Thioamides (aka Thionamides)

13-03-2009 DAE Group Friday Seminar

Yimon Aye (G5)Evans Group

Harvard University

Thioamides (aka Thionamides)

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13-03-2009 DAE Group Friday Seminar

Yimon Aye (G5)Evans Group

Harvard University

Thioamides (aka Thionamides)

I. General Characteristics

II. Utility in Organic Synthesis

Bond Strengths, Bond Lengths & Electronegativities

Linus Pauling The Nature of the Chemical Bond, 3rd ed.; 1960; p 88.

Small Difference in Electronegativity (bet. C & S) and the Larger size of S allows greaterCharge Transfer from N to S in Thioamides (wrt N to O in Amides)

H NMe2

O

H NMe2

O

vs.H NMe2

S

H NMe2

S

H NMe2

O

Importance of this resonance structuremarkedly reduced in thioamides

Average Bond Energies

CN

O180 kcal/mol

CN

S140 kcal/mol

Pauling Electronegativities

CN

O

CN

S

2.55

2.583.44

3.04 3.04

2.55

Bond Lengths (Å)H

C

O

N

H1

H2 H

C

S

N

H1

H2

1.19 1.64

1.35 1.32

Covalent Radii (Å) O

S

NC

1.02

0.730.750.77

Kenneth B. Wiberg Acc. Chem. Res. 1999, 32, 922; J. Am. Chem. Soc. 2001, 123, 2038

Resonance Contribution & Rotational Barrier: in Comparison with Amides

Kenneth B. Wiberg Acc. Chem. Res. 1999, 32, 922; J. Am. Chem. Soc. 2001, 123, 2038

- Relative Barriers for Amino Group Wagging

Amides-C=O shortens only by 0.01 Å-C−N lengthens considerably---> Electron population at O changes only slightly

H

O

H NMe2

S

H NMe2

O

N MeMe

!

!

H

S

N MeMe

!

Calculated Out-of-Plane Distortion Potentials:

- Rotational Barrier about C−N Bond (i.e. φ = 90o)

Thioamides-C=S shortens appreciably-C−N lengthens to similar degree as in amides---> Larger charge transfer from N to S => more polar

From Ground State to Rotational Transition State,

vs.

- N-Lone Pair Delocalization Energies

Me NMe2

O

Me NMe2

S

(DMA) (DMTA)

ca. 27 kcal/mol ca. 37 kcal/mol

H

C

O

N

H1

H2 H

C

S

N

H1

H2

1.19 1.64

1.35 1.32

H

C

O

NH1

H2

H

C

S

NH1

H2

1.60

1.40

1.18

1.41

distortions up to 10o possible

w/o significant energy change for amides

Me NMe2

O15!20 kcal/mol

Me NMe2

S Larger rotational barrier (5!7 kcal/mol higher)

Value increases with solvent polarity --> ground-state more polar than TS‡

e.g., Solvent effect for DMTA ~ 1.7 x that for DMA

(DMA)

(DMTA)

DMTA: Larger dipole moment --> Larger change in dipole moment on going to TS‡

Molecular Conformation: s-Trans vs. s-Cis in Secondary Thioamides

C. N. R. Rao et al. Inorg. Phys. Theor. 1971, 3077

R1 N

O

R2

H

s-cis favored

Amides

R1 N

O

H

R2

R1 N

S

H

R2

Thioamides

R1 N

S

R2

H

?

s-trans s-cis

Selected Data (in CHCl3) from Spectroscopic (IR, NMR) and Theoretical Studies

H N

X

H

Me

H N

X

Me

H

O

S

95%

90%

H N

X

H

Ph

H N

X

Ph

H

50%

0%

Ratio variable with solvent polarity

s-cis favored in general but extent of s-cis preference is less than that in amides

O

S

100%

100%

Me N

X

H

Me

Me N

X

Me

H

95%

60%

Me N

X

H

Ph

Me N

X

Ph

H

100%

40%

O N

X

H

Me

O N

X

Me

H

Me Me

Molecular Conformation: s-Trans vs. s-Cis in Secondary Thioamides

R. Stan Brown et al. Acta. Cryst. 2006, E62, o1513

R1 N

O

R2

H

s-cis favored

Amides

R1 N

O

H

R2

R1 N

S

H

R2

Thioamides

R1 N

S

R2

H

?

s-trans s-cis

Solid State Conformation of S

N

H

MeS

NH

Me

s-Cis Conformation

s-cis favored in general but extent of s-cis preference is less than that in amides

With Minimized A(1,3) strain

Polarity

NH

S

NH

O

3.79 D

SO

3.83 D* NHNH

NH

S

NH

O

5.07 D

5.15 D

4.83 D3.88 D*

Dipole Moments

in dioxane at 30o C

(* = in benzene, 25 o C)

IR frequencies C=O vs. C=S

1115 cm-1

1112 cm-1

1117 cm-1

1706 cm-1

1672 cm-1

1669 cm-1

W. D. Kumler J. Org. Chem. 1962, 27, 2052

Dipole Moments for Thioamides Higher than Amides

Dipole Moments & IR Frequencies for Selected Lactams & Thiolactams

IR C=S less affected by ring sizeν C=O ~ 1.5 x ν C=S

Site of Protonation: same as in amides

George A. Olah et al. Chem. Rev. 1970, 70, 561

--> Preferred Site of Protonation on S [as in Amides (on O)]

-Similar restricted rotation about C−N bond in protonated (thio)amides as in (thio)amides: R NR2

S R NR2

SH

R NR2

SH

H NHR2

S

H

H

vs.

Me NH2

SH

Me NH2

SH

Me NH2

S

SFO

O

OH

! 90o C

" 5.72

An example from NMR evidence (data given for 1H NMR chemical shifts):

R NH2

OH

! 10

amideprotonated

R R

OH

! 14"16

R OR

OH

! 12

ester ketone

Hydrogen Bonding Abilities

Young-Sang Choi et al. J. Phys. Chem. A 2002,106,7010; J. Mol. Str. 1998, 283

H-Bond Acceptor Ability (Thioamides vs. Amides)

Experimental Results (based on near-IR absorbance spectroscopy)

Results from Calculations (level of theory: B3LYP; basis sets 6-311++G)(In Solution Phase with Various H-Bond Donor Solvents) H N

S

H

H

H N

O

H

H

is a weaker H-bond acceptor than

Calculated Proton Affinities

H N

S

H

H

H N

O

H

H

203 kcal/mol 199 kcal/mol

---> Formation of protonated thioformamide more favorable than that of formamide

[DMTF: Keq (in CCl4 at 25o C) = 9.9 + 0.5 M-1]

Keq (thioamide) 6 times smaller than Keq (amide):

But !H twice as more negative for thioamide wrt amide:

["6 kcal/mol for DMTF:TA vs.

"3 kcal/mol for DMF:TA]

Me N

S

H

H

H N

S

Me

Me

H N

O

Me

Me

Me N

S

H

H

H N

O

Me

Me

Me N

S

H

H

Me N

S

H

H

H N

S

Me

Me

Data for 1:1 complex only

(solvent: CCl4, temp: 25o C ) +

+

(DMF)

(DMTF)

(TA)

(TA)

Keq ~10

Keq ~ 60

(In Gas Phase)

Hydrogen Bonding Abilities

Young-Sang Choi et al. J. Phys. Chem. A 2002,106,7010; J. Mol. Str. 1998, 283

H-Bond Donor Ability (Thioamides vs. Amides)

Thioamides are Better H-bond Donors than Amides

Thioamides are Less Good H-Bond Acceptors than Amides

NH

O

NH

S

O O

more favored than

~1 kcal/mol

NH

H

S

O NH

H

O

Omore favored than

~2 kcal/molAmino H-Bond

Formyl H-Bond

Outburst of Thiourea-based H-Bonding Catalysis

(cf. Urea)

Acidity

Robert H. Crabtree et al. Inorg. Chem. 1993,32, 3991

Representative pKa Values in DMSO at 25° C

Frederick G. Bordwell Acc. Chem. Res. 1988, 21, 456

Me N

S

Me

Me

CH2

N

O

Me

Me

CH2

N

S

Me

Me

PhPh

26.621.325.7

Me NHPh

S

Me N

O

Ph

H14.7 21.5

M

O

M

ON

S

S

N

M

S

M

SN

O

O

N

favored over

NiS

O

M−S−M Bridge Avoiding Tendency in Thiolate S-Donor Ligands

Values for corresponding amides

NR

S

NHR

S

LnM MLn

O

LnM MLn

Bad? Ok

vs.

O

Ni

O

Ni

NS

R2N

N

N S

NR

NR2

RR

R

R

R

R=alkyl

Acidity

Robert H. Crabtree et al. Inorg. Chem. 1993,32, 3991

Representative pKa Values in DMSO at 25° C

Frederick G. Bordwell Acc. Chem. Res. 1988, 21, 456

Me N

S

Me

Me

CH2

N

O

Me

Me

CH2

N

S

Me

Me

PhPh

26.621.325.7

Me NHPh

S

Me N

O

Ph

H14.7 21.5

M

O

M

ON

S

S

N

M

S

M

SN

O

O

N

favored over

NiS

O

M−S−M Bridge Avoiding Tendency in Thiolate S-Donor Ligands

Values for corresponding amides

In Analogy to Carboxylate:

O

O

syn-lone pairmore basic

syn

anti

Metal d-obrital

Metal d-obrital

NR

S

syn-lone pairmore basic

syn

anti

Deprotonated Thioamide

O

Ni

O

Ni

NS

R2N

N

N S

NR

NR2

RR

R

R

R

R=alkyl

Comparative Stability in Thiocarbonyl Family

Thioamides:

Stable to air

Easily synthesized in large amounts (see on)

Stability in Peptides (==> Thiopeptide Antibiotics)

Thioaldehydes:

Only prepared in situ (much less stable than corresponding RCHO)

Dithioesters & Thionoesters:

Simple to prepare & stable (but less stable than corresponding C=O analogues)

Thioketones:

Relatively tricky preparations, less stable than ketones

R1 H

S

R1 N

S

R2

R3

R1 S

S

R2

R1 O

S

R2

R1 R2

S

Syntheses of Thioamides

R1 N

O

R2

R3

R1 N

S

R2

R3

(A) Direct Treatment with Thionating Reagents (B) Via Prior Amide Activation with Electrophilic Reagents

(I) From Amides (most common)

(II) From Ketones (Willgerodt Carbonyl Transposition)

Ar

O

MeAr

n n

S

NR1

R2

Ar

O

NR1

R2

hydrolysisWillgerodt

rearrangement

Willgerodt-Kindler reaction

n

(A) Direct Treatment with Thionating Reagents

André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein

I. P2S5

S

PS

P

SP

SS

P

S

S

S S

S

Reflux in Toluene, xylene or HMPA

Common Additivies: (TMS)2O, Na2CO3, NaHCO3, etc.

O

PO

P

OP

OO

P

O

S

S S

S

NH

N

H

O

H

Et

CO2Me

P4S10, THF

rt, 1 dayNH

N

H

S

H

Et

CO2Me

76%

R1 N

O

R2

R3

R1 N

S

R2

R3



II. (EtAlS)n or B2S3

I. P2S5

O

N

R

S

Me

Me

Al

Et

(EtAlS)n

amide thioamide

(EtAlO)n

R1 N

O

R2

R3

R1 N

S

R2

R3

K. Yokota J. Organomet. Chem. 1975, 92, 139

R N

S

Me

Me

R N

O

Me

Me

(EtAlS)n

rt

R % yield

HMePh

807268


Martin Jesberger et al. Synthesis 2003, 1929 and references cited therein

III. Lawessonʼs Reagent (1)


I. P2S5

NMe3Si Ph

O

On

n = 1 (44%)n = 2 (52%)

no regioisomerdetected

1 (0.5 equiv)

!, Benzene, 1 h

NMe3Si Ph

O

Sn

A Regioselective Example:

Nigel S. Simpkins et al. Org. Lett. 2003, 5, 1673

SP

S P

S

S

O

Me

O

Me1

ArPS

S O

ArPS

S P

O

Ar

S

S

ArPS

O

O

PO

P

OP

S

Ar

S

Ar

S

Ar

(by-prodof rxn)

R2N R

SO

NR2

R2N

R2N

MeON

N O

O

Me

H

O H

O

Me

MeMe

MeON

N O

O

Me

H

S H

O

Me

MeMe1, THF, rt

MeON

N O

O

Me

H

O H

O

Me

MeMe

Me Me

MeON

N O

O

Me

H

S H

O

Me

MeMe

Me Me1, Toluene

100o C

80%

73%

Most Commonly-Employed Thionating Reagent



IV. Polymer-Supported Thionating Reagent (2)

-Low purity for complex substrates

-Only for 2o & 3o amides (Primary amides yield nitriles)

-Microwave heating enhances reaction rate (15 min vs. ~ 30 h)

N

S

H2N

H

OH

O

Me

Me

Ph

66 % GC Purity

> 99% GC Conversion

III. Lawessonʼs Reagent (1)


I. P2S5

Downsides:

Harsh conditions

Long reaction times

Painful chromatographic purification

High toxicity (both the reagent & side-prods.)

Malodour (both the reagent & side-prods.)

N NH

P

OEtS

NNH2

HPSEtO

ClCl

on shaker, rt, 4 h

, py

commercially available

2

N

S

Me

Me

Selected Examples

Me NHPh

SN

N

SSH

Ph

GC conversion (%) > 99 98 > 99 > 99

GC purity (%) 9398 92 98

Reaction Conditions:

Toluene, 90o C, 3!20 equiv. of 2

Steven Ley et al. J. Chem. Soc., Perkin Trans. 1 2001, 358

(B) Via Prior Amide Activation with Electrophilic ReagentsI. POCl3 ; Hexamethyldisilathiane, (TMS)2S

R1 N

O

R2

R3

R1 N

S

R2

R3

R1 = H, Me, Ph, t-Bu

R2 = Me, i-Pr, !(CH2)4!

R3 = H, Me, i-Pr, !(CH2)4!

N

O

n

R

N

S

n

R

n = 1!4

R = H, Bn, Me, Et

70!92 %30!100 %

Reagents & Conditions: i) POCl3, CH2Cl2; ii) TMS2S ; ! 78o C - 0o C - rt

TMS2S

POWERFUL

STENCH!

R1 N

Cl

R2

R3

R1 N

Cl

R2R3

S

TMS

TMS


(B) Via Prior Amide Activation with Electrophilic Reagents

II. (COCl)2 or POCl3 ; Benzyltriethylammonium tetrathiomolybdate, (BnNEt3)2MoS4

I. POCl3 ; Hexamethyldisilathiane, (TMS)2S

N

O

Me POCl3 , CH2Cl2N

Me

Cl

Cl

MoS42-, CH2Cl2

! 78o C - rt

40 min

N

S

Me

80 %

! 78 - 0o C

30 min

-MoS42- easier to prepare

-less expensive (& odour much less offensive) than TMS2S


R1 N

O

R2

R3

R1 N

S

R2

R3


R2 = Me, i-Pr, !(CH2)4!

R3 = H, Me, i-Pr, !(CH2)4!

N

O

n

R

N

S

n

R

n = 1!4

R = H, Bn, Me, Et

70!92 %30!100 %


TMS2S

POWERFUL

STENCH!

(B) Via Prior Amide Activation with Electrophilic Reagents

II. (COCl)2 or POCl3 ; Benzyltriethylammonium tetrathiomolybdate, (BnNEt3)2MoS4

I. POCl3 ; Hexamethyldisilathiane, (TMS)2S

N

O

Me POCl3 , CH2Cl2N

Me

Cl

Cl

MoS42-, CH2Cl2

! 78o C - rt

40 min

N

S

Me

80 %

! 78 - 0o C

30 min

R1 N

O

R2

R3

R1 N

S

R2

R3


R2 = Me, i-Pr, !(CH2)4!

R3 = H, Me, i-Pr, !(CH2)4!

N

O

n

R

N

S

n

R

n = 1!4

R = H, Bn, Me, Et

70!92 %30!100 %


TMS2S

POWERFUL

STENCH!

-MoS42- easier to prepare

-less expensive (& odour much less offensive) than TMS2S

III. Tf2O, Py ; 20% by wt. aq Ammonium sulfide, (NH4)2S

R1 N

O

R2

R3(H)

R1 N

OTf

R2

R3(H)

H2S, py, 0o C, 5 minTf2O, py, CH2Cl2

!50 - 0o CR1 N

S

R2

R3(H)

-H2S toxic gas

-Uncontrolled amount added

-Specialized equipment needed


Improved Method:

R1 N

O

R2

H

R1 N

N

R2

H

Tf2O, py, CH2Cl2

!50 - 0o CR1 N

S

R2

H

N

O

R2

R3

R1

N

N

R2

R3

R1|| aq (NH4)2S

!40o C - rt !5o C

N

S

R2

R3

R1

Both 2o, 3o amides & lactams

53!95 % yield

aq (NH4)2S

!5o C

(II) From Ketones (Willgerodt Carbonyl Transposition)

Ellis V. Brown Synthesis, 1975, 358 and references cited therein

cf.

Ph CH2N2

ONH4OH

NH2

O

PhArndt-Eistert

Arn

S

NR1

R2

Ar

O

Me

n

S8, HNR1R2 (dry)

! in open reflux equipmentKindler Modification 1923

- Historically well-utilized, particularly in chemical industry

- Ar = Any aromatic carbo/heterocycles

- Generally poor-yielding (ca. 20 - 60% max)

- In most cases, >60 % yields for methyl ketones only

Mechanism:

Labeling studies suggested no skeletal rearrangement is involved

One possible mechanism in the case of methyl ketones:

Ar

NR2

SS7

Ar

NR2

H

SH

Ar

NR2

H

SH

Ar

NR2

H

S

Ar

R2N

H

SH

H

Ar

H

NR2

SH

ArNR2

S

Ph Me

O[(NH4)2Sx]

NH2

O

Ph Conrad Willgerodt 1887

Ar

O

Me

n

Ar

O

NH

H

Willgerodt reactionn

S8, NH4OH

dioxane/ py

! in pressure apparatus

Methods of Desulfurization of Thioamides into Amides

I. Oxidation

NS

Me

Ph

NO

Me

Ph

m-CPBA (1.2 equiv)

CH2Cl2

72%

Simple acyclic, primary and secondary thioamides also give decent yields (72!98%)

Other oxidants: basic H2O2, SeO2, K3[Fe(CN)6], O3 , N2O4 but poor yielding and limited susbtrate scope in general

II. Reductive Raney Ni Desulfurization

Dale L. Boger et al. Org. Lett. 2005, 7, 4539

N

O

N

Me

O

Me

S OTIPS

OBn

Et

CO2MeH

N

O

N

Me

O

Me

OTIPS

OH

Et

CO2MeH

Ra!Ni, rt, 15 h

91%

HH

N

OH

N

Me

O

Me

OAc

Et

CO2MeH

i) H2 (45 psi), PtO2, 98%

ii) Ac2O, 97%

iii) TBAF, 89%

iv) PPh3, DEAD, 75%

Vindoline

H

Utility of Thioamides

Two Major Applications: Most Recent Reviews

I. Heterocycle Synthesis Tadeusz S. Jagodzinski Chem. Rev. 2003, 103, 197

II. Thiopeptide Antibiotics Mark C. Bagley et al. Chem. Rev. 2005, 105, 685 Dieter Seebach et al. Helv. Chim. Acta. 1999, 82, 2067

Attractive Characteristics:

-Relative ease of preparation-Stability in air-Crystallinity-Acidity of α-proton-Regioselective S-alkylation of enethiolates-High electrophilicity (C=S)-High nucleophilicity-Absence of obnoxious smell!

Downside:

-Limited precedence-S-alkylation (rather than C) limits electrophile/rxn scope-High C=S reactivity --> tolerates only mild reagents & conditions

Reactions Involving Thioamides

Nucleophilic Chemistry Electrophilic Chemistry

-Reactions with Nucleophilic Carbanion (Thiophilic vs. Carbophilic Additions)

-Radical Chemistry

-Reduction via Thioiminium Salts

Ambident Nucleophilie

Addition at C Addition at S

-Aldol Addition

-Conjugate Addition

-Alkylation

-Thio Contraction

-Pericyclic Reactions

Uses

-Organocatalysis

Nucleophilic Addition @ Carbon

Nucleophilic Additions (via Enethiols/Enethiolates)

Patrick Metzner et al. Chem. Eur. J. 2002, 8, 632 and references cited therein

Enethiolates

-Easily prepared with a variety of bases-Thermally more stable than corresponding amide enolates

-Ambident nucleophiles

N

S

or

E

E

Aldol Addition via Soft Enolization

N

N

S

E

E = CO2Me

H

O

O

O

H Et

Sn(OTf)2, N-ethylpiperidine, THF

N

N

S

E

HOH

O

O

Et

80%a single diastereomer

* undetermined

**

N

S

E

O

O

Et

i) TsOH, NEt3 (97%)

ii) DBU, CH2Cl2 (93%)

i) Raney Ni (deact.)

ii) H2, Pd/C [49% (2 steps)]N

N

H

O

O

Et

Vinblastine

O

OMe

(1.1:1 !:" @ *)

*

Philip Magnus et al. Tett. Lett. 1992, 33, 899

In Conjugate Additions (via Enethiolates)

Clayton H. Heathcock et al. J. Org. Chem. 1990, 55, 132

Solvents: THF; THF/Hexanes; THF/HMPA

Bases: LDA, NaHMDS, KHMDS

Stoichiometry: enolate (2 equiv)

Temp: !78o C

(1,4)

(1,2)

Softer thiolactam enolates have a greater propensity for (1,4)

Thioamides

Same Outcome as Amides but

N.B. (1,2)-products most often transform into (1,4)-adducts upon warming (but only at the expense of dr)

R1

O

R2N

X X

NMe

X = O, S

R

N

X X

NMe

R

M M

X

NMe

t-Bu

O

R2

(1,2) : (1,4)

< 3 : 97 (R2 = Me)

< 3 : 97 (R2 = i-Pr)

t-Bu

O

t-BuN

X

R

X = S

< 14 : 86 (R2 = Me)

< 57: 43 (R2 = i-Pr)X = O

54 : 46 ( X = O )< 3 : 97 ( X = S )

Base : LDA

Exclusive (Z)-enolate formation in amides & thioamides :Evans et al. Pure Appl. Chem. 1981, 53, 1109Yoshida et al. J. Am. Chem. Soc. 1982, 104, 4018

General Trends Observed under these Conditions:

(1,2) vs. (1,4) Selectivity

- Bulkier enolates prefer (1,4)

- (Thio)Lactam enolates prefer (1,2) more than (Z) enolates

- Larger R1 decreases (1,2) preference

- Larger R2 increases (1,2) preference

Amides

In Conjugate Additions (via Enethiolates)-continued:


R1

Me

N

XR2O

R1

H

NMe

H

R1

X O

M

HR2

HO

M

HR2

N

Me

X

Me

N

XR2O

R1

antisyn

H

N

X

Me

R2O

R1NH

H

R1

X O

M

Me

HR2

H

R1

OM

HR2

N

H

X

Me

N

X

Me

R2O

R1

antisyn

General Trends Observed under these Conditions: (1,4) Addition Diastereoselectivity

- Varying R1 has little or no effect in dr in both cases

- Lithium enolates of both lactams and amides are anti selective

- Lithium enethiolates, particularly those of thiolactams, have low selectivity

Na, K enolates of thiolactamspromote syn selectivity

t-Bu

O

t-BuN

X

R 3 : 97 ( X = O )3 : 97 ( X = S )Base : LDA

(1,4)-adduct dr (syn:anti)

X

NMe

t-Bu

O

R2

X = S

X = O

Base : LDA

(1,4)-adduct dr (syn:anti)

60 : 40 (R2 = Me)

52 : 48 (R2 = i-Pr)

< 10 : 90 (R2 = Me)

< 7 : 93 (R2 = i-Pr)Base: KHMDS, NaHMDS> 95 : 5> 95 : 5

Nucleophilic Addition @ Sulfur

K. Shiosaki In Comprehensive Organic Synthesis, Vol 2, (Trost, Fleming, Paquette, Heathcock, Eds.), 1991, Pergamon, Oxford, p 865

Alkylation @ S: Eschenmoser Sulfide Contraction(Thioamides ---> Vinylogous Urethanes)

Synthesis of Tetrasubstituted Olefins

A. I. Meyers et al. J. Am. Chem. Soc. 1995, 117, 5399

Eschenmoser 1971

Br

O

OMe

i)

ii) P(OMe)3, NEt3

ON

Ph

80%

H CO2Me

Me

ON

SPh

Me

ON

SPh

Me

CO2Me

Br

ON

SPh

Me

CO2Me

+ HBr

thioiminium salt ketene-N,S-acetal

G. Lhommet et al. Synthesis 1994, 1118

N

S

BnBr

Me

O

OEt

PPh3, NEt3

MeCN, !, 2 h

N Bn

MeEtO2C

E:Z = 85:15

80%

i)

ii)

via episulfide

Eschenmoser Sulfide Contraction: Application in Vitamin B12 Synthesis(Thioamides ---> Vinylogous Urethanes)

Eschenmoser et al. Science. 1977, 196, 1410

b) P(OEt)3, Xylene, !

a) 1.05 eqiv. (PhCOO)2

84%

(+)N

H

N

O

O

Me

Me

(CH2)2CO2Me

O

Me

(CH2)2CO2Me

Me

Me

O

S

NH

O

(CH2)2CO2Me

Me

MeO

N

Me

H

(CH2)2CO2Me

*

2:1 ":#

64%

N

H

N

O

O

Me

Me

R3

Me

Me

R3

Me

R2

Me

R3

O

R2

Me

R2

N

NH

Precursor Toward Cobyric acid & Vit-B12

t-BuOK, At-BuOH, 25 °C

iii) P(CH2CH2CN)3, TFA

NH

NMeO2CCH2

Me

MeO2CCH2

O

(CH2)2CO2Me

Me

MeO2CCH2

Me

Br

i) Lawesson's

ii)A

*

N

O

O

S

H

BnO

3

N

O

O

S

H

i) LDA, THF, 0o C, 30 min

ii) 0o C, 10 min

Me

O

Me

OBn

Me

Me

O

undetermined configuration @*

78 %

5:1 dr


N

O

O

SEt

H

OBn

Me

Me

O

*

O Et

Et

Et

BF4

via

thioimidate

salt

Conjugate Addition at C followed by S-Alkylation: An Example in Total Synthesis

N

Daphniphyllum alkaloid

i) Eschenmoser's salt,

CHCl3, rt, 3 h

ii) 2,6-di-t-Bu-Py, rt, 2 h

N

O

O

H

O

BnO

Me80%(a single

diastereomer)

CO2Me

Me

Me

Nucleophilic Addition @ S Followed by [3,3] Sigmatropic Shifts

From Bond Lengths, Angles & Energies, [3,3] Shifts with S proceed more easily than with O

ΔG‡ are smaller (although larger ΔH‡) ==> kinetically more favored with S than with O SS

1

2

3

3

2

1

1

2

3

3

2

1

[3,3] Shifts with Sulfur Most Popular with Thioamides ==> Thio-Claisen Rearrangement

S. Yamabe et al. J. Org. Chem.1996, 61, 6218

A. I. Meyers et al. J. Am. Chem. Soc. 1994, 116, 2633

O

N

Me

Me

S

MeO

Ph

*

1:1 !:"

O

N

Me

Me

S

MeO

Ph

Me

i) LDA (2 equiv), THF, 0o C

ii)Me Br

First Auxiliary-Controlled Thio-Claisen Example:

20o CO

N

Me

S

MeO

Ph

Me

Me

91:9 dr

79%

O

Me

Me

> 99% ee

An Example with Secondary Thiolactam

N

S

H

Cl

SO2Ph

Me3N

OTBS

BF4

CH2Cl2

N

S

Cl

TBSO

SO2Ph

SO2Ph

OTBS

N

Cl

S

92%

rt

P. L. Fuchs et al. J. Org. Chem. 1995, 60, 2692

Axially Chiral Thioamides in Thio-Claisen Rearrangement

Patrick Metzner et al. Chem. Eur. J. 2002, 8, 6322

Atropisomerism as well as Rotameric Equilibration Possible in Principle:

t-Bu

t-Bu

NMe

S

MeS N

t-Bu

Me

H

Recall Slide 4 (s-cis vs. s-trans conformations)

S

NMe/H

t-Bu

R

S

N

Me/H

R

t-Bu

(s-trans) rotamer (s-cis) rotamer

Secondary thioamide Tertiary thioamide

-NMR shows 1:1 s-cis : s-trans-Crystal structure shows one conformation

-Both NMR & X-ray structure show s-trans conformation

S

NMe

t-Bu

Mei) LDA (1.1 equiv)ii) prenyl bromide

S

NMe

t-Bu

Me

Me

Me

(Z)-enolateonly

S

NMe

t-BuMe

Me Me

78%

dr 86:14

- NMR show diastereotopic methylene protons in both

S

Me

N

Me

H

Me Me

Me

Me

N

Me

H

Me Me

Me

S

vs.

S

NMe

t-BuMe

Me Me

(minor)

Me N

S

SiMe3

Bn

i) MeOTf

ii) CsF ;

CO2Me

Me N

SMe

CH2

Bn

N

Bn

Me

CO2Me

N

Bn

CO2Me

Me

E/Z unknown 49% 20%

+ + MeSH (by product)

CO2Me

(xs reagent)

CO2MeMeS

E/Z mixture

Consistently Better Yieldswith Thioamides (wrt Amides)

due to this step (not possible with MeOH)

N

However,

MeS

CO2Me

NMeS

CO2Me

NEt3 CO2MeN

CO2Me

CO2MeMeO2C

minor productMeO2C

NEt3

NMeS

CO2Me

N

CO2MeMeS

H

MeO2C

MeO2C

CO2MeMeO2Cmajor product

In Cycloadditions (as Ylide Precursors)

Edwin Vedejs and Frederick G. West Chem. Rev. 1986, 86, 941

In Cycloadditions (via Thiocarbonyl Ylides)

Albert Padwa et al. Chem. Rev. 1996, 96, 223 and references cited therein

N

S

O

N2

O

O

i) cat. Rh2(OAc)4, PhH, !

ii) Ni Raney, Acetone N

O

O

O

N

OH

OH

HOH

indolizidine alkaloid

via

N

O

O

O

S

N

O

O

O

SH

episulfide enethiol (detected)

N

S

O

N2 Me

O

i) cat. Rh2(OAc)4, PhH, !

N

S

O

Me

O

N

S

O

Me

O

thiocarbonyl ylide (aromatic)

NPh

O

O

ii) Phenylmaleimide

N

SO Me

O

ca. 1:1 dr

N

S

O

O

Me

not via episulfide/enethiolpossibly due to ring-strain as well as having no aromatic stabilization

Samuel Danishefsky et al. J. Am. Chem. Soc. 1990, 112, 2003

Electrophilic Addition Chemistry

Peter Beak et al. J. Org. Chem. 1994, 59, 7410

Reaction with Carbanion Equivalents: Thiophilic vs. Carbophilic Additions

MeMe

EtS SIS

Me

Me

SEt

MeMe

EtS S Me

MeMe

i) t-BuLi (2 equiv)

THF, !78o C

ii) AcOH

73% 13%

+

cf. Thiophilic Radical Addition

A B

eg. A B (83%)n-Bu3SnH

AIBN

Thiophilic Addition Examples (NOT with Thioamides)

In Umpolung chemistry with sulfines:

Dithioester:

Thioketone:

R1 R2

S

O

R1

SMeS

O

i) RLi, !78o C

ii) E!X, !78o C

R

ER1 SMe

SO

R1 SMe

S

m-CPBA(1 equiv)

HBF4

(N.B. much easier hydrolysisthan dithiane analogues)

THF/H2O, rt R1 E

O

cf. Schlessinger Reagent: S

O

S

Base; Electrophile (El);

R

O

El

R

R1 R2

SMe3Si

TBAF

DMF, rt R1 R2

S

+

H. K. Lee et al. Tett. Lett. 1999, 40, 2173

Reaction with Carbanion Equivalents: Thiophilic vs. Carbophilic Additions

Carbophilic Addition Example (Thio-Reformatsky Reaction)

N

Boc

S

OTBS

Ph

N

Boc

OTBS

Ph

MeO2CEschenmoser Thio Contraction

Br

OMe

O

NBoc --> Low Nucleophilicity ?

Complementary to Eschenmoser Sulfur Extrusion with Electron Deficient Thiolactams

N

Boc

S

R

R'

n

n = 0 - 3

40 ! 73 %N

Boc

R

R'

n

BrZnCH2CO2Me

(R = H, OTBS; R' = H, Bn)

THF, "

MeO2C

Mario D. Bachi et al. J. Org. Chem. 1997, 62, 1896

Radical Additions on Thioamides

H

S

N

Boc

CO2t-Bu

OTMS

Me

SEt

E:Z mixture

N

Boc

CO2t-Bu

OH

Me

73%

i) n-Bu3SnH (2 equiv),

AIBN

ii) TBAF N

H

CO2H

Me

CO2H

(!)-"-kainic acid

Richard J. Sunberg et al. J. Org. Chem. 1981, 46, 3730

Reduction of Thioamides via Thioiminium Salts

N

O

OMeO

N

H

N

RN

H

Desired Transformation:

Amide ----> Amine

HH

Direct Reduction with Various Reagents Failed

eg. Even with LAH, only semi-reduction to enamine A observed in this skeletal system

N

N

H

A

OMeO

N

SMe

OMeO

N

H

i) P2S5

ii) MeI

I

NaBH4 (basic conditions)

NaBH3CN, H+

(acidic conditions)

N

N

H

HH

OMeO

Desired ReductionProduct

Deethylcatharanthine

An Alternative Route for Amide --> Amine Transformation

R''

S

N

R'

RR'' N

R'

R

NaBH4 (1.1 equiv), MeOH

NaBH3CNor

i) MeI (5 equiv)

ii)

MeOH, 1:1 AcOH:H2O

(1.1 equiv)ii)

S

NThioamides

Ph

Me

S

NHPh

Yield

of Amines

Ph

S

NH(s-Bu)

S

N

Ph

96

89

65 44 98

69

Thioamides in Organocatalysis

Dorota Gryko et al. Adv. Synth. Catal. 2005, 347, 1948

Recall Slide 7 (Thioamidesʼ H-Bonding Donor Abilities are Superior to Amides):NH

H

S

O NH

H

O

Omore favored than

~2 kcal/mol

Observations from Prolinamide-derived Organocatalysis: Reactivity & Selectivity Increase with N−H Acidity

Substitute with Thioamides ?NH

H

Me

S

NH

H

Me

O

pKa (DMSO, rt)

18.5 25.5

NBoc

N

O

R

H

i) Lawesson's reagent, Toluene, !

ii) Et3SiH, NEt3, CH2Cl2

N N

S

R

HH

R = Ph (racemization occurs during 1st step)

Catalyst Prep.

Me

O

Me Ar

O

H

5!20 mol% cat.

4o C

62!83 % yield72!>99 % ee

O

Me

OH

Ar

Thioamides in Organocatalysis

Jin Qu et al. J. Org. Chem. 2008, 73, 8558

An Example in Kinetic Resolution of Racemic Alcohols

O

OH

NO

5 mol% cat.

(i-PrCO)2O (0.5 equiv)

DIPEA (0.5 equiv)

CCl4, 0o C, 3 h

O

O

NO

O

OH

NO

O

i-Pr

+

X = S: 90% ee 97% ee @ 52% conversionX = O: 54% ee 53% ee @ 52% conversion

R

S

kR

kS

P

P

Selectivity Factor (S) = kR / kS

General Scheme for a Kinetic Resolution:

Single Crystal X-ray Structures

Thioamide Cat. Amide Cat.

! N-H (X = O) : 6.8 ppm (X = S) : 8.1 ppm

N.B.

Solution conformations (from NOE difference spectroscopy

in CCl4 & CDCl3 mixture) coincide with solid state conformation

Summary on Thioamides

I. General Characteristics

II. Formation & Desulfurization

- Structure and bonding similar to amides overall with some interesting differences

- Most commonly made directly from amides;

IV. Uses In Addition to Synthesis Applications

(Lawessonʼs reagent and P4S10 appear the most popular thionating methods)

- Preparation of Heterocycles

- Thioamide H-Bond Donor Catalysis

- Thiopeptide Antibiotics

III. Reactions (Nucleophilic & Electrophilic Chemistry)

- Interesting reactivity compared to amides

- C vs. S addiiton

- Ra-Ni most common desulfurizing agent

Thank you for your attention!

Thioamides (aka Thionamides)

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