Stereocontrolled synthesis of Z-dienes via an unexpected pericyclic cascade rearrangement of 5-amino-2,4-pentadienals

Article abstract of DOI:10.1021/ja8028125

Donor-acceptor dienes known as Zincke aldehydes, which derive readily from the ring-opening reactions of pyridinium salts with secondary amines, undergo a fascinating thermal rearrangement reaction to afford Z-α,β,γ,δ-unsaturated amides with excellent stereoselectivity. Efficient, stereocontrolled access to Z-trisubstituted alkenes with two different substitution patterns is possible in three steps beginning with the appropriately substituted pyridine derivative. Preliminary studies have shown that both the amide and the monosubstituted alkene termini can be selectively functionalized. Ease of access, generality of scope, and facile product manipulation render this process attractive for the synthesis of complex polyenes. Copyright

Full text of DOI:10.1021/ja8028125

Published on Web 05/28/2008
Stereocontrolled Synthesis of Z-Dienes via an Unexpected Pericyclic Cascade
Rearrangement of 5-Amino-2,4-pentadienals
Sarah E. Steinhardt, Joel S. Silverston, and Christopher D. Vanderwal*
1120 Natural Sciences II, Department of Chemistry, The UniVersity of California, IrVine, California 92697-2025
Received April 16, 2008; E-mail: cdv@uci.edu
Polyene natural products display an impressive array of important
biological activities.1 Polyunsaturated molecules have also dem-
onstrated significant utility in complex molecule synthesis because
they can be used in cascade reactions for the rapid buildup of
molecular complexity.2 They are ideally suited for pericyclic,
radical, cationic, and transition-metal-mediated polycyclizations.
Therefore, new methods for the synthesis of functionalized,
stereodefined polyenes are of great value. We report a new method
for the stereoselective synthesis of Z-R,ꢀ,γ,δ-unsaturated amides,
based on a pericyclic cascade rearrangement that was discovered
serendipitously during our investigations into the chemistry of
Zincke aldehydes. This particular polyunsaturated motif is fre-
quently encountered in important, biologically active molecules.3
The ring-opening reaction of pyridinium salts dates back over a
century to the pioneering work of Zincke and Ko¨nig.4 Activation
of pyridines as their pyridinium salts (1, Figure 1), followed by
treatment with primary amines, leads to the formation of new
pyridinium salts (2), while the use of secondary amines cleanly
affords the products of ring opening.5 Frequently, the ring-opened
5-amino-2,4-pentadienal products (3), now known as Zincke
aldehydes, can be obtained in high yield and purity, and in large
quantities, without chromatographic purification. Both the ring-
opening process and the products appear ideally suited for manifold
applications in synthesis; to date, however, this potential has
remained largely unrealized.6,7
Figure 1. Aminolysis of pyridinium salts. A ) activating group.
Scheme 1. Attempted Intramolecular Diels-Alder Cycloaddition of
4 Yielded Unexpected Rearrangement Product 5. Two Reasonable
Pericyclic Cascade Mechanisms Were Evaluated.
In the course of a projected alkaloid synthesis, we attempted
the intramolecular Diels-Alder reaction of tetrahydro-ꢀ-carboline-
derived Zincke aldehyde 4 (Scheme 1).8 Warming this polyunsatu-
rated precursor to 160 °C for 16 h did not afford cycloaddition
product; rather, clean but partial conversion occurred to yield a
product in which the Zincke aldehyde portion had been transformed;
the prospective dienophile was unchanged. The product was
Z-R,ꢀ,γ,δ-unsaturated amide 5, an isomer of the starting material,
which appeared to derive from an internal redox process. We next
performed this thermal reaction on the simple Zincke aldehyde
derived from pyridine and dimethylamine (6); Z-diene 7 was the
sole product.
We reasoned that two different pericyclic cascade reactions could
account for our observations with 6; a substituted Zincke aldehyde
substrate would be required to distinguish between them. 3-Picoline-
derived substrate 8 served this purpose. A thermally instigated E
to Z isomerization of the C2-C3 double bond of 8 might enable a
6-π electrocyclic ring closure of 11 to pyran 12. A [1,5]-H shift
would afford the isomeric pyran 13, which could undergo an
electrocyclic ring-opening reaction to deliver product 9; the cyclic
nature of the pyran intermediates would account for the Z geometry
of the product. Alternatively, a sequence proceeding via dihydro-
pyridinium intermediates 14, 15, and 16 would lead to 10, an isomer
of 9.9 Heating of 8 led exclusively to 10, which bears the methyl
group R to the carbonyl carbon; isomeric amide 9 was not observed.
Therefore, the reaction appears to involve transposition of the amino
group from one end of the carbon chain to the other, rather than
oxygen transposition. To the best of our knowledge, in the century
since pyridinium salt ring openings to form Zincke aldehydes were
discovered, no such rearrangement has been reported.10,11
The results shown in Table 1 demonstrate that this rearrangement
is general with respect to the amine and the substitution patterns
on the Zincke aldehyde substrates.12 Heating the substrates at
200-220 °C in o-dichlorobenzene under microwave irradiation
cleanly converted each into R,ꢀ,γ,δ-unsaturated amides. Excellent
Z-selectivity is observed in all cases except with some Zincke
aldehydes derived from unsubstituted pyridines; in these cases (see
7 and 17), the formation of the E isomer increases with prolonged
heating.13 The depressed yield of 7 reflects loss of this relatively
volatile compound during the removal of the high boiling reaction
solvent. The formation of trisubstituted alkenes (10 and 19-22)
9
7560 J. AM. CHEM. SOC. 2008, 130, 7560–7561
10.1021/ja8028125 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Z-R,ꢀ,γ,δ-Unsaturated Amides by Thermal
Rearrangement of Zincke Aldehydes
Acknowledgment. The authors would like to thank the School
of Physical Sciences of University of California, Irvine, for generous
startup funding. New Faculty Awards from Amgen and Eli Lilly
are also gratefully acknowledged.
Supporting Information Available: Complete experimental pro-
cedures and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a recent review, see: Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin
Trans. 1 2002, 999–1023.
(2) For a good lead reference, see: Sorensen, E. J. Bioorg. Med. Chem. 2003,
11, 3225–3228.
(3) For examples, see: (a) the potent antitumor agent zampanolide: Tanaka,
J.-i.; Higa, T. Tetrahedron Lett. 1996, 37, 5535–5538. (b) The potent
antitumor agents salicylihalamides and apicularens: Yet, L. Chem. ReV.
2003, 103, 4283–4306. (c) The antibiotic and antifungal agent virideno-
mycin: Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron
Lett. 1991, 32, 659–662. (d) The rifamycin antibiotics: Floss, H. G.; Yu,
T.-W. Chem. ReV. 2005, 105, 621–632. (e) The saliniketals, recently
identified ornithine decarboxylase inhibitors and potential antitumor
agents: Williams, P. G.; Asolkar, R. N.; Kondratyuk, T.; Pezzuto, J. M.;
Jensen, P. R.; Fenical, W. J. Nat. Prod. 2007, 70, 83–88.
(4) (a) Zincke, T. Liebigs Ann. Chem. 1903, 330, 361–374. (b) Zincke, T.
Liebigs Ann. Chem. 1904, 333, 296–345. (c) Zincke, T.; Wurker, W. Liebigs
Ann. Chem. 1905, 338, 107–141. (d) Ko¨nig, W. J. Prakt. Chem. 1904, 69,
105–137.
a See Supporting Information for reaction times and temperatures. b A
9:1 crude mixture of Z:E isomers, yield refers to purified Z isomer. c Z:E
isomer ratio; except for 7, ratio is unchanged after purification.
Scheme 2. Selective Manipulation of Amide 10
(5) (a) Becher, J. Synthesis 1980, 589–612. (b) Becher, J.; Finsen, L.;
Winckelmann, I. Tetrahedron 1981, 37, 2375–2378. (c) Cheng, W.-C.;
Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 587–608.
(6) (a) For a two-step azulene synthesis featuring 5-amino-2,4-pentadienals,
see: Hafner, K.; Asmus, K.-D. Liebigs Ann. Chem. 1964, 671, 31–40. (b)
For one application in natural product synthesis, see: Jakubowicz, K.;
Abdeljelil, K. B.; Herdemann, M.; Martin, M.-T.; Gateau-Olesker, A.;
Mourabit, A. A.; Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 7381–
7387. (c) For extensive applications of these compounds in the dye industry,
see: Mishra, A.; Behera, R. K.; Behera, P. K.; Mishra, B. K.; Behera, G. B.
Chem. ReV. 2000, 100, 1973–2011.
(7) Kearney, A. M.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2006, 45, 7803–
7806.
(8) Zincke aldehydes are known to be recalcitrant dienes in intermolecular
cycloadditions: Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel,
F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C. Chem.—Eur. J. 1999, 5,
3154–3161.
proceeds smoothly and with excellent stereocontrol. With C3-
substituted Zincke aldehydes (R2 * H), an interesting case of
stereoconvergence occurs; these aminodienal substrates are gener-
ated as thermodynamic mixtures of geometrical isomers about their
trisubstituted alkenes (ca. 3:1), and this mixture is rearranged to
the Z-products with selectivities of g10:1.14 The smooth formation
of morpholino amide 20 is noteworthy due to the known ability of
these amides to serve as effective acyl transfer substrates.15
Although more studies are needed, preliminary experiments have
shown that rearrangement rates are increased with the addition of
small amounts of camphorsulfonic acid, suggesting that catalysis
might result in milder conditions for this novel reaction.
(9) At this stage, we have no further experimental support for this hypothesis,
though it does fit the observed reactivity. The formation of 15 can also be
viewed as a carbonyl addition reaction by the nitrogen atom in 14 (non-
zwitterionic resonance structure) to generate the cyclic zwitterion.
(10) A related transformation of donor-acceptor enynes derived from Zincke
aldehydes, triggered by addition of an acid to the ynamine, provides related
products of E-configuration: Fischer, F.; Berger, D.; Neuenschwander, M.
HelV. Chim. Acta 1998, 81, 1792–1802.
(11) A thermal rearrangement of an unusual tetrachlorinated doubly vinylogous
thioester to the corresponding R,ꢀ,γ,δ-unsaturated thioester was proposed
to proceed via pyran intermediates and a [1,5]-Cl shift: Roedig, A.; Go¨pfert,
H. Chem. Ber. 1981, 114, 3625–3633.
(12) On the basis of literature precedent and our own exploratory experiments,
Zincke aldehydes with any substitution at C1 or C5 (derived from pyridine
C2 and C6) are not accessible from the pyridine ring-opening process. Due
to the regioselectivity of the ring-opening aminolysis/iminium hydrolysis
process, monosubstitution at C4 is also not possible using this route. Studies
to access substituted Zincke aldehydes by other means are underway.
(13) Presumably, the Z to E isomerization is not purely thermal but is instigated
by an impurity in the reaction medium. To date, we have been unable to
fully suppress the isomerization. Fortunately, those products that are most
difficult to access with high Z-selectivity (7 and 17) are those that might
be readily obtained by alkyne semi-hydrogenation.
The utility of the products can be demonstrated by selective
manipulation of either terminus of representative product 10.
Preliminary results include the reduction of the amide to alcohol
2316 and selective alkene cross-metathesis17 to afford Z,E-diene
24 (Scheme 2) in moderate, but unoptimized yields.
We have uncovered a new rearrangement of donor-acceptor
dienes known as Zincke aldehydes, which originate in two simple
steps from inexpensive pyridines. While we have not yet studied
the mechanism of the reaction in detail, it is consistent with a
multistep pericyclic process; this reaction might serve as the
prototype of a new type of rearrangement process of donor-acceptor
dienes. The high kinetic selectivity for Z-dienamides is a conse-
quence of the presumed mechanism of the rearrangement and
engenders great potential utility to this interesting transformation.
Facile and stereoselective access to Z-trisubstituted alkenes with
two different substitution patterns demonstrates the versatility of
the method. Further studies on the scope and mechanism, as well
as applications in natural product synthesis, will be reported in due
course.
(14) We have confirmed the alkene stereochemistry of our products spectro-
scopically and by comparison to known compounds. See the Supporting
Information for details.
(15) (a) Mart´ın, R.; Romea, P.; Tye, C.; Urp´ı, F.; Vilarrasa, J. Synlett 1997,
1414–1416. (b) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Díaz, P. J. Org.
Chem. 2007, 72, 7974–7979. Given the relative costs of morpholine (ca.
US $3/mol, 2007-08 Aldrich catalog pricing) and N,O-dimethylhydroxy-
lamine hydrochloride (ca. US $215/mol), we opted to synthesize morpholino
amides rather than the corresponding Weinreb amides, as both have
demonstrated smooth acyl transfer reactions to organometallic nucleophiles
without double addition, and the inconvenience of generating N,O-
dimethylhydroxylamine free base is avoided.
(16) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(17) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–
1923. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179. (c) For the structure of this
catalyst, please see the Supporting Information.
JA8028125
9
J. AM. CHEM. SOC. VOL. 130, NO. 24, 2008 7561