Intramolecular Diels-Alder reactions of 4-vinylimidazoles

Article abstract of DOI:10.1021/ol0352862

(Matrix Presented) The synthesis of a variety of unsaturated ethers, esters, and amides derived from urocanic acid and their Diels-Alder reactions are reported. Propargylic ethers and esters cyclize with reasonable efficiencies, but the related mono- and

Full text of DOI:10.1021/ol0352862

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3623-3626
Intramolecular Diels
4-Vinylimidazoles
−Alder Reactions of
Yong He, Yingzhong Chen, Haiyan Wu, and Carl J. Lovely*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu
Received July 11, 2003
ABSTRACT
The synthesis of a variety of unsaturated ethers, esters, and amides derived from urocanic acid and their Diels
−Alder reactions are reported.
Propargylic ethers and esters cyclize with reasonable efficiencies, but the related mono- and unactivated olefins did not cyclize. On the other
hand, the corresponding amines and amides, along with the doubly activated ester/amide derivatives participate in the cycloaddition reaction.
Our laboratory has been interested for some time in the
development of methods for elaborating simple imidazoles
into complex, marine-derived natural products.1,2 Of par-
ticular interest have been several members of the oroidin
class of molecules (Figure 1). The parent heterocycle (1),
through various modes of cyclization and/or dimerization,
provides a large variety of structurally interesting and
biologically active natural products.3 Among this class of
marine alkaloids, we have been interested in developing
approaches to palau’amine 2,4 ageliferin 3,5 and axinellamine
A 4.6 This interest arises as a result of the possibility of
utilizing Diels-Alder chemistry of vinylimidazoles to access
(1) (a) Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett. 2001, 3, 1319.
(b) Lovely, C. J.; Du, H.; Dias, H. V. R. Heterocycles 2003, 60, 1. (c)
Chen, Y.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379.
(d) Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Manuscript in preparation.
(2) Faulkner, D. J. Nat. Prod. Rep. 2002, 1.
Figure 1. Oroidin and some oroidin-derived alkaloids.
(3) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
(4) Isolation: Kinnel, R. B.; Gehrken, H.-P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281. Synthetic approaches:
Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem.
Soc. 1997, 119, 7159. (b) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 8793. (c) Dilley, A. S.; Romo, D. Org. Lett. 2001,
3, 1535. (d) Belanger, G.; Hong, F.-T.; Overman, L. E.; Rogers, B. N.;
Tellew, J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67, 7880. (e) Koenig, S.
although subsequently our own efforts1a,b and those of Ohta5d
G.; Miller, S. M.; Leonard, K. A.; Loewe, R. S.; Chen, B. C.; Austin, D.
the polysubstituted carbocycle in these alkaloids.1a,7 When
this project was initiated, little was known concerning the
Diels-Alder reaction of imidazoles or vinylimidazoles,8
J. Org. Lett. 2003, 5, 2203.
(5) Isolation: (a) Kobayashi, J.; Tsuda, M.; Murayama, T.; Nakamura,
H.; Ohizumi, Y.; Ishibashi, M.; Iwamura, M.; Ohta, T.; Nozoe, S.
Tetrahedron 1990, 46, 5579. (b) Williams, D. H.; Faulkner, D. J.
Tetrahedron 1996, 52, 5381. (c) Keifer, P. A.; Schwartz, R. E.; Koker, M.
E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991,
56, 2965. (d) Synthetic approaches: Kawasaki, I.; Sakaguchi, N.; Fuku-
shima, N.; Fujioka, N.; Nikaido, F.; Yamashita, M.; Ohta, S. Tetrahedron
Lett. 2002, 43, 4377.
10.1021/ol0352862 CCC: $25.00
© 2003 American Chemical Society
Published on Web 08/30/2003

have shed some light on these latter substrates as Diels-
Alder dienes (and dienophiles). In related work, Romo’s
group, in their approach to palau’amine, have investigated
the Diels-Alder chemistry of vinylimidazol-2-ones.4c To
date, all of these reported examples are intermolecular in
nature, and so recently our attention has been directed to
the extension of this methodology to the then unknown
intramolecular variants. It was our eventual intent to employ
this Diels-Alder variant as the key step in approaches to
ageliferin 3 and axinellamine A 4. Therefore the studies
described in this Letter serve as feasibility studies for this
undertaking.
Scheme 3
Our investigation commenced with the protection of
methyl urocanoate (5)9 with dimethylaminosulfonyl chloride
(DMASCl) to provide 6, which upon subsequent reduction
with DIBAL-H gave the key allylic alcohol (7, Scheme 1).10
Scheme 1
mide (Scheme 3, 7 f 17)12 or the propargyl sulfonamide
(Scheme 3, 7 f 18),13 or by acylation of the N-benzylamine
(Scheme 3, 9 f 19-21). The N-benzylamine (9) was
prepared from 7 by chlorination and subsequent treatment
with potassium phthalimide (Scheme 1, 7 f 8).14 Cleavage
of the N-alkylated phthalimide was achieved with hydrazine,
and the resulting primary amine was then reductively
alkylated with benzaldehyde in the presence of NaBH4
(Scheme 1, 8 f 9).
At this point the alcohol was alkylated with a variety of
representative allyl or propargyl halides or acylated with
related acyl chlorides or carboxylic acids (suitably activated)
to provide the corresponding ethers or esters, respectively
(Scheme 2, 10-15, Scheme 3, 16). The analogous amino-
With this variety of trienes in hand, they were subjected
to a thermal Diels-Alder reaction in benzene. The outcome
of these reactions is summarized in Table 1. In the O-linked
series, it is evident that only the acetylenic systems participate
effectively in cycloaddition (Table 1, entries 2 and 5), with
the notable exception of the fumarate derivative (Table 1,
entries 7 and 8). While the poor reactivity of the unactivated
systems can be understood in terms of unfavorable energetics,
Scheme 2
(7) In the case of palau’amine and axinellamine, a ring contraction of
the Diels-Alder adduct would be necessary to access the cyclopentane.
For our efforts toward this end see ref 1d and Romo’s report, ref 4c
(8) (a) Kosaka, K.; Maruyama, K.; Nakamura, H.; Ikeda, M. J. Hetero-
cycl. Chem. 1991, 28, 1941. (b) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A.
Tetrahedron Lett. 1993, 34, 6981. (c) Walters, M. A.; Lee, M. D.
Tetrahedron Lett. 1994, 35, 8307. (d) Wan, Z.-K.; Woo, G. H. C.; Synder,
J. K. Tetrahedron 2001, 57, 5497. (e) Neipp, C. E.; Ranslow, P. B.; Wan,
Z.; Snyder, J. K. J. Org. Chem. 2003, 68, 4345. (f) Deghati, P. Y. F.;
Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 1998, 39, 4561. See also
(g) Rothenburg, A. S.; Daulplaise, D. L.; Panzer, H. P. Angew. Chem., Int.
Ed. Engl. 1983, 22, 560.
(9) Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229.
(10) This compound has been described in the patent literature. Tozer,
M. J.; Kalindjian, S. B.; Linney, I. D.; Steel, K. I. M.; Pether, M. J.; Cooke,
T. PCT Int. Appl. WO 9905114 A2, 1999; Chem. Abstr. 1999, 130, 168369
(11) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
or amide-linked substrates were prepared from either the
alcohol, by a Mitsunobu amination11 with the allyl sulfona-
(12) Tehrani, K. A.; Nguyen Van, T.; Karikomi, M.; Rottiers, M.; De
Kimpe, N. Tetrahedron 2002, 58, 7145.
(13) Oppolzer, W.; Ruiz-Montes, J. HelV. Chim. Acta 1993, 76, 1266.
(14) Sellier, C.; Buschauer, A.; Elz, S.; Schunack, W. Liebigs Ann. Chem.
1992, 317.
(6) Isolation: Urban, S.; de Almeida Leone, P.; Carroll, A. R.; Fechner,
G. A.; Smith, J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64,
731. Synthetic approaches: (a) Starr, J. T.; Koch, G.; Carreira, E. M. J.
Am. Chem. Soc. 2000, 122, 8793. (b) See also ref 4c.
3624
Org. Lett., Vol. 5, No. 20, 2003

Table 1. Intramolecular Diels-Alder Cycloaddition Reactions of Vinylimidazoles
a Yields are not optimized. b Amide was used directly after aqueous workup.
the lack of reactivity of the acrylate and cinnamate systems
requires further explanation (Table 1, entries 4 and 6). It
has been found in intermolecular variants that there is a
regiochemical preference for orientation of an electron-
deficient substituent proximal to the imidazole;15 therefore
it is reasonable to assume that the entropic advantage
conferred by intramolecularity does not overcome the
intrinsic electronic bias of the system. This notion is
supported to some degree by the successful cycloaddition
of the fumarate-derived diester, which provides cycloadduct
25 in a modest 20% yield (Table 1, entry 7). Interestingly,
the DMAS-moiety appears to have migrated to the other
imidazole nitrogen (N3 in 16). There are reports in the
literature of the migration of DMAS groups on imidazoles,
and it has been assumed that this is a result of the relief of
steric crowding, leading to the thermodynamically most
stable isomer.16 A similar explanation can be forwarded in
this instance, since migration of the DMAS moiety would
relieve steric crowding between the CO2Et moiety and the
DMAS group.17 Ultimately it was found by reducing the
temperature to 135 °C and reducing the reaction time (Table
1, entry 8) that the anticipated cycloadduct (26) could be
obtained, although the yield was fairly low.18
The corresponding amino-linked substrates (17-21) were
investigated, and it was found that these were more effective
substrates, although for the unactivated systems rather high
temperatures and extended reaction times were required. The
N-allyl substrate provided two products (Table 1, entry 9),
a ca. 1:1 mixture of cis/trans aromatized cycloadducts (28,
54%), along with a 4:1 diastereomeric mixture of the initial
cycloadduct (27, 8%, cis/trans unassigned).19 The propargyl
system successfully cyclized (Table 1, entry 10), affording
the expected adduct 29 in 38% yield, plus a small amount
(17) We were concerned that under the reaction conditions employed,
migration of the DMAS group may have occurred with other substrates.
NOESY experiments were conducted on 22, 24, 29, 33, and 34, the results
of which indicated that the initially expected products were obtained.
(18) In an attempt to improve the yield of this cycloadduct, the reaction
was allowed to proceed for 9 days at 135 °C; however, under these
conditions the yield did not improve and migration of the DMAS group
occurred to provide 25.
(15) Du, H.; Lovely, C. J. Unpublished results.
(16) (a) Kim, J.-W.; Abdelaal, S. M.; Bauer, L.; Heimer, N. E. J.
Heterocycl. Chem. 1995, 32, 611. (b) Bhagavatula, L.; Premchandran, R.
H.; Plata, D. J.; King, S. A.; Morton, H. E. Heterocycles 2000, 53, 729.
Org. Lett., Vol. 5, No. 20, 2003
3625

of the fully aromatized adduct (30, 8%). By far the best
substrate was the fumaramide derivative (19); heating a
sample of this material in benzene at 68 °C led to the
formation of a single cycloadduct in 90% yield (Table 1,
entry 11). It was found that this substrate underwent
cycloaddition during purification as small amounts of cy-
(J4a,7a ) 12.8, 12.8 Hz respectively), which is consistent with
those observed for 25 and 32 for which X-ray structures have
been secured.
There is an interesting contrast in the results obtained with
the ether/ester series and the amine/amide series. Only the
acetylenic dienophiles participated in cycloaddition with the
O-linked systems, whereas all of the N-linked systems react
albeit with varying efficiencies. These results can be
interpreted in terms of reactive rotamer effects, that is, the
amines/amides have a greater population of the reactive
rotamer as a result of unfavorable nonbonded interactions
between the N-substituent (Ts or Bn) and the dienophilic
component.22,23
In summary, we have demonstrated that intramolecular
Diels-Alder reactions are feasible with 4-vinylimidazoles
derived from urocanic acid. The most efficient cycloadditions
are obtained with N-substituted amino-linkers, in particular
with activated dienophiles. In these cases, the reactions
appear to proceed via endo transition states, providing trans
ring-fused products as the major adduct.24 Both cycloadducts
35 and 36 contain the appropriate structural and stereochem-
ical elements for elaboration into ageliferin. We are currently
investigating the scope of this reaction with respect to
imidazole substitution patterns and its application in natural
product total synthesis. The results of these studies will be
reported in due course.
1
cloadduct were detected in the H NMR spectrum of 19;
therefore in subsequent reactions it was directly subjected
to cycloaddition after preparation. Under these circumstances,
the major product was the aromatized adduct (32), plus small
amounts of the initial adduct (31, Table 1, entry 12).
Presumably, under these conditions trace amounts of acid
catalyze the aromatization of the imidazole ring. Analysis
of the aromatized adduct by X-ray indicated that the ring
fusion was trans, resulting from an endo transition state. The
cinnamide 20 also participates in a cycloaddition reaction
providing two adducts (Table 1, entry 13), the initial adduct
(33, 61%) and the aromatized adduct (34, 32%). Prolonged
heating led to the formation of more of the aromatized adduct
(Table 1, entry 14), which is consistent with previous results
obtained in the intermolecular series.1a,b Each of these adducts
was obtained as a single diastereomer, which on the basis
of coupling constant data appear to contain a trans fused
lactam (J4a,7a ) 13.1, 12.8 Hz respectively). Given this, it
appears that these products are formed via an endo transition
state. The final system evaluated was the dimeric imidazolyl
substrate 21, which was to serve as a model for approaches
to ageliferin (and possibly axinellamine A). As can be seen,
this too is a competent substrate (Table 1, entry 15),
providing two products (35 and 36),20 although the reaction
rate is somewhat attenuated. Perhaps the most notable feature
of this derivative is that there is an additional selectivity issue
regarding the diene/dienophile pairing. Aromatic products
arising from both possible pairings were obtained, although
it appears that there is some intrinsic selectivity for the allylic
amine functioning as the diene. Furthermore, there is an
interesting disparity in the outcome of the cycloaddition
reactions of 20 and 21. Presumably, in the case of 21 the
cost of dearomatizing either imidazole (as required for
cycloaddition) is similar, whereas with 20 the energetics for
dearomatizing the benzene moiety are too prohibitive.21 Both
adducts appear to possess trans ring fusions as judged by
the magnitude of the coupling constant for the diaxial protons
Acknowledgment. This work was supported by the
Robert A. Welch Foundation (Y-1362), and the Texas
Advanced Research Program (003656-0004-1999). X-ray
diffraction studies were performed at the Texas Center for
Crystallography at Rice University funded by the Robert A.
Welch Foundation.25
Supporting Information Available: Experimental and
characterization data for all new compounds and X-ray plots
and data (in CIF format) for compounds 25 and 32. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0352862
(22) (a) He, Y.; Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely,
C. J. Tetrahedron Lett. 2002, 43, 1171. (b) Gschwend, H. W.; Lee, A. O.;
Meier, H. P. J. Org. Chem. 1973, 38, 2169. (c) Jung, M. E.; Gervay, J. J.
Am. Chem. Soc. 1991, 113, 224. (d) Jung, M. E. Synlett 1990, 186. (e)
Jung, M. E. Synlett 1999, 843. (f) Bur, S. K.; Lynch, S. M.; Padwa, A.
Org. Lett. 2002, 4, 473.
(19) We cannot rule out the possibility that this mixture of products is
in fact the 4- and 5-isomers, through migration of the N-sulfamoyl group,
rather than the cis/trans isomers on the basis of the NMR data.
(20) This cycloadduct was obtained as a mixture of products, which were
separable by preparative thin-layer chromatography.
(21) For comparison, see: Oppolzer, W.; Achini, R.; Pfenninger, E.;
Weber, H. P. HelV. Chim. Acta 1976, 59, 1186
(23) It was found that the NH-congener of 19 did not undergo cyclization
at temperatures up to 160 °C.
(24) The use of endo here refers to the relative location of the terminal
substituent on the dienophilic component rather than the carbonyl of the
amide.
(25) Inquiries regarding X-ray determinations should be directed to Dr.
Simon Bott (University of Houston) at sbott@uh.edu.
3626
Org. Lett., Vol. 5, No. 20, 2003