Chapter 5

CHAPTER 5

1. Boranes are fundamentally Lewis acids and, as such, have a limited range of reactivity. Once the Lewis acid
reacts with a Lewis base, however, an ate complete is formed. The wide variety of Lewis bases makes possible a
range of ate complexes. Ate complexes can react with a wider variety of reagents and undergo rearrangement,
displacement, cleavage, and elimination reactions.

For this reason, boranes are usually converted to the ate

complex to facilitate further transformations.

2. When drawn so that the conformation of the molecule is more representative, as in A, it is clear that borane can
be delivered to the alkene from only one direction. The final product is diastereomer B. The bridgehead methyl
group effectively blocks formation of the other diastereomer. This reaction is, therefore, diastereospecific or at
least highly diastereoselective. The alkene is symmetrical, so addition of boron to the two identical alkene carbons
generates opposite antipodes. The reaction therefore exhibits no enantioselectivity or regioselectivity.

Me
Me

Me

OH
H

Me
H

H
B

H
OH

3. The products are

Me

Me
B

Me
NH2

Me
D

OH

Me

All reactions are straightforward except for E and F. The iodine/hydroxide reagent converts vinylboranes to
vinyl iodides. It is not clear the same reaction occurs with A, and product E could generate D or it could form an
alkene product. The reaction labeled (v) usually gives ketones with trialkylboranes. In this case, 9-BBN was used,
and the most reasonable product is bicyclic ketone F.

Me
(a)

4.

Me
H
Me B
H Et
H

Et

Et
HO

Me
(b)

H Et

Me
Et
H
Me B
Et
H
Et
H

Et
HO
H

Et
Et

Organic Synthesis Solutions Manual

Me

Et
Me

Et

B
Me

(c)
H

Et

Me
Me Me

Et
OH

5. Three examples are shown. There are several other possibilities and a variety of possible alkene and polyene
substrates.
1. B 2H 6
2. NaCN
3. (CF 3CO) 2O
4. NaOH , H2 O2

Ph

1. B 2H 6
2. CO (70 atm)
150C

Ph Me Me

Ph

ethylene glycol
3. NaOH , H2O2

1. B 2H 6
2. acrolein , aq THF

OH

Ph

CHO

6. In this process, borane adds to the alkene, and the initially formed alkylborane reverts back to the alkene and
borane at this elevated temperature. When borane adds again, it can add to one of two alkene carbons. When
borane is lost, two possible alkenes are formed. Under these thermodynamic conditions, loss of borane to form the
alkene and re-addition to form a new borane will eventually accumulate the more stable borane, which has the
borane at the terminal carbon. A reasonable representation of this process is shown.

+ BH3
BH 3
+ BH 3

BH2

+ BH3

+ BH3

- BH 3
+ BH3

BH3
+ BH3

BH3

BH3

BH 2

BH2

BH3

7.

This reaction can be explained by initial addition of borane to the less hindered face of the molecule.

Chapter 5

Examination of the 3D model shows that path B is blocked by the isopropyl group, leaving path A less sterically
encumbered. Delivery of borane from face A leads to 1 as the is the borane product of this addition. The borane is
now situated to coordinate with the oxygen of the proximal carbonyl group as in 2, and transfer of hydrogen
intramolecularly from the top face reduces the carbonyl to give the alcohol with the stereo-chemistry shown.
O

Me

OH
Me

1. BH 3SMe 2
2. H2 O2 , NaOH

O
B
H

see J. Am. Chem. Soc., 1997, 119, 4130 O

O
BH3

H
B
Me

H
H

B
Me

O
1

8.

OH

(a) In this case, a hydroboration route would generate the anti-Markovnikov alcohol that would have to be

converted to a halide. The radical addition of HBr generates that bromide directly.
a

Br

CHO

OH

(a) HBr , t-BuOOt-Bu (b) 1. Mg , THF 2. CH2 O (c) PCC

(b) Without hydroboration this is a difficult synthesis. The alkyne coupling reaction is called a Glaser reaction
(see Sec. 13.8.C). Two sequential Lindlar hydrogenations (Sec. 4.8.B) set the cis geometry of the alkenes. The
problem with this approach is that the first hydrogenation may be difficult to control in terms of reacting with only
one alkyne.

In the second hydrogenation, over-reduction could be a problem, although this is usually not

significant with Lindlar hydrogenation.

a
H

n-C 3 H7
n-C 3H 7

c
n-C 3 H7

n-C3 H7

n-C 3 H7
n-C 3 H7

n-C 3 H7

(a) NaNH 2 ; n-C3 H7 I (b) CuCl2 , NH4 OH

(c) H2 , Lindlar (d) H 2 , Lindlar

(c) The major problem here is stereoselectivity. Most approaches would incorporate a halide or alcohol moiety
and then displace it with ammonia or an amine surrogate such as the phthalimide anion. Methods to incorporate

Organic Synthesis Solutions Manual

halides generally involve cation intermediates and will give the wrong stereochemical halide. Reaction with HBr
and peroxides will give the correct regiochemistry, but as a mixture of diastereomers which must be separated (if
possible). Reaction with potassium phthalimide inserts the nitrogen moiety, and treatment with hydrazine unmasks
the amine.

Me

Me
b

Me O

Me

c
N

Br

Br

Me

NH2

O
(a) HBr , t-BuOOt-Bu (b) chromatography (c) K phthalimide (d) NH 2NH2

(d) The following sequence is offered as a possible alternative synthesis. It is cumbersome and not particularly
attractive. To incorporate the additional carbon atom, a Grignard reaction with formaldehyde is used (see Sec.
8.4.C.i). Incorporation of the bromine via reaction with HBr will generate two regioisomeric bromides, which must
be separated chromatographically (not an easy task). Epoxidation and conversion of the alcohol to a halide is
followed by an internal Grignard ring opening (see Sec. 8.4.E). First, generating the Grignard reagent without
serious side reactions will not be easy. Second, the organometallic can attack the epoxide to form a five-membered
ring that will probably be the major product. Removal of the alkene and alcohol moieties via reduction give the
alkane. Radical bromination will be rather selective for the tertiary bromide, and elimination to the alkene is
followed by oxy-mercuration-demercuration to give the requisite alcohol.

Without question, hydroboration

transforms the hideous approach shown here into a very straight-forward synthesis.
It is noted that choosing a different starting material might allow a non-hydroboration syntheses with fewer
potential problems. It is also noted that the triene starting material must be independently synthesized. With an
alternative starting material to the targeted alcohol, an alternative synthesis may be attractive. Using disconnection
techniques (see Sec. 10.5), a useful exercise is to devise a synthesis of the alcohol and then look up the synthesis of
the triene used in the hydroboration sequence. Compare and contrast the two.

Br

OH
a

Br b

O
e

g
Br

OH

h
OH

(a) HBr - separate isomers (b) Mg ; HCHO (c) i. PBr 3 ii. MCPBA (d) Mg - separate isomers
(e) H 2 , Pd ; PBr 3 ; LiAlH 4 (f) Br2 , h
(g) KOH , EtOH (h) Hg(OAc)2 , H2 O ; NaBH4

Chapter 5

9. As shown in the cited reference, the product of the reaction is that shown (isolated in 7%% yield). Inspection of
the model suggests that top-face (1) is much more sterically hindered than the bottom-face (2). The conformation
of the two rings, along with the substituents effectively block the top face. Delivery of borane, and hence the OH
unit, from the bottom is predicted. In addition, examination of the tow alkene carbons (B,C) shown that carbon C is
less hindered, leading to high regioselectivity for hydroboration at that less crowded carbon atom.

CO2 Me
N
A

SEMO

CO2 Me
N

1. BH3 THF

(1)

2. 3N NaOH , 30% H2 O2

B
C

OBn

OBn

SEMO
OH

see J. Org. Chem., 2003, 68, 5274

( 2)

10.
H

Me Me
O

(a)

O
MeO
P
MeO

Ph

Ph O

OH

OH

(b)

(c)
O

see Indian J. Chem.,

1975, 13, 764

OSiMe2 t-Bu
H
J. Am. Chem. Soc., 2003,
125, 11893

OH

(d)

(e)
N
Me

see J. Am. Chem. Soc.,

1967, 89, 567

J. Org. Chem., 2003, 68, 9502

n-Bu

n-Bu
n-Bu

see Tetrahedron Lett.,

1986, 27, 977

OH

(h)

(i)
O
see Org. Lett., 2000, 2, 2695

Org. Lett., 2002, 4, 2043

(j)

Org. lett., 2003, 5, 27

Org. Lett., 2002, 4, 4681

OH OSi(i-Pr) 3

(k)

Et

see J. Chem. Soc., Chem.

Commun., 1973, 606

Ph

OH

Ph
see Org. Lett., 2000, 2, 1455

(l)
Ph

OH
N
CO2 t-Bu

TBSO
Me

(g)

MeOH2 CO

(f)

n-C 5H 11
Ph
see J. Organomet. Chem.,
1981, 213, C53

Organic Synthesis Solutions Manual

OH

(m)

(n)
n-C6 H13

Ph
see J. Org. Chem.,
1977, 42, 579

OH
n-C6 H13
n-C 6 H13

see J. Am. Chem. Soc.,

1967, 89, 2737, 5478

11. (a) The alkene moiety of the cyclohexene ring is effectively blocked from the bottom face, as it is drawn, by
the bicyclohexane moiety (also see the model). Borane will be delivered from the top face, accounting for the
stereoselectivity. The less sterically hindered carbon (not bearing the isopropyl group) will be the major site for
delivery of the boron, accounting for the regioselectivity.
BH3

BH3
H

Me H

Me

MeO2 C

H
MeO2 C

H
H

OH

(b) Taken from J. Med. Chem., 2003, 46, 1886. Regioselectivity for the less substituted position predicts the
product, and analysis of the model clearly shows that delivery from the bottom face is preferred.
OCH2 Ph
a
b
PhH 2CO

HO

1. catecholborane
LiBH4 , THF
2. NaOH , H2 O2

OCH 2Ph

PhH2 CO

a b

less hindered preferred

12. A synthesis is shown for each sequence. Other synthetic sequences are possible.

Chapter 5

n-Bu
H

H
c

n-Bu

n-Bu

n-Bu

Br

B Br

n-Bu

n-Bu

n-Bu
Br

(a) NaNH 2 ; n-Bu-I (b) i. HBBr 2 SMe2 ii. BBr 3 (c) I 2 , AcOH (d) t-BuLi ; MeOH
see pp 461-462 - text and Tetrahedron Lett., 1986, 27, 977
(a)

Me
a

Me

NH2

Br

N
H

Ph

(b) (a) KOH , EtOH (b) B 2 H6 , 165C , 1-hexadecene (c) 9-BBN ; NH2 SO3 H (d) benzoyl chloride

(c) This was included because it does not require a hydroboration step. The final step (c to d) may occur
spontaneously once the hydroxy-acid is formed. Step d is added as a formalism since sometimes six-membered
rings do not form spontaneously.
Me a

Me

b
Me

Br

HO2 C

Me

Me
OH

HO2 C

d
O

(a) KOH , EtOH (b) O3 ; H2 O2 (c) NaBH4 ; H3 O+ (d) H+

(d)
OMe
O

O
t-BuMe 2 SiO

OMe
O

OAc

O
t-BuMe2 SiO

t-BuMe2 SiO
OHC

O
OAc

t-BuMe 2 SiO

(d) O3 , CH2 Cl2 ; PPh3

(e)

OAc
t-BuMe2 SiO

(b) LiAlH(Ot0Bu) 3 ; Ac 2 O . NaOAc

B(Ipc) 2

OAc
t-BuMe2 SiO

(a) Hg(OAc) 2 , MeOH ; NaBH3 CN/THF

HO
O

; NaBO 3

(c) TMSOTf ,

SiMe 3

see Tetrahedron Lett., 2000, 41, 3801

(e) This sequence is taken precisely from the paper. Hydroboration with HBCl2 generates an intermediate that can

Organic Synthesis Solutions Manual

react with methyl azide to give the corresponding N-methylamine. Subsequent treatment with NaOH allows an
intramolecular SN2 reaction to give the bicyclic amine product.

Br

a
Br
(a) HBCl2

BCl2
(b) MeN3 ; MeOH

Br
b

(c) NaOH

NHMe

N
Me

see Bull. Soc. Chim. Fr., 1995, 1003