Intramolecular cyclization reactions of 5-halo- and 5-nitro-substituted furans

Article abstract of DOI:10.1021/ol035233k

(Matrix presented) Intramolecular cyclization reactions of 5-halo- and 5-nitro-substituted furanylamides were examined. The 2-alkoxy-5-bromofuran derivative 2 produced the rearranged dihydroquinone 6 (36%), a product from the rearrangement of the intermed

Full text of DOI:10.1021/ol035233k

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3337-3340
Intramolecular Cyclization Reactions of
5-Halo- and 5-Nitro-Substituted Furans
Kenneth R. Crawford,† Scott K. Bur,‡ Christopher S. Straub,§ and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received July 3, 2003
ABSTRACT
Intramolecular cyclization reactions of 5-halo- and 5-nitro-substituted furanylamides were examined. The 2-alkoxy-5-bromofuran derivative 2
produced the rearranged dihydroquinone 6 (36%), a product from the rearrangement of the intermediate oxabicycle 3. The 5-halo substituted
furoyl amide 18 was converted to the polyfunctional oxabicycle 20 in 82% yield and at a much faster rate than the unsubstituted furanyl
system 17. The 5-nitro-substituted furfuryl amide 33b underwent an unusual isomerization−cyclization reaction under microwave conditions
to provide 1,4-dihydro-2H-benzo[4,5]furo[2,3-c]pyridin-3-one 34.
The intramolecular Diels-Alder reaction of furans (IMDAF)
has proven to be a powerful tool for the rapid construction
of polycyclic skeletons.1 In earlier papers, we have exploited
the cycloaddition-rearrangement cascade reaction of 2-
amidofurans as a key disconnection for the construction of
alkaloid frameworks.2 As part of our broader interest in using
furan-cycloaddition products for the synthesis of natural
products, we examined the strategic incorporation of several
functional groups into the furan moiety that could be
leveraged for further transformations.3 After our initial
success using 2-alkylthio-5-amidofurans,2c,4 we decided to
use other substituents that would allow for the further
manipulation of the resulting cycloadducts. Herein, we report
some of the interesting results obtained from the thermolysis
of various 5-halo- and 5-nitro-substituted furans.
One useful route for the preparation of substituted furans
is through the Rh(II)-catalyzed cyclization of diazo 2-pro-
pynyl malonate esters.5 For example, we discovered that
heating a sample of diazo ester 1 with a catalytic amount of
Rh2(OAc)4 at reflux in benzene gave 2-bromofuran 2
(Scheme 1). Interestingly, when a solution of 2 in xylene
was heated to 145 °C (sealed tube) overnight, bromide 6
was isolated as the major product. Presumably, 6 arises from
† Current address: Gilead Sciences, Inc., 333 Lakeside Drive, Foster
City, CA 94404.
‡ NIH Postdoctoral Fellow (Grant GM20666). Current address: Depart-
ment of Chemistry, Gustavus Adolphus College, 800 West College Ave.,
St. Peter, MN 56082.
§ Current address: Novartis Pharmaceuticals Corporation, One Health
Plaza, East Hanover, NJ 07936.
(1) (a) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179-14233. (b) Sternbach, D. D.; Rossana, D. M.; Onon, K. D. J. Org.
Chem. 1984, 49, 3427-3428. (c) Jung, M. E.; Gervay, J. J. Am. Chem.
Soc. 1989, 111, 5469-5470.
(2) (a) Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643-
4645. (b) Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4135-4137. (c) Ginn,
J. D.; Padwa, A. Org. Lett. 2002, 4, 1515-1517. (d) Padwa, A.; Brodney,
M. A.; Dimitroff, M.; Liu, B.; Wu, T. J. Org. Chem. 2001, 66, 3119-
3128. (e) Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001,
66, 1716-1724.
(3) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J.
Org. Chem. 2002, 64, 3412-3424.
(4) (a) Padwa, A.; Eidell, C. K.; Lynch, S. M. Heterocycles 2000, 58,
227-242. (b) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org.
Chem. 1998, 63, 1144-1155.
(5) (a) Padwa, A.; Straub, C. S. J. Org. Chem. 2003, 68, 227-239. (b)
Padwa, A.; Straub, C. S. Org. Lett. 2000, 2, 2093-2095.
10.1021/ol035233k CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003

to the tether.6 In contrast to this finding, it was necessary to
heat the unsubstituted amidofuran 11 for 1 week at 110 °C
in order to complete the cycloaddition of 11 to 13. Alter-
natively, furans 7 and 8 could directly be converted to
cycloadducts 13 and 14 by conducting the N-allylation at
reflux temperatures. After 48 h, the bromofuran 8 was
completely transformed to cycloadduct 14, whereas the
unsubstituted variant 7 gave a mixture of 11 (40%) and
cycloadduct 13 (48%).
Scheme 1a
The rate enhancement observed by incorporating a halogen
at the 5-position appears to be general.7 Accordingly, when
the analogous 5-chloro- and 5-iodofurans 9 and 10 were
subjected to the allylation conditions in benzene at reflux,
cycloadducts 15 and 16 were isolated in 92 and 94% yields,
respectively.
The presence of the bromo substituent also dramatically
influenced the rate of the IMDAF cyclization of substituted
alkene tethers. For example, while the cycloaddition of 17
was only 40% complete after 6 days of constant heating at
80 °C, bromofuran 18 was completely converted to 20 after
only 36 h.8
The origin of the increased rate of cycloaddition for the
halo-substituted furans when compared to unsubstituted
examples is unclear.7 While FMO theory predicts that
electron-releasing groups should facilitate a normal-demand
Diels-Alder reaction,9 predicting the electronic effect of a
halo group is complicated by their σ-withdrawing nature
juxtaposed with their weak π-donating ability. Recent
theoretical work, however, predicts the transition state-
stabilizing effect of halogen substituents in the Diels-Alder
reaction and suggests that this is a result of the high
polarizability of these substituents.10
The remarkable enhancement in the rate of the cycload-
dition involving bromofurans, combined with our recent
success with cycloadditions across an indole C(2)-C(3)
π-bond,2a prompted us to examine these reactions in the
context of a (()-morphine synthesis.11 Ciganek had previ-
ously reported the intramolecular Diels-Alder reaction of
21 to provide the ACDE core 22, albeit in only 10% yield
(Scheme 3).12 R-Pyrone derivative 23, however, produced
24 in 53% yield. Inspired by this report, we envisioned an
IMDAF reaction of furanyl amide 26 to furnish the cycload-
duct 25.
a Reagents: (a) Rh2(OAc)4, PhH, 2; (b) xylenes, 145 °C, 36%.
an initial intramolecular Diels-Alder reaction of furan 2 to
give oxabicycle 3. Fragmentation of the oxabridge results
in a zwitterionic intermediate 4, which can ketonize with
the expulsion of a bromide ion, producing oxonium ion 5.
The ejected bromide ion then attacks the oxonium ion at the
adjacent methylene position, leading to the observed product.
Intrigued by these initial results, we decided to examine
related systems that could provide polyfunctional oxabi-
cycles. Thus, 5-bromo-2-furoyl amide 12 was prepared by
N-allylation of the secondary amide 8 under phase transfer
conditions (Scheme 2). Heating a sample of furan 12 at 110
°C for 90 min provided the stable oxatricycle 14 as a single
diastereomer, resulting from an exo cyclization with respect
Scheme 2a
(6) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org. Chem.
1999, 64, 4617-4626.
(7) For a study of substituent effects in related IMDAF reactions, see:
Klepo, Z.; Jakop, K. J. Heterocycl. Chem. 1987, 24, 1787-1791.
(8) Slow conversion of furan 17 to oxabicyclo 19 (40%) over a 6 day
period was followed every 24 h and was shown not to be the result of a
retro Diels-Alder equilibrium.
(9) Sustmann, R. Tetrahedron Lett. 1971, 2721-2724.
(10) Robiette, R.; Marchand-Brynaert, J.; Peeters, D. J. Org. Chem. 2002,
67, 6823-6826.
(11) (a) Sza´ntay, C.; Do¨rnyel, G.; Blasko´, G. In The Alkaloids: Chemistry
and Pharmacology; Cordell, G. A., Brossi, A., Eds.; Academic Press:
London, 1994; Vol. 45, pp 127-232. (b) Maier, M. In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 357-369.
(c) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R. In
Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier:
Amsterdam, 1996; Vol. 18, pp 43-154. (d) Novak, B. H.; Hudlicky, T.
Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343-362.
(e) Bentley, K. W. Nat. Prod. Rep. 2000, 17, 247-268. (f) Blakemore, P.
R.; White, J. D. Chem. Commun. 2002, 1159-1168.
a Reagents: (a) NaOH, K2CO3, n-Bu4NHSO4, allyl bromide,
PhH, rt (11 or 12) or 2; (b) PhCH3, 2, 1 week (13, 90%) or 90 min
(1, 100%); (c) PhH, 2, 6 days (19, 60%) or 36 h (20, 82%).
(12) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261-6162.
3338
Org. Lett., Vol. 5, No. 18, 2003

At this point in time, we decided to attempt an inverse
electron-demand Diels-Alder reaction using an electron-
withdrawing nitro group, rather than a bromo substituent.
Accordingly, we prepared the 5-nitro-furan variant 29b
through the acylation protocol using 28b as an acylating
agent. Again, all of our attempts to effect IMDAF cyclization
of 29b failed.
Scheme 3. Approach to Morphine’s ACDE Core
Undeterred by these initial results, we also examined the
thermolysis of furfuryl amides 33a,b, where the amide
carbonyl group is transposed onto the opposite side of the
nitrogen atom (Scheme 5). These substrates were prepared
Scheme 5a
a Reagents: (a) pyridine, CH2Cl2, 0 °C, 39% (31a) or 41% (31b);
(b) NMP, µW (300W), 15 min, 36%.
Acylation of tert-butylamine 27 with acid chloride 28a,
derived from commercially available 5-bromo-2-furoic acid,
gave the desired tertiary amide 29a in good yield (Scheme
4). Unfortunately, all of our attempts to effect the cycload-
dition of 29a only resulted in the removal of the labile tert-
butyl group to give 30. Thermal conditions, microwave
assistance, and the addition of several Lewis acids (i.e.,
SnCl4, TiCl4, ZnCl2‚OEt2, BF3‚OEt2, TMSOTf) all failed to
promote the desired cycloaddition.
in modest yields (ca. 40%) by the acylation of secondary
tert-butylamines 31a,b, derived from the reductive amina-
tion13 of tert-butylamine and the corresponding 2-furfurals,
with acid chloride 32.11 Attempts to effect the cycloaddition
of 33a,b under thermal conditions once again resulted in the
removal of the tert-butyl group. Most interestingly, when
Scheme 6
Scheme 4a
a Reagents: (a) Et3N, CH2Cl2, 0 °C; (b) 2, µW or Lewis acid.
Org. Lett., Vol. 5, No. 18, 2003
3339

nitrofuran 33b was exposed to microwave irradiation for 15
min in N-methyl-2-pyrrolidinone (NMP), furan 34 was
isolated as the major product.
amides. Investigation into the rearrangements of the resultant
7-oxabicyclo[2.2.1]heptene cycloadducts, as well as the
application of this approach to the synthesis of alkaloid
natural products, is currently under investigation and will
be fully disclosed in due course.
Compound 34 was unequivocally assigned by a single-
crystal X-ray analysis.14 Catalytic amounts of 2,6-lutidine
enhanced the formation of 34, suggesting a mechanism
involving base-catalyzed tautomerization of the furfuryl
moiety via intermediates 35 and 36 as shown in Scheme 6.
In conclusion, our studies have uncovered some interesting
thermal transformations that arise from 5-halo- or 5-nitro-
substituted furans. In particular, the presence of a 5-halo
substituent on the furan greatly enhances the rate of the
intramolecular [4 + 2]-cycloaddition reaction of 2-furoic acid
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM59384) for generous sup-
port of this work. We also thank Dr. Kenneth Hardcastle
for his assistance with the X-ray crystal structure of
compound 34.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds,
together with an ORTEP drawing for compound 34. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
(14) The authors have deposited coordinates for structure 34 with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.
OL035233K
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Org. Lett., Vol. 5, No. 18, 2003