13-03-2009 DAE Group Friday Seminar
Yimon Aye (G5)Evans Group
Harvard University
Thioamides (aka Thionamides)
Burma Flags Before & after Independence
. The first identifiable civilization around 300 BC. Powerful Bagan kingdom by 849 followed by several others till 1820 when the British took over. Gained Independence in 1948
. The Size of France and Britain combined. Population 45 million (a union of 135 ethnic groups; many with their own languages and dialects); in total, speaking 111 languages. Burmese alphabet constitutes 33 characters (shown below)
The worldʼs largestgolden monument rises326 feet on a hill 168feet above the city.
Largest ringingbell on earth(26 feet, 91
tonnes)
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-Population: 60.5 million i.e. 250 people per km2
- UK is just a bit smaller than Wyoming
- Daily weather forecast: cloudy with scattered showers in summer; gale force winds in the winter
- Most popular dish in Britain: Chicken Tandoori- Most popular ʻfast foodʼ take away: Fish & Chips
Over 900 years old tower Famous drawbridge (1894)
800 feet long;opens in 90 seconds
Most famous prehistoricmonument dating back 5000 years
Oxford1096
Somerville1879
The big bellin a 320ft-tall clock tower
chimes on the hour-York: the Viking City-Captured by the Danes (865 AD); transformed into the Viking kingdom of York (Jorvik)
The Sheep County Yorkshire dales
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
(A) Direct Treatment with Thionating Reagents
André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein
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
(A) Direct Treatment with Thionating Reagents
Martin Jesberger et al. Synthesis 2003, 1929 and references cited therein
III. Lawessonʼs Reagent (1)
II. (EtAlS)n or B2S3
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
(A) Direct Treatment with Thionating Reagents
André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein
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)
II. (EtAlS)n or B2S3
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
André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein
(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
André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein
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!
(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
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!
-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
André B. Charette et al. J. Org. Chem. 2003, 68, 5792 and references cited therein
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:
Clayton H. Heathcock et al. J. Org. Chem. 1990, 55, 132
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
Clayton H. Heathcock et al. J. Org. Chem. 1992, 57, 2531
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!
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