Chapter 11 1

CHAPTER 11
1. Predict the major product and explain the stereochemistry of the following reaction.
1. The initial reaction with BF3 leads to elimination of the methoxy unit with formation of an iminium
salt. The iminium salt reacts with MeMgBr from the less hindered side to give the methylated final
product, with the stereochemistry shown. The stereochemistry is predicted from the conformational
model in which path B is blocked by the bicyclic ring system and the TBDMS protected alcohol.
Delivery of the Grignard reagent from the less hindered path A leads to the product shown.
A
t-BuMe2SiO t-BuMe2SiO t-BuMe2SiO H CO2Et
H
N Boc
Me
CO2Et CO2Et CO2Et O
MeO N N Me N Si

Boc Boc Boc

B
see J. Org. Chem. 1999, 64, 4304

2. The Grignard reaction of compound 86 in the text gave alcohol 87. Offer an explanation for
this selectivity.
2. This reaction is taken from J. Org. Chem. 2004, 68, 619. Inspection of the model suggests that face A
is less sterically hindered. Delivery of the methyl group from that face is consistent with product
formation. The acetoxy group provides the steric hindrance to the bottom face.

Me O Me O

Me MeMgCl , THF Me
Me
Cl -78 °C → 0 °C Cl
O
H HO H
OAc OAc B
2 Organic Synthesis Solutions Manual

3. Given the reaction sequence, give a mechanistic rationale for formation of the cyclohexanone
product.
3. A reasonable mechanism involves formation of a ketone moiety via the alkoxide, with transfer of the
negative charge to the carbon adjacent to the sulfur. An internal Michael addition of this carbanion
gives an enolate anion (see 13.2 and 13.7), which is hydrolyzed to the final product.

O O O
OH O
KH aq H+

SPh SPh
SPh SPh SPh
see J. Org. Chem. 1985, 50, 4596

4. In each case, draw the transition state for the Cram, Karabatsos and Felkin-Anh models of the
reaction of each molecule with (1) MeMgBr (2) PhMgCl (3) CH3C≡C:-Na+ (4) EtLi.
O O O
MeO O
Me
(a) (b) Ph (c) Me (d) Me (e)
Me
Et
H O Me
Me Me Me Me
Draw the major product(s) that result from each reaction, after hydrolysis.
4. See 7.9.1 for a discussion of these three models
(a) All models predict the same incorrect stereochemistry for all nucleophiles since the actual product
will have the R and OH stereochemistry reversed (see 7.9.4).

OH
Me
Me O Me R
H O Me
Me O

Me Me
1-5
1-5
H 1-5 Predicted for all three models
H H
Me H
H
R = (1) Me (2) Ph (3) MeC≡C: – (4) Et (5)
Cram Karabatsos Felkin-Anh 1,3-dithiyl
 Chapter 11 3

(b) The models predict the same angle of approach for all five nucleophiles. Note that each model
predicts a different product. The Cram and Karabatsos models predict the same diastereomer, but
different enantiomers. Assuming each reaction is not enantioselective, these two models predict the
same diastereomer. The Felkin-Anh model, however, predicts a different diastereomer.

Me Me Me Ph
O O H Me R OH HO R HO
H Me O R
Me H
• Ph Me Ph H
• • Ph Me Me
Ph Ph Ph
Ph H
Me H Me Me Me Me
Ph Me Me Me Me
HO R
Cram Karabatsos Felkin-Anh OH OH
R R
Approach for all five nucleophiles R = (1) Me (2) Ph (3) MeC≡C : – (4) Et (5) 1,3-dithiyl

(c) In this molecule, the OMe group can interact with both Grignard reagents but probably not very well
with the sodium or lithium derivatives. The Cram chelation model is used nonetheless. In the other
models, the OMe group is positioned as close as possible to the carbonyl oxygen. All three models
predict the same major product. Unfortunately, the steric hindrance provided by methyl vs. ethyl is
minimal, and this lack of facial bias means that the reaction is predicted to proceed with poor
diastereoselectivity.

MeO OMe
OMe MeO HO R
OMe O HO R HO
O O Et R
OMe Et Me
Me Me Et Me
• • Et • Me Me
OMe Me
Et Me Et Me Me MeO Me OMe
Me Me Me Me Me Me
Me
Cram Karabatsos Felkin-Anh
R OH R OH R OH
Approach for all five nucleophiles R = (1) Me (2) Ph (3) MeC≡C: – (4) Et (5) 1,3-dithiyl

(d) Both the Cram and Karabatsos models predict the same diastereomer. The Felkin-Anh model
predicts the diastereomer with the opposite stereochemistry of the alcohol moiety.

O
H O R R OH
O HO HO R
• Me
• • Me Me Me

Me Me
Me H Me Me Me
H Me
Me
Cram Karabatsos Felkin-Anh R = (1) Me (2) Ph (3) MeC≡C: – (4) Et (5) 1,3-dithiyl

Approach for all five nucleophiles

4 Organic Synthesis Solutions Manual

(e) All three models predict the same diastereomer.

Me O
O OH
Me H O H Me R
• Me •
Predicted from all models
•
Me Me
H
Me Me R = (1) Me (2) Ph (3) MeC≡C: – (4) Et (5) 1,3-dithiyl
Cram Karabatsos Felkin-Anh

Approach for all five nucleophiles

5. The following reaction gives a diastereomeric ratio of about 3:1. Draw both of these products,
and predict the major product.
5. The selectivity is explained by the Cram model. Attack of BuLi over the less steric hindered H, as
shown in the model, leads to the diastereomer indicated as the major product.

Et
H Bu HO Bu Et
CHO O
HO H
BuLi Via O
O + H • O
O O O
O O H
Et
Et Et Et
see Org. Lett. 2000, 2, 207 Et :
Et 1) Attack here via
(3 less hindered side
 Chapter 11 5

6. Give a mechanistic explanation for the formation of the product shown from the designated
starting material.
6. Initial reaction with the strong base generates the α-carbanion of the sulfoxide. Acyl addition to the
ketone generates the alkoxide as it forms the new C—C bond. The alkoxide regenerates a carbonyl with
concomitant breakage of the bond to generate an ester enolate (see 13.4.2). Acetic acid protonates the
carbanion in a second step to give the final product.

O O
1. LiN(SiMe3)2
Ph Ph
S S
CO2Et CO2Et
O O O O
Ph
O
S O S O S
Ph 2. AcOH Ph
O

CO2Et CO2Et CO2Et

see Tetrahedron Lett. 2000, 41, 377

7. Give the major product for (a-c) when treated with (1) n-BuLi/THF/–78 °C; (2) MeI/–78→0 °C;
(3) aq NH4Cl.
7.
H3C CH3
(a) (b) N (c)
CH3 C≡C—CH3
O CH3 O

8. For each of the following give a complete reaction that illustrates its use for the formation of a
carbon–carbon bond:
8.
(a)
O
CdCl2 Cl
O
2 MgBr )2Cd Ph

Ph
1. n-BuLi , TMEDA
2. allyl bromide

(b)
O 1. BuMgBr , FeCl3 O
2. H3O+

Cl Bu
(c)
6 Organic Synthesis Solutions Manual

O
1. NaCN , THF
Br
2. MeMgBr , THF
(d) 3. H3O+
1. NaNH2
2. MeI
C≡C-H C≡C-Me
(e)
1. NaH , THF Ph
Ph
2/ PhCH2Br Ph
(f)

9. Rationalize formation of the indicated product in this reaction.

9.

O
O O
OMe CH2=CHMgBr O OMe H2O
Ph N HN OMe OMe
THF Ph N Ph N
Me Ph Me
Me Me
Taken from Org. Lett. 2000, 2, 11. Initial acyl substitution of the Weinreb amide generated the
conjugated ketone, along with the amine (MeONHMe). Subsequent Michael addition gave the enolate
anion, and workup with water gave the final β amino ketone product.

10. Each of the following molecules can be used to standardize a solution of an organolithium
reagent. Describe, with reactions, the acid-base chemistry involved in each reaction.
10. In reaction (a), the first equivalent of ethyllithium reacts with the more acidic H2O, but the second
equivalent deprotonates at a carbon of the benzene ring, leading to the two dilithio derivatives shown.
See J. Chem. Soc., Chem. Commun. 1980, 87.
In reaction (b), the first equivalent of ethyllithium removes the more acidic H—N, but the second
equivalent deprotonates at the carbon α to the imine moiety. see J. Organomet. Chem. 1980, 186, 155.

O – Li+
OH O – Li+ O – Li+

Li OMe
OMe EtLi OMe EtLi OMe +
(a)

MeO
MeO MeO MeO
Li
H H Li
N EtLi N EtLi N
(b) N Ph N Ph N Ph

OH O Li O Li
 Chapter 11 7

11. Provide a suitable synthetic sequence for each transformation (a-d).

11. The following are reasonable reagents for each transformation.
A. 1. DIBAL-H , -78 °C 2. H2O
B. 1. aq NaOH 2. pH 7
C. 1. Excess PhMgBr 2. H2O
D. 1. aq NaOH 2. pH 7 3. SOCl2 4. MeMgBr , FeCl3, -78 °C

12. Give the major product of this reaction, with correct stereochemistry, and justify your choice.
12. The epoxidation of the alkene occurs from the face opposite the sterically blocking methyl group
to give A. Once the epoxide stereochemistry is set, reaction with butylmagnesium bromide occurs from
the less hindered face, and at the less hindered carbon (distal to the bridgehead carbon bearing the
methyl group).

Me Me
Me H H
H
HO Me HO Me
HO Me

O HO Bu
A B

13. In each of the following reactions, predict the major product, with the correct stereochemistry
where appropriate:
13.
O
t-BuO2C H Me
N
OH
(a) HO (b) (c) N O
SiMe3 HO2C
O OMe
H
MeO O
O
J. Am. Chem. Soc. 2002, 124, 5380 see J. Org. Chem. 1998, 63, 1704 Org. Lett. 2003, 5, 269
OTBDPS

O Boc
Me
N O
(d) (e) O (f)
N O
O Me
Me H
OMe
Org. Lett. 2003, 5, 1115 J. Am. Chem. Soc. 2002, 124, 4716 Angew. Chem. Int. Ed. 2004, 43, 739
HO
OH O O
H
O NH2 CO2H
(g) (h) (i) O O
O H
Bu
H OAc
see Tetrahedron Lett. 2000, 41, 2369 J. Org. Chem. 2003, 68, 10030 J. Org. Chem. 2003, 68, 6905
8 Organic Synthesis Solutions Manual

PhO2S CO2H
OH OTIPS
O
(j) (k) (l)
N N
OTIPS HO2C CO2H
HO
H
J. Am. Chem. Soc. 2003, 125, 5415 see Tetrahedron Lett. 2000, 41, 2203 Eur. J. Org. Chem. 2003, 848

O O MOMO O
(m) N (n) (o)
MeO CO2Me
HO2C
see J. Org. Chem. 2000, 65, 2824 see J. Org. Chem. 1992, 57, 1047 see Tetrahedron Lett. 1987, 28, 731

Ph
OMe
HO
MeO N O OH
(p) (q)
O O
OMe
NO2 J. Org. Chem. 2003, 68, 8162 J. Org. Chem. 1992, 57, 1047

OMe
MeO

(r) O (s)

BnO O CHO

Org. Lett. 2002, 4, 643 Org. Lett. 2003, 5, 3931

14. Provide a synthesis for each of the following transformations. Show all reagents and
intermediate products.
14. In each case, a possible synthesis is presented. Other solutions are possible for each problem.

(a)
MeO
N O C11 H23 O
Me
C8H17 (CH2)7COOH c
a, b

C8H17 C8H17
Weinreb amide
C8H17 C18 H35
d, e C8H17 C18 H35 f

O
(a) SOCl2 (b) MeNHOMe (c) C11 H23MgBr , THF (d) TsNHNH2 (e) NaBH4 (f) m-CPBA
 Chapter 11 9

(b) All reagents are taken from J. Am. Chem. Soc. 2002, 124, 9718. Asymmetric dihydroxylation
(6.5.2.2), followed by protection of the diol as an acetonide (5.3.3.1), allowed removal of the para-
methoxyphenyl protecting group with ceric ammonium nitrate (5.3.1.1). TPAP oxidation (6.2.6.1i) and
reaction with ethylmagnesium bromide (11.4.3.1) was followed by a second TPAP oxidation to the
ketone, and reaction with vinylmagnesium bromide. Deprotection liberated the diol.

a b c d CHO
HO O O O
OPMP OPMP OH
OPMP HO O O O

e f g h
O O O
OH O OH HO
OH
O O O
HO
(a) AD-mix-β , t-BuOH , H2O (b) Me2C(OMe)2 , TsOH (c) CAN (d) TPAP , NMO
(e) EtMgBr (f) TPAP , NMO (g) CH2=CHMgBr (h) Dowex 50 (H+) , MeOH

(c) Reaction d will generate ortho and para isomers. The para isomer must be separated
chromatographically. A milder Lewis acid may be used for this Friedel-Crafts acylation since phenol is
highly activated (see 16.4.4).
OH
OH
NO2 NH2 OH
a b c d e

OH OH O
O
f g h (a) HNO3 , H2SO 4 (b) H2 , Ni(R) (c) NaNO2 , HCl ; H2O , reflux
O
OH OTs (d) , AlCl (e) Zn(Hg) , HCl (f) 1. 9-BBN 2. H2O2 , NaOH
3
Cl
(g) TsCl , pyridine (h) t-BuOK , t-BuOH , reflux
10 Organic Synthesis Solutions Manual

(d) This sequence is taken from J. Org. Chem. 2003, 68, 9983. Initial oxidation with
tetrapropylammonium perruthenate (6.2.6.1) was followed by addition of the sulfone anion (see 12.2.1)
to the aldehyde. Deprotection of pivaloyl group (5.3.1.3) and a second oxidation to the aldehyde with
the Dess-Martin reagent (6.2.4) was followed by addition of the alkyne anion (11.3.3) to give the
propargyl alcohol. Lindlar hydrogenation provided the cis-alkene (7.10.3) and a final Dess-Martin
oxidation to the ketone completed the sequence.

OPiv OPiv OPiv OH CHO

a b c d e
OH OH OH
OH CHO SOPh SOPh SOPh

MeO2C MeO2C

CO2Me
HO HO O
f g
OH OH O
SOPh SOPh
SOPh

(a) TPAP , NMO , CH2Cl2 (b) PhSOMe , LDA, THF (c) NaOMe , MeOH (d) Dess-Martin
(e) HC≡CCO2Me , LDA , THF (f) H2 , Lindlar catalyst (g) Dess-Martin , pyridine
 Chapter 11 11

(e) All reagents are taken from J. Org. Chem. 2003, 68, 6905. Oxidation of the secondary alcohol
with the Dess-Martin periodinane (6.2.4) was followed by mild basic hydrolysis of the acetate.
Oxidation of the resulting alcohol with tetrapropylammoniumperruthenate (TPAP; 6.2.6.1) gave a
ketone. Ozonolysis under reductive conditions led to the aldehyde unit (6.7.2), and intramolecular aldol
condensation gave the targeted compound as a mixture of diastereomeric alcohols.

HO O O

O O O
a b c
H H H
O H O H O H
OAc OAc OH
H H H
O O O
CHO
O O O
d e
H H H OH
O H O H O H
O O O
H H H
(a) Dess-Martin periodinane, Py , CH2Cl2 (b) K2CO3 , aq MeOH (c) TPAP , NMO , MS 4Å , CH2Cl2
(d) O3 , Py , CH2Cl2/MeOH, Me2S (e) NaOH , MeOH