Umpolung Synthesis

-see Furhop, J.-H.; Li, G. Organic Synthesis-Concepts and Methods , Wiley-VCH, 2003.

Organic molecules have innate reactivity patterns imposed upon them by virtue of the functional groups within their structures. This was taken advantage of extensively in the 331 course; for example:

O due to the difference between O and C R δδδ R + _ O O O base and due to R' R' R' R _ R R δδδ-

In fact, this pattern of alternating reactivity can continue infinitely as long as the conjugated multiple bonds continue, as in O δδδ+ δδδ+ δδδ+ δδδ+ R δδδ+ δδδ- δδδ- δδδ- δδδ-

As a result, certain patterns are easy to make, such as 1,3-dioxygenated compounds, or 1,5-dioxygenated compounds. The same could be said for nitrogen containing compounds, but we will focus on the former.

1,3-dioxygenated cpds can manipulate oxidation states O O O OH by oxidation/reduction reactions 1 R + 2 2 R _ R2 H R 1 3 R R1

1,5-dixogenated cpds

O O O O _ R2 R2 1 + 2 4 R1 R 1 3 5 2 + R _ R R R O R1 O

So, the question then becomes, how does one go about making 1,2-dioxygenated and 1,4-dioxygenated compounds?

What is required is some way of inverting reactivity of carbonyl or carbonyl-like compounds. This ‘inverted’ reactivity is called reactivity (or Umpolung synthesis).

O δδδ- δδδ- δδδ- δδδ- Umpolung reactivity δδδ R - δδδ δδδ δδδ δδδ + + + + 1

-For a text, see Umpoled , Hase, T. A., Ed.; Wiley Interscience, 1987.

Let’s start with 1,2-dioxygenated compounds

1,2-Dioxygenated compounds

Reasoning from first principles, making these compounds with require one of two approaches, either:

" " O O O _ + R1 R H R1 R acyl anion OH

or _ O O O 1 R1 R1 + " +O-R2 " R R R _ R electrophilic OR2 oxygen

A. We’ll start with the 1 st approach. What can we possibly do for an acyl anion equivalent? (see Wyatt, Warren, Ch. 14; Furhop, Ch. 1.7)

1) Acetylide anions. Recall that terminal alkynes are relatively acidic, especially for hydrocarbons. This can be used; so…

H MeLi Li ≡≡≡ _ not normally isolated but stable C at low temperature H H C THF or Et2O H

pKa = 25

O 1) add OH OH Li + R H R or R H 2) H O workup R1 O 2 H H or R R1

This can be convertable into a 1,2-dioxygenated compound, by an electrophilic addition of water across the triple bond. Recall that this requires an Hg 2+ salt to make this happen.

2

OH

OH 2+ favoured Hg H R H OH OH + R H3C H+,H O H H R R H 2 OH OH O H disfavoured + R H

This is somewhat limited, because it is only applicable to the anion of acetylene (ethyne) itself. If there are more substituents on the alkyne, there is a problem with the regiochemistry of H 2o addition to the propargyl alcohol. On the other hand, since acetylene/acetylide is small, this transformation often works with sterically hindered carbonyl partners.

OH OH 1 OH Hg2+ R neither strongly preferred R R1 R or -get mixture of H O addition + + R 2 1 + products R H ,H2O H H

Other Sources of X- ̅CH 2

Cyanide ̅CN commercially available as NaCN, KCN, from H-CΞN pK a = 9.2

Nitroalkanes _ O base O NO2 _ N _ H C N _ 3 H2C O H2C O pKa = 10 (H2O) 17.2 (DMSO - Bordwell pKa)

Dithianes

anion stabilized by base -polarizability of weaker C-S bond SS SS σσσ _ -overlap with * of C-S (negative hyperconjugation) R H R

pKa = 36.5 - 39 pKa LDA = 41-44 (DMSO), 35.7 (H2O)

2. Ion

Cyanide ion will add to most and reversibly to give a cyanohydrin. It is more often base catalyzed, but acid and Lewis acid catalyzed versions are known as well.

3

H + OH O O + + HCN  R CN R R1 R R1 CN R1

O O  + H-C≡≡≡N + base base-H+ + CN + R R1 R R1

_ OH O + base R CN base-H+ + 1 R CN R R1

This sometimes has problems with forcing the reaction to the product side, and a competing , so the reaction is usually performed by trimethylsilyl cyanide and a Lewis acid.

O O-SiMe BF3-OEt2 3 OH Me Si C≡≡≡N + R R1 3 R CN R CN CH Cl 1 2 2 R R1

Hydrolysis of the nitrile function can now give the α-hydroxy acid. Acidic conditions are usually used because of the competing cyanohydrin reversal under basic conditions.

For some related chemistry, see the Strecker amino acid synthesis, and the benzoin condensation.

O Strecker NH2 synthesis + NaCN + NH4Cl R R1 R CN R1

O O Benzoin Ar condensation 2 + KCN Ar Ar H OH

Note: The benzoin condensation is becoming increasingly important

The benzoin condensation is becoming increasingly important, so it is worth some elaboration. The original version is cyanide ion catalyzed, and involves yet another acyl anion equivalent in the process. The reaction is most often accomplished on aldehydes without acidic α- protons, to avoid aldol type

4 reactions competing; there are exceptions. In addition, it is normally a dimerization of two identical aromatic aldehydes or an intramolecular reaction, so that ‘crossed’ Benzoin regiochemistry issues are avoided. Finally, practically, cyanide sources largely have been replaced by things like thiazolium . Note that the deprotonated thiazolium may be considered as an N-heterocyclic carbene (NHC); it is the NHC that would serve in an analogous manner to cyanide ion.

_ O O OH O _ + -CN + Ar H Ar H Ar CN Ar H NC

_ O O H OH Ar H Ar + -CN Ar Ar Ar NC Ar OH NC _ OH O

N+ base N+ N H _ : S S S thiazolium carbene ion

3. Dithianes

See Clayden p 1254 (1 st ed), p. 660 (2 nd ed)

Dithianes are for most purposes simply the sulphur version of acetals. They are made quite similarly, usually using a or , a Lewis acid (instead of a protic one), 1,3-propanedithiol, and an appropriate solvent.

O BF3-OEt2 + 1 SS R R SHSH CH2Cl2, rt R R1

These will function as protecting group in for many of the same transformations as conventional acetals, but if one of R or R 1 is an H, a strong base (such a n-BuLi) will abstract that proton. The resultant anion is highly nucleophilic, and will attack aldehydes and many ketones.

5

1) n-BuLi, THF, -20 o 3) H2O SS SS SS 2) H C H3C H3C H CHO 3 LiO HO -78 o to RT

There are several methods of ‘ ‘ of dithianes; since S is a ‘soft’ base, a proton has much less affinity for S thanfor O. As a result, Hg 2+ , a soft Lewis acid, is excellent where S is concerned.

OH Hg(ClO4)2, MeOH SS H3C CH Cl , RT H3C 2 2 O HO (or HgCl2,H2O)

See Comprehensive Organic Synthesis, VI, p. 677; Yus, M. Tetrahedron 2003 , 59 , 6147. For other deprotection conditions, see Wuts, P. G. M. Protective Groups in Organic Synthesis (2 nd , 4 th Ed –my office; 3 rd Ed-Dr. Eichhorn)

There is an issue sometimes, that the dithiane anions are more susceptible to steric hindrance than acetylide ions.

o 1) NH3 (l), -35 SS H S S H Na H3C Li 2) H O OH O 2 OH

Note: There are other version of dithianes which are partially oxidized ones, i.e.,

SS O

4. And what about nitro compounds ? H3C H

It is possible to get aldol type reactions with nitro compounds and aldehydes or ketones; it is well known as the Henry reaction.

-in fact, the nitro group is so electron withdrawing that a dianion nitroalkanes can be made

The problem with the Henry reaction approach, though, is that the ‘hydrolysis’ of the nitro function to a carbonyl is not successful for these types of compounds. Elimination reactions and ‘retro’-Henry

6 reactions compete. On the other hand, there are other transformations of a nitro compound that do work to give other types of 1,2-difunctionalized compounds.

Pr-i N - NO2 N ClCrO3 P 10 mol% R N N N + i-Pr i-Pr NO H PCC O NO2 2

MgSO4 (2.2 equiv) R OH R-CHO NH2 Kisanga, P. B.; Verkade, J. G.* H2, R J. Org. Chem. 1999, 64, 4298. 5% Pd-C OH

For reviews on the Henry reaction, see; Rosini, G. Comprehensive Organic Synthesis , II, Ch. 1.10 (p. 321) Rosini, G.; Ballini, R. Synthesis , 1988 , 833. Luzzio, F. A. Tetrahedron , 2001 , 57 , 915. An example of its use in synthesis….

1) H3C-NO2, O H HO NaOEt HO 2 H OO Pd-C N 2) H+ O2N O H

Brown, E. Tetrahedron 1973, 29, 455.

B. Oxygen for Enolates

The alternative approach to doing an aldol- type reaction on an acyl anion equivalent, is to react a fairly conventional enolate with some O + equivalent. This is obviously very difficult due to the electronegative nature of oxygen, and the representation below is the six valent electron, O + species that you’ve been told is not accessible.

_ O O O _ O+-R1 + OR1 R R R

In truth, it’s really not quite as bad as that, since many reactions of enolates are S N2, and so we don’t really need a truly cationic oxygen. What we really need is for …….

7

δδδ- O O X O + _ O O OR1 + X- R R1 X R δδδ R - 1 R to be better than….

δδδ- O O OR1 O + _ X X + R1-O- X R R O δδδ- R R1

As a result, there is a reasonable chance at being successful with reagents such as..

2 O EWG O R or 1 R1 O R N EWG X X especially using the relief of ring strain to help the reaction.

There are two particularly well known manifestations of this.

1) The Vedejs reagent , known of MoOPh, which is MoO 5-pyr-HMPA.

It’s prepared by oxidation of MoO 3… O O Mo O O O MoO + H O + HMPA +pyridine 3 2 2 N O

P NMe Org. Synth. 1985, 64, 127. Me2N 2 NMe2

"MoOPh"

It reacts with enolates by attack on one of the oxygen atoms, with opening of the 3 membered ring.

8

O O O O Mo O O _ O O O Na2SO3(aq) O N O Mo O O O- OH P pyr HMPA NMe Me2N 2 NMe2

An actual example..

1) LDA, THF, -78 o H + O 2) MoOPh, -20 o O O O 3) Na2SO3(aq) OH 77% trace D-(+)-camphor

Advantages - This works well with enolates derived from.. Ketones, (or lactones), amides, nitriles.

Disadvantages – i) One can get some α-diketone as side- product

ii) It works poorly with unhindered (i.e., methyl derived) enolates

iii) HMPA is a carcinogen – on the other hand, the DMPU adduct (known as MoOPD) is known, and it seems to work reasonably well (Anderson, J. D.; Smith, S. C. Synlett 1990 , 107)

O

NN 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone = DMPU

2) The Davis Oxaziridines If you substitute a 3 membered ring with an oxygen and a nitrogen (oxaziridine) with a strong electron withdrawing group on N, the N - is actually the better … O O oxaziridine S pKa 17 (DMSO) O pKa's Ar NH Ar ?? (H2O) N R Ar S OH O pK 29-30 (DMSO) O a R Ar 17 (H2O) strong electron withdrawing group See Davis, F. A.; Shepperd, A. C. Tetrahedron 1989 , 45 , 5703 (general) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992 , 92 , 919. (asymmetric)

9

So if an enolate is reacted with an N-sulfonyl oxaziridine…

O O-M+ O Ph O _ N _ R R Ph S O N 1 R SO Ph R R1 O 2 O R1 Ph hemi N,O-acetal (ate)

O H2O O SO Ph OH _ 2 R O + N R R1 R1 Ph ααα-hydroxy carbonyl There is one drawback - if the breakdown of the N,O-acetal ate intermediate is too fast relative to the O Ph SO Ph R N 2 attack of the enolate on the oxaziridine, you’ll get a competing amount of … R1 H

This is the major side product for oxygenation of ketone and enolates. It is substantial with lithium enolates, but much less significant with sodium or (especially) potassium enolates. For amide enolates, which tend to be more reactive, the lithium enolates are normally fine. So…. _ SiMe K+ 3 KHMDS = N 1) KHMDS SiMe3 O O 85% 2) PhSO N(O)CHPh 2 yields often better than with MoOPh 3) H2O OH

Aside: There is also an excellent method for α- hydroxyl incorporation using silyl enol ethers, involving an epoxidation. It is sometimes called the Rubottom oxidation. (COS VII, p. 163)

Me_3 O O OSiMe3 m-CPBA Me3SiO Si H O O O OSiMe 2 OH O R 3 R R + R 1 1 1 1 R R R R R R1

10