2H-chromenes from salicylaldehydes by a catalytic petasis reaction

Article abstract of DOI:10.1021/ol006710r

(Matrix presented) The Petasis condensation of vinylic or aromatic boronic acids, aromatic aldehydes, and amines is assisted by a hydroxy group adjacent to the aldehyde moiety. The products derived from salicylaldehydes and vinylboronic acids undergo cycl

Full text of DOI:10.1021/ol006710r

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4063-4065
2H-Chromenes from Salicylaldehydes by
a Catalytic Petasis Reaction
Qian Wang and M. G. Finn*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
mgfinn@scripps.edu
Received October 9, 2000
ABSTRACT
The Petasis condensation of vinylic or aromatic boronic acids, aromatic aldehydes, and amines is assisted by a hydroxy group adjacent to
the aldehyde moiety. The products derived from salicylaldehydes and vinylboronic acids undergo cyclization to 2H-chromene compounds
with ejection of amine upon heating. A catalytic preparation of 2H-chromenes using resin-bound amine is reported, allowing the convenient
incorporation of a variety of components.
The in situ assembly of amine, carbonyl compound, and
vinyl- or arylboronic acid (eq 1) has been developed by N.
Petasis and co-workers1 as a modern variation of the Mannich
reaction.2 Mannich-type processes lend themselves to mul-
remarkable chemistry that is enabled by the ready access to
intermediates of expanded coordination number provided by
certain main group elements (primarily B, Si, and Sn).
A perusal of the literature reveals that the overwhelming
majority of non-glyoxylate electrophiles in the Petasis
reaction bear a hydroxyl group R to the carbonyl unit. It has
been noted that a vinylboronic acid is unreactive with an
isolated iminium salt, suggesting that the formation of a
vinylboronate adduct with a pendant heteroatom on the
electrophile is important.1a Such a hypothesis has been made
in a related reaction involving N-acyliminium ions,5 and
R-heterocyclic aldehydes have recently been shown to
participate in the boronic acid Mannich process, presumably
for the same reason.6
ticomponent condensations.3 What makes the Petasis process
remarkable is the reactivity of the boronic acid component,
which is inert to the carbonyl group but efficiently traps the
CdN double bond of its derived iminium ions. Petasis has
made the insightful connection between the propensity of a
vinylboronic acid to take on a donor group to form an
electron-rich “ate” complex and its utility as a selective
nucleophile.4 The Petasis reaction is thus an example of the
In the course of designing a system that uses the Petasis
(4) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567-
570.
(5) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am. Chem. Soc.
1999, 121, 5075-5076.
(1) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583-
586. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-
446. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798-
11799.
(2) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1045-1070.
(3) Ugi, I.; Lohberger, S.; Karl, R. In ComprehensiVe Organic Synthesis,
Volume 4; Pergamon: London, 1999; pp 1083-1109.
(6) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000,
41, 1303-1305.
(7) Wirsching, P.; Ashley, J. A.; Lo, C.-H. L.; Janda, K. D.; Lerner, R.
A. Science 1995, 270, 1775-1782. Wagner, J.; Lerner, R. A.; Barbas, C.
F. I. Science 1995, 270, 1797-1800. Lo, C.-H. L.; Wentworth, P., Jr.; Jung,
K. W.; Yoon, J.; Ashley, J. A.; Janda, K. D. J. Am. Chem. Soc. 1997, 119,
10251-10252.
10.1021/ol006710r CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/21/2000

reaction as the covalent bond-forming event in reactive
immunization,7 we sought to explicitly test the proposition
that, by coordinating to the boron center, a pendant hydroxyl
could both activate the nucleophile and make the capture
event intramolecular. Salicyladehyde derivatives were em-
ployed as shown in Scheme 1.
Table 1. Synthesis of 2H-Chromenes (5) from Alkenylboronic
Acids (3) and o-Hydoxyaromatic Aldehydes (1) Using
Resin-Supported Base 8 as Catalysta
Scheme 1
Phenylboronic acid condenses with morpholine and alde-
hydes 1a-c under standard conditions to give amines 2a-c
in good yields.8 The Petasis group has independently reported
related chemistry.9 No reaction is observed when the
hydroxyl group is omitted, moved to the meta or para
positions, replaced by a halogen substituent, or capped as
the methyl ether, strongly supporting the proposed role of
the o-hydroxyl group. While a pendant amino group has been
thought to be an effective activating unit,1a 2-aminobenzal-
dehyde is an unreactive substrate. An o-hydroxy group is
unable to overcome the sluggish reactivity of ketones; thus,
2-hydroxyacetophenone and 2-hydroxybenzophenone are
unreactive.
As shown in Scheme 2, vinylboronic acid 3a10 also reacts
with salicylaldehyde, providing 4 in 80% yield along with a
Scheme 2
highly chromophoric compound, which was isolated and
characterized as 2-butyl-2H-chromene, 5a, presumably aris-
a All reactions were performed using 40 mol % of 8 at 90 °C for 24 h.
b Products isolated as pure compounds by filtration in the indicated yields.
(8) Imine formation from salicylaldehydes is particularly facile: Green,
R. W.; Sleet, R. J. Aust. J. Chem. 1969, 22, 917-919.
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Org. Lett., Vol. 2, No. 25, 2000

ing by cyclization of the pendant hydroxyl group. Incubation
of the mixture of 4 and 5a with 2,6-lutidine afforded 5a as
the exclusive product. The 2H-chromene could likewise be
prepared from salicylaldehyde and 3a using catalytic (5 mol
%) dibenzylamine in high yield. The proposed catalytic cycle
is shown in Scheme 3. The key intermediate 6 is assembled
Primary amines are poor catalysts for the process, and
commercially available aminomethyl polystyrene does not
promote the assembly/cyclization sequence very well (after
24 h at 90 °C, approximately 25% of the starting aldehyde
and boronic acid remain). However, the corresponding
N-benzyl material 811 is effective (Scheme 4). While high
Scheme 4
Scheme 3
loadings (40-50 mol % of amine relative to aldehyde) are
required to achieve good yields,12 the resin is easy to prepare
and pure products are obtained simply by filtration of the
reaction mixtures. As shown in Table 1, a selection of alkenyl
boronic acids and o-hydoxyaromatic aldehydes are converted
to the corresponding 2H-chromenes in high yields by this
procedure.
The 2H-chromene (benzopyran) moiety is found in a wide
variety of natural products and dye compounds.13 The
convenient method described here complements existing
synthetic procedures12,14 and highlights the importance of a
neighboring hydroxy group to organize electrophilic and
nucleophilic components for the C-C bond-forming event.
by iminium ion formation and coordination of the phenolate
oxygen to the boronic acid. Intramolecular vinyl group
transfer provides 7, the immediate precursor to allylic amines
such as 4. Cylclization to 5 is likely promoted by protonation
of the amine as shown, regenerating the catalyst.
Acknowledgment. We thank The Skaggs Institute for
Chemical Biology for support of this work.
(9) (a) Petasis, N. A.; Boral, S.; Zavialov, I. A. Abstracts of Papers,
217th National Meeting of the American Chemical Society, Anaheim, CA,
March 1999; American Chemical Society: Washington, D.C., 1999; ORGN
083. (b) Petasis, N. A.; Boral, S. Tetrahedron Lett. In press.
(10) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1973, 95, 5786-
5788.
(11) Bra¨se, S.; Enders, D.; Ko¨bberling, J.; Avemaria, F. Angew. Chem.,
Int. Ed. 1998, 37, 3413-3415.
(12) Equivalents of 8 vs yields of 5a, obtained after 12 h reaction: 0.05,
20%; 0.10, 68%; 0.20, 75%; 0.30, 87%; 0.40, 95%.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006710R
(13) Some recent examples: (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao,
G.-Q. Angew. Chem., Int. Ed. 2000, 39, 734-739. Nicolaou, K. C.; Cao,
G.-Q.; Pfefferkorn, J. A. Angew. Chem., Int. Ed. 2000, 39, 739-743. (b)
Maggiani, A.; Tubul, A.; Brun, P. HelV. Chim. Acta 2000, 83, 650-657.
(c) Tronchet, J. M.; Zerelli, S.; Bernardinelli, G. J. Carbohydr. Chem. 1999,
18, 343-359. (d) Ishii, F.; Honda, H.; Konno, F.; Okada, T.; Kaihoh, T.;
Nagao, Y.; Sato, S.; Matsuda, H. European Pat. Appl. EPXXDW EP 906910
A1 19990407, 1999; Chem. Abstr. 1999, 130, 252245. (e) Engler, T. A.;
Letavic, M. A.; Iyengar, R.; LaTessa, K. O.; Reddy, J. P. J. Org. Chem.
1999, 64, 2391-2405. (f) Subburaj, K.; Trivedi, G. K. Bull. Chem. Soc.
Jpn. 1999, 72, 259-263. (g) Loncar-Tomaskovic, L.; Mintas, M.; Trotsch,
T.; Mannschreck, A. Enantiomer 1997, 2, 459-472.
(14) (a) Harrity, J. P. A.; La, S. D.; Cefalo, D. R.; Visser, M. S.; Hoveyda,
A. H.; J. Am. Chem. Soc. 1998, 120, 2343-2351. This method was used
for the synthesis of an antibiotic: Wipf, P.; Weiner, W. S. J. Org. Chem.
1999, 64, 5321-5324. (b) An alternative preparation of 2H-chromenes from
salicyaldehydes employs nitroalkenes as the active olefin component;
conjugate addition of the phenolate anion is followed by a second addition-
elimination step using cyanide: Tronchet, J. M. J.; Zerelli, S.; Bernardinelli,
G. J. Carbohydr. Chem. 1999, 18, 343-359. (c) Catalytic antibodies have
been developed to promote phenolic cyclization reactions to give chroman
derivatives: Tietze, L. F.; Peters, J. H.; Djalali, B. F.; Seibel, J. Ger. Offen.
DE 19852905 A1 20000511, 2000; Chem. Abstr. 2000, 132, 333447 (AN
315046).
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