Ynamines in Synthesis
IBS
Baran Seminar
January 23, 2008
I.B. Seiple
Ynamines in Synthesis
General Outline
I
II
III
IV
V
Baran Group Meeting
1/23/2008
- More reactive than their counterparts the ynol ethers due to lack of electronegative O atom
- Usually colorless liquids (sometime solids) that are usually moisture sensitive
- Very reactive species in general, but usually thermally stable
- Ynamides retain stability but reactivity is attenuated
- Reactivity as a function of N substitution: alkyl > morpholino > aryl/alkyl > bisaryl > (CF3)2
- Reactivity as a function of C substitution: H > alkyl > aryl > Si > COOR
- Ynamines - A Brief History
- General Reactivity
- Preparation of Ynamines
- Ynamine Methodologies
- Ynamines in Total Synthesis
III - Preparation of Ynamines
Three methods to prepare ynamines: A) Elimination B) Substitution C) Isomerization
Also, ynamides are sometimes more easily prepared (D)
I - Ynamines - A Brief History
A - Ynamines by Elimination
-First report of an Ynamine in 1892 by J. Bode (Liebigs Ann. Chem. 267, 268)
-Other reports in 1943 and 1951
-In 1958, all previous reports had been proven false, and Zaugg et. al reported an
accidental synthesis of an ynamine (JOC 23 1389):
S
Cl
Cl
NMe2
-In 1960, Wolf and Kowtz cast doubt on Zaugg's report, and claimed the first ynamine for
themselves (Liebigs Ann. Chem. 638 33):
Li
+
Cl
NEt2
Ph
R1
R1
X
COCl2
R
NEt2
54%
R
Cl
R
NR12
NR*2
LiNR22
Cl
NR12
+
NR*2
Ph
- From carbazoles and trichloroethylenes (Chrzaszcz, B.S.C. Belg. 104, 117):
X
NR*2
X
X
Cl
Mg, THF
TEBACl, NaOH
HN
N
Cl
Cl
N
55 - 87%
Cl
Cl
77%
R1
If R = H
R2N
N
NEt2
O
II - General Reactivity
R2N
N
- From amide chlorides (Viehe, ACIE 5, 584):
NEt2
1.7%
-However, in 1965 Dumont reproduced Zaugg's work and proved the 1958 ynamine
-First general method of synthesis by Viehe in 1963 (ACIE 2, 477)
-Since this date, ynamines have been extensively studied and reviewed:
- Viehe - ACIEE 6, 767
- Viehe - Chemistry of Acetylenes, Marcel Dekker: NY, 1969; Ch. 12, pp 861-912
- Ficini - T 32, 448
- Pitacco - The Chemistry of Funcitonal Groups John Wiley & Sons: NY, Ch 15, pp
623-713
- Collard-Motte - Top. Curr. Chem. 130, p 89
- Himbert - Methoden Der Organischen Chemie (Houben-Weyl)Georg Thieme:
Stuttgart, pp. 3267
- Hsung - T 57, 7575
Cl
Cl
Cl
Me
N
NEt2
X=
SnR3
2eq BuLi
Bu3SnCl
Cl
Cl
Ph
Ph
Cl
N
Br
n-BuLi
NEt2
Ph
S
NaH, HCONMe2
N
H
- From chloroenamines (Neuenschwander, Helv. Chim Acta 82, 326):
X
X
N
X
(same method also works to make N-ethynylpyrrole)
- "push-pull" enamines from vinyligous amides (Dell, J.C.S. Perkin Trans. 1, 3055)
R1
R2N
Nu:
A
B
R1
E+
A+B-
B-
R2N
R1
A+
R2N
A
R2N
O
Br2, Et3N
Br
R2N
O
15 - 69%
DCM
B
R1
R1
O
t-BuOK, THF
R2N
R1
1
I.B. Seiple
- "push-pull" ynamines from trichloroenamines and acid chlorides (pp. 1 Neueschwander ref.):
Cl
O
BuLi, Et2O; R1(O)Cl
From tertiary amines and haloalkynes (Viehe, ACIEE 3, 582)
NR3
Ph
NR2
NR2
Cl
X
X = Cl or Br
R1
Principle:
- From esters and lithioaminals (Katritzky, JOC 62, 4142):
Li
OMe
;
N
N
N
NNHTs
N N
N
R
N
A
X
NaOMe, MeCN
or NaOH/THF
> 90%
X
LiNR2
usually > 60%
70 - 96%
NR2
N
NBS or Br2, heat X
67 - 85%
KOtBu
N
R
R1
N
O
X
N
40 - 88%
R1 Br
X = O, NMe, CH2
R = Ph or pentyl
R1= iPr or Ph
R
R1
~ 8:1 E/Z
Tosylynamides from 2º tosylamines (Brückner, Synlett 2000, 1402)
LiNR2
1) R2NH, Et2O, -70 to reflux
2) 2 eq BuLi, -70 to -10 ºC
NR2
R1
O
R
N N
Li
NR2
A
NR2
X
NR2
HNR2 =
3) TMSCl, -10 to rt
Cl
base
R1
60 - 90%
O
R
R
TMS
NH
N
H
Ts
X = OR, H
R
N
Ts
R
PPh3, CCl4, THF
85 - 99%
N
Ts
BuLi
R
N
Cl
Cl
OMe
NH
Alkynyl isocyanates from alkynylacids
1) (COCl)2
R
COOH
NCO
Acetyl bromides and amides (Hsung, JOC 71, 4170; Danheiser OL 5, 4011)
R
CuX, base
H
Ph
EWG
NH
R
Ph
R
2) NaN3, heat
N
R
R1
R1
Br
rt to 75 ºC
Finally, from terminal alkynes and "amides" (Stahl, JACS 130, 833)
+
X
formylation
O
A = vinyl, phenyl, EWG; X = Cl, sometimes even OMe
- A can be alkyl (even tBu), but heat and very polar solvents required
Most recently, X can be –(–I–Ph)+ –OTf, Prepared from stannyl alkynes and Stang's
reagent, >15 examples (Stang, JACS 115, 2590)
-these alkynes are so reactive that often a lithium amide is not necessary, just base.
Chiral TMS ynamines from dichloroacetylene (Pericas, JOC 65, 7291)
Cl
NR2
R1
From chiral enamides (Hsung OL 1, 1237)
-78 to rt
42%
N
Nucleophilic substitution on haloalkynes by metal amides
-More facile on fluoroalkynes than chloroalkynes (different mechanisms)
F
NR2
D - Special Syntheses of Ynamides
B - Ynamines by Substitution
H
Ph
- RX
Al2O3, KNH2, 50 - 80 ºC
R1
6 eq. BuLi
- From benzotriazoloketones (Katritzky, OL 2, 3789):
a) Tf2O, 2,6-Lut
R
> 88%
R
O
X–
NR2
NR2
TsNHNH2,
TsOH, PhH
N
NR3
When R = aryl, this can be done with KOH in DMSO
For R = alkyl:
N
N
X
R1
N
O
Ph
40h, 55 ºC
C - Ynamines by Isomerization
Cl
R
Baran Group Meeting
1/23/2008
Ynamines in Synthesis
R1
H
N
20% CuCl2, 2eq py.
R2
2eq Na2CO3, 1atm O2
toluene, 70 ºC
N
EWG
R2
R
N
R1
2
Ts
I.B. Seiple
Baran Group Meeting
1/23/2008
Ynamines in Synthesis
IV - Ynamine Methodologies
- Ynamines react with acidic CH's (see Ficini Review):
A - Addition Reactions
B - "Cycloadditions"
1. - [2 + 1]
2. - [2 + 2]
3. - [4 + 2]
4. - [3 + n]
C - Functioalizations
Et2N
Et2N
Me
Me
O
O
O
R
O
H3O+, heat
R
Et
R
O
O
A - Addition Reactions
-Electron-rich ynamines react readily with water:
R1
R2N
CO2Me
O
H2O
R1
R2N
Et2N
CO2Me
Me
Et
-This has been taken advantage of in anhydride synthesis and peptide coupling:
O
Et2N
R
O
Ph
96+%
OH
R
NEt2
O
O
Et2N
R
R = alk or Ar
O
O
NH2
+
R
O
O
R2
R2N
H
N
R1
R1
R
O
R2N
LA
- Reaction with anhydrides:
Me
Alk
OH
PNBSA (0.2 eq)
70-80 ºC
>80% de
Ph
Ph
O
R1
N
X
X
Ph
X
Alk
Ph
PNBSA (0.1 eq)
80-85 ºC
modest yields and de's
N
Ph Alk
R1
O
CF3
CF3
H
O
O
O3, DCM, -50 ºC
R
42 - 93%
PhMeN
O
R
PhMeN
O
- Katrinsky created a homologation sequence for acid chlorides (OL 2, 3789):
O
R
Ph
O
2. Electrophile
NPh2
72 - 92%
- Himbert's push-pull ynamines can be ozonized to give 1,2,3-triones (Synthesis 1998, 1718):
N
Ph Alk
O
- Reginato studied ynamine umpolung chemistry (TL 34, 3311):
1. TMS2CuCNLi2
THF/HMPA, -23 ºC
TMS
E
O
OH
N
Et2N
TFAA
Me
Ph2N
O
Ph
- and with propargylic alcohols (T 62, 3928)
O
Et2N
O
O
- Hsung applied this stereoselectively with ynamides (OL 4, 1383):
X
O
R2N
OH
O
O
Et2N
-Ynamines react with allylic and propargylic alcohols to give 4-alkenyl amides:
R1
H2O
O
OH
Very careful reagent control needed to achieve high yields. See reviews for details.
R1
Me
R
Cl
N
N N
1. TsOH
2. -OH, TBAF
45 - 98%
OH
R
O
3
I.B. Seiple
Baran Group Meeting
1/23/2008
Ynamines in Synthesis
- Ynamines can be used to "enaminate" indoles at C3 (Y. Zhang, T 62, 3917)
R2N
+
R2N
10% Tf2NH
DCM, -35 ºC
Alk
N
H
2. [2 + 2] Cycloadditions
Alk
- Enamines react with CO2 to give highly reactive ketene-amides (Ficini review)
O
Z
NR2
H
R1
74 - 90%
N
H
- Internal capture can yield nitrogen heterocycles (Ficini Review)
NH2
R2N
Alk
N
R1
R2N
O
O
CO2
R1
R2N
NR2
R1
NR2
O
R1 O
R2N
R1
R2N
O
O
CO2R
R1
Alk
R1
OH
R2N
- Reaction with phosgene or thiophosgene yields a useful synthon (Ficini Review):
O
Cl
X
Cl
R2N
X
R2N
NR2
- Similarly, reaction with ketones and LA give vinylamides (or imides, for ynamides):
Cl
Cl
R1
O
Nu:
O
R1
R1
O
pyridines
oxazoles
etc.
O
R1
NR2
O
NR2
B - "Cycloadditions"
1. [2 + 1] Cycloadditions
X
- Ynamines can react with Rhodium carbenoids to cyclopropenate (Pirrung, TL 35, 6229)
O
N2
alkynyl pyrrole
N
Rh(OAc)2
O
X
O
O
O
N
40%
O
O
- Ynamides react with DMDO to make reactive oxirenes (Hsung, OL ASAP, DOI: ol703083k)
X
- This effectively accomplishes a 2-carbon homologation/functionalization of ketones
Hsung recently applied this intramolecularly to ynamides and called it "yne-carbonyl
metathesis" (OL 8, 231)
O
O
BF3OEt2 (cat)
DCM, rt
N
n
Ph
O
O
O
33-88%
ketones, heterocycles,
maleimides tolerated
N
n
Ph
- Reactions with aryl isocyanates yield quinolones (Ficini Review, 1468)
O
R2N
NCO
NR2
R1
R1
R1
+
N
H
NR2
favored in polar solvent
N
H
O
favored in non-polar solvent
4
I.B. Seiple
Baran Group Meeting
1/23/2008
Ynamines in Synthesis
- Reactions with cyclohexenones achieve stereoselectivity with an equatorial methyl!
O
O
H
NEt2
DEAP
Me
Me
O
Ts N
Ts N
O
O
O
H
Me
neutral or basic workup
acidic workup
- A tribute to MRL's demolished shin: Gold cycloisomerizations (Cossy, ACIEE 45, 6726)
MeO2C
AuCl, DCM
TsN
O
cat BF3•OEt2
-78 to rt
> 20:1 E:Z
58 - 91%
O
LiOH
N
HO
90%
Me
R
Me
3. [4 + 2] Cycloadditions
- Much better than vinyl ketenes for making pyranes from MVK (Ficini Review)
O
NEt2
Me
NEt2
Me
O
NEt2
TsHN
Me
Me
O
- Complex bicyclic enamines are accessed easily (TL 1976 1025)
> 95:5 dr!!
AuCl, DCM
Ph
O
H
O
65%
among other examples MeO2C
OH
Me
OH
H
Me
TsN
N
O
+
NEt2
>10 examples
R
O
1. DEAP
2. workup
Ts N
O
80 - 100% trans
- When reacted with cyclopentenone, selectivity of the R1 group is achieved:
O
O
H
57%
89%
70% H
Bn
Bn
Bn
- Finally, two-carbon oxidative homologation of aldehydes (Hsung, OL 1, 1237)
Me
H
O
Ts
N
CO2Me
CO2Me
DEAP
CO2Me
80 ºC
NEt2
CHO
NEt2
- ethylene
61%
among other examples
Me
Me
H3O+; NaBH4
- Ring expansions of cyclic imines (Viehe, ACIE 5, 585):
- and pyridines:
Ph
BF3•OEt2
Ph
N
NEt2
N
O
NEt2
N
N
N
O
N
R
NEt2
Ph
- Pauson-Khand chemistry can be used on ynamides (Witulski ACIE 37, 489)
Ts
(OC)4Co Co(CO)4 alkene, TMANO
Co2(CO)8
rt to 40 ºC
Ts
N
Bn
Ts N -stable under CO >95:5 dr
Bn
atm, chromatograhable
NEt2
DEAP
35 ºC
Bn
H
Me
HO
R
Me
- Nitro groups react readily with ynamines to give oxazoloisoxazoles (Nesi, T 55 13809)
O
Ph
Ph
N
NO2
O
N
CO2Me
R
N
DEAP
52 - 63%
R = H or Ester
O
R
N
O
Me CONEt2
5
R
I.B. Seiple
Ynamines in Synthesis
- Boger studied DA's with tetrazines approaching Ningalin D and Purpurone(JOC 68, 3593)
O
Ar
N
N
DEAP
N
N
rt
100%
O
O
Ar
Ar
NEt2
N
N
- Ynamines can make kinetic anions:
NEt2
Zn, HOAc
N
Me
O
Ar
R2N
X
- "push-pull" ynamines react with hydrazines to give pyrazoles (Zakhartsova, IVVZKKT 41, 28)
Ar
- "click" like chemistry in 1963 (Huisgen, ACIE 2, 565)
N3
H2N-NHR1
R
? yield?
N N
Ph
2 eq n-BuLi
Ph
N
NMe2
OR... with
E = elemental
S, Se, or Te
N
X
X = S, Se, or Te
45 - 49%
E2
O
- Sn and Zn ynamines can be made and used in couplings (Helv. Chim. Acta 83, 641)
N
Ph
E1
N
E1 = BuI, DMF, TMSCl
E2 = H or TMSCl
-78 to rt
33 to 78%
Me
89%
Ph
NR1
N
N
N
O-
N
R
NR1
N
- Brandsma studied the bis-functionalization of ethynylpyrrole (Russ. JOC 32, 1164)
O
Ph
71%
Me2N
R moderate selectivity
- similarly, nitrone 1,3-dipoles give isoxazolines (Viehe ACIE 5, 585)
Me
O
NEt2
Ph
Et2N
X = R3Si or H
R2N
Me2N
O
R2N
BuLi or LHMDS
R2N
Me
O
C - Functionalizations
Ar
O
4. [3 + n] Cycloadditions
N
Baran Group Meeting
1/23/2008
Ph
- "push pull" ynamines can give isoxazoles and pyrazoles (Sukhova JOC 29, 1028 and 30, 49)
ZnCl2 or
ClSnBu3
R2N
R2N
X
M
O
Pd(PPh3)4
THF
NEt2
O
R2N
- Bicyclic aniline derivs. were synthesized by Ranier and Imbriglio (JOC 65, 7272; OL 1, 2037)
Et2N
O
O
PhCNO or
27%
N
Cl
N
H
N
O
N
TMS
Ar
33 - 48%
n
TsN
TsN
O
Ar
TMS PhMe, 100 ºC
n
Ph
O
Fe(CO)5,
O
N
TMS
TMS [O] then
dienophile
O
TMS (H)
n
TsN
(OC)3Fe
R1
(H) TMS
- Witulski used yne-ynamines in [2+2+2] rxns do make indolines (Synlett 2000 1723)
NEt2
Ph
TsN
H
H
Ph
R
Grubb's or Wilkenson's
PhMe
54 - 70%
E
TsN
R
Grubbs selective for meta
Wilk's selective for ortho
6
I.B. Seiple
Baran Group Meeting
1/23/2008
Ynamines in Synthesis
V - Ynamines in Total Synthesis
2004 - Hsung - Desbromoarborescidines A and C (OL 7, 1047)
- Keteniminium Pictet–Spengler cyclization
1994 - Boger's synthesis of bleomycin A2 (JACS 116, 5619)
- Report #2 in a series - synthesis of the pyrimidine metal binding domain
NTs 15% PNBSA
PhMe, 70 ºC
N
67%
N
H
4
N
H
4
BnO
NMe
H
NTs 8 steps
BnO
HO
2006 - Cossy's Heck–Suzuki–Miyaura to lennoxamine (TL 47, 767)
O
Br
N
N Br
OMe
MeO
1. SOCl2, reflux
2. Et3N, DMAP, rt
CO2H
OMe
MeO
O
CO2H
aq. NaOH, rt
100%
MeO
OMe O
Bn2N
CO2Et
N
EtO2C
1.
N
Me
N
O
N
NHBoc
H2N
N
H2N
CO2Et
Me
Xc
N
98 - 100%
NHBoc
CONH2
N
H2N
CONH2
SiMe3
MeO
N
Ph
Br
2. TBAF, 90%
H
O
Pd(OAc)2 (5%)
O
Ar
MeO
MeO
N
OMe O
N
1. H2, cat Pd/C (65%)
H
N
1. Bu3SnH (89 - 95%)
2. NH3•EtOH (80 - 85%)
3. LiOH (90 - 96%)
1. H2, cat Pd/C (80%)
2. H2SO4 (60%)
N
OMe O
THF, 0 ºC, 12h, 85%
O
MeO
OMe
PPh3 (10%)
77%
Me Ph
O H2N
MeO
OMe O
O
MeS
H2N
OMe
B(OH)2
O
N
CO2Et
I
Br
Sn
O
NH2
N
4. HCl•EtOAc (100%)
CO2Et
Me
NHBoc
Me
H
N
N
N
H2N
O
MeS
TfO
N
CONH2
MeO
OMe O
KHMDS, PhMe, then
2. MnO2, 83%
CO2Et
Me
2. TfOH, DCM; 75%
OMe
Br
TfO
N
H
1. NaBH4, EtOH, 5 ºC
6d, 70%
N
101 ºC
CO2Et dioxane,
H2N
95 - 98%
N
MeO
CO2Et
OMe
OMe
H2N
H2N
N
O
CO2H
lennoxamine
O
O
O
7