (16 h) O N N NH2 8.3:1, 79% (16 h) 17:1, 89% (16 h) N S NH2 N N NH2 9:1, 81% (16 h) N NH2 14:1, 88% (16 h) O N OH NH2 F 20:1, 84% (2 h) 27:1, 69% (2 h) NH2 O O

What About Ammonia?

• Substrate scope:

56 N N N Cl Cl O F S F N CH3 S CO2H SO2CH3 O N CH3 H3C

CRTH2 VX-745

S CH3 N O OH NH2

Zileuton

S

Raloxifene

OH HO O N O

• Traditional methods to prepare C-S bonds often require harsh conditions
• Catalysis offers several advantages, e.g., selectivity, mild conditions, etc.

Sulfur-Containing Compounds of Interest

• Aryl thiols are common in the structure of natural products and

compounds of biological and medicinal interest

15 15

57

Metal-Catalysed Sulfination

• Current state-of-the-art in ligand design for sulfination

KOtBu (3.0 equiv.) 99 % in 6h LiOiPr (20 %) toluene 80, then RT Pd-PEPPSI-IPent Cl Me 98 % in 2h LiOiPr (20 %) toluene 80, then 40 Pd-PEPPSI-IPent Br Me 98 % Bu2Mg (8%) toluene RT Pd-PEPPSI-IPent Br Me 99 % Morpholine (2.5%) toluene 40 Pd-PEPPSI-IPent Br Me 0 %

• toluene

40 Pd-PEPPSI-IPent Br Me

• Additive

0 % DME 110 Josi-Phos Cl Me ~85 % DME 70 Josi-Phos Cl H ~90 % DME 90-110 Josi-Phos Br Me Br X 50

• Temp. oC

~90 % DME Josi-Phos H Yield Solvent Catalyst (2 mol%) R

X R R HS

+ Cat. Temp., Solvent KOtBu (1.5 equiv.)

S R R

N N Pd Cl Cl N Cl 58

Metal-Catalysed Sulfination

• Scope study using Pd-PEPPSI-IPent

+

• 1. Pd-PEPPSI-IPent (2 %)

LiOpr (20%), KOtBu (1.5 equiv.), Ar1X, Toluene, 70 oC, 30 min.

• 2. cool to rt
• 3. add Ar2SH, 40 oC, 24h

(1 equiv.) (1.2 equiv.) Ar1-X HS-Ar2 Ar1-SAr2

S

X = Br (61 %)

S

X = Cl (91 %) (3.0 equiv. KOtBu) 50 oC

S

X = Br (89 %)

OBn S

X = Cl (99%)

S O

X = Br (93 %)

S Si

X = Br (83 %)

OBn S Si

X = Br (94 %) X = Br (99 %)

S S

X = Br (99 %)

S S Si N

(60 oC) X = Br (99 %)

N S O Sayah, M.; Organ, M. G. Chem. Eur. J. 2011, 17, 11719-11722

59

Investigating Precatalyst Activation

• What is formed in situ?

N N Pd Cl Cl N ll Br S PhSH (4 equiv.) KOtBu (4.5 equiv.) C6D6, RT, 2h (4 equiv.) N N Pd SPh PhS N ll N + (60%) (40%) + (0%) (40%) Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar = 2,6-diisopropylphenyl Ar N N Ar Pd SPh

No coupling

60

Investigating Precatalyst Activation

• What is formed in situ?

N N Pd Cl Cl N ll Br S PhSH (4 equiv.) KOtBu (4.5 equiv.) C6D6, RT, 2h (4 equiv.) N N Pd SPh PhS N ll N + (60%) (40%) + (0%) (40%) Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar = 2,6-diisopropylphenyl Ar N N Ar Pd SPh

No coupling

16 16

61

Investigating Precatalyst Activation

• What is formed in situ?
• Does LiOiPr make a difference?
• Again, at RT - yes!

N N Pd Cl Cl N ll Br S PhSH (4 equiv.) KOtBu (4.5 equiv.) C6D6, RT, 2h (4 equiv.) N N Pd SPh PhS N ll N + (60%) (40%) +

(20%)

(40%)

+ LiOiPr (2 equiv.)

Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar = 2,6-diisopropylphenyl Ar N N Ar Pd SPh N N Pd Cl Cl N ll Br S PhSH (4 equiv.) KOtBu (4.5 equiv.) C6D6, RT, 2h (4 equiv.) N N Pd SPh PhS N ll N + (60%) (40%) + (0%) (40%) Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar = 2,6-diisopropylphenyl Ar N N Ar Pd SPh 62

Investigating Precatalyst Activation

• What species are catalytically active?
• The tri-Pd complex is dead under standard reaction conditions, however…

Br HS

+

• Cat. (2%)

70 oC, Toluene KOtBu (2 equiv.)

S

(1.2 equiv.) Cat. trace

Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar N N Ar Pd SPh

Add 6% pyridine 92% yield Use 2 equiv. KOEt 89% yield

• OtBu is too hindered

63

Investigating Precatalyst Activation

• The tri-Pd complex is dead under standard reaction conditions, however…

Br HS

+

• Cat. (2%)

70 oC, Toluene KOtBu (2 equiv.)

S

(1.2 equiv.) Cat. trace

Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar N N Ar Pd SPh

Add 6% pyridine 92% yield Use 2 equiv. KOEt 89% yield

• The monomeric disulfide is active (and is likely the actual precatalyst)

Br HS

+

• Cat. (2%)

70 oC, Toluene KOtBu (2 equiv.)

S

(1.2 equiv.) Cat. 90 %

N N Pd SPh PhS N ll

with LiOiPr (10%) 80 % at 40 oC

• LiOiPr strongly activates (on-cycle, off-cycle, or both)
• OtBu is too hindered
• What species are catalytically active?

64

Investigating Precatalyst Activation

• Mechanism of precatalyst activation: sulfide oxidation

N N Pd SAr ArS N ll N N Pd Cl Cl N ll

MgBu2 (1 equiv.) C6D6, 0 oC, 30 min.

N N Pd N

60% conversion + octane ArSSAr

• Is the reduction reversible?
• Suggests that the more oxidized form of the complex is more stable

N N Pd SAr ArS N ll N N Pd Cl Cl N ll

KOtBu (4.1 equiv.) C6D6, RT, 30 min.

N N Pd N

+ ArSSAr ArSH (4 equiv.)

• xidative

addition reductive elimination

17 17

65

Investigating Precatalyst Activation

• Role of the Bases Outside of the Catalytic Cycle

LiOiPr (3 equiv.) No Reaction KOtBu (5 equiv.) 20% conv. LiOiPr (3 equiv.) & KOtBu (5 equiv.) 100% conv. Additives

• Both bases appear involved in sulfide precatalyst activation

N N Pd SAr ArS N ll

Additives C6D6, 60 oC, 16h

N N Pd N

Trapped Complex

N Br

N N Pd ArS ll

N

+ ArSSAr

66

Investigating Precatalyst Activation

• Role of the Bases Inside of the Catalytic Cycle

None No Reaction MgBu2 (2%) 67% conv. LiOiPr (30 mol %) + MgBu2 (2%) 100% conv. Additives KOtBu (30 mol %) + MgBu2 (2%) 100% conv.

• Base role in activation is more clear

Br S- K+

+ Pd-PEPPSI-IPr (2%) Toluene, 40 0C, 24h Additives

S

(1.2 equiv.) KOtBu (30 mol %) 0% conv. KOiPr (30 mol %) 100% conv.

• Bases have a role inside the catalytic cycle (or at least after activation)
• Use thiolate salt - should eliminate the need for base all together

67

Cation and Solvent Effects

• Role of the Bases Inside of the Catalytic Cycle
• Only K-thiolate salt works

35% heterogeneous K THF 4 0% fully soluble K isopropanol 7 0% fully soluble K NMP 6 0% fully soluble K DMSO 5 0% fully soluble Li toluene 3 0% heterogeneous Na toluene 2 100% heterogeneous K toluene 1 Conversion Appearance Cation Solvent Entry

• The less polar the solvent, the less soluble the salt, the better the coupling!

Br HS

+ Pd-PEPPSI-IPr (2%) 70 oC, Solvent MOtBu (2 equiv.) 24h

S

(1.2 equiv.)

68

Improving The Entire Sulfination Process

• How Does Catalyst Structure Affect Activation?

N N Pd

R1 R1 R1 R1

Cl Cl N ll

R5 R4 R6

+ ArS -

• Cl -

R2 R3

N N Pd

R1 R1 R1 R1

SAr ArS N ll

R5 R4 R6 R2 R3

Electronic Influence Catalyst Activity Steric Influence (and electronic?) Catalyst Activity and Activation Steric Influence Catalyst Activation Electronic Influence Catalyst Activation

18 18

69

Improving The Entire Sulfination Process

• How Does NHC Structure Affect Activation and Reactivity?

N N Pd Cl Cl N N N Pd Cl Cl N N N Pd Cl Cl N CH3 N N Pd Cl Cl N CH3 N N Pd Cl Cl N CH3 Cl Cl CH3 H3C

60 60 oC C: trace : trace 70 70 oC C: 89% : 89% 70 70 oC C: NR : NR 80 80 oC C: NR : NR 40 40 oC C: NR : NR 50 50 oC C: 99% : 99% 60 60 oC C: NR : NR 70 70 oC C: NR : NR 23 23 oC C: NR : NR 40 40 oC C: 99% : 99%

• Some bulk at the 2-position of pyridine helps

Br SH

+ Pd-PEPPSI (2%) KOtBu (2 equiv.) Toluene, 24h Temperature

S

(1.2 equiv.)

• Using the IPent NHC platform

70

Improving The Entire Sulfination Process

• How Does NHC Structure Affect Activation and Reactivity?

N N Pd Cl Cl N N N Pd Cl Cl N N N Pd Cl Cl N CH3 N N Pd Cl Cl N CH3 N N Pd Cl Cl N CH3 Cl Cl CH3 H3C

60 60 oC C: trace : trace 70 70 oC C: 89% : 89% 70 70 oC C: NR : NR 80 80 oC C: NR : NR 40 40 oC C: NR : NR 50 50 oC C: 99% : 99% 60 60 oC C: NR : NR 70 70 oC C: NR : NR 23 23 oC C: NR : NR 40 40 oC C: 99% : 99%

• Some bulk at the 2-position of pyridine helps
• Electron-withdrawing groups on the imidazole greatly enhance reactivity

Br SH

+ Pd-PEPPSI (2%) KOtBu (2 equiv.) Toluene, 24h Temperature

S

(1.2 equiv.)

• Using the IPent NHC platform

71

Improving The Entire Sulfination Process

• How Does NHC Structure Affect Activation and Reactivity?

S N S S X= Br: Cat 1: 90 % Cat 2: trace O Ar-X + R SH

KOtBu (1.5 equiv.) Toluene, RT, 24 h

(1.2 equiv.) S S O S N N S N S S N S Ar-SR

Catalyst (2 mol %) LiOiPr (20 %)

X= Cl: Cat 1: 84 % Cat 2: trace X= Br: Cat 1: 95 % Cat 2: trace X= Br: Cat 1: 60 % Cat 2: trace X= Br: Cat 1: 92 % Cat 2: trace X= Br: Cat 1: 50 oC, 96 % Cat 2: 50 oC, trace X= Br: Cat 1: 61 % Cat 2: trace X= Br: Cat 1: 81 % Cat 2: trace

N N Pd Cl Cl N N N Pd Cl Cl N CH3 Cl Cl

Cat 2 Cat 1

For commercial availability of catalysts, see: http://totalsynthesis.ca

72

Putting All of The Pieces Together

• NHC bulk is critical to high catalyst activity
• NHC electronics are equally, if not more important to catalyst

activity

• Pyridine structure is very important for pre-catalyst activation
• Thiolate solubility (actually insolubility) is critical for avoiding
• ff-cycle resting states
• Combining precatalyst activation studies with active catalyst
• ptimization has led to a high-performing system for sulfination

under the most mild conditions reported for the most challenging substrates

19 19

73

Putting All of The Pieces Together

• On- and Off-Cycle Analysis of Sulfination with NHC-Pd Catalysts

Off-Cycle Off-Cycle Off-Cycle Off-Cycle

Pd Cl Cl N ll NHC KOtBu KCl ArSH ArX Pd SAr ArS N ll NHC Active Inactive R R N R + Pd0-NHC

• ArSSAr

+ ArSSAr 'enhanced' by LiOiPr Pd X Ar ll NHC Pd SAr Ar ll NHC

ArSAr

NHC Pd S S Ar NHC Pd Ar Ar Ar ll ll Possible Resting State

ArX

Reductive Elimination Oxidative Addition Ligand Exchange ArSH + KOtBu KX + HOtBu Pd Cl Cl N ll NHC R X H base Ar N N Ar Pd S Pd S S S Ph Ph Ph Ph PhS Ar N N Ar Pd SPh 74

Summary

• Selectivity need not always come at the expense of reactivity
• An understanding of the physical/chemical properties of organometallic

complexes is key to predicting catalytic behaviour

• It is nice when steric and electronic structural features lead to similar

catalytic outcomes

• Selective secondary alkyl cross-coupling is possible when a strong

working knowledge of mechanism and an interplay with catalyst design

• Selective mono-arylation of primary amines is possible using new

generation derivatized NHC cores

• More structurally complex target molecules are possible using

cross-coupling methodology to enrich discovery in the search for novel therapeutics, catalysts, and materials