GM 24June2017 PRESENTATION€¦ · Tet. Lett. 1985, 26, 275. N 1. Et2Mg, EtLi, 18-c-6 2. H2O 3. [O]...

Justine deGruyterBaran Lab Group Meeting

06.24.2017fascinATEing complexes

Ate complexes are salts formed from the stoichiometric reaction of a Lewis base and Lewis acid, wherein the acidic moeity formally increases its valence and becomes anionic.

Two standard reaction pathways:Non-oxidative charge

neutralization (ligand transfer)Oxidative charge

neutralization (non-ligand transfer)

RM

R

R (n)

RMR

(n)

R RM

R

R (n) ER

MR (n+2)

RE

Helpful resources.

Structure and reactivity.

(Very) brief history.- first alkali-metal ate complex, NaZnEt3, synthesized in Wanklyn (1858)- the term "ate" coined by Wittig (1951); first synthesis of magnesiate

Weiss motifs.

N

NLi

PhMg

Ph

PhMg

Ph

PhLi

Ph

N

N

Me Me

Me Me Me Me

MeMelower-order

N

NLi

MeMg

Me

MeLi

Me

Me Me

Me Me

N

NMe Me

Me Mehigher-order

N

NLiH2C

MgH2C

CH2Ph

CH2Ph

Me Me

Me Me Ph

Ph

N

NLi

Me Me

Me Me

N

NMe Me

Me Mesolvent-separated higher order

- enhanced solubility in organic solvents is a reliable indicator of ate formation- two types: contact-ion pair (CIP) and solvent-separated ion pair (SSIP)- lower-order: (AM)MR3, higher-order: (AM)2MR4

"Much of this synthetic and structural chemistry has a synergic element to it, in the sense that compounds with a heterobimetallic (ate) combination of an alkali metal (usually Li, Na, or K) and

magnesium or zinc or aluminum, can effect (often surprising) reactions which cannot be replicated by the corresponding homometallic (non-ate) alkali-metal, magnesium, zinc, or alumnium compounds."

(Mulvey, 2007)

[GM] Literature seminar, T. Mashiko (2007)[review] Top Organomet. Chem. 2014, 47, 129.

[review] Angew. Chem. Int. Ed. 2007, 46, 3802.[review] Organometallics 2006, 25, 1060.

Magnesium ate ("Magnesiates" or "Magnesates").alkyllithium > lithium trialkylmagnesate > alkylmagnesium

Reactions of diethylmagnesium–ethyllithium solutions with pyridine.Richey. Tet. Lett. 1985, 26, 275.

N

1. Et2Mg, EtLi, 18-c-62. H2O

3. [O] N Etminor

N

Et

majorEt2Mg or EtLi alone lead exclusively to 1,2-add'n

Deprotonation of thiophenes using lithium magnesates. Mongin. Tetrahedron 2005, 61, 4779.

SR

1. Bu3MgLi(TMEDA) (0.33 equiv.)

THF, rt

Mg

S

S

SR

R

R

Li(TMEDA)2. E

3. H2O

(0.33)

SR E

R= H, Cl, OMe

O E O DDO

D2O quench(48%)

OE

(85–89%)

Deprotonation of furans using lithium magnes-ates. Mongin. Tet. Lett. 2005, 46, 7989.

(65–85%)

*can be trapped with E or engaged in a Pd-cat.cross-coupling event with 2-bromopyridine

Two common formulations: R3ZnLi and R4ZnLi2.

x LiR + y MgR2

+ nL

(LixMgyRz)(LixMgyRz·Ln)

"Ordinary" structure. Molecular architecture construction is a two-stage process:- anchoring bonds: stronger, more covalent (α-based Mg–R interactions)- ancillary bonds: more ionic, enable lithium ions to affix to framework (CIPs)

"Extraordinary" structure.

O

Mg

Mg

LiLi

N N

NN

Me Me

MeMe

Me Me

MeMe

"... a special type of chemistry beyondthe scope of mainstream organometallicreagents is operating here."



Zincates.

[first reports] Wanklyn. Liebigs Ann. 1858, 108 , 67.; Wanklyn. Proc. R. Soc. London 1858, 9, 341.

PvO Me CHO

Me

NaBH4–CeCl3

or Zn(BH4)2Me

Me O OMe Me

Me

OH

Me

MePvO OHMe

Me O OMe Me

Me

O

Me

MePvO OH

MeMe O OMe Me

Me

O

Me

MePvO O

CSA,tBuOH

H

MeMe O OMe Me

Me

Me

MePvO O

H

HMe

Me O OMe Me

Me

Me

MePvO O

H

H

O

MeMe O OMe Me

Me

Me

MePhS O

H

H

O O

Me

MePhS

H

O O

Me Me

MeH

MeMeHO

O

Me

Me

H

HO MeH

MeHO

target

A =

DDQ

mCPBA

nBuLi,Bu2Mg

Ito-Kodama cyclization. Tet. Lett. 1975, 16 , 3065.

[review] Recent developments in the synthetic and structural chemistry of lithium zincates.Wheatley. New. J. Chem. 2004, 28, 435.[review] s-Block metal inverse crowns: Synthetic and structural synergism in mixed alkali metal–magnesium (or zinc) amide chemistry. Mulvey. Chem. Commun. 2001, 1049.

X

FG

1. R3MgLiTHF

2. E

E

FG

Halogen–magnesium exchange via trialkylmagnesates for the preparation of aryl and alkenyl-magnesium reagents. Oshima. Angew. Chem. Int. Ed. 2000, 39, 2481.

R I

1. iPrBu2MgLiTHF

2. ER E

Deprotonation of fluoro aromatics using lithium magnesates. Mongin. Tet. Lett. 2004, 45, 6697.

N

F

N

FE

1. Bu3MgLi (0.33 equiv.)THF, –10 °C

2. E3. H2O

NR F

1. Bu3(TMP)MgLi2THF, –10 °C

2. I2 NR F

I

Enantiospecific synthesis of the 14-membered diene unit of methyl sarcophytoate. Nakata. Synlett. 1997, 899.

MeMe

Me

OH

MeMe O OMe Me

OMe

Me MeMe O OMe Me

Me

O OH

Me

MePvO1. LiHMDS

2. A

PolymersEffects of dibutylmagnesium on alkyllithium-initiated polymerizations. Hsieh. Macromolecules. 1986, 19 , 299.

Preparation of azulenyllithium and magnesium reagents utilizing halogen–metal exchange reactionof several iodoazulenes with organolithium or magnesium ate complex. Ito. Tet. Lett. 2004, 45, 2891.

InBu3MgLi

MDMF

CHO

"Although...(n-Bu)(s-Bu)Mg (DCM) was not suitable as the sole initiator to polymerize butadiene andsytrene, its "ate" complex with... (sec-BuLi)... could initate the polymerization of both."- Dispersity of 1.06 obtained in all cases; indicative of a "living" anionic polymerization.

or nBuLi


06.24.2017fascinATEing complexesRegiocontrolled deprotonative-zincation of bromopyridines using aminozincates.Kondo. Chem. Commun. 2001, 2450.

N Br

N BrI

N Br

I N

Br

N

BrI

N

Br

I

TMPZntBu2Li, Et2O, rt;

I2

DAZntBu2Li, Et2O, –20 °C;

I2

TMPZntBu2Li, Et2O, rt;

I2

DAZntBu2Li, THF, rt;

I2no pyridyne formation!(66%)

(68%)(86%)

(72%)

R2R1

XH •

R2

R1

ZnL

R3 •R2

R1

D

R3D2O

E–X R2R1

ER3

(R3)3ZnM

THF, –85 to 0 °C

Reaction of propargylic substrates with triorganozincates: A novel method for the preparation of allenic zinc reagents associated with carbon–carbon bond formation.Oku. J. Org. Chem. 1993, 58, 6166.

TMP–Zincate as highly chemoselective base for directed ortho metalation.Kondo. J. Am. Chem. Soc. 1999, 121 , 3539.

N I N I NI

N

I(76%) (26%) (61%) (93%)

TMPZntBu2Li

THF, rtHet

Synthesis of 5-pyridyl-2-furaldehydes via palladium-catalyzed cross-coupling with triorganozincates.Gauthier. Org. Lett. 2002, 4, 375.

Ar–X + O ZnLiEtO

EtO

3

0.33

1. Pd(dppf)Cl2THF, 50 °C

2. 5N HCl

O ArH

O

Br

BrR2

R1

R3Li

R33ZnLi

Li

BrR2

R1

Zn

BrR2

R1

R1 R2

R3

HR2

R1

Generation and alkylation reaction of 1-bromoalkenyl-zincate. Oku. Tet. Lett. 1988, 29, 3821.

Generation and alkylation reaction of lithium1-halocyclopropylzincate. Oku. Tet. Lett. 1989, 30, 6035.

R1BrBr

H

R1

H

HBr

R1

H

R2

H

H+, –85 °C

H+, 0 °C

see also: J. Org. Chem. 1993, 58, 2958.; Tetrahedron 1994, 50, 7987.

Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: Synthesis of an α2/3-selective GABA agonist. Gauthier. J. Org. Chem. 2005, 70, 5938.

CN

F

TMPZnBu2Li

THF

CN

F

LiBu2ZnCN

FF

XX

FBr

[Pd]

"All attempts to cross-couple aryl-zincate (sic)... were unsuccessful, generally giving no reaction."

"We believe the complete lack of reactivity... is due to the electron-withdrawing effects of the aryl substituents."

A highly convergent total synthesis of leustroducsin B. Trost. J. Am. Chem. Soc. 2015, 137 , 11594.

O N

O O

EtBn

H

O

TES

Bu2BOTf, Et3NO N

O O

EtBn

TES

OH

OO

Et TES

OH

O

Et

O OH

TES

+

Fragment 1

X

+ R33ZnLi



O

Et

OMe

I

1. TsOH, MeOH;K2CO3

2. Cp2ZrHCl;I2

Fragment 2

H OEt

O

EtO OEtH

O

EtO OEt EtO OEt

OH OTBS

SiMe2Bn

EtO OEt

O OTBS

SiMe2Bn

PMBO

PMBO Cl

DIPEA

O OTBS

SiMe2Bn

PMBO

O

N3

AcOH, H2O, Me2CO;

NaN3

Fragment 3

OO 1. BnOH

tBuOK cat.

2. ClCO2MeEt3N

BnO

OOCO2Me

O

O

Me

HHO

Me

3

1. Dess-Martin

2. (Ph3PCH2I)I, NaHMDSO

O

Me

H

MeI

Chelation-controlled addition of 1 and 2

O

Et

OMe

I

nBuLi

Me2Zn

O

Et

OMe

ZnMe2·Li

2O

EtMeO

OH

N3

OTBSOPMBO

SiMe2Bn

3

APh Me

B(pin) Ar–Li

THF–78 °C Ph Me

B(pin)Ar

LiHet, Troc–Cl

THF, –78 °CN

R

PhHMe

H

R1N

R

PhMeH

H

R1

Boronates.Asymmetric addition of chiral boron-ate complexes to cyclic iminium ions. Aggarwal. Chem. Sci. 2014, 5, 602.

N3

OO

R2

R

ZnMe2·Li

R1

N3

OO

R2

R

ZnMe2·LiR1

H2O N3

OHO

R2

R

R1

OEtMeO

OH

H3NOHOP

O

HOO H

O

O

MeMe

3

A

leustroducsin B

Total synthesis of roseophilin. Fürstner. J. Am. Chem. Soc. 1998, 120 , 2817.

RO Cl

NO Bn

PhO2S

iPrMe2ZnMgCl

tBuOK (excess)N

O Bn

iPr

NO Bn

iPr

- shielding exerted by rigid ansa-chain provides facial guidance in Michael add'n- forces protonation of enolate to occur from the same side- corresponding cuprate proved ineffective

possible pathway to undesired



N N

NEt2

O

N

NEt2

O

N

OMe

O

R1 R2

Bpin

R1 R2

B OO

solvent swap(THF to MeCN)

R1 R2

E

Synthesis of enantioenriched alkylfluorides by the fluorination of boronate complexes. Aggarwal. J. Am. Chem. Soc. 2015, 137 , 10100.

Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis. Aggarwal. J. Am. Chem. Soc. 2011, 133 , 16794.

RArLi E

R1 R2

X

R1 R2

F

R1 R2

NHNRO2C CO2R

R1 R2

OH

R1 R2 R1 R2

Me2N

R1 R2

NN

OMe

JACS. 2015, 137 , 10100. X = Cl, Br, I

Histidine-directed arylation/alkenylation of backbone N–H bonds mediated by copper(II).Ball. J. Am. Chem. Soc. 2016, 138 , 7472.

NH

R1 HN

O

O

NNH

R–B(OH)2Cu(OAc)2

rt, HEPES bufferNR

R1 HN

O

O

NNH

lysozyme with solitary His

copper-bound ATCUN motif, illustrating activation of amide backbone N–H neighboring a His residue

Fast and selective labeling of N-terminal cysteines at neutral pH via thiazolidino boronate formation. Gao. Chem. Sci. 2016, 7, 4589.

HSNH2

O

H O

B(OH)2 B(OH)2

NHS

H

Iminoboronates: A new strategy for reversible protein modification.Gois. J. Am. Chem. Soc. 2012, 134 , 10299.

O

NH2

H O

B(OH)2

N

H

B(OH)2

B(pin)

R

Cy2BH Cy2B

B(pin)R Me2Zn MeZn

B(pin)R R1CHO

B(pin)RR1

OZnMe

B(pin)RR1

OH

ORR1

OH

R2RR1

OH

H [O] R2X, [Pd]

Applications of 1-alkenyl-1,1-heterobimetallics in the stereoselective synthesis of cyclopropylboronate esters, trisubstituted cyclopropanols and 2,3-disubstituted cyclobutanones.Walsh. J. Am. Chem. Soc. 2009, 131 , 6516.

R

Bpin

Cu(OAc)2, Et3N

OH rt

R

O78–90% Bpin

BnO

O

BnO

40%(neat)

Cu(OAc)2, Et3N

OH rt(neat)

Copper-promoted coupling of vinyl boronates and alcohols: A mild synthesis of allyl vinyl ethers.Merlic. J. Am. Chem. Soc. 2010, 132 , 1202.

improper use of nomenclature?



MIDA Boronates. (see M. Farmer, "Boron" GM 2014)

N Boc

Ph

N2

O

NHPh

(HO)2B

HO2C(10 mol%)

diol (12 mol%)CH2Cl2, 4Å ms

Ph NHPh

ONBoc

Ph OH

OHAr ArAr = 2-PhC6H4

In situ assembled boronate ester assisted chiral carboxylic acid catalyzed asymmetric trans-aziridinations. Maruoka. J. Am. Chem. Soc. 2013, 135 , 17667.

Palladium catalyzed asymmetric three-component coupling of boronic esters, indoles, and allylic acetates. Ready. J. Am. Chem. Soc. 2017, 139 , 6038.

NMe

NMe

H

PhBpin

NMe

Ph

NMe

H

PhBpin

PhPh

NMe

Ph

PhPh

tBuLi, 0 °C to rt;PhBpin, –78 °C to rt;((S)-H8-BINAP)PdCl2

(5 mol%)

OAc

H2O2, NaOH

0 °C to rt

tBuLi, 0 °C to rt;PhBpin, –78 °C to rt;((S)-H8-BINAP)PdCl2

(5 mol%)

Ph

OAc

Ph

H2O2, NaOH

0 °C to rt

[initial report] A simple and modular strategy for small molecule synthesis: Iterative Suzuki–Miyaura coupling of B-protected haloboronic acid building blocks. Burke. J. Am. Chem. Soc. 2007, 129 , 6716.- "indefinitely" bench-top stable under air- chromotography compatible - unreactive under standard anhydrous cross-coupling using either mild base- rate of hydrolysis is (mostly) unaffected by substrate; can be controlled by reaction conditions

Total synthesis of synechoxanthin through iterative cross-coupling. Burke. Angew. Chem. Int. Ed. 2011, 50, 7862.

MeMe

MeO

O

I

B

MeB O

O

MeNOOO

OMe Me

MeMe

[PdCl2dppf]·CH2Cl2

K3PO4

MeB O

O

MeNOO

MeMe

MeO

O

MeI

MeMe

MeO

O

NaOMe; I2B

B[Pd]

K3PO4

MeB O

O

MeNOO

MeMeMe

MeO

O

synechoxanthinBu3Sn

MeB O

O

MeN

OO

SnBu3BOO

NMeOO

pinacol, NaHCO3;

NaHCO3, CaCl2

SnBu3BO

OMe Me

MeMe

I

MeB O

O

MeNOO

+

Synthesis of B:

MIDA boronates are hydrolysed fast and slow by two different mechanisms. Cheong, Burke, and Lloyd-Jones. Nat. Chem. 2016, 8, 1067.Two distinct mechanisms.1. Base-mediated: 3 orders of magnitude faster, RLS = attack by hydroxide at MIDA carbonyl C2. Neutral: No exogenous acid or base, RLS = B–N cleavage by a small water cluster, (H2O)n

B

I2

PdCl2(MeCN)2



Total synthesis of auripyrone B using a non-aldol aldol–cuprate opening process. Jung. Org. Lett. 2010, 12 , 2872.

TESO O

Me Me

OTBDPS 1. TESOTf, DIPEA

2. Ph3P=CHCO2Etreflux

Me Me

OTBDPSOTESEtO2C

Me Me

OPGOTESOHO

Me Me

OPGOTESOH OH

MeMe Me

OPGOTESOO

PMP

Me

Me Me

OPGOTESOPMBO

MeH

1. DIBAl, –50 °C2. Ti(iPrO)4, tBuO2H

(+)-DIPT

Me2CuLi

1. DIBAL

2. DMPO

Me

MeO

Me

O

Me

OMe

OMe Me

EtMeMe

O

O

Me

Et

PG = TBDPS

PMP

OMe

OMe

PPTS

CuI

Si(CH3)3CF3 (2.6 equiv.), TMEDA (1 equiv.)K2CO3 (2 equiv.), N2 or air

DMF, 100 or 20 °C"CuCF3"

[Cu(CF3)4]

[Cu(CF3)2]

Practical methods for the synthesis of trifluoromethylated alkynes: Oxidative trifluoromethylation of copper acetylides and alkynes. Blanchard and Evano. Adv. Synth. Cat. 2014, 356, 2051.

Cuprates.

N

NCu I

R H+

base

N

NCu R

N

NCu

R

R

K

R R

O2

N

NCu

CF3

R

K

O2

R CF3

R H

N

NCu CF3

CF3

Copper-mediated aerobic oxidative trifluoromethylation of terminal alkynes with Me3SiCF3.Qing. J. Am. Chem. Soc. 2010, 132 , 7262.The role of ate complexes in the copper-mediated trifluoromethylation of alkynes.Koszinowski. Chem. Eur. J. 2016, 22, 11310.

R H Me3SiCF3+CuI / phen

KF, DMF, airR CF3

Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl)tri-methylsilane as a nucleophilic CF3 source. Qing. Acc. Chem. Res. 2014, 47, 1513.

CF3



Molybdenum or tungsten alkylidyne ates.The triple-bond metathesis of aryldiazonium salts: A prospect for dinitrogen cleavage.Fürstner. Angew. Chem. Int. Ed. 2015, 54, 12814.

M ORROORRO

Ar1

Ar2

N

NBF4

K

KBF4

MRORO

OR

OR

NAr1

N Ar2

MRORO

OR

OR

NAr1N Ar2

MRORO

OR

Ar1

ORN

N Ar2

M ORROORRO

NAr2

Ar1 N

EWG

NRCO

Bu2SnI2–MgBr2(cat.)

DCM, rt

NOR

EWG

+

Tin ates.Catalytic [3+2] cycloaddition through ring cleavage of simple cyclopropanes with isocyanates.Shibata. Org. Lett. 2015, 17 , 4010.

Bu SnBu

IH

IMgBr2

Sn IBu

BuI

Br

BrMg

Aluminum ates.

R2

R1

R3

HR2

R3

HR1

R1

H2

CO2

EtAlCl2

N

R2

R1

R3

CO2HR2

R3

R1

CO2H

R1

CO2H2

EtAlCl2/2,6-disubstituted pyridine-mediated carboxylation of alkenes with carbon dioxide.Tanaka, Hattori. Org. Lett. 2016, 18 , 2576.

Regioselective Fischer indole synthesis mediated by organoaluminum amides. Yamamoto. J. Org. Chem. 1993, 58, 7638.

N N

R1

R3

NEt2Al

N N

R1

R3

R2

AlEt Et

N

R2

HDAMTP

N NH

R1

R3

R2

N

R2

R1

R3

DAMTP

Regio- and chemoselective direct generation of functionalized aromatic aluminum compounds usingaluminum ate base. Uchiyama. J. Am. Chem. Soc. 2004, 126 , 10526.

iBu3Al(TMP)Li

THF, rt

O NiPr2 O NiPr2

Al(iBu)3Li

O NiPr2

O NiPr2

Ph

O

O NiPr2

OHO NiPr2

D

Econds.

(100%)

(100%)

(81%)

(56%)

O NiPr2

Br

O NiPr2

Br

I1. iBu3Al(TMP)Li

THF, –78 °C

2. I2

Pr2Ni OO Ph

Ph

iBu3Al(TMP)LiTHF, rt

1,3-diphenyl-isobenzofuran

(65%)(100%)

Br Br

GM 24June2017 PRESENTATION€¦ · Tet. Lett. 1985, 26, 275. N 1. Et2Mg, EtLi, 18-c-6 2. H2O 3. [O]...

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Transcript of GM 24June2017 PRESENTATION€¦ · Tet. Lett. 1985, 26, 275. N 1. Et2Mg, EtLi, 18-c-6 2. H2O 3. [O]...