ynamides by marie-eve mayer – november 16 th, 2010

YnamidesBy Marie-Eve Mayer – November 16th, 2010

Alkyne directly substituted by an amide or a N atom connected to a EWG group An electron-deficient ynamine

ynamides Ynecarbamates(yne-

urethanes)

ynureas ynesulfonamides

ynimides

What is an ynamide?

Utilities of EWG group :• Stabilization• Directing group• Chiral auxilary

Ynamines vs ynamides

Ynamines : imposing an electronic bias

1st isolated ynamine : Zaugg, in 1958 Ynamines are sensitive to hydrolysis

Difficult storage, handling and synthesis

Ynamides : tempering the polarization by resonance

Enhanced stability towards heat, silica and aqueous workups

Electrophiles add on the βpositionNucleophiles add on the αposition

Richard P. Hsung

Ph. D. in 1994 at the University of Chicago under supervision of William D. Wulff

Post. Doc. in 1996 at the University of Chicago under supervision of Lawrence R. Sita

Professor of Pharmaceutical Sciences and Chemistry at the University of Wisconsin-Madison

Associate professor at the University of Minnesota

150th publication will be out lately Pioneer in ynamides chemistry Visited UdeM in Spring 2005

This evening’s program...

Synthesis of ynamides Elimination of halo-enamides Starting from alkynyl iodonium salts Isomerization of propargyl amides Amidative Cross-Coupling with Cu

Reactivity of ynamides Addition reactions

At the α-position At the β-position (Umpolung) Cycloadditions

Oxidation reaction Ring-closing metathesis

First pathway of synthesis: Elimination

Using a strong base to eliminate HX First ynamide : Viehe et. al. in 1972 using

phosgeneimmonium chloride

Procedure used by Hsung et. al. in 2001

H. G. Viehe et. al., Angew. Chem. Int. Ed. 1972, 11, 917.R.P. Hsung et. al. Tetrahedron 2001, 57, 459-466.

Only the Z-isomer

undergoes elimination

Starting from β,β-dichloro-enamides

D. Brückner, Synlett 2000, 1402 – 1404.D. Rodriguez, M. F. Martnez-Espern, L. Castedo, C. Sa, Synlett 2007, 1963 – 1965.D. Rodriguez, L. Castedo, C. Sa, Synlett 2004, 783 – 786.S. Couty,M. Barbazanges, C. Meyer, J. Cossy, Synlett 2005, 905 –910.

Starting from alkynyl iodonium salts

Increase of publications about ynamides in late 90’s 1st breakthrough: Feldman’s chiral ynamide synthesis (1996)

Based on Stang’s pionner work :

Stang worked with push-pull ynamines Limited method due to the limited library of alkynyl iodonium salts

Only substituted by silyl, aromatic or EWG groups

Feldman, K.S. et. al .J. Org. Chem. 1996, 61, 5440-5452Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255


B. Witulski, T. Stengel, Angew. Chem. Int. Ed. 1998, 37, 489 – 492

Entry PG RYield SM→ A

(%)Yield A→ B

(%)

1 TolSO2 nBu 86 95

2 TolSO2 PhCH2 75 95

3 CF3SO2 PhCH2 65 55

4 CF3CO PhCH2 77 -

5 PhCO PhCH2 81 98

6 TolSO2 CH2CH(CH2)2 89 93

7 TolSO2 CH2CH(CHPh)CH

2

70 78

8 TolSO2 CH2CHCH2CH(Ph

)28 89

9 TolSO2 CH2CHCH2CH(Bu

)50 91

10 TolSO2 (CH2CHCH2)2CH 43 83

Steric hindrance complicates nucleophilic

attack


Ring-opening of aziridines

Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037

Isomerization of propargyl amides

Method restricted to simple amides Base-induced isomerization of acridone

Method not efficient on oxazolidinones or imidazolidinone

This paper shows the synthesis of allenamides and the failure to isomerise them into ynamides.

Hsung et. Al. Tetrahedron, 2001, 57 459-466, Org. Lett. 2002, 4, 2417.

Isomerization of propargyl amides

Base-induced isomerization on propargyl urethanes is still ineffective

Propargyl amides substituted with alkyl linear chains readily isomerize to the ynamide

Hsung et. Al., Org. Lett. 2002, 4, 2417.

First synthesis of ynamides by a metal-mediated reaction Undesired side product by Balsamo and Domiano in 1985

Alkynylation of N nucleophiles using Bromoalkynes Terminal alkynes Vinyl dibromides

Amidative Cross-Coupling with Cu

Balsamo, A. Domiano, P. Tet. Lett. 1985, 26, 4141

Amidative Cross-Coupling with Cu using bromoalkynes

Conditions Hsung (2003) Danheiser (2003) Hsung (2004)

Cu source CuCN (5%) CuI (1 eq) CuSO4⋅5H2O (5-20%)

Ligand (10%) - (10-40%)

Base K3PO4 KHMDS K3PO4

Solvent, T (°C)

Toluene, 110°C Pyridine, rt Toluene, 60-95°C

Examples 23 19 44

Yield (%) 10-85% 40-82% 37-98%

Pros First time using method Room temp Efficient with amides

ConsHigh temp, sulfonamides not

suitableStrong base Quality of K3PO4 is crucial

R. P. Hsung, J. Am. Chem. Soc. 2003, 125, 2368 – 2369. Org. Lett. 2004, 6, 1151 – 1154 , J. Org. Chem. 2006, 71, 4170 – 4177 Org. Synth. 2007, 84, 359. R. L. Danheiser, Org. Lett. 2003, 5, 4011 – 4014; Org. Synth. 2007, 84, 88 – 101.[

Amidative Cross-Coupling with Cu using bromoalkynes

Since we love macrocyclizations in our group... Hsung applied his method to make macrolactones

including enamides

Securine B Securamine B

Hsung, R. P.; J. Org. Chem. 2006, 71,4170

isolated from the marine bryozoan Securiflustra securifrons

Amidative Cross-Coupling with Cuusing bromoalkynes

Other catalysts with a different metal ? Y. Zhang reports use of FeCl3 as efficient catalyst

But Buchwald publishes a paper about contaminants in FeCl3 that might do all the work...

Y. Zhang, J. Org. Chem. 2009, 74, 4630 – 4633.S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586 – 5587

FeCl3 98 % (Merck)

98 % (Aldrich)

99.99 (Aldrich)

99.99 % + 5 ppm Cu2O

99.99 % +10 ppm Cu2O

no Fe + ligand +5 ppm Cu2O

no Fe + no ligand +5 ppm Cu2O

Yield (%)

87 26 9 78 79 77 23

Amidative Cross-Coupling with Cu using terminal alkynes

Stahl (2008) comes up with a catalytic process :

Limitations of the method : Use of 5 eq of the nucleophile

Inhibits Glayser-Hay competitive reaction Low reactivity of some susbstrates (pyrrolidinones,

acyclic amides etc)

= =

Stahl, S. S.; J. Am. Chem. Soc. 2008, 130, 833

Amidative Cross-Coupling with Cuusing terminal alkynes

Proposed mechanism by Stahl

Stahl, S. S.; J. Am. Chem. Soc. 2008, 130, 833

L substitution

Red. Elim.

L substitution

Red. Elim.

A

B

C

D

Excess of the amide favors formation of CuII(alkynyl)(amidate) species C over bis-alkynyl-CuII species D

Amidative Cross-Coupling with Cu using vinyl dibromides

Using vinyl dibromides : synthetic equivalent of bromoalkynes

Proposed mechanism :Isolated at low T°C

Coste, A; Angew. Chem. Int. Ed. 2009, 48, 4381-4385

Ox. Ad.

Red. Elim.Mild base and low T°C discards the hypothesis

Chemistry of ynamides

Addition reactions At the α-position

Brönsted acid-catalyzed Transition metal catalyzed Radical processes

At the β-position (Umpolung) Cycloadditions

[2+2] [4+2] [2+2+2] Cyclotrimerization

Oxidation reaction Ring-closing metathesis

αβ

Additions : to the α-position Brönsted Acid catalyzed addition

Hsung synthesis of (E)-α-haloenamides MgX2 and DCM forms HX in situ


No yield with CuI,

ZnCl2, NaBr

Arene-Ynamide cyclization via a Keteniminium Pictet-Spengler Cyclization



Z

Z

Arene-Ynamide cyclization via a Keteniminium Pictet-Spengler CyclizationE:Z selectivity is inversed with PtCl4 (π-acid) is used instead



With Bronsted acid : With π-acid :


Asymmetric Ficini-Claisen rearrangement

Approach of the allylic alcohol from the same side of the hetero-cumulene H gives a E-ketene aminal


Entry R R1 Yield (%) Syn : Isomers

1 n-C5H11 Me 70% 93 : 7

2 n-C4H9 Ph 77% 96 : 4

3 n-C4H9 CH2OBn 63% 95 : 5


Asymmetric Saucy-Marbet rearrangement Stereochemistry of the allene is transmitted from

the chiral propargyl alcohol


Forced mismatched reaction give

dr : 1:1

Additions : to the α-position Transition metal catalyzed addition

Starting point: desired [2+2+2] product not obtained with change of silver salt

Pro-M

Pro-P

Yield : 94% M : P = 4 : 1


Bidentate coordination of ynamide to the rhodio(I) intermediate : Accepted pathway for [2+2+2]

cycloaddition

Demethylation-cyclization sequence using Wilkinson catalyst

Ag salts increases coordinating ability of Rh catalyst by stripping of Cl-

Nu : H2O Sodium tetrafluoroborate works synergistically with Wilkinson

Cat to promote demethylation




Demethylation vs cycloaddition


Aminoindoles synthesis o-aminoaryl-ynamide intermediates obtained by

amination of the o-halo corresponding derivative or by Sonogashira coupling

Hsung et. Al., Org. Lett. 2008, 10, 4275.Skrydstrup, T. et. Al. Org Lett. 2009, 11, 221.

Metal-mediated hydroamination

Additions : to the α-position Radical addition

Radical cascade : 5-exo-dig cyclization followed by a 6-endo-trig radical trapping

Malacria, M. Org. Lett. 2003, 5, 5095.

Terminal alkynes seems compatible only with o-iodo

substituted arylsActivated alkynes make

possible the addition of tin on C≡C : Yield ↓


Radical cascade : 5-exo-dig cyclization followed by a 6-endo-trig radical trapping



Radical cascade with ynamides bearing an aromatic terminator Type I

Type 2


Carbonyl plays an electronic

and steric effect in the radical

trapping

Additions : to the β-position

Can be considered as Umpolung addition

Controlled either by Steric hindrance Chelation with the EWG group

β α

Additions : to the β-position Electrophilic trapping of α-metalated derivatives

Regiochemically controlled carbometallation

Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098.

E R Yield (%)

Method A Method B

H n-Bu 72 81

H Ph 84 90

allyl n-Bu 55 N.D.

I n-Bu 60 N.D.

Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.

Single-pot preparation of an aldol surrogate Retrosynthesis :



One-pot carbocupration/Zn-homologation/allylation sequence In situ generation of Simmons-Smith-Furukawa zinc

carbenoid

Transmetallation of Cu to Zn using ZnBr2 prevents the direct addition to the aldehyde



One-pot carbocupration/Zn-homologation/allylation sequence In situ generation of Simmons-Smith-Furukawa zinc

carbenoidZimmerman-Traxler T.S.

With R3 in pseudo-equatorial position can rationalize the absolute

stereochemistry


Sulfonamides intramolecular addition via a 6-endo-dig mechanism

The sulfonylamino group next to the acetylene moiety promotes endo-type closure

Additions : to the β-position Intramolecular addition

Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820.

Addition6-endo-dig

αAddition5-exo-dig

Ti cyclopropene complex leading to β–hydroxy-enamines

Additions : to the β-position ynamide-titanium complexes

Entry R1 R2CHO Yield (%)

1 SiMe3 PhCHO Quant

2 C6H13 93

3 SiMe3 C8H17CHO 91

4 C6H13 Quant

5 SiMe3 i-PrCHO 94

6 C6H13 71

7 SiMe3 87

8 C6H13 54

H. Urabe et al. Org Lett 2003, 5, 67-70.

Additions : to the β-position ynamide-titanium complexes

Acetylene-titanium complexes leading to dienamides

S. Hirano et al. Tetrahedron 2006, 62 3896–3916

Additions : to the β-positionβ-hydroxy enamines by catalytic process

Oppolzer’s synthesis of asymmetric secondary E-allyl alcohol from acetylenes based on Srebnik’s work

Applied on ynamides : (not an Umpolung process)

Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. Srebnik, M. Tetrahedron Lett. 1991, 32, 2449 Walsh, P. J. Et. Al. J. Am. Chem. Soc. 2010, 132, 14179.

Alkenyl boranes undergo reversible transmetalation with dialkylzinc reagents to generate vinylzinc

intermediates

δ+

δ-

Asymmetric synthesis of (E)-trisubstituted β–hydroxy enamines

Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. Srebnik, M. Tetrahedron Lett. 1991, 32, 2449 Walsh, P. J. Et. Al. J. Am. Chem. Soc. 2010, 132, 14179.

(-)-MIB

Addition does not strongly depend on the nature of the

Ar group

Hindered amides: ↓ yield

Aldehydes that lack α-branching :

↓ ee

Additions : to the β-positionβ-hydroxy enamines by catalytic process

Danheiser,R. L. et al. Tetrahedron 2006, 62, 3815.

[2+2] Cycloadditions

Synthesis of 3-aminocyclobutenones derivatives

Intramolecular [2+2] cycloaddition

LA catalyzed intramolecular hetero [2+2] cycloaddition/ring-opening sequence

Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.

N-acyl imidinium intermediate


•Ag salts gives Rh(I) species•Thermolysis gives mixture of tetrahydroindole and rearomatised product

Entry R EWG AgSBF6 T (°C) Y (%)

1 SiMe3 Ts None 20 to 100 0

2 SiMe3 Ts 5mol% 20 89

3 H CF3CO 5mol% 20 83

4 SiMe3 Ts 5mol% 20 86

5 Ph Ts 5mol% 20 70

6 n-Bu Ts 5mol% 20 79

Witulski, B.; Lumtscher, J.; Berstraber, U. Synlett 2003, 708Hsung, R. P.; J. Org. Chem. 2006, 71,4170

1st example : Witulski et. al. (2003)

Hsung applies protocol to intermolecular reactions (2006)

Conjugated enynes with ynamides (C4 = H)

Utility of BHT : Suppress polymerization of enyne Eases isomerization

Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776.


Conjugated enynamides with alkynes (C1 = H)

Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776.


[2+2+2] Cycloaddition

Rh(I) catalyzed cyclotrimerization

With acetylene

Entry R1 R2 Yield (%)

1 H Ph 85

2 H TMS 68

3 Ph TMs 93

4 CH2OTHP TMS 95

5 CO2Me TMS 92

N-(3-butynyl)-1-alkynylamide

Entry R1 Yield (%)

1 H 91

2 (CH2)2OH 70

3 (CH2)2OBzI 55

4 CH2OTHP 57

5 NHTs 65

6 Ph 65

7 CO2Me 43

44

7

[2+2+2] Cycloaddition

Rh(I) catalyzed cyclotrimerization

With substituted alkynes

N-(3-butynyl)-1-alkynylamide

n R Yield (%)

rr

1 H 60 1.3:1

2 H 85 1.0:1

3 H 63 1.0:1

2 Ph 68 10:1

2 TMS 60 2.7:162%

Witulski, B. & Stengel, T. Angew. Chem. Int. Ed. 1999, 38, 2426

The elimination of the sulfonamide group is the driving force

Cyclotrimerization of nitriles leading to pyridines

R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780

dialkoxytitanacyclopentadienes

Using α-methoxyacetonitrile with bulky amino-protecting group favors elimination of the sulfonyl group

Cyclotrimerization of nitriles leading to aminopyridines

B

A


Elimination of the sulfonyl group

Cyclotrimerization of nitriles leading to aminopyridines

Ti-C and N-Si bond are perpendicular to place bulky amino group in less hindered

position : favorable for elimination of SO2Ar

ArSO2 Yield (%) of B

A : B

TolSO2 51% 35:65

MesSO2 62% 16:84


A

B

Oxidation: Chemoselective epoxydation of Ene-ynamides

Hetero-substituted triple bond enhances nucleophilicity towards the oxidizing reagent

α-aza- α-oxocarbene

Method not suitable with terminal-substituted alkynes

No diastereoisomeric inductionCouty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819.

RCM : Cyclic amido-dienes synthesis

1st synthesis : Ene-ynamide RCM using Grubbs II (2002) Pyrrolidine derivatives

Hsung uses same RCM conditions the same year

Piperidine derivatives

N. Saito, Y. Sato,M. Mori, Org. Lett. 2002, 4, 803 – 805J. Huang, H. Xiong, R. P. Hsung, C. Rameshkumar, J. A. Mulder, T. P. Grebe, Org. Lett. 2002, 4, 2417 – 2420.

RCM products are good Diels-Alder dienes

Conclusion

Ynamides are storable, stable upon aqueous work-ups, silica gel, heating

Take home message :

Reviewing all ynamide chemistry within an 1-2h talk is a hard task! Left behind reactions:

Pt and Au cycloisomerizations Different types of formal ‘’stepwise’’ cycloadditions

Recent reviews : Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840-

2859 DeKorver, K.A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung,

R. P. Chem. Rev. 2010, 110, 5064-5106

Electrophiles add on the βpositionNucleophiles add on the αposition

ynamides by marie-eve mayer – november 16 th, 2010

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