Chapter 14 1

CHAPTER 14

1. Using the tables in this chapter (where possible), particularly Tables 14.1 and 14.2, evaluate the
relative rate of reaction for each of the following. For the faster reaction, predict the structure, and
where data is available predict the regiochemistry and stereochemistry of the major product(s).
1. (a) From Table 14.1, HOMO/LUMO values for methyl acrylate are used for styrene: HOMO = –8.48
eV; LUMO = 0.8 eV. The values for 2-butyne are HOMO = –9.9 eV; LUMO = –3.43 eV. From Table
11.2), values for 2-methoxybuta-1,3-diene are HOMO = –8.62 eV; LUMO = +3.60 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene).
Therefore, the coefficients of the LUMO are required for the alkenes and those of the HOMO for the
diene. Styrene has the following coefficients: c3 = 48; c4 = –.33. No values are given for but-2-yne, but
this is a symmetrical system, and the orbitals coefficients should be the same (0.5). The orbital
coefficients for the HOMO of methoxy-butadiene are: c1 = 0.352; c2 = 0.103.
The rate of reaction is determined by the HOMO-LUMO energy difference. The ΔE for styrene
and methoxybuta-1,3-diene is 9.42 eV. The ΔE for but-2-yne is 12.05 eV. Since the energy gap for
styrene is smaller, that reaction is expected to be faster. For the styrene reaction, the larger coefficients
are correlated and the para product shown is expected to be the major product as a racemic mixture. A
single diastereomer (cis) is produced as a racemic mixture, with none of the trans diastereomer.
.103
Ph Ph
-.33

MeO .352 .48 MeO

(b) From Table 14.1, the HOMO/LUMO values for maleic anhydride are: HOMO = –11.95 eV;
LUMO = –0.57 eV. The values for cyclopentenone are: HOMO = –9.34 eV; LUMO = –0.64 eV. From
Table 11.2, the values of 2-methylbuta-1,3-diene are: HOMO = –9.04 eV; LUMO = +3.38 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene).
Therefore, the coefficients of the LUMO are required for the alkenes and those of the HOMO for the
diene. No values are given for either maleic anhydride or cyclopentenone. Maleic anhydride is a
symmetrical molecule so the coefficients are expected to be 0.5 for both carbons. The coefficients for
acrolein are known (the only conjugated ketone or aldehyde available) so, using these data as a basis, the
coefficient proximal to the carbonyl is the largest. The orbital coefficients for the HOMO of methyl-
butadiene are c1 = 0.340; c2 = 0.296.
The rate of reaction is determined by the HOMO-LUMO energy difference. This ΔE for maleic
anhydride and methyl-buta-1,3-diene is 8.47 eV. The ΔE for cyclopentenone is 8.40 eV. Since the
energy gap for cyclohexenone is slightly smaller, that reaction is expected to be slightly faster. The
regiochemistry is not an issue because maleic anhydride is symmetrical, and the cycloadducts is the one
shown. Only the cis diastereomer will be produced.
O O

O O

O O
(c) From Table 14.1, the HOMO/LUMO values for chloroethene are: HOMO = –10.15 eV;
LUMO = 0.5 eV. The values for methyl vinyl ether are: HOMO = –9.05 eV; LUMO = +2.0 eV. From
2 Organic Synthesis Solutions Manual

Table 11.2, the values of pyrrole are HOMO = –8.2 eV; LUMO = +2.38 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene).
Therefore, the coefficients of the LUMO are required for the alkenes and those of the HOMO for the
diene. Chloroethene has the following coefficients: c3 = 0.67; c4 = -0.54. Methyl vinyl ether has: c3 =
0.66; c4 = 0.72. The orbital coefficients for the HOMO of pyrrole are not given but those for
CH2=CHNMe2 suggest the coefficient distal to the N is larger.
The rate of reaction is determined by the HOMO-LUMO energy difference. This ΔE for
chloroethene and pyrrole is 8.7 eV. The ΔE for methyl vinyl ether is 10.2 eV. Since the energy gap for
chloroethene is smaller, that reaction is expected to be faster.
Since pyrrole is a symmetrical diene, regioselectivity is not important. The cycloadduct is a
bicyclic amine, however, and both endo and exo diastereomers can be formed but endo approach is
favored, and the endo diastereomers is shown as the major product. It is noted, however, that secondary
orbital interactions for chloroethene may not be great. The reaction may be driven more by steric
considerations and will give more exo product.
H
Cl N
NH

Cl
(d) From Table 14.1, the HOMO/LUMO values for acrolein are HOMO = –10.89 eV; LUMO =
0.60. The values for nitroethene are HOMO = –11.4 eV; LUMO = +0.7 eV. From Table 11.2, the values
for 2-cyanobuta-1,3-diene are HOMO = –9.58 eV; LUMO = +2.12 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene).
Therefore, the coefficients of the LUMO are required for the alkenes and those of the HOMO for the
diene. Acrolein has the following coefficients: c3 = 0.404; c4 = –0.58. The coefficients for nitroethene
are c3 = 0.54 c4 = –0.32. The orbital coefficients for the HOMO of cyanobuta-1,3-diene are c1 = 0.595;
c2 = 0.490.
The rate of reaction is determined by the HOMO-LUMO energy difference. The ΔE for acrolein
and cyanobutadiene is 10.18 eV. The ΔE for nitroethene is 10.28 eV. The energy gap for acrolein is
slightly smaller, and that reaction is expected to be slightly faster. The orbital coefficient of the diene is
largest proximal to the cyano group and proximal to the CHO unit in acrolein. This leads to the meta
regioisomer shown.
.490 .404

NC CHO
NC .595 -.581 CHO
 Chapter 14 3

2. In Section 14.8.1, Boger and coworker's conversion of tetrazines to diazines via inverse electron
demand Diels-Alder reactions was mentioned. Give a mechanistic rationale for the transformation
shown, based on this paper, that accounts for formation of the indicated product.
2. This reaction is taken from J. Org. Chem. 2003, 68, 3593. An initial Diels-Alder reaction of the
tetrazine leads to the bicyclic species shown. Boger and coworkers reported that this cycloaddition was
an inverse electron demand reaction. Subsequent retro Diels-Alder reaction releases nitrogen, and
rearomatization generates the diazine product.

OMe OMe

MeO MeO

O O
Ar
N
Me N
- N≡N Me
O N
N N N Me
N N N N
NEt2
NEt2 Ar NEt2
O
O O

MeO MeO

OMe OMe

3. The macrocyclic compound shown, generated in situ, spontaneously reacted to give the indicated
product in 63% yield. Explain the formation of this product.
3. This reaction was taken from J. Am. Chem. Soc. 2003, 125, 13531. The sequence involves a normal
electron-demand transannular Diels-Alder reaction, followed by an inverse electron-demand hetero-Diels-
Alder reaction.

OTBS
TBSO
TBSO CO2Et CO2Et Me
TBSO
TBSO Me Me
Me O O Me Br
OTBS

OTBS OTBS
Me O
CO2Et
Br Br
Me Me
OTBS OTBS Me
OTBS
Me Me

Br Br
OTBS OTBS

CO2Et
Me O
CO2Et Me OTBS
O
H
Me
H
OTBS Me
4 Organic Synthesis Solutions Manual

4. In a synthesis of merrilactone A (see J. Am. Chem. Soc. 2002, 124, 2080), Danishefsky reports the
Diels-Alder reaction gives the cycloadduct shown. This product results from an exo approach of
the anhydride to the diene, assuming a disrotatory motion of the OTBS group. Although this result
is not discussed in the cited reference, offer a suggestion why the Alder endo rule does not predict
the major diastereomer.
4. See J. Am. Chem. Soc. 2002, 124, 2080. This result is not discussed in the cited reference. There are
two possible explanations. One is that the OTBS group offers significant steric hindrance to the methyl
groups, destabilizing the endo transition state and forcing the methyl groups endo and the anhydride unit
exo. Alternatively, one could argue formation of the endo product, but under the thermal conditions of
the reaction, the product epimerizes at both centers adjacent to the carbonyl units, leading to the product
shown. Models are shown for both the isolated exo product, and the endo product that would be predicted
by the Alder endo rule. Energy minimization of the two models shown reveal energies of -16.4 kcal for
the exo and –18.8 kcal for the endo. Without calculating the thermodynamic energies and the transition
state energies, we cannot document a potential effect, but it seems unlikely that an initially formed endo
product would equilibrate to the exo. It is more likely that steric hindrance drives the reaction to give the
exo product. Models shown for the endo and exo approach suggest that an endo approach leads to a steric
interaction of one methyl group with the OTBS unit that apparently overrides the energy gain of a
secondary orbital interaction. Without further information, this is a reasonable explanation.

O t-BuMe2SiO
Exo approach t-BuMe2SiO O Endo approach
mesitylene , 165 °C
+ O
metylene blue, collidine O
74%
O
O
Exo

Exo Endo
 Chapter 14 5

5. For each of the following reactions give the major product, with correct regiochemistry and
stereochemistry:
5.
O H
t-BuMe2SiO CO2Et CO2Et
(a) (b) (c)
N
Ph CO2Et H Me
NO2
J. Am. Chem. Soc 2002, 124, 4628 Org. Lett. 2003, 5, 239
4:1 endo NO2:exo J. Org. Chem. 1999, 64, 6042

OBn
O O
CF3
O N O
(d) (e) (f) N
H H O O
Me
MOMO
see Org. Lett. 2000, 2, 1835 Org. Lett. 2003, 5, 3839 see J. Org. Chem. 1985, 50, 3816
Via internal Diels-Alder reaction
of an acylnitroso compound
Me
N
HO CO2Me

(g) O (h) (i)

CO2Et CO2Me CN
O
CO2Et OH
MeO
MeO
see J. Org. Chem. 1999, 64, 6677 see J. Org. Chem. 2002, 67, 3127 see J. Org. Chem. 1998, 63, 1706

O OH O N OEt
Me OMe
(j) (k) (l) O
N
MeO OH
BnO OMOM
O
J. Am. Chem. Soc. 2003, 125, 13155 J. Org. Chem. 2003, 68, 5274 see J. Chem. Soc., Perkin Trans. 1 2000, 1245

CO2Me
Me
(m) CO2Me
Me

Me Me see J. Org. Chem. 2000, 65, 4189

6. In each case, provide a suitable synthesis. Show all intermediate products and all reagents.
6. Of the following problems, only (c) is taken from published syntheses. If you devise your own
synthesis, you may find that some of the steps you used were tried in the literature and discussed. Other
solutions are possible, however. You may also devise a novel and useful alternative synthesis. In all
cases, your syntheses should be critiqued by and discussed with your instructor.
6 Organic Synthesis Solutions Manual

(a) All reagents are taken from the cited reference. The ketone is converted to an alkene by Horner-
Wadsworth-Emmons olefination (12.5.1.3) and catalytic hydrogenation of the double bond is followed by
LiAlH4 reduction of the ester to an alcohol (7.6.1). Conversion of the alcohol to the bromide using
CBr4/PPh3 (3.4.1) allowed a substitution reaction with the methyl malonate anion, and Krapcho
decarboxylation gave the ester. Condensation with the anion from CH2Br2 was followed by an internal
Diels-Alder reaction to give the target.

a b c d
O O O
O
O
CO2Et EtO2C
HO

Me
e O f O g O h
O O
Br2HC
EtO2C
EtO2C Br
O Me
Br EtO2C O
(a) (EtO)2P)=CHNaCO2Et , toluene , reflux (b) H2 , Pd-C , EtOH (c) LiAlH4 , ether see Tetrahedron Lett. 2000, 41, 1375
(d) CBr4 , ether , PPh3 (e) MeCNa(CO2Et)2 , DMF , 100°C (f) LiCl , DMSO-H2O , 180 °C
(g) CH2Br2 , LDA , THF , -78 °C (h) CF3CH2ONa/CF3CH2OH , RT , 6 d

(b) All reagents are taken from the cited reference. The initial reaction involves conjugate reduction with
Dibal-H and cuprous ion (7.7.1.2), and the resultant enolate anion is trapped with formaldehyde.
Protection with tert-butyldimethylsilyl chloride is followed by heating to induce a retro-Diels-Alder
reaction, and the product is a cyclopentenone. Catalytic hydrogenation of the conjugated ketone allows a
Baeyer-Villiger rearrangement (6.6) to give the lactone. The lactone is opened with the amine shown to
give a Weinreb's amide, which reacts with methyllithum to give the ketone target (11.4.3; 11.6.5).

O O O b O
a
OH OTBS

Me Me Me
O Me
O O
c d e f
OTBS OTBS O
OTBS
Me Me
Me Me
g OTBS
N
MeO OTBS OH see Tetrahedron Lett. 2000, 41, 3631
O
OH
O
(a) DIBAL-H , CuI , THF-HMPA ; HCHO (b) TMSCl , NEt3 , DMAP (c) PhOPh , 280 °C (– cyclopentadiene)
(d) H2 , Pd-C , AcOEt (e) MCPBA , NaHCO3 , CH2Cl2 , 3 d (f) MeONHMe•HCl , Me3Al , 3 h (g) MeLi
 Chapter 14 7

MeO N
N N
H OH
a O b c O
OH MeO
MeO
MeO MeO
MeO MeO
MeO MeO
OMe OMe MeO
MeO MeO
N
O
d O e f
MeO
N N

MeO O
MeO MeO
MeO OMe OMe OMe
(a) , toluene , reflux (b) H2, Pd-C, MeOH (c) (3,4-dimethoxyphenyl)acetyl chloride see Synthesis 1999, 907
N O
(d) Collins oxidation (e) KOH (f) LiAlH4 , AlCl3 , ether-THF

(c) All reagents are taken from Tetrahedron 2003, 59, 1349. A Diels-Alder reaction with cyclopenta-1,3-
diene gave the cycloadduct. Substitution of Cl with SMe was accomplished under phase transfer
conditions, allowing a retro-Diels-Alder reaction to generate the bis-methylthio-substituted quinone. A
hetero Diels-Alder reaction with the azadiene generated the imine, and treatment with acid liberated the
conjugated lactam unit.

O O O O
Cl Cl SMe MeS
a b c

Cl Cl SMe MeS
O O O O O O
MeS OTBDMS MeS O
d e

N NH
MeS MeS
O OTBDMS O
(a) cyclopentadiene , heat (b) 2 eq NaSMe , CH2Cl2-water , phase transfer catalyst (c) 170 °C , 0.2 mmHg
(d) TBDMSO-CH=N-C(OTBDMS)=CH2 , PhH , reflux (e) conc HCl