Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Quick Timeline
- Born Derek Harold Richard Barton on Sept. 18, 1918
- Father died in 1935 and had to take over the family
wood business.
- In 1937 decided to leave family business and enrolled
at London University.
- Entered Imperial College in 1938 after passing entrance
exams and graduated two years later. Graduate work
focused on the synthesis of vinyl chloride
- Completed his Ph.D. 1942 and started working with
military intelligence developing nonaqueous secret inks.
- At the end of the war he started work with Albright and
Wilson, Ltd. on the synthesis of organophosphorus
compounds.
- In 1946 he took the "most junior position" at Imperial
College as an assistant lecturer.
- From 1949-1950 he was a visiting lecturer at Harvard
- In 1950 he was appointed reader at Birkbeck College,
then to professor in 1953.
- 1955 he moved to University of Glasgow
- In 1957 he moved (yet again) to Imperial College
- Received the Nobel Prize with Odd Hassel in 1969 for
his development of Conformational Analysis
- Knighted in 1972 (but only known as "Sir" in Britain)
- Moved to France in 1978 to become director of ICSN Gif Sur-Yvette
- Forced to retire, moved to Texas A&M in 1986
- Died 1998 at the age of 79
Flour Beetle Study
Main Areas of Research:
- Conformational Analysis
- Stucture Elucidation
- Phenol Oxidation
- Biosynthesis (lignans, phenolic
alkaloids, steroids, triterpenes)
- Radical Chemistry
- Photochemistry
- Fluorine Chemistry
- Organometallics
- Much, much more
In all of these fields Barton made
important contributions, if now start the
field altogether. He frequently changed
fields stating"
"... I have worked in many fields, but as
soon as these fields became popular, I
have moved on. I have made the joke
of saying that if you cannot remember
all the published papers in the field you
are working in, then it is time to move
on." Gap Jumping, page 111.
6 days
Flour + dead beetle
pink (and unpalatable) flour surrounding beetle
Compound isolation:
500-1000 adult beetles (ca. 5 mL) are placed in a distilling flask. A stream of dry air
is passed through the flask for 6 hours. Every 2 hours, cool to 0° C for 20 minutes.
The excretion condensed long yellow needles on the cold finger (0.5 mg). Return
beetles to flour for 3 days and repeat. Yields reduce with each interation. After 3 or
4 operations the insects were too feeble for further excretion.
O
Biochem. J. 1943, 37, 463-465
O
ethylquinone!
After a battey of tests, Barton determined that the compound was ethylquinone and
when the paper was submitted the journal's editor initially thought it was a joke. This
early study was performed during his free time when he was working for military
intelligence, stating, "I though then, as now, that chemistry is more interesting that
spare time." Gap Jumping, page 9.
Derek H. R. Barton
Baran Group Meeting
Method of Molecular Rotation Differences
Me
Vinyl chlorides
Studied the thermal decomposition of various polychlorinated hydrocarbons and found that can
occur through three different pathways.
Me
J. Chem. Soc. 1945, 813-819
Will Gutekunst
Me
Cl
cis-elimination
H
Me
H
H
H
~300–500° C
Cl
H
+
H Cl
+
H Cl
Cl
H
RO
Cl
cholesterol
Cl
Cl
radical chain
H
Cl
Cl
Cl
Cl
+
Cl
+
Cl
Cl
H
R
H
R
H
R
H
R
Cl
Me
H
H
RO
Me
H
H
Me
H
RO
H
H
R
Me
H
RO
H
Me
H
RO
R
H
Me
H
R
H
Cl
H
Notably, 1,1 dichloroethane cannot participate in radical chain processes
Cl
Cl
Cl
Me
HCl
H
+
Cl
Cl
Me
Established "rules" for the decomposition of any chlorinated hydrocarbon.
Later extended to polyunsaturated compounds, hormones and bile acids
J. Chem. Soc. 1946, 512
J. Chem. Soc. 1946, 1116
H Cl
J. Chem. Soc. 1949, 155.
H
H
RO
"surface"
surface catalyzed
H
H
H
RO
H
H
H
Me
H
RO
H
Me
Cl
Cl
Cl
!
Cl
+
H Cl
Cl
At a given temperature and surface area/volume ratio, all three mechanisms
operate at the same rate.
This method, while empirical, was accurate. Barton used to correct numerous structures in the
literature - even one assigned by Nobel laureate Leopold Ruzicka! "It was perhaps unwise for a young
man to criticize a distinguished professor at the prestigious ETH... I showed that L. Ruzicka had made
an error in the assignment of configuration at the C-3 position in ring A of triterpenoid alcohols.
Ruzicka, one of the greatest organic chemists of the day, had received the Nobel Prize just before the
war. He was a passionate and fiery man. Our relations for some years were confied to print and
somewhat strained"
J. Am. Chem. Soc. 1950, 72, 988.
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
cis-Elimination
Me
Me
Δ
H
AcO
AcO
OBz
H
H
Originally reported by Plattner (ETH), refuted by MMRD
Me
Me
Δ
H
H
AcO
AcO
OBz
H
H
Inspired by previous work, realizes it is requisite cis-elimination!
J. Chem. Soc. 1949, 2174.
J. Chem. Soc. 1949, 2459.
Me
Me
Me
Δ
Cl
Me
+
unimolecular
Me
Me
Me
Me
Me
J. Chem. Soc. 1953, 453.
Further support with menthyl chloride pyrolysis
Using this analysis, he was able to rationalize the relative rates of esterification of
equatorial and axial (polar) alcohols, thermodynamic isomerizations, anti-periplanar
geometries for elimination, neighboring group participation, etc.
"Conformational Analysis for the sutdy of the stability and reactivity of saturate or
partly saturated cyclic systems promises to have the same degree of importance as
the use of resonance in aromatic systems." – Arthur J. Birch, 1951
Conformational Analysis
"Conformational Transmission"
Insprired by Odd Hassl's paper on decalin conformation, Barton became interested in calculating
the preferred conformations using force field calculations (logarithmic tables and slide rule!)
Remote conformational effects drastically change the relative rates of aldol reaction.
Nature 1946, 157, 765.
J. Chem. Soc. 1948, 340.
H
H
or
H
preferred!
?
H
H
H
H
or
H
H
Me
H
H
H
Me
H
?
H
H
H
This eventually led to the application of these concepts to steroid conformation
Experientia 1950, 6, 316.
O
H
4
Me
H
O
H
1
H
H
O
H
645
J. Chem. Soc. 1960, 1297.
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Structure Elucidation
Me
O
O
Me
H
Me
Me H
Me
Me
Me
O Me O
Me
H
Me
O
H
Me Me
glauconic acid
HO
O
byssochlamic acid
J. Chem. Soc. 1965, 1769.
Me
Me
Me
Me
Me
Me
H
Me
Me
HO
H
Me Me
Cl
RO2C O
OH
R = Me; geodin
R = H; erdin
culmorin
Me
Me
Me
O
Me OH
OH
Me
H
Cl
OMe
O
Me
H
O
J. Chem. Soc. 1951, 2988.
J. Chem. Soc. 1952, 2210.
!-amyrin J. Chem. Soc. 1953, 1027.
Me
O
O
caryophyllene
Me
Me
O
Me Me
Me
O
O
Me
J. Chem. Soc. (C) 1968, 1148.
J. Chem. Soc. 1958, 1767.
H
Me Me
cycloartenol
lanosterol
J. Chem. Soc. 1953, 576.
O
H
J. Chem. Soc. 1951, 1444.
HO
Me
N
H
HO
Me
Me
Me
O
HO
Me Me
H
onocerin
J. Chem. Soc. 1955, 2639.
AcO
H
HO
OH
Me
OH
OH
OH
Me
OAc
Me
H
O
O
Me Me H
clerodin
limonin
H
J. Chem. Soc. 1961, 255.
Me
Me OH
H
cevine
J. Chem. Soc. 1954,3950.
O
OAc
J. Chem. Soc. 1961, 5061.
OH
H
AcO
O
Me
O
O
O
HO
HO
Me
O
H
O
OH
Me
Me
Me
Me
O
H
H
H
Me Me
H
O
O
MeO
fusicoccin
`
J. Chem. Soc. 1971, 1259; 1265.
Me
Me
H
HO2C Me
H
abietic acid
VO5, HNO3
"good yield"
meso compound
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Structure Elucidation
Me
O
O
Me
H
Me
Me H
Me
Me
Me
O Me O
Me
H
Me
O
H
Me Me
glauconic acid
HO
O
byssochlamic acid
J. Chem. Soc. 1965, 1769.
Me
Me
Me
Me
Me
Me
H
Me
Me
HO
H
Me Me
Cl
RO2C O
OH
R = Me; geodin
R = H; erdin
culmorin
Me
Me
Me
O
Me OH
OH
Me
H
Cl
OMe
O
Me
H
O
J. Chem. Soc. 1951, 2988.
J. Chem. Soc. 1952, 2210.
!-amyrin J. Chem. Soc. 1953, 1027.
Me
O
O
caryophyllene
Me
Me
O
Me Me
Me
O
O
Me
J. Chem. Soc. (C) 1968, 1148.
J. Chem. Soc. 1958, 1767.
H
Me Me
cycloartenol
lanosterol
J. Chem. Soc. 1953, 576.
O
H
J. Chem. Soc. 1951, 1444.
Me
HO
Me
N
H
HO
Me
Me
Me
O
HO
Me Me
H
onocerin
J. Chem. Soc. 1955, 2639.
AcO
H
HO
OH
Me
OH
OH
OH
OAc
OAc
H
O
clerodin
limonin
J. Chem. Soc. 1961, 255.
J. Chem. Soc. 1961, 5061.
Me
Me OH
fusicoccin
`
J. Chem. Soc. 1971, 1259; 1265.
Me
Me
MeO
O
Me Me H
H
H
cevine
J. Chem. Soc. 1954,3950.
Me
Me
OH
H
AcO
O
Me
O
O
O
Me
O
H
O
HO
HO
Me
Me
Me
O
OH
O
H
H
H
Me Me
H
O
O
H
HO2C Me H
abietic acid
CO2H
VO5, HNO3
Me
"good yield"
HO2C
CO2H
Me
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Oxidative Phenol Couping and Biosynthetic Implications
These studies were initiated by a disbelief of the proposed structure of "Pummerer's ketone,"
despite being commonly held as true for 25 years.
J. Chem. Soc. 1956, 530.
Me
Me
NMe
HO
O
O
Me
MeO
Me
K3[Fe(CN)6]
high dilution
LAH
NMe
O
NMe
O
1.4%
O
Me
OH
O
O
H
K3[Fe(CN)6]
OH
OH
MeO
MeO
narwedine
"Pummer's ketone"
galanthamine
J. Chem. Soc. 1962, 806.
OH
O H
K3[Fe(CN)6]
OH
Me
Me
Me
O
Me
O
MeO
Me
Barton's Proposal
SeO2;
hydrolysis
AcO
H+
MeO
O
MeO
HO
NaBH4, H+
NMe
OH
O H
Me
MeO
OH
Me
Me
Me
NMe
MeO
O
NMe
H
MeO
OH
O
acetylreticuline
salutaridine
thebaine
MeO
OH
Ac
H
HO
Na2CO3, H2O
K3[Fe(CN)6]
Ac
O
Ac
OH
HO
O
H2SO4
O
HO
O
OH
15%
Me
Me
OH HO
Me
Ac
Me
Me
OH HO
Ac
usnic acid
methylphloractophenone
The natural extension of these concepts led to the formalization of modern phenolic alkaloid and lignan
biosynthesis, and Barton even proposed compounds as necessary biosynthetic intermediates that were
later isolated (e.g. crotonosine, reticuline).
Festschrift Arthur Stoll 1957, 117.
Chem. Brit. 1967, 330.
HO
HO
HO
NH
MeO
MeO
HO
O
H
H
MeO
NH
O
crotonosine
HO
NH
H
NMe
HO
morphine
Proc. Chem. Soc. 1963, 189.
J. Chem. Soc. 1965, 2423.
Barton was also actively engaged in elucidating the biosynthesis of many of these phenolic alkaloids
though the use of radiolabelling studies.
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
This allowed for an expedient synthesis of dimethylcrocetin
Photochemistry
OH
Me
Initially thought that irradiation would result in racemization of the quaternary center via:
Me
Me
Br
Br
O
Me
Me
Me
O
Me
Me
Chem. Ber. 1977, 110 3582.
Me
Br
Br
Br
O
AcO
O
AcO
Me Me
O
AcO
Me Me
O
Me
Me
Me Me
CO2Me
MeO2C
Me
J. Chem. Soc. 1957, 929.
h!
H
Me
O
Me
AcOH
H
O
OAc
H
H
O
Me
Me
O
Me
Me
O
O
OH
Me
O
Me
Br
Synthesis of aldosterone acetate
O
O
Me
Me
Me
Nitrite Ester Photolysis
H
Me
O
O
Me
Br
Me OH
H
Me
O
h!, MeOH;
base
dimethylcrocetin
But only a single new product was formed whose identity was unknown. To investigate
the reaction, a simpler and more readily available model substrate, santonin, was studied.
Me
Me
H
H
OAc
ON
OAc
O
O
NOCl
Me
H
O
H
toluene
H
H
ON
OH
h!
H
py.
O
H
H
Me
H
H
H
O
H
O
corticosterone acetate
Me
J. Chem. Soc. 1958, 140.
O
O
OAc
OH
OH
O
O
Me
AcO
h!
O
H
Me
Me
AcO
Me Me
O
J. Chem. Soc. 1961, 1215.
H
H
AcOH
HNO2
O
OH
H
Me
15% overall
H
H
H
H
O
O
Me Me
OAc
N
aldosterone acetate
As a natural extension, the photochemistry of linear cyclohexadienones were studied and were
found to also have interesting behavior.
J. Am. Chem. Soc. 1961, 83, 4083.
Rearrangement to 18-nor-D-homosteroids
O
R4
R1
R2
h!
O
O
R4
Nu:
R4
Nu
R2
R3
R3
R1
Me O
ONO
R2
R3
R1
J. Chem. Soc. 1960, 1.
h!
H
H
H
toluene
HO
O
H
H
H
J. Am. Chem. Soc. 1961, 83, 4481.
Derek H. R. Barton
Baran Group Meeting
Converstion of lanosterol into cycloartenol
J. Chem. Soc. (C) 1969, 332.
Will Gutekunst
Even higher oxidations states!
O
Me
Me
H
Me
Me
Me R
HO
Me
Me
Me
HO
NH2
Me
H
H
H
Me Me
BzO
lanosterol
I
Me R
O
Me
BzO
HO2C
basic reductive workup
44%
H
MsO
Me
CO2H
H
H
H
H2CrO4
H
Me Me
H
H
h!, I2;
Pb(OAc)4
I2, h!;
H
H
MsO
H
Me Me
J. Chem. Soc. (C) 1968, 2283.
KOt-Bu
t-BuOH
Me
Me R
Me
H
Me
H
LiAlH4
Me
Me
HO
O
Barton some work on the biosynthesis of steroids in the 1970's (feeding studies, etc) but due to
time (and my knowledge of the subject) it will not be discussed.
H
dioxane
Me
BzO
H
Me Me
cycloartenol
Steroid Biosynthesis
Ecdysone Synthesis
H
Me Me
J. Chem. Soc. C. 1970, 1584.
Me R
Me
Modification for directed oxygenation
J. Chem. Soc., Perkins Trans. 1 1973, 2402.
H
Me
Me
Me
H
Me
H
H
AcO
H
Me Me
H
h!, O2
Me
Me
Me
44%
ONO
ONO2
O2
OH
N O
OH
O
AcO
O
OH
O
O
Me
H
Me
NO
OH
Me
AcO
H
Me
HO
Me
Me
AcO
O
H
O
Me
OH
H
Me Me
H
H
Me
H
H
AcO
H
c. MnO2
57–64%
Me
TsOH;
LiBr, DMF
Me
ergosterol
R = C9H17
Me
Me
H
HO
Me R
Me R
a. TsCl, py.
b. KHCO3, H2O
acetone
H
AcO
O
ecdysone
Me R
CO3H
Me
H
H
CO2H
OH
O
Et2O
Me
AcO
H
AcO
H
Light Free Oxygen [4+2]
Me R
Lactone synthesis
J. Chem. Soc. 1965, 181.
Me
Me
NH2
O
hydrolysis
O
Me
Me
Me R
O2, Ar3NSbCl6
Me
O
h!, I2
t-BuOCl;
H
H
AcO
dark, -78° C
DCM, 5 min
quant.
O
AgOAc, I2
AcOH;
Ac2O
cat. HClO4
Me R
OH
H
Me
O
H
O
H
AcO
ergosterol acetate
R = C9H17
J. Chem. Soc., Chem. Comm. 1972, 447.
OAc
Derek H. R. Barton
Baran Group Meeting
Tetracycline Studies
Fluorination
O
O
OMe
H
h!, benzene
O
O
O
CO2Me
OMe
Will Gutekunst
benzoic acid
35%
At the time, most fluorine chemistry was perfomed electrochemically, with the only known
electrophilic fluorine reagent known being the explosive FClO4. Barton developed a number of
hypofluorite reagent, especially CF3OF for this purpose
OMe
H
O
O
O
CO2Me
Me
OMe
AcO
Me
Me
H
H
AcO
OH
-75° C
"good yield"
H
CONH2
OH
OH
H
H
O
O
O
S
OH
H
F
H
H
Me O
H
LHMDS
60%, [gram-scale]
S
H
H
H
O
OH
H
O
F
H
MeO
h!, benzene
CO2Me
Me
same
J. Chem. Soc., Perkins Trans. 1 1973, 2402.
S
O
AcO
S
CO2Me
OH
OH
Me
same
Me
F Me
Me
F
O
Me
O
O
O
Me
H
H
OAc
Me
Me O
6-methylpretetramid
OH
Me
F3COF, CFCl3
OH
OH
OAc
Me
OH
benzeneselenic
anhydride
64%
CO2Me
O
OCF3
same
F
O
OH
O
J. Chem. Soc., Perkins Trans. 1 1981, 1840.
same
Olefin migrations with RhCl3
O
F
cat. RhCl3
EtOH/CHCl3
O
Me
48 hr, 70° C
quant
J. Chem. Soc., Perkins Trans. 1 1977, 359.
"the major effort on tetracycline synthesis convinced me that this sort of work should
be left to Industrial friends who have the money and the resources to finish any multistep synthesis, if it is economically justified. So it is the originality in the reactions
and the reagents and any new principles that finally justify academic effort in
synthesis. We are far away from the Woodwardian dogma of completely planned
synthesis" Reason and Imagination, page 407
Me O
Me O
H
H
F3CO2C
Br
Me
same
H
H
F3CO2C
Br
H
Br
F
Br
"Acid-sensitive substrates have been protected by the inclusion of CaO, MgO, or NaF. Use of pyridine
for this purpose led to the formation of a highly explosive by-product and is therefore discouraged."
Additionally, he discovered that these reagents add to olefins with exclusively Markovnikov cis-addition.
The current process for manufacturing 5-fluorouracil is still the one he developed in 1972.
Chem. Comm. 1968, 804.
Chem. Comm. 1968, 806.
Nouveau J. Chimie 1980, 4, 239
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Me
Vitamin D Syntheses
J. Am. Chem. Soc. 1973, 95, 2748.
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
1. SO2, PhH/H2O
2. EtOH, NaHCO3
heat
H
Me
Me
Me
H
H
H
Me
O
Me
H
HO
HO
Li/NH3, NH4Cl
THF
60%
H
O
cholesterol
Me
Me
Me
AcO
Me
H
h!
H
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
1. h!, acridine
2. TBAF
H
H
71%
H
H
H
HO
Me
Me
Me
OH
HO
OTBS
1"-Hydroxy vitamin D3
J. Am. Chem. Soc. 1986, 51, 1637.
Me
Me
cholecalciferol
H
HO
Me
AcO
Me
HO
3. P(OMe)3
34%
OH
Me
1. Ac2O, DMAP
2. DMDBH
AcO
1. TBSCl
2. SeO2, NMO
MeOH, DCM
55%
H
H
45%
H
H
H
90%
Me
1. DDQ
2. NaOH
H2O2
Me
Me
H
1. 75° C
2. MeOH, KOH
Me
H
Me
H
H
AcO
HO
OH
1"-Hydroxy vitamin D3
Me
Derek H. R. Barton
Baran Group Meeting
Will Gutekunst
Phenylselenic Anhydride
Barton Olefin Synthesis
Since many of the olefin forming methods of the time were adversely affected by steric hindrance,
Barton decided to develop a new olefin synthesis through the use of a two-fold extrusion process. This
would allow the C–C formation ot be intramolecular, and therefore less affected by sterics. Tetra tButyl ethylene was viewed as the holy grail olefin, but was never successfully prepared.
Phenylselenic anhydride proved to be a highly efficient reagent for ketone dehydrogenation and
could also be used in catalytic amounts with hypervalent iodine reagents acting as the reoxidant.
J. Chem. Soc. Perkin Trans. I 1982, 1947.
Me
Me
Me
Concept:
Me
Me
R1
X
R3
R1
R3
R2
Y
R4
R2
R4
+
+ Y
X
H
Me
H
3 mol% BSA
4 eq
H
H
Me
H
73%
H
Systems considered:
R1
R2
Me
J. Chem. Soc. Perkin Trans. I 1972, 305.
S
S
O2
O
R3
R1
R4
R2
S
O2
R3
R1 S S
R4
R2
S
O
R3
R4
S
R2
H
S
R2
R4
R1
R1
R2
O R4
R2
N N R
3
S
R1
R2
R4
N N R
3
S
O
R1
S
O2
Me
O
cat. BSA
m-iodoxybenzoic acid
Me
Me
Me
H
Me
H
H
64%
R4
H
O
H
H
O
HO
Preparation
Me
H
N N R
3
R2
R4
CO2Me
CO2Me
HO
N N R
3
H
S R
3
R1
R4
H
H
O
HO
S
O R
3
R1
H
H
J. Chem. Soc. Perkin Trans. I 1976, 2079.
R1 N N R3
R1 HN NH R3
R2
R2
R4
H2S
S
[o]
R1 N N R3
R2
R4
S
S
R1
R4
R2
Application to the degradation of the Cholic Acid side chain
N2
+
R3
J. Chem. Soc. Perkin Trans. I 1985, 1865.
Me
CO2H
Me
Me
Ph
N2
Me
Ph
S
Me
Me
Me
Ph
Ph
Me
Me
t-Bu
PBu3, !
Me
S
t-Bu
64%
HO
Me
Me
N2
H
96%
Me
Me
Se
PBu3, !
t-Bu
64%
N2
H
H
BSA, py.
quant.
O
t-Bu
Me
Me
O
H
Me
H
H
Me
Cl3OCO
H
Me
N
Me
COCl3
Me
Me Me
Me Me
O
Me
Me
t-Bu
H
H
HO
H
t-Bu
Me
H
Me
B(OH)3, xylene
H
Me
O
OH
H
O
Me
NH2
Me
H
Me
Me
Me
Me
O
PPh3, !
90%
Me
N
R4
N
Me
Cl3CCOCl
Me
O
H
Me
H
H
H
HO
H
H
Me
Derek H. R. Barton
Baran Group Meeting
Radical Revolution
O
Me
Me
O
O3;
saponification
H
Me
H
H
S
H
H
S
H
O
N
Me
Me
Me
H
H
H
Me
H
N
H
N
H
Phenol Oxidations
Me
55%
Me
Me
OH
O
Me
Me
OH
Me
Me
O
Me
Ph
Me
Ph
10%
H
O
S
Me
Bu3SnH
Toluene reflux
O
Me
O
O
Me
Me
H
O
O
Me
O
Me
80–90%
H
O
Me
Selenobenzoates were also examined, but were too reactive and gave large amounts of the free
alcohol. The tellurium analogs, on the other hand, behaved differently during preparation.
Ph
NSePh
Se N
65%
Me
O
MeS
J. Chem. Soc. Chem. Comm. 1977, 147.
J. Am. Chem. Soc. 1993, 115, 948.
O
BSA, HMDS
Me
O
O
OH
Me
DCM
OH
In the mid 1970's, there was a need to replace the secondary hydroxyl groups in amino-glycoside
antibiotics with a hydrogen. Since traditional methods were ineffective, Barton devised a plan to
use radicals to deoxygenate the substrate inspired by the Game-of-Bridge reaction.
Deoxygenation
J. Chem. Soc. Perkin Trans. I 1975, 1574.
Me
NaH, BSA
Ph
55%
J. Chem. Soc. Chem. Comm. 1975, 301.
OH
Me
Ph
H
S
SePh
lysergol
Me
H
h!
O
H
J. Chem. Soc. Perkin Trans. I 1973, 1580.
THF, 40° C
97%
N
H
Me
H
Me
S
Ph
NMe
H
quant.
O
Application to lysergol synthesis
0.5 eq. BSA
3 eq. indole
H
H
H
H
Ph
Me
Me
ambient light
5 days
H
Tetrahedron 1985, 41,4727.
J. Chem. Soc. Perkin Trans. I 1990, 707.
H
OEt
Me
Me
Amines can also be oxidized (primary amines to nitriles, secondary amines to imines, hyroxylamines to
nitroso, hydrazines to azo and amides to imides). Nitrogen containing heterocycles can also be oxidized.
HOH2C
Me
H
H
S
NMe
H
S
S
J. Chem. Soc. 1961, 1967.
Me
H
H
35-40%
H
HOH2C
- CO
OEt
H
Me
AcO
AcO
O
Et2O
97%
S
O
Me
O
BSA
iodoxybenzene
H
Me
S
Thiobenzoate Photolysis (Game-of-Bridge Reaction)
Me
O
h!
OEt
O
H
H
Me
Due to the strong UV absorption of xanthates, Barton reasoned that they may be photochemically
susceptible and lead to bond fissions products. He was pretty much correct.
Acyl xanthates to form acyl radicals.
H
Me
HO
O
Me
O
80%
H
Cl3OCO
Me
N
Me
COCl3
Me
Will Gutekunst
Ph
N
Se
Se
N
N Se
Ph
NMe2
Ph
R OH
Cl
NMe2
Ph
RO
Ph
NaHTe
RO
Ph
Derek H. R. Barton
Baran Group Meeting
The deoxygenation method could also be extended to deamination using isonitrile and thioformates
as substrates.
J. Chem. Soc. Perkin Trans. I 1980, 2657.
OAc
O
AcO
AcO
OAc
Bu3SnH
C
Instead of reduction, the formed alkyl radical can also react with a variety of coupling partners
S
O
AcO
AcO
> 81%
Will Gutekunst
O
O
N OAc
N
98%
This method is now a staple of organic synthesis and many modifications have been made. Olefins
can be made from 1,2 dixanthates and less toxic alternatives to tin have been demonstrated
(hypophosphorous acid being especially cheap and benign).
Radical Anion Deoxygenation
Me
Me
Me
H
S
Et2N
H
H
O
Me
In a strange example, these radicals also react with arsenic, antimony and bismuth phenylsulfides.
Upon exposure to air, these intermediate species immediately oxidize to the corresponding alcohols.
Me
K, 18-crown-6
t-BuNH2/THF
H
Me
In the presence of oxygen hydroperoxides are formed, nitroolefins give nitrosulfides, allyl
sulfides to allylated products, sulfur dioxide to thiosulfonates, white phosphorus to
phosphonic acids, diazirines, etc. See Reason and Imagination pages 597-696.
J. Chem. Soc. Perkin Trans. I 1981, 1501.
J. Chem. Soc. Perkin Trans. I 1981, 1510.
Me
H
H
Me
86%
H
Me
O
H
H
H
H
O
Me Me
H
Me
S
12 hr, 79%
N
S
Me Me
AcO
(PhS)3Sb
DCM
air, water
Sb(SPh)2
OH
This method is particularly well suited to sugar synthesis.
Radical Decarboxylation
S
O
Me
H
S
H
Simple bulky ester reduce in a similar manner, though are less efficient.
Me
Br
BrCCl3
110° C
OAc
N
O
Me
H
t-BuSH
toluene, 3hrs
Me
85%
H
AcO
H
OAc
Me
Me
O
O
O
O
Et3CSH
benzene
N
S
70%
CbzHN
h!
45%
CO2Bn
Me
NH2
N
NH2
O
N
O
O
adenine
S
62%
H
OAc
Me
O
N
CO2Bn
H
NH2
h!
O
N
O
O
Me
Me
NH2
H
O
adenine
N
CbzHN
H2N
CO2H
O
O
SPh
CbzHN
These ideas led to the deoxygenation of tertiary alcohols (these substrates were previously
inaccessible due to rapid Chugaev elimination)
Me
CO2NH2
O N
HO
OH
sinefungin
CO2Bn
O
O
Me
Me
J. Chem. Soc. Perkin Trans. I 1991,981.
Derek H. R. Barton
Baran Group Meeting
Sodium Hydrogen Telluride
Will Gutekunst
OH
Nucleophilic opening of epoxides and reduction of quaternary ammonium salts
Me
Ph5Bi
benzene
Me
Tetrahedron Lett. 1985, 26, 6197.
Me
Me
TsCl, py.
15
O
Me
NaHTe
EtOH
OH
Me
TeH
Ni2B
Me
15
NaHTe
EtOH
Me
Bn N
Me
Me
OH
Me
83%
Me
Me
Me
J. Chem. Soc. Perkin Trans. I 1985, 2667.
OH
78%
Ph
Enolates were also reactive, again under basic conditions C-arylation predominated. Free enols
can be O-arylated under acidic or neutral conditions, but normal ketones are unreactive.
Nitronates, ester enolates and sulfinates were also viable substrates for arylation under basic
conditions.
92%
15
15
O
Me
O
Me
Ph5Bi
KH, 60° C
Ph
Ph
Ph
93%
Me
O
Ph
Bn N
97%
Me
Reactions with olefins
CO2Et
2.5 eq NaHTe
EtOH
Ph
CO2Et
N
HO
2.5 eq. Ph3BiCO3
DCM reflux
O
N
73%
92%
2.5 eq NaHTe
EtOH
Me
Ph
Ph
2.5 eq NaHTe
EtOH
K
Ph
Ph3BiCO3
Ph
Ph
44%
Ph
Ph
no reaction
Me
Later it was found that copper catalyzed these reactions and now anilines and amines were viable
substrates for N-arylation. Similar results were seen with aryl lead (IV) reagents as well.
3 eq NaHTe
EtOH
HO2C
N
Me
100%
Me
MeO
N
MeO
R1
Ni2B
R2
HO2C
HO2C
8
8
8
R1 = H, R2 = Te-alkyl
R1 = Te-alkyl, R2 = H
Me
NH2
1.1 eq Ph3Bi(TFA)2
0.1 eq Cu
DCM
Me
95%
Me
quant.
Me
Organobismuth Chemistry
Me
NHPh
Me
Me
Tetrahedron Lett. 1986, 27, 3619.
Tetrahedron Lett. 1986, 27, 3615.
Tetrahedron Lett. 1987, 28, 3111.
Tetrahedron Lett. 1996, 53, 4137.
Barton initally investigated bismuth chemistry to explore its potential as an oxidant (which it does
well), but also discovered its exceptional ability to arylate a variety of substrates.
Phenol Arylation
Phenols can provide either O-or C- arylated products depending on the bismuth reagent and the
pH of the reaction.
Ph4BiOCOCF3
OPh cat. Cl3COOH
91%
Ph4BiOCOCF3
OH
BTMG
Ph
These bismuth reagents also proved to be effective at cleaving alpha glycols, even trans-diols.
0.1 eq Ph3Bi
NBS
MeCN/H2O
OH
OH
94%
J. Chem. Soc. Perkin Trans. I 1985, 2657.
O
0.1 eq Ph3Bi
NBS
MeCN/H2O
OH
OH
2.5 hr, 72%
O
3.7 hr, 77%
OH
Derek H. R. Barton
Baran Group Meeting
Miscellaneous Chemistry
Will Gutekunst
A Tropone Synthesis
Tetrahedron 1987, 43, 5031.
Sterically Hindered Guanidine Bases; Barton's Base
A number of bulky guanidine bases were prepared from the corresponding ureas or thioureas.
This resulted in the strongest organic bases known at the time and Barton employed them
frequently in his chemistry.
J. Chem. Soc. Perkin Trans. I 1982, 2085.
X
R2N
COCl2
Cl
R2HN
NR2
Cl
OH
Me
Me
CHCl3
PTC
aq NaOH
NR2
R2N
Me
CHCl2
Me
NR2
O
Bu3SnH
AIBN, PhH
Me
Me
80° C, quant.
59%
NR
RNH2
O
Me
Me
Me
X = O,S
Ergosterol Isomerization with Chromium
Nt-Bu
Me2N
Nt-Bu
NMe2
(i-Pr)2N
N
N(i-Pr)2
Me R
N
Barton's Base (BTMG)
pKa = 14
Synthesis 1979, 4, 265.
Me R
Cr(CO)6
octane
Me
DBN
pKa = 13.5
H
H
H
81%
AcO
Synthesis of Vinyl Iodides from Hydrazones
Me
NNH2
2.5 eq I2
3.5 eq BTMG
THF
Me
Me
H
Me R
NNH2
Me R
Cr(CO)6
octane
Me
SePh
10 eq PhSeBr
6 eq BTMG
H
Me
88%
AcO
Tetrahedron 1988, 44, 147.
I
Me
AcO
THF
88%
78%
H
Me
AcO
H
Interestingly, Fe(CO)5 performs the reverse process.
Also vinyl selenides!
Rhenium Catalyzed Silylation
Synthesis of a Stable Dithiet
Me
H
Me R
Ph
Me
H
Me Me
heptane
S
AcO
Me R
Me
S
H
Me Me
H
Me Me
Me R
hν
Me
S
S
S
Me R
POCl3
py.
AcO
Me
AcO
S
Me Me
Me
1.5 mol% Re2(CO)10
4 eq. PhSiH3
Me
quant.
Me
S
Me
AcO
Me Me
S
S
O
OSiH2Ph
Me
86-88%
hν
Me
S
OH
Me
R
H
AcO
Tetrahedron Lett. 1992, 33, 5041.
J. Chem. Soc. Perkin Trans. I 1977, 515.
Me
Me Me
Si
H
O
12-14%
Me
Me
Me
Derek H. R. Barton
Baran Group Meeting
p-Dimethylamino-N-thiosulphinylaniline
P4S10
DCM
Me2N
J. Chem. Soc. Perkin Trans. I 1974,1245.
Me2N
N
N
rt
O
S
N S
S S
Will Gutekunst
Another Side Chain Degradation
Tetrahedron 1989, 45, 3741.
O
Me
OH
H
O
Me
3 eq. SOCl2
py.; CSA;
OMe
H
MeOH
crystalline purple compound
O
Me
OMe
SO
Me2N
Trifluoronitrosomethane
Ac2O
H O
Me
O
J. Chem. Soc. Perkin Trans. I 1974, 2344.
cat. Cu(OAc)2-bipy
DABCO, O2, DMF
H
75-80% from acid
ONO
h!
F3C
CF3
Barton-Zard Pyrrole Synthesis
N N
F3CNO
AdO
Tetrahedron 1989, 46, 7587.
OAd
R
R1
O
+
C N
R2
R1
base
R
R2
O2N
O
N
H
another pyrrole synthesis
R2
F3C
CF3
HS
CO2H
N N
AdO
NH
"
OAd
F3C
DIPEA
NOAd
F
AdO
R3
R1
"wet" MeOH
NaOMe
R4
O NO2
R2
PhSSPh
Bu3P
R1
R3
R2
R4
O NH
AdO NH2
F
R3
R1
N
H
R4
Things I did not cover:
Enolate Anions as Protecting Groups for Ketones
Me
Me
O
Me
H
H
H
O
J. Chem. Soc. Perkin Trans. I 1977, 1075.
Me
O
2 eq Ph3CLi, rt;
LAH, -78° C
Me
HO
Me
50%
O
H
H
H
O
11-oxo-progesterone
Barton also mentions the potential use of this method in Grignard additions, Wittig reactions, etc.
- hundreds and hundreds of papers
- Penicillin research
- Gif chemistry (see alkane hydroxylation group meeting)
"...I found my true role in chemistry as an inventor of chemical reactions. Although, like an artist, I
seek elegance and personal satisfaction, I am still pleased when I do something useful. I realize
that there is a direct relationship between the utility of chemistry and how much academic research
can be funded. It is strange that the same restrictions do not seem to apply for physics or
molecular biology." Gap Jumping, page 109