Solutions Manual for Advanced Organic Chemistry Part B: Reactions and Synthesis

260 Pages·2007·19.51 MB·English

by  Francis A. Carey

Solutions to the Problems
Chapter 1
1.1. These questions can be answered by comparing the electron-accepting capacity
andrelativelocationofthesubstituentsgroups.Themostacidiccompoundsare
those with the most stabilized anions.
a. In (a) the most difficult choice is between nitroethane and dicyanomethane.
Table 1.1 indicates that nitroethane (cid:2)pK=8(cid:3)6(cid:4) is more acidic in hydroxylic
solvents,butthattheordermightbereversedinDMSO,judgingfromthehigh
pK (17.2)fornitromethane.Forhydroxylicsolvents,theordershouldbe
DMSO
CH CH NO >CH (cid:2)CN(cid:4) >(cid:2)CH (cid:4) CHC=O(cid:2)Ph(cid:4)>CH CH CN.
3 2 2 2 2 3 2 3 2
b. The comparison in (b) is between N−H, O−H, and C−H bonds. This
order is dominated by the electronegativity difference, which is O>N>C.
Of the two hydrocarbons, the aryl conjugation available to the carbanion
of 2-phenylpropane makes it more acidic than propane. (cid:2)CH (cid:4) CHOH >
3 2
(cid:5)(cid:2)CH (cid:4) CH(cid:6) NH>(cid:2)CH (cid:4) CHPh>CH CH CH .
3 2 2 3 2 3 2 3
c. In (c) the two (cid:7)-dicarbonyl compounds are more acidic, with the diketone
being a bit more acidic than the (cid:7)-ketoester. Of the two monoesters, the
phenylconjugationwillenhancetheacidityofmethylphenylacetate,whereas
the nonconjugated phenyl group in benzyl acetate has little effect on the pK.
O O O O
(CH C) CH > CH CCH CO CH > CH OCCH Ph > CH COCH Ph
3 2 2 3 2 2 3 3 2 3 2
d. In(d)theextrastabilizationprovidedbythephenylringmakesbenzylphenyl
ketone the most acidic compound of the group. The cross-conjugation in
1-phenylbutanone has a smaller effect, but makes it more acidic than the
aliphatic ketones. 3,3-Dimethyl-2-butanone (methyl t-butyl ketone) is more
acidic than 2,2,4-trimethyl-3-pentanone because of the steric destabilization
of the enolate of the latter.
O O O O
PhCCH Ph > PhCCH CH CH > (CH ) CCH > (CH ) CCH(CH )
2 2 2 3 33 3 33 32
1
2 1.2. a. This is a monosubstituted cyclohexanone where the less-substituted enolate
is the kinetic enolate and the more-substituted enolate is the thermodynamic
Solutionstothe
enolate.
Problems
CH CH
3 3
O– O–
C(CH ) C(CH )
33 33
kinetic thermodynamic
b. Theconjugateddienolateshouldbepreferredunderbothkineticandthermo-
dynamic conditions.
–O
CH
3
kinetic and
thermodynamic
c. Thispresentsacomparisonbetweenatrisubstitutedanddisubstitutedenolate.
The steric destabilization in the former makes the disubstituted enolate
preferred under both kinetic and thermodynamic conditions. The E:Z ratio
for the kinetic enolate depends on the base that is used, ranging from
60:40 favoring Z with LDA to 2:98 favoring Z with LiHMDS or Li 2,4,6-
trichloroanilide (see Section 1.1.2 for a discussion).
O–
(CH ) CH
32
CHCH
3
kinetic and thermo-
dynamic; E:Z ratio
depends on conditions
d. Although the deprotonation of the cyclopropane ring might have a favorable
electronicfactor,thestrainintroducedleadstothepreferredenolateformation
occurringatC(3).Itwouldbeexpectedthatthestrainpresentinthealternate
enolate would also make this the more stable.
CH
3
–O
CH
3
CH
3
kinetic and
thermodynamic
e. Thekineticenolateistheless-substitutedone.Noinformationisavailableon 3
the thermodynamic enolate.
Solutionstothe
O– Problems
CH
3
CH
3
CH
3
C2H5O OC2H5
kinetic, no information
on thermodynamic
f. Thekineticenolateisthecross-conjugatedenolatearisingfrom(cid:8)(cid:2)-ratherthan
(cid:9)-deprotonation. No information was found on the conjugated (cid:8),(cid:9)-isomer,
which, while conjugated, may suffer from steric destabilization.
CH CH
3 3
O– O–
CH3 CH3 CH2 CH3
kinetic α,γ -isomer
g. Thekineticenolateisthecross-conjugatedenolatearisingfrom(cid:8)(cid:2)-ratherthan
(cid:9)-deprotonation.Theconjugated(cid:9)-isomerwouldbeexpectedtobethemore
stable enolate.
O– O–
CH CH
3 3
CH CH
2 2
CH CH
3 3
kinetic γ -isomer
h. Onlyasingleenolateispossibleundereitherthermodynamicorkineticcondi-
tions because the bridgehead enolate suffers from strain. This was demon-
strated by base-catalyzed deuterium exchange, which occurs exclusively at
C(3) and with 715:1 exo stereoselectivity.
CH
3
O–
kinetic and
thermodynamic
1.3. a. This synthesis can be achieved by kinetic enolate formation, followed by
alkylation.
O O
CH3 1) LDA CH3 CH2Ph
2) PhCH Br
2
4 b. This transformation involves methylation at all enolizable positions. The
alkylation was effected using a sixfold excess of NaH and excess methyl
Solutionstothe
iodide. Evidently there is not a significant amount of methylation at C(4),
Problems
which could occur through (cid:9)-alkylation of the C(8a)-enolate.
O O
6 eq. NaH CH3 CH3
CH
CH I 3
3
(excess)
CH3 CH3
c. ThisalkylationwasaccomplishedusingtwoequivalentsofNaNH inliquid
2
NH . The more basic site in the dianion is selectively alkylated. Note that
3
the dianion is an indenyl anion, and this may contribute to its accessibility
by di-deprotonation.
O O– O
2 NH – PhCH Cl
2 2
-
Ph Ph Ph CH2Ph
d. This is a nitrile alkylation involving an anion that is somewhat stabilized
by conjugation with the indole ring. The anion was formed using NaNH
2
in liquid NH .
3
CH
3
CH CN CH CN
2 2
1) NaNH
2
N 2) CH I N
3
CH Ph CH Ph
2 2
e. This silylation was done using TMS-Cl and triethylamine in DMF. Since
no isomeric silyl enol ethers can be formed, other conditions should also
be suitable.
f, g. These two reactions involve selective enolate formation and competition
between formation of five- and seven-membered rings. The product of
kinetic enolate formation with LDA cyclizes to the seven-membered ring
product. The five-membered ring product was obtained using t-BuO− in
t-BuOH. The latter reaction prevails because of the 5>7 reactivity order
and the ability of the enolates to equilibrate under these conditions.
O O O O CH3
CCH3 LDA CCH3 KOt Bu C
THF t-BuOH
CH2CH2CH2Br CH2CH2CH2Br
86–94%
77–84%
1.4. a. Therearetwoconceivabledissections.Thesynthesishasbeendonefrom4-B 5
with X=OTs using KO-t-Bu in benzene. Enolate 4-A also appears to be a
suitable precursor. Solutionstothe
Problems
H
X CH X
2
b A –O H 4-A
O–
a
O X
B
O– 4-B
b. There are two symmetrical disconnections. Disconnection c identifies a
cyclobutane reactant. Disconnection d leads to a cyclohexane derivative,
with the stereochemistry controlled by a requirement for inversion at the
alkylation center. Disconnection e leads to a considerably more complex
reactant without the symmetry characteristic of 4-C and 4-D. The trans-
3,4-bis-(dichloromethyl)cyclobutane-1,2-dicarboxylate ester was successfully
cyclized in 59% yield using 2.3 eq of NaH in THF.
XCH CH X
2 2
CO CH
2 3
C
CH3O2C 4-C
X
CO CH CH O C
c d 2 3 D 3 2
CH O C X
3 2
CH3O2C e 4-D
HH
E
X CO2CH3 CO2CH3
4-E
c. There are four possible dissections involving the ketone or ester enolates.
Disconnection f leads to 4-F or 4-F(cid:2). Both potentially suffer from competing
base-mediated reactions of (cid:8)-haloketones and esters (see Section 10.1.4.1).
Potential intermediate 4-G suffers from the need to distinguish between the
ketone enolate (five-membered ring formation) and the ester enolate (six-
memberedringformation).Disconnectionhleadstoatertiaryhalide,whichis
normallynotsuitableforenolatealkylation.However,thecyclizationhasbeen
successfully accomplished with KO-t-Bu in t-BuOH in 70% yield as a 3:2
mixture of the cis and trans isomers. This successful application of a tertiary
halidemustbetheresultofthefavorablegeometryforcyclizationasopposed
to elimination. The required starting material is fairly readily prepared from
5-hydroxy-cyclohexane-1,3-dicarboxylic acid. The disconnection i leads to a
cycloheptanonederivative.Successfuluseofthisroutewouldrequireaspecific
6 deprotonation of the more hindered and less acidic of the two methylene
groups, and thus seems problematic.
Solutionstothe
Problems
CO CH
X CO2CH3 X2 3
O or O
CH CH CH3 CH3
3 3
F 4-F 4-F′
f CO CH CO2CH3
2 3 G
4-g O X
i
O
h H
CH3 CH3 4-G
CH3 CH3
CO CH
2 3
I
O
CO2CH3 C(CH3)2
Cl
O 4-H
X
CH CH 4-I
3 3
d. There are two possible dissections. Route J has been accomplished using
excessNaHinDMF(90%)yieldwithOTsastheleavinggroup.Enolate4-K
doesnotappeartobestructurallyprecludedasanintermediate,aslongasthe
leaving group has the correct stereochemistry.
X O–
J
j 4-J
O
k
K
O–
H
X
O–
X
H
4-K
e. There are two disconnections in this compound, which has a plane of
symmetry. A synthesis using route L has been reported using the dimsyl
anion in DMSO. This route has an advantage over route M in the relatively
large number of decalone derivatives that are available as potential starting
materials.
X 7
CH
3
Solutionstothe
L Problems
CH
3 O– 4-L
l
m
CH
O X 3
M
–O 4-M
f. There are three possible disconnections. Route N leads to a rather complex
tricyclic structure. Routes O and P identify potential decalone intermediates.
Thereisnoevidentadvantageofoneovertheother.RouteOhasbeenutilized.
The level of success was marginal with 10–38% yield, the best results being
with dimsyl anion or NaHMDS as base. KO-t-Bu, NaOMe, and Ph CNa
3
failedtogiveanyproduct.Eliminationofthetosylatewasamajorcompeting
reaction. No information is available on route P.
X CH3 CH3
N –O 4-N
n CHp3 CH3 O CH3 CH3 –O H CH3
O
o –O
P X CH3 X 4-O
X
CH3 CH3 CH3 X
CH
3
–O
–O
4-P
1.5. This question can be approached by determining the identity of the anionic
species and the most reactive site in that species. In (a) CH(2) will be depro-
tonated because of the phenyl stabilization at that site. In (b) a dianion will be
formed by deprotonation of both the carboxy and CH(2) sites. The CH(2) site
willbeamuchmorereactivenucleophilethanthecarboxylate.In(c)thecarboxy
group and CH (cid:2)3(cid:4) will be deprotonated because of the poor anion-stabilizing
2
capacityofthedeprotonatedcarboxygroup.Methylationwilloccuratthemuch
more basic and reactive CH(3) anionic site.
8
O–
Solutionstothe CH3 Ph OEt
Problems (a) PhCHCO2Et (1) 1 equiv LiNH2/NH3 PhCCO2Et via CH2CO2Et
CH2CO2Et (2) CH3I CH2CO2Et 55%
CH O–
3
PhCHCO Et Ph
(b) 2 (1) 2 equiv LiNH2/NH3 PhCCO2Et via OEt
CH2CO2Et (2) CH3I CH2CO2H 86% CH2CO2–
PhCHCO2Et (1) 2 equiv LiNH2/NH3 PhCHCO2H Ph CO2–
(c) via
CH2CO2Et (2) CH3I CHCO2Et O–
CH3 91%
OEt
1.6. These differing outcomes are the result of formation of the monoanion at C(2)
in the case of one equivalent of KNH and the C(2),C(3) dianion with two
2
equivalents. The less stabilized C(3) cite is more reactive in the dianion.
Ph Ph Ph Ph
PhCH Cl PhCH Cl
2 2
Ph CHCCC N Ph CHCC N Ph CCC N Ph CCHC N
2 – 2 2–– 2
monoanion CH Ph dianion CH Ph
2 2
1.7. a. This compound can be made by alkylation of the phenylacetonitrile anion
with a phenylethyl halide.
PhCH2CH2CHPh PhCH2CH2X + PhCHCN
–

CN
b. This alkylation can be done with an allylic halide and the dianion of an
acetoacetate ester. The dianion can be formed both by sequential treatment
with NaH and n-BuLi or by use of two equivalents of LDA.
O O– O–
(CH3)2C CHCH2CH2CCH2CO2CH3 (CH3)2C CHCH2X+ H2C CCH COCH3
c. The readily available ketone 5,5-dimethylcyclohexane-1,3-dione (dimedone)
is a suitable starting material. It can be alkylated by ethyl bromoacetate to
introduce the substituent, then hydrolyzed to the desired carboxylic acid.
O O
CH3 CH3
CH3 CH2CO2H CH3 + BrCH2CO2C2H5
O O
d. This preparation has been done by alkylation of a malonate ester anion,
followed by LiI/DMF dealkoxycarboxylation. Direct alkylation of an acetate
ester might also be feasible.
CH3CH CHCH CHCH2CH2CO2H CH3CH CHCH CHCH2X +–CH(CO2R)2
e. Thisreactioncanbedonebybenzylationoftheanionofdiphenylacetonitrile. 9
Solutionstothe
2,2,3-triphenylpropanonitrile PhCH Cl + Ph CCN
2 2– Problems
f. This 2,6-dialkylation was done as a “one-pot” process by alkylation
of the pyrrolidine enamine using two equivalents of allyl bromide and
N-ethyldicyclohexylamine as a base to promote dialkylation.
2,6-diallylcyclohexanone cyclohexanone + CH CHCH Br
2 2
g. This reaction can be done by sequential alkylations. There should be no
serious regiochemical complications because of the stabilizing influence of
the aryl ring. One sequence employed the pyrrolidine enamine to introduce
the ethyl group (cid:2)C H I(cid:4) followed by deprotonation with NaH and alkylation
2 5
with allyl bromide.
+ C2H5X + CH2 CHCH2X
CH3O CH3CH2 CH2OCH CH2 CH3O O
h. A potential stabilized nucleophile can be recognized in the form of (cid:8)-
cyanophenylacetamide, which could be alkylated with an allyl halide. In the
cited reference, the alkylation was done in liquid ammonia without an added
base, but various other bases would be expected to work as well.
O
CN
H2C CHCH2CPh CH2 CHCH2Br + PhCHCNH2
CN
CNH
2
O
j. Thedesiredproductcanbeobtainedbytakingadvantageofthepreferencefor
(cid:8)-alkylationinenolatesof(cid:8),(cid:7)-unsaturatedesters.Thereactionhasbeendone
using LDA/HMPA for deprotonation and propargyl bromide for alkylation.
CH2 CHCHCH2C CH CH2 CHCH2CO2CH2CH3 + HC CCH2X
CO CH CH
2 2 3
1.8. a. The required transformation involves an intramolecular alkylation. In
principle,theadditionalmethyleneunitcouldinitiallybeintroducedateither
the distabilized or monostabilized cite adjacent to the ketone. In the cited
reference, the starting material was methylated at the distabilized position.
Theketonewasprotectedasadioxolaneandtheesterwasthenreducedtothe
primary alcohol, which was converted to a tosylate. The dioxolane ring was
hydrolyzed in the course of product isolation. Sodium hydroxide was used
successfully as the base for the intramolecular alkylation.
10
Solutionstothe O CH3 O O CH3 O O CH3 O CO2C2H5
Problems CH OH
2 CO C H
1) TsCl 2 2 5
1) LiAlH4 1) NaOEt
CH I
2) NaOH 3
2) (HOCH ) , H+
22
b. Thisringsystemcanbeconstructedfromcyclohexenonebyconjugateaddition
of a malonate ester enolate, decarboxylation, reduction, conversion to an
alkylatingagent,andcyclization.Thesyntheticsequencewasconductedwith
a ketal protecting group in place for the decarboxylation and reduction
O O O O O O
O
KOtTBsuO pyTrsidCinlHeO 1) LCiA2HlH5O42C 1(C) 2(HH5OOC2HC2)2)2C, HH+ CCH2H(C5OO–CH)
2) H+, HO 2) –OH, H+, heat 2 2 2 52
2
c. This reaction can be effected by reductive enolate formation followed by
methylation.Thestereochemistryiscontrolledbytheadjacentangularmethyl
group.
O O
H3C CCH3 H3C CCHC3H
1) Li, NH 3
H3C 3 H3C
O O
2) CH I
3
CH3CO CH3CO
d. The phosphonate ester group is an EWG of strength comparable to an ester
group. The dianion undergoes alkylation at the monostabilized position.
O O O O– O O
n-BuBr
1) NaH
(CH3O)2PCH2CCH3 (CH3O)2PC–HC CH2 (CH3O)2PCH2C(CH2)4CH3
2) n-BuLi
e. This reaction was originally done by forming the enolate with NaNH and
2
thenalkylatingwith2-phenylethylbromide.Otherenolate-formingconditions
should also be acceptable.
1) NaNH
2
PhCH2CO2C2H5 PhCH2CH2CHCO2C2H5
2) PhCH CH Br
2 2 Ph
f. Theuseofmethyl2-butenoateasastartingmaterialidentifiestheothercarbon
fragment as an acetate ester enolate. Conjugate addition was done using