Boronic acid Mannich reaction (Petasis reaction)

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The boronic acid Mannich reaction (or Petasis reaction) is a three-component coupling reaction involving boronic acids or boronate esters, carbonyl compounds, and amines. Like the traditional Mannich reaction, the electrophile of the Petasis reaction is an iminium ion generated in situ from the amine and carbonyl compound. Iminium ions including a nearby Lewis basic group react with boron-based nucleophiles to afford α-allyl, -alkenyl, -aryl, and -alkynyl amines.[1]

Introduction

Multicomponent reactions are efficient transformations that involve the coupling of three or more reactants in an atom-economical manner. In 1993, Petasis reported that secondary amines and paraformaldehyde react with 1-alkenyl boronic acids in a one-pot, multicomponent reaction to afford allylic amines.[2] Since this initial report, additional studies have shown that the Petasis reaction is quite general: a variety of amines and carbonyl compounds react with allylic, alkenyl, aryl, and alkynyl boronic acids, boronate esters, or trifluoroborates to yield products of addition of the organoboron species across an iminium ion generated in situ (Eq. 1).

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Petasis-Gen.png

An important feature of the boronic acid Mannich reaction is its requirement for a proximal Lewis basic group in the carbonyl component—it has been proposed that the Lewis base activates and orients the organoboron species prior to addition. The mechanism of the reaction is not known with certainty, but a number of observations point to the importance of a zwitterionic intermediate in the mechanism (see Mechanism and Stereochemistry below). Many boronic acid Mannich reactions of chiral carbonyl compounds are diastereoselective, and enantioselective variants of the reaction based on chiral biphenols have been developed. The reaction is applicable to a broad array of substrates: the carbonyl component may be an α-hydroxyaldehyde, salicylaldehyde, or glyoxylic acid; the amine may be primary, secondary, or ammonia; and the organoboron species may be an allyl-, alkenyl-, aryl-, or alkynylboronic acid or boronate ester. The reaction has been applied to several syntheses of natural products and is particularly appealing for syntheses starting from aldose sugars, which bear an α-hydroxyaldehyde group.

Mechanism and Stereochemistry

Prevailing Mechanism(s)

The mechanism of the boronic acid Mannich reaction is not known with certainty, but three observations support the currently accepted mechanism for three-component, fully intermolecular reactions. First, the reaction works well only for α-hydroxyaldehydes, salicylaldehydes (2-hydroxy aromatic aldehyes), and glyoxylic acid. Second, when chiral α-hydroxyaldehyes are employed, anti 1,2-amino alcohol products are produced with high selectivity. Third, the reaction works better generally in polar, protic solvents with the ability to stabilize ionic intermediates.[3] For reactions involving glyoxylic acid as the carbonyl component, these observations point to a mechanism involving formation of zwitterionic iminium boronate 1, followed by intramolecular delivery of the nucleophilic organic group to the iminium carbon (Eq. 2).[3]

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Petasis-Mech-1.png

A similar mechanism has been proposed for reactions of α-hydroxy- and salicylaldehydes (Eq. 3).[4] The anti diastereoselectivity of reactions of chiral α-hydroxyaldehyes has been rationalized by appealing to a reactive conformation that minimizes 1,3-allylic strain in the iminium boronate intermediate 2 (Eq. 3).[5]

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Petasis-Mech-2.png

Studies of solvent effects suggest that polar solvents improve the rate and yield of the reaction.[6] In many cases, protic solvents perform better than aprotic solvents as well. In particular, the solvent hexafluoroisopropanol (HFIP) has proven to be effective in a variety of boronic acid Mannich reactions. The effectiveness of this solvent may be due to its ability to stabilize zwitterionic intermediate 1.

Diastereoselectivity and Enantioselectivity

Reactions of chiral α-hydroxyaldehydes are often highly diastereoselective, and show a preference for formation of the anti-1,2-amino alcohol product. This result has been attributed to a conformation of intermediate 2 that minimizes 1,3-allylic strain (Eq. 3, above).

A catalytic, enantioselective variant of the reaction employing allylic boronates, secondary amines, and ethyl glyoxylate has been developed (Eq. 4).[7] A number of chiral biphenols are effective catalysts, and the polyaromatic VAPOL performs best.

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Petasis-Stereo-1.png

A general method for the enantioselective synthesis of anti-1,2-amino alcohols from vinyl sulfones takes advantage of enantioselective dihydroxylation with AD-mix followed by elimination and diastereoselective Petasis reaction (Eq. 5).[8] The high enantioselectivity of Sharpless dihydroxylation and diastereoselectivity of the Petasis reaction combine to enforce high enantioselectivity in the overall transformation.

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Petasis-Stereo-2.png

Scope and Limitations

The Petasis reaction is applicable to a variety of substrates, although particular classes of substrates have some specific limitations. Broadly, the carbonyl component must contain a nearby group with the ability to coordinate boron. α-Hydroxyaldehydes and salicylaldehydes work well, but the corresponding methyl ethers are not useful substrates for the reaction. Glyoxylic acid (oxoethanoic acid) and glyoxylate esters are useful substrates, although the scope of the latter is limited. The remainder of this section focuses on typical examples of the reaction and the scope of possible products.

When glyoxylic acid is combined with an amine and alkyenyl- or arylboronate ester, the products are monosubstituted α-amino acids. Secondary amines are more effective than primary amines in this reaction (Eq. 6).[9]

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Petasis-Scope-1.png

α-Hydroxyaldehydes work quite well in the Petasis reaction, and react well with alkenyl-, aryl-, and heteroarylboronic acids. Few examples of reactions with boronate esters are known. One interesting method for generating α-hydroxyaldehyes involves oxidative cleavage of protected, reduced sugars. The resulting two equivalents of aldehyde react with added amine and alkenylboronic acid to afford the products of addition of two equivalents of the organoboron reagent (Eq. 7).[10]

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Petasis-Scope-2.png

Salicylaldehydes possess a hydroxyl group in an appropriate position to orient the organoboron species for addition to the iminium carbon. These substrates react best with secondary amines rather than primary amines, and alkenyl-, aryl-, and heteroarylboronic acids have been used with success (alkenylboronic acids may afford heterocycles, see Eq. 11 below). A typical example is shown in Eq. 8 below.[11] As with α-hydroxyaldehydes, boronate esters are much less effective than boronic acids in reactions with salicylaldehydes.

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Petasis-Scope-3.png

Aromatic aldehydes react with allylic boronate esters and secondary amines to afford homoallylic amines. This is a rare class of reactions in which ammonia also works well as the amine component. The combination of liquid ammonia, benzaldehyde, and the pinacol ester of (Z)-but-2-en-1-ylboronic acid produces the homoallylic benzylamine resulting from addition at the γ-carbon of the boronate in 85% yield with extremely high diastereoselectivity (Eq. 9).[12] Although the aldehyde does not possess an additional Lewis basic group in this case, this reaction works well only for allylboronates.

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Petasis-Scope-4.png

The boronic acid Mannich reaction can also be applied to the synthesis of heterocycles. 2H-Chromenes are the products when substituted salicylaldehydes react with a substoichiometric amount of amine and alkenylboronic acid. It has been proposed that initial formation of an allylic amine is followed by intramolecular, vinylogous displacement of an ammonium leaving group. In the example in Eq. 10 below, the amine is held on a solid support and is easily separated from the 2H-chromene product.[11]

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Petasis-Scope-5.png

Alkynyl trifluoroborates are useful substrates for the synthesis of propargylic amines. Yield is highest when the solvent employed is the ionic liquid BmimBF4(1-butyl-3-methylimidazolium tetrafluoroborate), and secondary amines are required. One equivalent of benzoic acid may be required in reactions of salicylaldehydes (Eq. 11).[13]

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Petasis-Scope-6.png

In another example highlighting the unique reactivity of allylic boronic acids, allylboronic acid reacts with ketones in the presence of ammonia to afford homoallylic amines (Eq. 12).[14] This reaction works only with allylboronic acids and ammonia, but is a rare example of a ketone reacting successfully in a Petasis reaction.

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Petasis-Scope-7.png

Applications to Synthesis

The Petasis reaction is very relevant to synthetic targets containing a 1,2-amino alcohol motif, particularly since the corresponding starting materials are α-hydroxyaldehydes that may be readily available as aldose sugars. Several syntheses have applied the Petasis reaction to the synthesis of natural products containing 1,2-amino alcohols. One route to calystegine B4 started from the aldohexose D-lyxose, which was subjected to Petasis reaction with benzylamine and (E)-β-styrenylboronic acid to afford a anti-1,2-amino alcohol in good yield and high diastereoselectivity. This synthetic intermediate was carried on to the natural product (Eq. 13).[15]

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Petasis-Synth-1.png

The dihydroxylation-Petasis reaction method for enantioselective synthesis of 1,2-amino alcohols from vinyl sulfones has been applied to the synthesis of hyacinthacine B3. After formation of the α-hydroxyaldehyde, Petasis reaction with a chiral allylic amine and (E)-β-styrenylboronic acid proceeded with moderate yield and high diastereoselectivity (Eq. 14).[16]

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Petasis-Synth-2.png

Comparison to Other Methods

In general, alternatives to the boronic acid Mannich reaction tend to possess more limited scope and/or require harsher reaction conditions. The Petasis reaction stands out for its transition-metal-free and mild reaction conditions. Allylic boronate esters react with some aldimines, but this reaction requires high temperatures and a large excess of the boronate reagent (Eq. 15).[17]

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Petasis-Alt-1.png

Allylic boronates also react with electron-poor aldimines in the presence of rhodium(I) catalysts (Eq. 16).[18] This reaction has been rendered enantioselective through the use of chiral ligands, but electron-poor amines bearing a sulfonyl group are a requirement of this class of reactions.

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Petasis-Alt-2.png

Copper catalysts may be employed for the synthesis of propargylic amines in very small amounts (Eq. 17).[19] Yields of this reaction are generally higher than those of comparable Petasis reactions of alkynylboronates.

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Petasis-Alt-3.png

Experimental Conditions and Procedure

Typical Conditions

Petasis reactions are often carried out without special care to prevent the intrusion of atmospheric water or oxygen, although such care is necessary in reactions employing liquid ammonia. In a typical experiment, the amine is first introduced to a solution of the carbonyl component, and the boronic acid or boronate is added last. Reaction times are generally long, on the order of a few hours to a few days. In some cases, when the reaction solvent is not particularly polar, precipitation may occur and the product may be isolated by simple filtration. Highly polar protic solvents such as ethanol and HFIP are commonly employed for the reaction, although some examples that take advantage of precipitation use less polar, aprotic solvents such as dichloromethane.

Example Procedure[20]

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Petasis-Ex.png

To a stirred solution of glyoxylic acid monohydrate (92 mg, 1 mmol) in CH2Cl2 (7 mL) was added benzhydrylamine (183 mg, 1 mmol), followed by phenylboronic acid (122 mg, 1 mmol). After the flask was purged with argon and sealed, the reaction mixture was stirred vigorously at rt for 48 h. The resulting precipitate was isolated by filtration, washed with CH2Cl2 (10 mL), and purified by ion-exchange chromatography (Dowex 50W-X8) to afford the title compound (266 mg, 84%): 1H NMR (360 MHz, DMSO-d6) δ 7.8–7.0 (m, 15H), 4.78 (s, 1H), 4.17 (s, 1H); 13C NMR (90 MHz, DMSO-d6) δ 172.8, 142.4, 133.6, 129.6, 128.1, 127.5, 127.1, 126.9, 126.7, 63.6, 62.2. Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41; Found: C, 79.48; H, 6.17; N, 4.32.

References

  1. Pyne, S. G.; Tang, M. Org. React. 2014, 83, 1. (doi: 10.1002/0471264180.or083.01)
  2. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
  3. a b Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023.
  4. Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
  5. Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097.
  6. Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.
  7. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
  8. Evans, P.; Leffray, M. Tetrahedron 2003, 59, 7973.
  9. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965.
  10. Hong, Z.; Liu, L.; Sugiyama, M.; Fu, Y.; Wong, C.-H. J. Am. Chem. Soc. 2009, 131, 8352.
  11. a b Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
  12. Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182.
  13. Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron Lett. 2004, 45, 729.
  14. Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2005, 5551.
  15. Moosophon, P.; Baird, M. C.; Kanokmedhakul, S.; Pyne, S. G. Eur. J. Org. Chem. 2010, 3337.
  16. Au, C. W. G.; Nash, R. J.; Pyne, S. G. Chem. Commun. 2010, 46, 713.
  17. Wuts, P. G. M.; Jung, Y. W. J. Org. Chem. 1991, 56, 365.
  18. Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637.
  19. Okamura, T.; Asano, K.; Matsubara, S. Synlett 2010, 3053.
  20. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.