Chem 201 Van Vranken

Problem Set 7 - Key

Due Tuesday, November 15, 2016

1. a. Suggest a plausible arrow-pushing mechanism for the following transformation. (n-Bu)4N+ is a non-
coordinating cation.
O Bu 4N + -OH O Bu
+ +
OEt O- Bu N Bu + H OEt
Bu

Answer:
-
O :O OH O - O
- OH : OEt + H OEt
OEt .. H
OEt O ONa

b. For reactions involving metal alkoxides, avoid the following types of elementary reaction steps for metal-
oxygen bonds.
..
RO
.. Na H OR' ROH +Na -OR (use the oxygen lone pairs, not the O-Na sigma bond)

no - SN 2
RO Na : O R' R' OH Na OR (don't break the O-Na bond as you attack;
+ break the O-Na bond in a second step )
H
no
SN1
RO Na RO- +Na (ionization of neutral species to give two ions is energetically..costly;
there's nothing you can do with RO- that you can't do with RONa)

Suggest a plausible arrow-pushing mechanism for the following transformation.

O O
Na-OH
Na + H OEt
OEt O

Answer:
Chem 201 Van Vranken

here is the most plausible mechanism following Chem 201 rules

Na Na B H
O - - O O
.. :O O+ :O O
H Na : OEt + H OEt
OEt Na-OH O - ONa
OEt :B OEt

not good; costs immense energy to separate Na+ and -OR

no O - O
: OH : O OH O -
- : OEt + H OEt
Na OH H
OEt +Na OEt O ONa

not so good; draw a C=O resonance structure to see why

O - Na O
O -
.. :O O+ : OEt
H H + H OEt
OEt Na-OH ONa
O+
OEt
Na

c. For reactions involving alkali organometallics, avoid the following type of elementary reaction step for
metal-carbon bonds.

Li -
H 3C H 3C: +Li

Suggest a plausible arrow-pushing mechanism for the following transformation.

2 equiv.
O Bu Li OLi
Bu + Li OEt
Ph OEt Ph
Bu

Answer:
Chem 201 Van Vranken

plausible
- Li+ O +Li
O :O
Li Bu -
Ph Bu : OEt Li OEt
Ph OEt Bu
Ph OEt

O +Li -
Li :O Bu OLi
Ph Bu Bu Bu
Ph Bu Ph
Bu

equally plausible
+Li -
Li : OEt - OEt
O - + O Li Li
Li :O Bu :O Bu +O
Ph OEt Bu
Ph OEt Ph OEt Ph Bu Ph Bu

+Li Li
O -
Li :O Bu :O Bu
Ph Bu Bu
Ph Bu Ph Bu

2. Suggest a plausible arrow-pushing mechanism for the following transformation. In this mechanism, do
not abbreviate the potassium alkoxide base as (B:-); instead clearly show any steps that lead to formation or
cleavage of bonds to potassium.1
n-Hex
K
O O
cat. t-BuOK
+
n-Hex 91% after aq. workup
DMSO
23 °C, 15 h
Answer:
H
+
K Ot-Bu H O t-Bu
.. -K K
.. K Ot-Bu
- O O- + O O
H
C C: RC C RC C RC C
C C
R R

3. Suggest a plausible arrow-pushing mechanism for the following transformation.2 Note the very low
temperature used for these reactions.

O i) n-BuLi O
THF, -100 °C
t-BuO t-BuO 75%
OLi
ii) PhCOPh Ph after workup
Br -100 °C, 5 min
Ph
Chem 201 Van Vranken

Answer:
O
Ph O R Li+
R R ..
t-BuO O-
Li+ Ph Ph product
Br Li Br Li
- Bu Ph
Bu

4. Suggest a plausible arrow-pushing mechanism for the following transformation without using an SN2
displacement. Assume an aqueous workup.3
2.1 equiv.
H MgBr H
BnO N CO2Me BnO N CO2Me
60%
O Cl THF O
- 70 °C

Answer:
:B
H B
H - - ..
.. workup
BnO N CO 2Me BnO N CO 2Me BnO N CO 2Me BnO N CO 2Me
product
O Cl O Cl O O
Mg
Br

5. Suggest a plausible arrow-pushing mechanism for the following transformation.4 Me3SiOH is quite acidic
with a pKa of 10.5

Bu 4N + -OH
OSiMe3 + H 2O Me 3Si SiMe3 91%
EtOH O
23 °C

Answer: (No SN2 reactions)

-
: OH Me
SiMe3 - Si O H ..
-
O H OSiMe3 : OSiMe3
O Me O
Me -
-
: OSiMe3 Me
SiMe3 - Si OSiMe3 .. H OH
O O Me O O OH
Me Me 3Si SiMe3 -

6. Suggest a plausible arrow-pushing mechanism for the following transformation.6

i) n-BuLi OLi
EtO SnBu3 THF, -78 °C EtO
≥ 72%
OEt ii) H 2C=CHCHO OEt
Chem 201 Van Vranken

Answer:
Bu +Li Bu - .. Li+
Bu O
EtO Sn Bu Li Sn - O
Bu EtO Bu EtO Li product
Bu Bu EtO
OEt OEt OEt
OEt

Additional Problems for Your Amusement and Enjoyment

7. Suggest a plausible arrow-pushing mechanism for the following transformation.7

O O
0.6 M HO
H H aq. NaOH CO 2Na
HO OH OMe
80 °C, 2.5 h MeO
HO
MeO OMe 80%
OH

Answer: I think opening of the lactone would precede formation of the quinone methide, but I would accept
the opposite order.
Na
..OH .. H B
H :B NaO -O
+
O Na O O Na O O O
O
H
-O -O
.. Ar O
Ar R Ar R Ar R HO
OMe

H
NaO 2C OH NaO 2C O :B NaO 2C - O: NaO 2C O NaO 2C
Ar Ar Ar Ar CH 2 Ar
B
H
HO ..
sticking
.. to ..
O- O O O O-
3-arrow
OMe OMe OMe OMe OMe
rule
quinone methide
intermediate

8. The Felkin-Anh analysis is used for acyclic carbonyls, not for cyclic ketones. To predict the
stereochemistry of addition to cyclic ketones it often helps to assess the conformation of the substrates and
the steric interactions that affect the nucleophile trajectory. Based on those considerations, predict the
stereochemistry of the products.
a. 8
Chem 201 Van Vranken

NaBH 4

THF
O 25 °C, 18 h OH
Answer:
: Nu
H
=
O HO OH
H

b.9
O OH
LiAlH(OR) 3
t-Bu
75%
OR =
O t-Bu

Answer:
OH
Me Me
Nu
Me H Me
Me Me
O OLi Me Me
Me

9. Suggest a plausible arrow-pushing mechanism for the following transformation.10

O
O
NaOMe
66%
MeOH CO 2Me
23 °C, 2 h
O

Answer:
Na epimerizes
OMe Na + O OMe
.. CO 2Me
OMe OMe
O ..
-O -O
..
-O O

O O O B H

10. Formation of Me3SiOSiMe3 can be used to drive a wide range of reactions. Suggest a plausible arrow-
pushing mechanism for the following transformation.11

cat.
Me 3SiOTf
OSiMe3 Me 3Si-O-SiMe3
+ Me 3SiO O +
CH 2Cl 2
O O O
20 °C, 3 h O
84%
Chem 201 Van Vranken

Answer: Remember that silicon does not undergo concerted SN2 substitution; it involves two steps.
Nu:
Me 3SiO
.. SiMe3
O
OSiMe3 +
O O
.. O O+ O O+ O
Me O
Me -Si Me SiMe3 OSiMe3
SiMe3
SiMe3
TfO OTf

..
O O O O
..
O O +O O O + O
:O O . O O
OSiMe3 Me 3Si + SiMe3OSiMe3 Me 3SiO . Me 3Si
SiMe3
SiMe3
Nu Nu:

11. Suggest a plausible arrow-pushing mechanism for the following transformation.12

OMe OMe
OMe OMe
sealed
tube
MeNH 2
O O
O EtOH N
O 78 °C, 12 h O
Me

Answer: There is some variability in order, but the key steps are elimination of the carboxylate and
conjugate addition of the amine.
Chem 201 Van Vranken
Ar - Ar - Ar Ar Ar
O :O O O
O Me
+N Me N MeHN MeHN
O O
..
-B: H H O O H
O O -O
.. O HO O
Me NH 2 +B H
Ar Ar Ar Ar Ar
O O O O
- O product
MeHN MeHN .. N N: ..
HO O HO O- Me H O Me O N O-
H Me
-B: H
or via B
iminium ion

Ar Ar Ar Ar
O O O O

MeHN MeHN Me MeHN .. MeHN : Me

HO O HO N+ HO NHMe N+
.. or
H H imino H
Me NH 2 -B:
tautomer
Ar
Ar
O product
.. O
N NHMe Me
N N+
Me
H Me HO: H
B -

12. Suggest a plausible arrow-pushing mechanism for the following transformation.13,14

MeO
250 mol% n-BuLi
250 mol %
O + n-BuLi THF 88%
-78 °C - 25 °C, 1 h OLi

Answer:
Li
MeO MeO Li+ MeO MeO MeO Li
H R -. Li
. + Li Bu Bu
O O O Li product
O- OLi
carbenoid

References
1
Babler, J. H.; Liptak, V. P.; Phan, N. “Alkoxide-Catalyzed Addition of Terminal Alkynes to Ketones“ J. Org. Chem. 1996;
61(1); 416-417. Note: R3COH (pKa = 17); RCOCH2R (an enolizable ketone, pKa = 19-20); RCCH (pKa = 25); NH3 (pKa =
38); and CH3CH2H (pKa = 50)
2
William E. Parham, Lawrence D. Jones “Halogen-metal exchange in esters of haloaryl acids” J. Org. Chem.; 1976; 41(16);
2704-2706.
3
Castelhano, A. L.; Horne,S.; Billedeau, R.; Krantz, A. Tetrahedron Lett. 1986, 27, 2435.
4
Šefcík, J.; Rankin, S. E.; Kirchner, S. J.; McCormick, A. V. “Esterification, condensation, and deprotonation equilibria of
trimethylsilanol” J. Non-Cryst. Solids 1999, 258, 187-197. In this paper the reaction was run with sodium hydroxide.
Chem 201 Van Vranken

5
Šefcík, J.; Rankin, S. E.; Kirchner, S. J.; McCormick, A. V. “Esterification, condensation, and deprotonation equilibria of
trimethylsilanol” J. Non-Cryst. Solids 1999, 258, 187-197.

6
Parrain, J-L.; Beaudet, I.; Cintrat, J.-C.; Duchene, A.; Quintaro, J.-P. Bull. Soc. Chim. Fr. 1994,131,304-312.
7
Patrik C. Eklund,* Annika I. Riska, and Rainer E. Sjöholm “Synthesis of R-(-)-Imperanene from the Natural Lignan
Hydroxymatairesinol” J. Org. Chem. 2002, 67 (21), 7544 –7546.
8
Boger, D. L.; Mullican, M. D.; Hellberg, M. R.; Patel, M. J. Org. Chem. 1985, 50 (11), 1904.
9
Haubenstock, H. ”Stereoselectivities of lithium aluminum trialkoxyhydrides” J. Org. Chem. 1973, 38, 1765–1767.
10
Buono, F.; Tenaglia, A. Synlett 1998, 1153-1155.
11
Collins, D. J.; Downes, L. M.; Jhingran, A. G.; Rutschmann, S. B.; Sharp, G. J. Aust. J. Chem. 1989, 42, 1235.
12
Jeffs, P.W.; Redfearn, R.; Wolfram, J. J. Org. Chem. 1983, 48, 3861
13
a) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. “Substituted Alkenediols by Alkylative Double Ring Opening of
Dihydrofuran and Dihydropyran Epoxides” Org. Lett. 2001, 3, 3401–3403; b) Satoh, T. “Oxiranyl Anions and Aziridinyl Anions”
Chem. Rev. 1996, 96, 3303–3326.
14
Doris E; Dechoux L; Mioskowski C “ Recent advances in the chemistry of carbenoids derived from epoxides” SynLett 1998, 4,
337-343.