(1; R,R = -(CH2)3-)

[33884-43-4]  · C6H11BrO2  · 2-(2-Bromoethyl)-1,3-dioxane  · (MW 195.06) (2; R,R = -(CH2)2-)

[18742-02-4]  · C5H9BrO2  · 2-(2-Bromoethyl)-1,3-dioxolane  · (MW 181.03) (3; R,R = Me,Me)

[36255-44-4]  · C5H11BrO2  · 3-Bromopropionaldehyde Dimethyl Acetal  · (MW 183.04)

(a group of bifunctional three-carbon reagents having the capacity to serve as electrophiles or as nucleophiles;1 once the latent carbonyl is unmasked, annulation reactions of various types can be implemented; the application range of these reagents can be further enhanced by initial bromide displacement with nucleophiles possessing useful functionality)

Physical Data: (1) bp 67-70 °C/2.8 mmHg, d 1.431 g cm-3; (2) bp 68-70 °C/8 mmHg, d 1.542 g cm-3; (3) bp 58-60 °C/17 mmHg, d 1.341 g cm-3.

Form Supplied in: all three acetals are colorless, commercially available liquids.

Preparative Methods: 3-bromopropionaldehyde acetals are prepared by bubbling anhydrous gaseous Hydrogen Bromide into a dichloromethane solution containing Acrolein and the alcohol or diol at or below rt.2 More recently, the discovery has been made that Chlorotrimethylsilane can promote the conjugate addition of NaX (X = Br, I, SCN) to a,b-unsaturated acetals.3

Handling, Storage, and Precautions: these bromides are recognized to possess irritant properties and should therefore invariably be handled with gloved hands inside an efficient hood. It is also advisable that these reagents be refrigerated for long-term storage in order to minimize the potential for acid liberation.

As Electrophile in Alkylation Reactions.

These three-carbon bifunctional reagents have proven to be very serviceable electrophiles in a variety of settings. Doubly activated anions such as those derived from b-diketones,4 b-keto esters (eq 1),5 malonate esters,6 and phosphono esters7 are readily homologated by this means. This level of activation is hardly necessary as demonstrated by the fact that anions derived from esters,8 nitriles (eqs 2 and 3),9 imines,10 and isocyanides11 behave comparably. Generally, the carbonyl group is subsequently unmasked and utilized in further chemical transformations. Where (2) and (3) are concerned, aqueous acid suffices to accomplish the hydrolysis. Dioxanes derived from (1) are much less reactive and often require prior conversion to the dimethyl acetal.12 Sulfur-containing nucleophiles including a-sulfonyl,13 thioallyl,14 and 1,3-dithianyl anions15 are also readily alkylated. In addition to (4) (eq 4), it has proven possible to prepare polyprenols stereoselectively,14 to produce substituted 1,5-dienes, and to synthesize estrone in a modest number of steps.15b

Birch reduction of benzoic acid followed by direct exposure to (2) produces (5).16 Bromide displacement by sodium cyclopentadienide, in situ hydrolysis, condensation with Ph3P=CHCO2Me, and ultimately warming to 115 °C to effect intramolecular Diels-Alder cycloaddition delivers (6).17 The means for fusing a pyran ring to an existing oxygenated ring to arrive at a polyether backbone such as (7) begins by condensation of (2) with a metalated vinyl ether (eq 5).18

Alkynyl anions have frequently been combined with (1)-(3).19 For example, the directness with which (8) is constructed underscores the abbreviated route that produces both diastereomers of (9) (eq 6).20 Similarly, the generation of enediyne (10) is central to the successful realization of an intramolecular [2 + 2 + 2] cycloaddition that gives rise to diene (11) (eq 7).21 Allenyllithiums have proven equally effective (eq 8).22

Since the lateral metalation of methyl-substituted aromatics can often be directly implemented, introduction of a functionalized sidechain is made possible by reaction of these anions with (2) and (3).23 When dianions such as (12) and (13) are involved, chemoselectivity is manifested such that C-C bond formation is heavily favored kinetically (eqs 9 and 10).24,25

The (h5-cyclohexadienylidene)2[Cr(CO)3]2 dianion (14) reacts regioselectively with (2) to give intermediate (15); its further treatment, as shown in eq 11, leads ultimately to the doubly functionalized aromatic product (16).26 The discovery has been made that the condensation of (2) with the anion of ethyl phenylsulfinylfluoroacetate leads to the a-fluoro acrylate (17) (eq 12).27

Alcohols and amines are also capable of condensing with these halo acetals. The conversion of a suitably protected hydroxyproline to (18) (eq 13)28 and of the methylamino derivative to arecolone (19) are illustrative (eq 14).29

Use as Grignard Reagents.

The Grignard reagents derived from (1)-(3) exhibit a stability order that parallels their hydrolytic behavior. That derived from (1) is thermally stable,12 while the dimethyl acetal (3-MgBr) is too labile to be useful.30 Since the magnesium reagent derived from (2) decomposes at rt and above,30,31 it must be generated and used below 25 °C. As expected, examples of simple additions of (1-MgBr) and (2-MgBr) to aldehydes32 and ketones33 abound. In the first instance, this process has evolved into a facile means for preparing 5-substituted butyrolactones.34 The conversion of ketone (20) to norbisabolide (21) shows that ketones can be analogously processed (eq 15).35 Clever use has been made of this condensation reaction in a total synthesis of clavukerin A,36 where Grob fragmentation of adduct (22) was utilized to obtain the functionalized 3-cycloheptenone (23) (eq 16).

These Grignard reagents can be condensed directly with activated halides (eq 17).37 Alternatively, related carbon-carbon bond formation can be realized by promoting the coupling with Dilithium Tetrachlorocuprate(II) (eq 18).38

The presence of acetal oxygen atoms has been recognized to moderate the chemical reactivity of these Grignard reagents. As seen in eq 19, addition to cyclic enones at -78 °C affords principally the product of conjugate addition without the benefit of a CuI salt.39 Additionally, these organometallics are widely known to react with acid chlorides to produce ketones without significant further conversion to tertiary alcohols.12a,40 The substantial synthetic latitude provided by this process is reflected in eqs 20-22.41-43

Other notable uses of (2-MgBr) can be found in syntheses of estafiatin (1,6-addition to tropone),44 eupolauramine (displacement of an aryl oxazoline),45 substituted eudistomins (capture by a nitrile group),46 a tripeptide ACE inhibitor (addition to a thio ester),47 the 1,7-dioxaspiro[5.5]undecane subunit of milbemycin b3 (directed oxirane cleavage),48 and the lipophilic sidechain of the cyclic hexadepsipeptide antibiotic L-156,602 (addition to an a-chloroboronate).49

Use as a Cuprate.

As noted above (eq 18), (1-MgBr) and (2-MgBr) give coupling reactions with halides and tosylates under conditions of copper catalysis.38,50 Cuprate formation also results in successful condensation with allylic acetates (eq 23),51,52 epoxides,53 vinyl epoxides (eq 24),54 and alkynes (eq 25).55 Conjugate addition to a,b-unsaturated ketones can also be realized in this way,56 this process often constituting the first step of an annulation sequence.

Annulation Reactions.

The keto acetals formed upon CuI-promoted 1,4-addition of acetal-containing Grignard reagents have found wide application in cyclopentene annulation.57 When no a-substituent is present, the aldol condensation leads to a conjugated bicyclic enone (eq 26).58 Dehydration is, of course, not spontaneous when an angular group is already in place; in such cases, dehydration must be implemented separately (eq 27).59

When the site of connectivity is external to an aromatic ring, cyclodehydration results in the elaboration of a six-membered ring.60 Depending upon the method employed and the degree of substitution, the annulated ring may be singly unsaturated (eq 28)61 or fully aromatic (eq 29).62

Pyridoannulations are also possible (eq 30).63 Other nitrogen-containing rings have been elaborated either by radical means (eq 31)64 or via the involvement of N-acyliminium ions (eq 32).65 The potential for spirocyclic ring construction has been explored as well (eq 33).66

Allied Compounds.

The lithium derivative of (1) has been satisfactorily generated by exposure of the iodide to t-Butyllithium in n-pentane-ether (3:2) at -78 °C.67 Bromo acetals (1)-(3) are quite amenable to functional group exchange in the manner represented by (24a-h).68-73 Of these, (24b)69 has held particular fascination as a consequence of its ability to serve as a reaction partner in [3 + 2] cycloadditions (eq 34).69d The dithianyl acetals of type (25) are notably serviceable as cyclohexane annulating agents (eq 35).72b,74 Ynamine acetal (26) has found similar application (eq 36).75

Related Reagents.


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Leo A. Paquette

The Ohio State University, Columbus, OH, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.