Ynamides
By Marie-Eve Mayer – November 16th, 2010
What is an ynamide?

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
Utilities of EWG group :
• Stabilization
• Directing group
• Chiral auxilary
ynimides
Ynamines vs ynamides

Ynamines : imposing an electronic bias
Electrophiles add on the position
Nucleophiles add on the  position



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
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 WisconsinMadison

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  -position
At the -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
Only the Z-isomer
undergoes
elimination
H. G. Viehe et. al., Angew. Chem. Int. Ed. 1972, 11, 917.
R.P. Hsung et. al. Tetrahedron 2001, 57, 459-466.
Starting from ,-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, 5440-5452
Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255
Starting from alkynyl iodonium
salts
Entry
Steric hindrance complicates
nucleophilic attack
PG
R
Yield 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)CH2
70
78
8
TolSO2
CH2CHCH2CH(Ph)
28
89
9
TolSO2
CH2CHCH2CH(Bu)
50
91
10
TolSO2
(CH2CHCH2)2CH
43
83
B. Witulski, T. Stengel, Angew. Chem. Int. Ed. 1998, 37, 489 – 492
Starting from alkynyl iodonium
salts

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.
Amidative Cross-Coupling with Cu
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
Balsamo, A. Domiano, P. Tet. Lett. 1985, 26, 4141
Amidative Cross-Coupling with Cu
using bromoalkynes
Conditions
Cu source
Hsung (2003)
Danheiser (2003)
Hsung (2004)
CuCN (5%)
CuI (1 eq)
CuSO45H2O (5-20%)
Ligand
Base
(10%)
-
(10-40%)
K3PO4
KHMDS
K3PO4
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
Cons
High temp, sulfonamides not suitable
Strong base
Quality of K3PO4 is crucial
Solvent, T (°C)
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
isolated from the marine bryozoan Securiflustra securifrons
Hsung, R. P.; J. Org. Chem. 2006, 71,4170
Amidative Cross-Coupling with Cu
using 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...
FeCl3
Yield (%)
98 %
(Merck)
87
98 %
(Aldrich)
99.99
(Aldrich)
26
9
99.99 %
99.99 %
no Fe + ligand no Fe + no
+ 5 ppm Cu2O +10 ppm Cu2O +5 ppm Cu2O ligand +5 ppm
Cu2O
78
Y. Zhang, J. Org. Chem. 2009, 74, 4630 – 4633.
S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586 – 5587
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 Cu
using terminal alkynes

Proposed mechanism by Stahl
B
Red. Elim.
L substitution
L substitution
A
D
Red. Elim.
C
Excess of the amide favors formation of CuII(alkynyl)(amidate) species C
over
bis-alkynyl-CuII species D
Stahl, S. S.; J. Am. Chem. Soc. 2008, 130, 833
Amidative Cross-Coupling with Cu
using vinyl dibromides

Using vinyl dibromides : synthetic equivalent of
bromoalkynes

Proposed mechanism :
Isolated at low T°C
Ox. Ad.
Red. Elim.
Coste, A; Angew. Chem. Int. Ed. 2009, 48, 4381-4385
Mild base and low T°C
discards
the
hypothesis
Chemistry of ynamides

Addition reactions

At the  -position





At the -position (Umpolung)
Cycloadditions






Brönsted acid-catalyzed
Transition metal catalyzed
Radical processes
[2+2]
[4+2]
[2+2+2]
Cyclotrimerization
Oxidation reaction
Ring-closing metathesis


Additions : to the  -position
Brönsted Acid catalyzed addition

Hsung synthesis of (E)- -haloenamides
 MgX2
and DCM forms HX in situ
No yield with
CuI, ZnCl2,
NaBr
Hsung et. Al., Org. Lett. 2003, 5, 1547.
Additions : to the  -position
Brönsted Acid catalyzed addition

Arene-Ynamide cyclization via a Keteniminium
Pictet-Spengler Cyclization
Z
Z
Hsung et. Al., Org. Lett. 2005, 7, 1047.
Additions : to the  -position
Brönsted Acid catalyzed addition


Arene-Ynamide cyclization via a Keteniminium
Pictet-Spengler Cyclization
E:Z selectivity is inversed with PtCl4 (π-acid) is used instead
With Bronsted acid :
Hsung et. Al., Org. Lett. 2005, 7, 1047.
With π-acid :
Additions : to the  -position
Brönsted Acid catalyzed addition

Asymmetric Ficini-Claisen rearrangement

Approach of the allylic alcohol from the same side of the
hetero-cumulene H gives a E-ketene aminal
Hsung et. Al., Org. Lett. 2002, 4, 1383.
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
Additions : to the  -position
Brönsted Acid catalyzed addition

Asymmetric Saucy-Marbet rearrangement

Stereochemistry of the allene is transmitted from the
chiral propargyl alcohol
Forced
mismatched
reaction give
dr : 1:1
Hsung et. Al., Org. Lett. 2003, 5, 2663.
Additions : to the  -position
Transition metal catalyzed addition

Starting point: desired [2+2+2] product not obtained
with change of silver salt
Pro-M
Yield : 94% M : P = 4 : 1
Pro-P
Bidentate coordination of ynamide to the rhodio(I) intermediate
: Accepted pathway for [2+2+2] cycloaddition
Hsung et. Al., Org. Lett. 2007, 9, 2361.
Additions : to the  -position
Transition metal catalyzed addition

Demethylation-cyclization sequence using Wilkinson
catalyst



Ag salts increases coordinating ability of Rh catalyst by stripping
of ClNu : H2O
Sodium tetrafluoroborate works synergistically with Wilkinson Cat
to promote demethylation
Hsung et. Al., Org. Lett. 2007, 9, 2361.
Additions : to the  -position
Transition metal catalyzed addition

Demethylation vs cycloaddition
Additions : to the  -position
Transition metal catalyzed addition

Aminoindoles synthesis

o-aminoaryl-ynamide intermediates obtained by amination
of the o-halo corresponding derivative or by Sonogashira
coupling
Metal-mediated hydroamination
Hsung et. Al., Org. Lett. 2008, 10, 4275.
Skrydstrup, T. et. Al. Org Lett. 2009, 11, 221.
Additions : to the  -position
Radical addition

Radical cascade : 5-exo-dig cyclization followed by a 6endo-trig radical trapping
Terminal alkynes seems
compatible only with o-iodo
substituted aryls
Activated alkynes make possible
the addition of tin on CC : Yield

Malacria, M. Org. Lett. 2003, 5, 5095.
Additions : to the  -position
Radical addition

Radical cascade : 5-exo-dig cyclization followed by a 6endo-trig radical trapping
Malacria, M. Org. Lett. 2003, 5, 5095.
Additions : to the  -position
Radical addition

Radical cascade with ynamides bearing an aromatic
terminator

Type I

Type 2
Carbonyl plays an
electronic and
steric effect in the
radical trapping
Malacria, M. Org. Lett. 2003, 5, 5095.
Additions : to the -position

Can be considered as Umpolung addition


Controlled either by
 Steric
hindrance
 Chelation with the EWG group

Additions : to the -position
Electrophilic trapping of  -metalated derivatives

Regiochemically controlled carbometallation
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.
Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098.
Additions : to the -position
Electrophilic trapping of  -metalated derivatives

Single-pot preparation of an aldol surrogate

Retrosynthesis :
Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.
Additions : to the -position
Electrophilic trapping of  -metalated derivatives

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
Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.
Additions : to the -position
Electrophilic trapping of  -metalated derivatives

One-pot carbocupration/Zn-homologation/allylation
sequence

In situ generation of Simmons-Smith-Furukawa zinc
carbenoid
Zimmerman-Traxler T.S.
With R3 in pseudoequatorial position can
rationalize the absolute
stereochemistry
Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.
Additions : to the -position
Intramolecular addition

Sulfonamides intramolecular addition via a 6-endo-dig
mechanism
Addition
6-endo-dig
 Addition
5-exo-dig

The sulfonylamino group next to the acetylene moiety
promotes endo-type closure
Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130,
Additions : to the -position
ynamide-titanium complexes

Ti cyclopropene complex leading to –hydroxyenamines
H. Urabe et al. Org Lett 2003, 5, 67-70.
Entry
R1
R2CHO
1
SiMe3
2
C6H13
3
SiMe3
4
C6H13
5
SiMe3
6
C6H13
71
7
SiMe3
87
8
C6H13
54
PhCHO
Yield (%)
Quant
93
C8H17CHO
91
Quant
i-PrCHO
94
Additions : to the -position
ynamide-titanium complexes

Acetylene-titanium complexes leading to dienamides
S. Hirano et al. Tetrahedron 2006, 62 3896–3916
Additions : to the -position
-hydroxy enamines by catalytic process

Oppolzer’s synthesis of asymmetric secondary E-allyl
alcohol from acetylenes based on Srebnik’s work
Alkenyl boranes undergo reversible
transmetalation with dialkylzinc reagents
to generate vinylzinc intermediates

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,
Additions : to the -position
-hydroxy enamines by catalytic process

Asymmetric synthesis of (E)-trisubstituted –hydroxy
enamines
(-)-MIB

Addition does not strongly
depend on the nature of the Ar
group
Hindered amides:
 yield
Aldehydes that lack
 -branching :
 ee
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,
[2+2] Cycloadditions

Synthesis of 3-aminocyclobutenones derivatives
Danheiser,R. L. et al. Tetrahedron 2006, 62,
Intramolecular [2+2] cycloaddition

LA catalyzed intramolecular hetero [2+2]
cycloaddition/ring-opening sequence
N-acyl imidinium intermediate
Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.
Intramolecular [4+2] cycloaddition

1st example : Witulski et. al. (2003)
•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
Hsung applies protocol to intermolecular reactions
(2006)
Witulski, B.; Lumtscher, J.; Berstraber, U. Synlett 2003, 708
Hsung, R. P.; J. Org. Chem. 2006, 71,4170
Intramolecular [4+2] cycloaddition

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.
Intramolecular [4+2] cycloaddition

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
N-(3-butynyl)-1-alkynylamide

With acetylene
Entry
R1
Yield (%)
1
H
91
2
(CH2)2OH
Entry
R1
R2
Yield
(%)
70
1
H
Ph
85
3
(CH2)2OBzI 55
2
H
TMS
68
4
CH2OTHP
57
3
Ph
TMs
93
5
NHTs
65
4
CH2OTHP TMS
95
6
Ph
65
5
CO2Me
92
7
CO2Me
43
4
TMS
4
7
[2+2+2] Cycloaddition

Rh(I) catalyzed cyclotrimerization
N-(3-butynyl)-1-alkynylamide

With substituted alkynes
Witulski, B. & Stengel, T. Angew. Chem. Int. Ed. 1999, 38, 2426
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
2.7:1
62%
Cyclotrimerization of nitriles leading
to pyridines

The elimination of the sulfonamide group is the driving
force
dialkoxytitanacyclopentadienes
R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780
Cyclotrimerization of nitriles leading
to aminopyridines

Using  -methoxyacetonitrile with bulky aminoprotecting group favors elimination of the sulfonyl group
A
B
R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780
Cyclotrimerization of nitriles leading
to aminopyridines

Elimination of the sulfonyl group
A
ArSO2
Yield (%) of B
A:B
TolSO2
51%
35:65
MesSO2
62%
16:84
B
Ti-C and N-Si bond are
perpendicular to place bulky amino
group in less hindered position :
favorable for elimination of SO2Ar
R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780
Oxidation: Chemoselective
epoxydation of Ene-ynamides

Hetero-substituted triple bond enhances nucleophilicity
towards the oxidizing reagent
 -aza-  -oxocarbene
Method not suitable with terminal-substituted alkynes
Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819.
No diastereoisomeric
induction
RCM : Cyclic amido-dienes synthesis

1st synthesis : Ene-ynamide RCM using Grubbs II
(2002)
 Piperidine derivatives


Pyrrolidine derivatives
Hsung uses same RCM conditions the same year
RCM products are good Diels-Alder dienes
N. Saito, Y. Sato,M. Mori, Org. Lett. 2002, 4, 803 – 805
J. Huang, H. Xiong, R. P. Hsung, C. Rameshkumar, J. A. Mulder, T. P. Grebe, Org. Lett. 2002, 4, 2417 – 2420.
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!


Electrophiles add on the position
Nucleophiles add on the  position
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