Clemmenson Reduction, etc.

1
Clemmensen reduction is the classical method for removing a ketone carbonyl via
reaction with zinc amalgam (Zn/Hg) in HCl.
Another use of this reduction is for removal of a hydroxyl group from an acyloin
such as 538, to give cyclodecanone, 539.
Reaction of the acyloin 540 with acidic zinc chloride, in the presence of 1,3-
propanedithiol, reduced the alcohol via hydrogenolysis, and converted the carbonyl to
a dithioketal (541) in 82% yield.
The dithiane moiety was reduced to 542 in 85% yield with Raney nickel.
O
OH
O
OH
S
S
HS SH
O
Ni(R)
Zn , AcOH
77%
538 539
ZnCl
2
, H
+
540
541 542
CO
2
H
O
MeO
Me
CO
2
H MeO
Me
Zn(Hg) , HCl
536 537
Reduction with tin: Stephen Reduction
2
A classical use of tin that is still used occasionally is the so-called
Stephen reduction Stephen reduction, where a nitrile is converted to the corresponding , where a nitrile is converted to the corresponding
aldehyde. aldehyde.
This intermediate is reduced by stannous chloride to give 547 and
SnCl
2
is converted to tin tetrachloride (SnCl
4
).
Stannous bromide (SnBr
2
) often gives better yields of aldehyde than
stannous chloride.
Most aromatic nitriles give good yields of the aromatic aldehyde.
C!N
C
9
H
19
HCl C
9
H
19
N
H
Cl
SnCl
2 C
9
H
19
NHCl
H
H
H
2
O
C
9
H
19
O
H
545 546 547
NH
4
Cl
548
Radical tin reductions
3
Trialkyltin hydrides, for example, are important for radical hydrogen
transfer in reductions of alkyl, alkenyl, and aryl halides.
This reaction can be made catalytic when the tin hydride is generated
in situ by photolysis of a mixture of trimethyltin chloride and ethanolic
sodium borohydride.
Tributyltin chloride can be used as well.
Vinyl bromides are reduced to the alkene with tin hydride.
O
S
O
Cl
Cl
N(CO
2
t-Bu)
2
O O
n-Bu
3
SnH
O
S
O
N(CO
2
t-Bu)
2
O O
549 550
cat Et
3
B , PhH
reflux

Barton-McCombie reaction
4
An alcohol is converted to a thionocarbonate and then reduced with
Bu
3
SnH and AIBN, which circumvents the need for conversion of the
alcohol to a halide.
This transformation is known as the Barton deoxygenation or the
Barton-McCombie reaction.
In the general reaction, treatment with sodium hydride and then In the general reaction, treatment with sodium hydride and then
formation of a formation of a xanthate xanthate ester (-O-C(=S)R, a ester (-O-C(=S)R, a thionocarbonate thionocarbonate), is ), is
followed by treatment with followed by treatment with tributyltin tributyltin hydride and AIBN to give hydride and AIBN to give
reductive cleavage of the C-O bond. reductive cleavage of the C-O bond.
HO
OCH
2
OMe
PhO
Cl
S
OCH
2
OMe
551 552
1.
, Py
2. Bu
3
SnH , AIBN

Wolff-Kishner Reduction
5
In the presence of base, a hydrazone anion intermediate can be formed
that removes a proton from the acidic solvent leading to reduction.
This process has been termed the Wolff-Kishner reduction.
There are several modications of this procedure, including isolation
of the hydrazone, and using an alkoxide base.
Perhaps the most important change in this reaction is the Huang-
Minlon modication, which uses reuxing diethylene glycol as the
solvent and has been shown to be much more efcient for this
transformation.
Hydrazine is also used to convert an alkyl phthalimide to an alkyl
amine by replacing the H
2
C-NR-CH
2
moiety with a O=C-NHNH-C=O
unit, in what is often called the Ing-Manske procedure.
SO
2
Ph
CHO
MeO
SO
2
Ph
CH
3
MeO
571 572
NH
2
NH
2
, K
2
CO
3
, heat
O(CH
2
CH
2
OH)
2
57%

Diimide Reduction
6
Diimide (NH=NH) is a transient species generated by reaction of acids with
potassium azodicarboxylate, by thermolysis of anthracene-9,10-diimine, from
hydrazine derivatives or tosylhydrazone.
Diimide reduces isolated C=C units to the corresponding saturated derivatives.
It is known that diimide gives primarily cis reduction of alkenes and reduces
symmetrical ! bonds faster than polarized ! bonds.
Diimide can be generated in situ from tosylhydrazine.
Corey showed that the course of a reduction with diimide could be altered by
addition of cupric salts [such as cupric acetate, Cu(OAc)
2
]. This new reagent is highly
selective for the reduction of conjugated alkenes, with specicity for the less
substituted double bond of the diene.
O
O
Me
N
N
CO
2
K
CO
2
K
O
O
Me
DME , AcOH
45C
577 578
+
MeO
NEt
3
MeO
579 580
p-TsNHNH
2
, MeOH
Hydrosilation
7
Alkyl silanes can be used for the reduction of carbonyls and alkenes.
Methylcyclohexene was reduced to methylcyclohexane using a
mixture of triethylsilane (Et
3
SiH) and triuoroacetic acid
(CF
3
CO
2
H), in 72% yield. Under the same conditions, however, 1-
pentene was not reduced.
Ph
Me
O
N
N
H
Me
Ph
Ph
Me
HO
H
+
1. H
2
SiPh
2
2. H
2
O
583
581 582
O O
1. 1.5 Et
3
SiH , 80C
1% ClRh(PPh
3
2. HF , aq MeCN , rt
Formic Acid
8
The most common application of formic acid reduction involves enamines,
presumably via conversion to an iminium salt, which is the actual species
reduced by formic acid.
Reduction of iminium salts proceeds by hydride transfer, with formation of
carbon dioxide.
The hydride approaches from the more sterically accessible face.
A proton catalyzed tautomerization converts enamines to iminium salts,
which are then reduced to the corresponding amine.
Reduction of iminium salts is apparently responsible for the classical
reductive methylation procedure of amines and formaldehyde in the
presence of formic acid.
O
H
O
H
N
Me
CO
2
H
H Me
N
Me
CO
2
H
H Me
N
CO
2
Et
N
O
Me
H
HCO
2
H
N
CO
2
Et
N
O
Me
CH
3
N
Me
CO
2
H
H Me
H
H
+
CO
2
585
586
587
reflux
588 589
35% aq HCHO
88% aq HCOOH
Electrolytic Reductions
9
Read 4.9.J
Bakers Yeast Reductions
10
4.10.E Read Photoreduction
4.10.F. Read Enzymatic reductions
Predit stereochemical induction based on identifying Large (L)
and Small (S) groups around the carbonyl (Prelog's rule).
L
O
S
L
S
HO H
601
enzyme
602

Reduction of ethyl acetoacetate (388) with baker's yeast gave the
(S)-alcohol (603), but reduction of ethyl !-ketovalerate (604) gave
the (R)-alcohol (605).
CO
2
Et
O
CO
2
Et
OH
CO
2
Et
O
CO
2
Et
OH
baker's yeast
67%
388
603
baker's yeast
604
605
Chapter 5. Hydroboration
11
Diborane (B
2
H
6
) reacted with alkenes in ether solvents to
form trialkylboranes (1).
Although the "reaction of diborane with pure olens is
indeed quite slow, addition of mere traces of ether changed
the initially slow reaction to a fast one."
This enhanced acceleration allowed alkylboranes to be
readily formed under relatively mild conditions, allowing
them to be used in synthesis.
R
R
B
6 2
1
+ B
2
H
6
3

C5 Homework
12
2 3 8 10 17a,e
Regioselectivity
13
Borane adds selectively to the less sterically hindered carbon of the
alkene or alkyne, but mixtures are usually observed.
No intermediate, so selectivity is best understood by examining the
four-center transition state required for the addition (see 4).
In 8, the BH
2
moiety is positioned over the less hindered carbon
bearing the hydrogen atoms because this minimizes the destabilizing
steric interactions with the methyl groups on the alkene found in the
other orientation (9).
This interaction destabilizes 9 and leads to selective delivery of
boron to the less hindered carbon via 8.
Me
H
Me
H
H B
H
H
Me
H
Me
H
H B
H
H
8
9
Dialkyl and Trialkylboranes
14
Reaction of 2-methyl-2-butene gives 14, diisoamylborane (diisoamylborane = disiamylborane
= Sia
2
BH)
2,3-dimethyl-2-butene gives 15 (tertiary hexylborane = thexylborane, ThexBH
2
) and "-
pinene (6) gives 16 (diisopinocampheylborane = Ipc
2
BH).
Dienes form cyclic boranes, as with the reaction of reaction of 2,4-dimethyl-1,4-pentadiene
(17) to give 18 (3,5-dimethylborinane).
A highly useful borane reagent is prepared by the reaction of 1,5-cyclooctadiene (19) and
borane, giving 20 (9-borabicyclo-[3.3.1]nonane = 9-BBN).
Me
Me
B
Me
H
Me
Me
Me
B H
2
2
Me
Me
Me
Me
Me
Me
BH
3
BH
3
Me
Me
Me
Me
Me
Me
BH
3
BH
3
Me
Me
Me
BH
2
Me
B H
Me
Me
14 15
6 16 18 17

BH
3
B
H
B
H
H B
20 19

Regioselectivity
15
BH
3 9-BBN
Cl
Ph
Alkene
a
Sia
2
BH
a b a b a b
b
a
b
a
b
a
b
a
b
a
b a
b
a
b
a
b
a
45 45 57 33
56 43 87 3 90 3
51 39 86 5
98 2 94 1
94 06 99 1 99.9 0.1
60 40 98 2
57 43 97 3 99.9 0.1
81 19 98.5 1.5
48 40 60 40

a
Ca is always the less sterically hindered carbon. For disubstituted alkenes, Ca is the carbon distal (most
distant from) a pedant substituent. a and b refer to the points of attachment of the boron atom.
Alkoxyboranes
16
Diborane reacts with alcohols such as methanol to form dimethoxyborane dimethoxyborane
[( [(MeO MeO) )
2 2
BH]. BH].
Similarly, alkyl glycols react to give cyclic dialkoxyborates but these are
somewhat unreactive in subsequent reactions with alkenes.
Catecholborane Catecholborane ( (36 36, formed by the reaction of borane with catechol, , formed by the reaction of borane with catechol, 35 35) )
reacts with alkenes to give an alkoxyborinate, but the hydroboration
reaction requires heating to ~ 100C.
An advantage in using catecholboranes is that the boronic acid byproducts
are more easily hydrolyzed than the corresponding dialkylboranes.
OH
OH
OSiMe
2
t-Bu
OMe
BH
3
O
B
O
H
OSiMe
2
t-Bu
OMe
HO
O
B
O
H
H
35 36 37
100C
38 39
1. 36 , ClRh(PPh
3
)
3
THF
2. NaOH , H
2
O
2

Vinylboranes
17
Boranes add to one # bond of an alkyne just as they add to the # bond of an
alkene and the product is the corresponding alkenyl (vinyl) borane, which
undergoes many of the same reactions as alkylboranes.
Internal alkynes such as 3-hexyne react with diborane to give the
trialkenylborane (53) in moderate yield, but terminal alkynes such as 1-
hexyne give predominantly the 1,1-diboranyl derivative (54), plus unreacted
alkyne.
The 1,1-disubstituted product is formed because hydroboration of the alkene
product competes with reaction of the starting alkyne, but hindered boranes
such as 9-BBN or Sia
2
BH react faster with alkynes than with vinylboranes
leading to less of the 1,1-disubstituted product.
H
BR
2
BR
2
BH
3
THF
H
54
+
BH
3
THF
B
3
53
Oxidation to Alcohols
18
B
R
R
R
O O
H
R
B
R
OR
RO
B
RO
OR
HO
B
OH
OH
R
B
R
OR
HO
2

+ H
2
O
+ OH

+ 3 ROH
H
2
O
2
+ OH

R
3
B + HOO

119 120
120 121

The two-step hydroboration-oxidation sequence is the preferred
method for conversion of alkenes to the less substituted alcohol.
Oxidation of the alkylborane with basic hydrogen peroxide
proceeds by initial attack at the boron to give an ate complex
(119), followed by a rapid B$O alkyl shift to form borinate 120.
Additional hydroperoxide anion reacts to transfer the other R groups,
generating 121.
Final hydrolysis liberates the alcohol.
Oxidation to Alcohols
19
Me
B
3
Me
H
2
O
2
NaOH
Me
OH
OH
1. Sia
2
BH
2. H
2
O
2
, NaOH
124 125
3
BH
3
, heat
122
123
C
5
H
11 OH
C
5
H
11 OH
HO
OH
HO
9-BBN
C
5
H
11
H-B
B n-C
7
H
15
n-C
7
H
15
B
NaOH
H
2
O
2
H
2
O
2
NaOH
+
126 127
2
+
2
128
2
must separate
Asymmetric Hydroboration
20
The most common synthetic application is to prepare chiral alcohols
from alkenes, using diisopinocampheylborane (14, Ipc
2
BH) or
monoisopinocampheylborane (147, IpcBH
2
) derived from "-pinene
(6), as well as dilongifolylborane (148, Lgf
2
BH), which is derived from
longifolene 149.
These chiral non-racemic reagents react with alkenes in the usual
manner to give a chiral, non-racemic alcohol after oxidation with basic
hydrogen peroxide.
BH
Me
Me
Me
HB
R
1
R
2
R
3
H
BH
2
H
R
2
B
H
R
1 R
2
R
3
NaOH
H
2
O
2
R
1
HO
H
R
1
R
2
R
3
Me
Me
Me
Ipc
2
BH
151 150 152
6 14 147 148 149
2
2
Asymmetric Hydroboration
21
The stereogenic center of the newly formed alcohol usually has the opposite
chirality relative to the organoborane [()-IpC
2
BH gives the (R)-alcohol and (+)-
IpC
2
BH gives the (S)-alcohol].
R
1
R
2
R
3
H
H
R
2
B
H
R
1 R
2
R
3
NaOH
H
2
O
2
R
1
HO
H
R
1
R
2
R
3
Ipc
2
BH
151 150 152
Hydroboration of cis alkenes with 14 gives higher
enantioselectivity than obtained from trans alkenes or hindered
terminal alkenes.
BH
14
2
153 155 154 156
cis-2-butene
trans-2-butene
cis-2-butene
trans-2-butene

Asymmetric Hydroboration
22
Monoisopinocampheylborane (147) is another important
chiral borane formed by reaction of "-pinene with the
triethylamine complex of thexylborane to give the
monoisopinylcamphylboranetriethyl-amine complex.
The highest enantioselectivity is observed with trans
alkenes (see 165).
cis alkenes show the worst selectivity.
BH
2
147
cis-2-butene
trans-2-butene
trans-2-butene
R
1
R
2
R
3
H R
2
B
R
1
R
2
R
3
H
H
NaOH
H
2
O
2
R
1
HO
H
R
1
R
2
R
3
IpcBH
2
166 165 167
168 169a 169b

Asymmetric Hydroboration
23
Dilongifolylborane (148) was prepared by reaction of the
dimethyl sulde complex of borane with (+)-longifolene
(149), which is readily available [the () antipode is rare
however].
This reagent gives good enantioselectivity with both cis
and trans alkenes, as well as 1,1-disubstituted alkenes.
Me
Me
Me
HB
148
2
cis-2-butene trans-2-butene
171
170
Protonolysis
24
Alkylboranes can be hydrolyzed with aqueous mineral acids, but
only under vigorous conditions.
Conversion of tri-n-butylborane to di-n-butylboronic acid (64)
required heating with 48% HBr at reux, and proceeded through the
intermediate bromoborane 63.
A more useful method for protonolysis is the reaction of
alkylboranes and carboxylic acids at temperatures near 100C.
Me CO
2
H
BR
3
Me
O
O
H
B R
R
R
Me
O
O
B
R
R
+ RH
66
65
Bu
B
Bu
n-C
4
H
9
Bu
B
Bu
Br
H
2
O
Bu
B
Bu
OH
48% HBr
reflux , 1 h
+ n-C
4
H
10
+ HBr
63 64
100C
Protonolysis
25
Potonolysis of alkenylboranes to generate an alkene is
faster than protonolysis of alkylboranes.
Protonolysis proceeds stereospecically with retention
of conguration.
C
4
H
9
(CH
2
)
7
O
O
C
4
H
9
(CH
2
)
7
O
O
1. (c-C
6
H
11
)
2
BH , THF
2. AcOH , 45C
3. aq NaOH , H
2
O
2
72 73

Bu
B
Br
B-H
2
2
Bu Br
NaOMe
Bu
B
OMe
AcOH
Bu
60 89 90 91

Diene Formation
26
H
O
2
, MeOH
86
Cu(OAc)
2
pyridine
1. Sia
2
BH
2. AcOH
97 98
Bu Cl
BH
2
Bu
Bu
B
MeO
NaOMe
B
H
Cl Bu
Bu
Bu
Bu H
B
Cl
Bu
Bu 99
25C , 1 h
AcOH , reflux
100
101
102 103

Bu Br
Bu
B
Br
Oi-Pr
Oi-Pr
KHB(Oi-Pr)
3
Br
n-C
6
H
13
Bu
n-C
6
H
13
1. HBBr
2
SMe
2
2. i-PrOH
1.
2.
60 107 108
Bu H
Bu
B Br
Br
Bu
AcOH
I
2
Br
Bu
Bu
Bu
Bu
1. HBBr
2
SMe
2
2. BBr
3
1. t-BuLi
2. MeOH
104 105 106
Z,Z
E,E
E,Z
Z,Z
Carbonyl Formation
27
R
B
R
C
R
N
C
O
CF
3
N
C
O
B
C
R
R
R
CF
3
C
O
CF
3
F
3
CCOO
R
B
R
R
CN
(CF
3
CO)
2
O
F
3
C
C
O
O
NaOH
F
3
CCO
2
B
C R
R
R
O
C
N
C
O
CF
3
CF
3
H
2
O
2
NaOH
C
R
R
R
OH
BH
2
B
MeO
NaCN
B
MeO
CN
Na
OMe
MeO
O
1.
2.
1. (CF
3
CO)
2
O
78 ! 20C
2. mCPBA
191
192 193 194
186 187
188 189 190

carbonylation
R
B
R
R
R C
R
R
B O
NaOH
H
2
O
2
R C
R
R
OH
B
2
H
6
B
H
H H H
H
H OH
1. CO , 70 atm, 150C
2. NaOH, H
2
O
2
201 202 203
CO (70 atm)
150C
199
200
Amine Formation
28
B
Et
Et
Et
N
Ph
N N
B
Et
Et
Et
N
Ph
N
2
B
Et
Et
N
Et
Ph
N Et
Ph
H
+
xylene
reflux
9 h
1. MeOH
2. NaOH ,
H
2
O
2
229 230 231

Hydroxylamine O-sulfonic acid
Aryl azides
NH
2
Bu
Bu
B
Bu
Bu
B N
H
2
Bu Bu B
Bu
Bu
NH
2
-X
X
2
Bu B
Bu
Bu
:NH
2
X
Ph
:NH
2
X
2 X
Ph
NH
2
2 NaOH
Bu NH
2
2
221 222 223 220
224
1. BH
2
ClSMe
2
, CH
2
Cl
2
2. Me
3
Al , hexanes
3. NH
2
OSO
3
H, THF
B
H
2
N-OSO
3
H
ClNH
2
NH
2
3
220
NH
2
220
Chapter 6. Stereocontrol & Ring Formation
29
Regiocontrol
Me
Br
H
t-BuO
-
K
+
t-BuOH
Me
51 52
Me
H
H
Br
2. mcpba
Me
H
H
S
O
Ph
Me
H
heat
1. PhS

53 54 55
Br
HBr
OH
PBr
3
Br
1. Sia
2
BH
2. NaOH , H
2
O
2
Homework - chapter 6
30
1, 2, 7, 9, 11, 12a,b,d,e
Regiocontrol
31
H
H
Me
H
H
EtO
H
H
56 57 58
1. H
3
O
+
2. MeLi
3. SOCl
2
,
Py
1. H
3
O
+
2. Ph
3
P=CH
2
1
2
3
4
Retention vs. Inversion
32
Stereocontrol: Retention vs. Inversion
Me
OH
H
SO
2
Cl
Me
O
H
S
O
O
Me
NaN
3
Me
H
N
3
Py
Me
OH
H
SOCl
2
Me
O
H
S
Cl
O
Me
Cl
H
SO
2
1 2
Me
OH
H
SOCl
2
N
N H
Cl
Me
O
H
S
Cl O
S
N
2
Me
H
Cl
3 4
+
1
S
N
i
Mitsunobu
33
Stereocontrol: Retention vs. Inversion
O
O
O
O
O
NHCO
2
Me
OMe
O
O
O
O
OH
NHCO
2
Me
OMe
O
O
O
O
OBz
NHCO
2
Me
OMe
9 10
11
NaBH
4
, CeCl
3
MeOH
80%
DEAD , PBu
3
BzOH , THF
75%
Cis vs. trans
34
Stereocontrol: cis vs. trans
n-C
4
H
9
(CH
2
)
5
-OTHP
HO
O
HO
O
(CH
2
)
5
-OTHP
n-C
4
H
9
H
2
, Lindlar catalyst
20
21
quinoline , MeOH
Na , NH
3
22
23
Chelation Effects
35
Henbest Reaction
OH
RCO
3
H
O
H O
H
O
O
R
OH
O
34 35 36
Coordination of the Reagent
Me
O
OH
Zn(BH
4
)
2
OH
O
Me
Zn
H
4
B
BH
4
H
3
O
+
Me
OH
OH
Me
OH
OH
39 40
41 42
+
Chelation Effects
36
Sharpless Epoxidation
Coordination of the Reagent
PhMe
2
Si OH
PhMe
2
Si OH
O
t-BuOOH , CH
2
Cl
2

Ti(Oi-Pr)
4
()-diisopropyl tartrate
mol sieve 4 37 38
Cyclic Systems
37
Diastereoselection
O
O
O
HO
CO
2
Me MeO
2
C
t-BuO
2
CNH O
O
O
O
CO
2
Me MeO
2
C
t-BuO
2
CNH
NaBH
4
O
O
O
HO
CO
2
Me MeO
2
C
t-BuO
2
CNH
74 75 76
TPAP , NMO
Cyclic Systems
38
O O
CO
2
R
O
CO
2
R
O
(CH
2
)
n
(CH
2
)
n
CO
2
R
(CH
2
)
n
b
a
65 64 66
n = 5
n > 6
a
b
t-BuO

K
+
t-BuOH
a
b
a
b
Br
t-BuO

K
+
t-BuOH
59 60 61 62 63

The transition state energy required for elimination to a
bridgehead carbon in small systems is typically very high,
and small bicyclic systems cannot accommodate this great
increase in strain.
The observation that carbon-carbon double bonds cannot be The observation that carbon-carbon double bonds cannot be
formed to bridgehead atoms in small bicyclic rings is formally formed to bridgehead atoms in small bicyclic rings is formally
called called Bredt's rule Bredt's rule. .
Reactions that should lead to such compounds will be
hindered or will take a different course.
Prelog and co-workers established that cyclization of 64 gave 65 when n > 6.
Cyclic Systems
39
1. For homologs with different S values, the ring strain varies inversely with S.
2. For a given S, the ring strain varies inversely with the size of the larger of the two rings with respect to
which bridgehead bond is endocyclic.
3. For a given bicyclic ring skeleton, the ring strain varies inversely with the size of the bridge containing
the bridgehead double bond.
_
_ _ _
_ _ _ _ _
_ _ _ _ _ _
_ _ _ _ _ _ _
_ _ _
_ _ _
[2.2.2]
[2.2.1]
[2.1.1] [2.1.1]
[1.1.0]
[1.1.1] [2.1.0] [2.1.0]
[3.1.0] [3.1.0] [2.2.0]
[4.1.0] [4.1.0] [3.1.1] [3.1.1] [2.2.1]
[3.2.1] [3.2.1] [3.2.1] [4.1.1] [5.1.0] [4.1.1]
[5.1.1] [5.1.1] [4.2.1] [3.2.2] [3.2.2] [3.3.1]
S = 2
S = 3
S = 4
S = 5
S = 6
S = 7
S = sum of the numbers of the bridged atoms

Control of Acyclic Selectivity by Cyclic Systems
40
",%-functionalization
OH
OH
n-C
7
H
15
O
1. O
3
2. NaBH
4
135 136
4 steps

O
H
2
NNHTs
NNHTs
O
137 138 139
MeOH , cat AcOH
reflux
3 eq MeCO
3
H
toluene-water

O HO
HO
OH
NH
3
+
Cl

OH
O
O
O
O
2
CPh
N
3
OH
Ph
OH
NH
2
OH
OH OH n-C
11
H
23
140 141 142
4 steps 7 steps

Control of Stereochemistry