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Modern Organic Synthesis in the Laboratory

Page 109

Reference: Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67,
5176–5183.

4.3.4.2 Reduction of a Lactone

A solution of the lactone (3.40 g, 13.18 mmol) in dry THF (10 mL) was added drop-
wise to a solution of lithium borohydride (2 M in THF, 16 mL, 32 mmol) in THF
(80 mL) at 0 °C. The mixture was stirred overnight allowing room temperature to be
reached. The reaction was poured into a cold mixture of saturated ammonium
chloride (300 mL) and diethyl ether (300 mL), the phases were separated, and the
aqueous layer extracted with ether. The combined organic extracts were washed
with water and brine, dried (magnesium sulfate), and concentrated. The residue was
purified by chromatography [150 g silica gel, hexanes/EtOAc (3:1 to 3:2)] to afford
3.391 g (98%) of the diol as a colorless oil.

Reference: Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.;
Öhler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026–3042.

4.3.5 Sodium Borohydride/Boron Trifluoride Etherate

Sodium borohydride (5.06 g, 133 mmol) was added in portions to a solution of
2-(carboxymethyl)-4-nitrobenzoic acid (10.0 g, 44.4 mmol) in THF (220 mL). The
contents were cooled to 0 °C, and boron trifluoride diethyl etherate (21.3 mL, 133 mmol)
was added dropwise over 1 h. The mixture was allowed to warm to 25 °C and stirred
for 16 h. The reaction mixture was then cooled to 0 °C and cautiously quenched with
aqueous sodium hydroxide (1 N, 178 mL). The contents were stirred for 3 h, and the
THF was removed under vacuum. The resulting aqueous suspension was cooled to 0 °C
and the product was filtered off. After drying, 7.78 g (89%) of the diol was afforded
as a white solid.

Reference: Quallich, G. J.; Makowski, T. W.; Sanders, A. F.; Urban, F. J.;
Vazquez, E. J. Org. Chem. 1998, 63, 4116–4119.

4.4. Esters and Other Carboxylic Acid Derivatives to Aldehydes

4.4.1 Diisobutylaluminium Hydride

Diisobutylaluminium hydride (DIBAL–H) is a bulky hydride reducing agent that is
very useful for the stereoselective reduction of prochiral ketones and reductions at

88 MODERN ORGANIC SYNTHESIS IN THE LABORATORY

Page 110

low temperatures of the carbonyl functionality. Saturated esters are reduced to
aldehydes at temperatures below −70 °C; however, α, β unsaturated esters are
reduced to the allylic alcohols even with careful monitoring of the internal reaction
temperature. N-Methyl-O-methyl amides (Weinreb amides) are reduced to aldehydes.
In addition, a lactone can be reduced to a lactol or further reduced to the diol.
Reviews (a) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in
Organic Synthesis; Wiley-VCH: New York, 1997, 2nd edition. (b) Brown, H. C.;
Krishnamurthy, S. Tetrahedron 1979, 35, 567–607. (c) Winterfeldt, E. Synthesis
1975, 617–630.

4.4.1.1 Reduction of an Ester

To a solution of the methyl ester (3.72 g, 6.87 mmol) in CH2Cl2 (70 mL) at −78 °C was
added DIBAL-H (8.2 mL of a 1.0 M solution in toluene, 8.2 mmol) slowly, maintain-
ing an internal temperature below −76 °C. The reaction was stirred for 30 min and
then quenched with methanol (3 mL). A saturated aqueous solution of Rochelle’s
salt (sodium potassium tartrate, 130 mL) was added, and the biphasic mixture stirred
overnight. The layers were separated and the aqueous layer was extracted with CH2Cl2
(3 × 40 mL). The combined organic extracts were washed with brine, dried over magne-
sium sulfate, and concentrated. Purification of the crude product by chromatography on
SiO2 (5% EtOAc/hexane) gave 3.28 g (94%) of the aldehyde as a clear oil.

Reference: Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043–2046.

4.4.1.2 Reduction of a Weinreb Amide

To a solution of the N-methyl-O-methyl amide (1.65 g, 3.06 mmol) in THF (30 mL)
at −78 °C was added DIBAL-H (2.90 mL of a 1.5 M solution in toluene, 4.35 mmol).
After the reaction was stirred for 45 min, a saturated solution of potassium sodium
tartrate (100 mL) was added and the mixture extracted with ether. The combined
organic layers were dried, filtered, and concentrated. Purification by flash chromatog-
raphy afforded 1.37 g (93%) of the aldehyde as a colorless oil.

REDUCTIONS 89

Page 218

Ring-closing metathesis, 160–162
Ring-opening metathesis, 160
Rochelle’s salt, 89, 91, 93, 96, 103, 107
Roush crotylation, 138–139

Safety glasses, 3–4
Safety, 3–5
Sakurai reaction, 139

traditional, 139–140
Denmark’s modification, 140

Samarium iodide, 95
Saponification, 53
Schlenk flask, 132, 146, 156
Schotten–Baumann reaction, 51
Schrock’s catalyst, 160, 161
Schwartz hydrozirconation, 140–141
Schwartz’s reagent,

Cp2Zr(H)Cl, 140–141
L-Selectride, 94
Shapiro reaction, 103–104, 141
Sharpless asymmetric

aminohydroxylation, 74–75
Sharpless asymmetric dihydroxylation, 73–74
Shi epoxidation, 75–76
Sideshields, 3
Silica gel:compound ratio, 21
Simmons–Smith reaction, 167
Single solvent crystallization, 23
SnCl4, 139
Sodium amalgam, 155
Sodium azide, 31
Sodium bis(2-methoxyethoxy-

(aluminum hydride), 107
Sodium bis-trimethylsilylamide, 122
Sodium borohydride, 87, 88, 91–92
Sodium bromite, 66
Sodium chlorite, 69, 70, 77
Sodium cyanoborohydride, 101
Sodium hypochlorite, 66, 69, 70
Sodium iodide, 31
Sodium potassium tartrate.

See Rochelle’s salt
Sodium triacetoxyborohydride, 83
Sodium/benzophenone, 6
Solvent purification unit, 7–8
Sonogashira coupling, 141–142
(–)-Sparteine, 116–117
Stabilized ylides, 165–166
Staudinger reaction, 109–110
Still’s flash chromatography

technique, 20–22

Stille reaction, 142–143
Stille–Kelly reaction, 143–144
Sulfide, 78, 79
Sulfinimine, 43
Sulfonamide, 183–184
Sulfone, 79
Sulfoxide, 78
Sulfur trioxide.pyridine, 59
Supercritical carbon dioxide, 8
Suzuki coupling, 144–148, 149
Suzuki–Miyaura coupling.

See Suzuki coupling
Swern oxidation, 58, 62

Takai olefination, 164
TASF [(Et2N)3S

+(Me3SiF2)
−], 128

TBAF. See Tetrabutylammonium
fluoride

TBDPS ether, 175
TCCA, 51, 66
Tebbe reagent, 157, 159
Teledyne ISCO, 22
TEMPO. See 2,2,6,6-

Tetramethylpiperidine 1-oxyl
Tetrabutylammonium

fluoride, 128, 129, 142
Tetrahydropyran, 176
Tetramethylammonium

triacetoxyborane, 95–96
Tetra-n-butylammonium

bromide, 126
2,2,6,6-Tetramethylpiperidine

1-oxyl, 66, 67, 69
Tetrapropylammonium

perruthenate, 67–68
Thexyl borane, 38
Thin layer chromatography, 17–20, 120,

124, 126, 137, 139, 161
Thioimidazoyl carbamate, 81, 82
Thioketone, 43
Thionyl chloride, 45
THP. See Tetrahydropyran
Ti(Oi-Pr)4, 130
TiCl3(DME)1.5, 155–156
TiCl4, 116, 139, 145
Titanocene dichloride, 157–158
Titanocene–methylidine reagent, 159
TLC. see Thin layer chromatography
TLC stains, 17–20

p-anisaldehyde stain, 19
cerium sulfate stain, 19

INDEX 197

Page 219

TLC stains, (cont.)
Hanessian stain, 19

(see also Cerium molybdate stain)
I2 or I2 in silica gel, 19
KMnO4, 19
ninhydrin stain, 19–20
phosphomolybdic acid, 20

(see also PMA)
vanillin stain, 20

TMEDA, 116, 141, 156
TMSCHN2. See

Trimethylsilyldiazomethane
TPAP. See Tetrapropylammonium

perruthenate
p-Tolualdehyde, 155
p-Toluenesulfonic acid

monohydrate, 103–104
p-Toluenesulfonylhydrazide

(TsNHNH2), 101, 103, 104
o-Tolylboronic acid, 146
o-Tolylmagnesium chloride, 132
Tosyl chloride, 51
Tosylhydrazine, 101–102, 144
Tosylhydrazones, 101, 103–104
1,1,1-Triacetoxy-1,1-dihydro-1,2-

benziodoxol-3(1H)-one, 15–16
Trialkylsilanes, 81,105
Tribenzoyl chloride, 49
Tributyltin hydride, 81, 82, 104, 105
2,4,6-Trichloro-[1,3,5]-triazine, 61
Triethylborane, 104, 105
Triethylsilane, 90–91, 103
3-Triethylsilyloxy-1-

iodopropene, 151
Trifluoroacetic anhydride, 60
Trifluoroacetyl amides, 184
Trifluoroacetyl protection of

an amine, 184–185
Trimethylphosphonate, 152

N1,N1,2-Trimethylpropane-1,
3-diamine, 182

Trimethylsilyl diazomethane, 14, 50
Triphenylphosphine, 28, 29, 30, 33, 34, 35,

38, 109, 110, 126, 149, 150, 159
Triphenylphosphine oxide, 109
Triphenylphosphonium methyl

bromide, 159, 165
Tsuji–Trost reaction, 149–150
Two-dimensional TLC, 18–19

Unstabilized ylides, 159, 165
α,β-Unsaturated ketones, 39

(R)-Valinol, 171
Valinol–derived oxazolidinone, 122
Vanadyl acetoacetate

(VO(acac)2), 76
Vanillin stain, 20
Vinylmagnesium bromide, 131
Vinylsilanols, 128

Wacker oxidation, 68
Weinreb amides, 89
Wittig reaction, 159–160, 164–166
Wolff–Kishner reduction, 98–100
Wurtz coupling, 135, 145

Yamada coupling, 48, 49
Yamaguchi esterification, 49
Yb(OTf)3, 166
Ynone, 186

Zimmerman–Traxler
transition state, 112

Zinc amalgam, 102
Zinc borohydride, 92–93
Zinc reagent, 13–14
Zinc–Copper couple, 156

198 INDEX

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