Zinc-Acetic Acid1

Zn-AcOH
(Zn)

[7440-66-6]  · Zn  · Zinc-Acetic Acid  · (MW 65.39) (AcOH)

[64-19-7]  · C2H4O2  · Zinc-Acetic Acid  · (MW 60.06)

(reducing agent; causes reductive elimination of vicinal heteroatoms;2-15 cleaves heteroatom-heteroatom bonds;16-27 reduces allylic, benzylic, or a-carbonyl-substituted heteroatoms,28 -34 activated carbonyls,35-37 and alkenes38-40)

Physical Data: see entries for Zinc and Acetic Acid.

Form Supplied in: although zinc is available in a variety of forms, the overwhelming majority of zinc-acetic acid reductions use zinc powder.

Purification: acid washing is not uncommon, but not always vital.

Introduction.

Zinc in acetic acid is capable of a wide range of reduction reactions. Although many of these can also be performed by a great number of other reagents, this reagent is of particular value in that good chemoselectivities can often be achieved. Some such instances are noted in the text and equations below; many of the references have also been chosen to demonstrate selective reduction in sensitive, polyfunctional molecules.

Reductive Elimination of Vicinal Heteroatoms.2-15

A great variety of combinations of heteroatom substituents has been successfully reductively eliminated by Zn/AcOH (eq 1 and Table 1). Cosolvents such as ether, THF, CH2Cl2, i-PrOH, or water have all been used. Reaction temperatures vary from case to case, but yields reported are typically good to excellent.

A set of protecting groups, based upon Zn/AcOH elimination of the 2,2,2-trichloroethoxy group, has been developed, and is discussed below as a special case. Table 1 records several of the combinations of heteroatoms successfully eliminated under these conditions. Perhaps surprisingly, the relative stereochemistry of the two carbon centers does not have to permit trans coplanarity of the heteroatoms.4,7

Heterocyclic rings may be cleaved by these reactions. Thus, effective reversal of iodolactonization (eq 2)8 or of epoxidation (after iodide ring opening) (eq 3)9 may be achieved.

Halogenated oximes (1) eliminate to give the nitrile in variable, but often good to excellent, yields (eq 4).10

2,2,2-Trichloroethoxy-Based Protecting Groups.11-15

Valuable protecting groups for alcohols,11 phenols,11c amines,11c and carboxylic acids,12 and an introduction/protection reagent for thiols,13 all dependent upon the lability of this group to Zn/AcOH reductive elimination, have been developed. They are summarized in Table 2.

The trichloroacetylidene acetal has also been proposed as a potential protection for diols, similarly deprotectable.14 Also, along similar lines, the 2-iodoethyl carbamate protection for amines, deprotectable by Zn dust alone in MeOH, has been proposed,15 but has found relatively little use.

Heteroatom-Heteroatom Cleavage.16-27

N=N double bonds can be cleaved16 by Zn/AcOH; less frequently, hydrazines17 may be obtained from the reduction (eqs 5 and 6).17 Hydrazones may also be reduced to amines,18 as used18b in a variant of the classical Knorr pyrrole synthesis. Diazo ketone (2) has been successfully reduced, despite the apparent potential for adverse side reactions (eq 7).19

Aromatic nitro groups20a (aliphatic nitro groups can yield oximes,20b even though not all such would be stable under all reaction conditions), hydroxylamines,21 oximes22 (once again, finding use22b in a Knorr pyrrole synthesis), N-nitro-23a and N-nitrosoamines,23b aromatic N-oxides,24 and aromatic N-S bonds25 have all been reduced to amines with Zn/AcOH. These references include ample evidence of the ability of this reagent to perform the desired reaction, while leaving intact, for example, bromides,22 carbon-bonded sulfur atoms,20,23b and isolated C=C double bonds.21 It will, of course, be understood that the newly liberated amines often undergo spontaneous intramolecular reactions. Sulfonamides26 can also be reduced to the thiols.

Zn/AcOH can act as a useful alternative reagent for reductive workup of ozonolysis reactions,27 which can be considered, at least formally, to involve O-O bond cleavage (see Ozone).

Curiously, the vigor of the conditions reported to have been employed for these disparate reactions does not seem to follow any consistent pattern; reaction conditions, therefore, may need individual determination in many cases.

Carbon-Heteroatom Cleavage.28-34

Substitution of N,28 O,29 S,30 or halogen,31 for example, at an allylic, benzylic, or a-carbonyl-substituted carbon atom renders the heteroatom liable to cleavage with Zn/AcOH. In allylic systems, double bond migration usually occurs. If conjugated to a carbonyl group, migration still occurs, giving the b,g-product (eq 8),32a but these can be easily reconjugated (eq 9).32b Homoallylic reduction33 has also been reported in a constrained system (eq 10).

Cleavage a to a carbonyl group has been exploited in the use of phenacyl protecting groups.34 The reduction of compounds such as (3) (for their formation, via Dichloroketene see Trichloroacetyl Chloride) retains the strained four-membered ring, and often gives excellent yields (eq 11).31c

Carbonyl Reduction.35-37

Quinones are reduced to hydroquinones by Zn/AcOH at reflux.35a Incorporation of Ac2O into the reaction mixture gives the respective diacetate.35a Under milder conditions (rt), the intermediate g-hydroxycyclohexenone may be intercepted in surprisingly high yield (72-90%).35b

Diaryl ketones may be reduced to the alcohols,36a but a competing dimerization has also been reported36b in some unusual cases. Reduction of phthalimide (4) proceeds well and, notably, with regiospecificity (eq 12).37

Reduction of Activated Alkenes.38-40

Carbonyl (mono-38a or di-38b) substitution renders a C=C double bond liable to reduction by Zn/AcOH. a,b,g,d-Dienones may yield either a,b-38a or b,g-enones38c in equally high yields. A recent modification,39 at lower temperature (rt), and with much shorter reaction times, uses ultrasonication; excellent yields were achieved.

a,b-Unsaturated nitro compounds can also be reduced.40 Under mild conditions an oxime can be obtained (eq 13)40a (cf. Sodium Borohydride, which reduces the C=C double bond); more vigorous reaction leads to the corresponding ketone.40b

Aza-Heterocycle Ring Contraction.

A variety of polyaza six-ring heterocycles undergo contraction with formal excision of N, e.g. eq 14.41a Further heteroatoms in the ring are tolerated: 1,2,3-triazines yield pyrazoles41b and 1,2,4-triazines yield imidazoles,41c with the latter usually requiring reflux temperature. The utility of indole syntheses from cinnolines41d by this method should be noted. Adjacency of heteroatoms is not required: conversions of pyrimidine to pyrrole42a,b and 1,3,5-triazine to imidazole42c have been recorded. The mechanism of these conversions is unclear, but ring dihydro derivatives41a,42b are thought to be involved.

Reduction of Aryl Substituents.

Although, as mentioned above, many potentially labile functionalities are stable to Zn/AcOH, aryl iodides may be dehalogenated.43 Substitution of Cl or Br at the 2-position of heteroaromatics also renders them liable to reduction, often with superb selectivity (eqs 15 and 16).44

Related Reagents.

Iron; Tin; Zinc Amalgam; Zinc-Zinc Chloride.


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Peter Ham

SmithKline Beecham Pharmaceuticals, Harlow, UK



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