Halo substituent effects on intramolecular cycloadditions involving furanyl amides

Article abstract of DOI:10.1021/jo0602322

Intramolecular Diels-Alder reactions involving a series of N-alkenyl-substituted furanyl amides were investigated. Stable functionalized oxanorbornenes were formed in high yield upon heating at 80-110 °C. The cycloaddition reactions include several bromo-substituted furanyl amides, and these systems were found to proceed at a much faster rate and in higher yield than without substitution. This effect was observed by incorporating a halogen in the 3- or 5-position of the furan ring and appears to be general. The origin of increased cycloaddition rates for halo-substituted furans has been investigated with quantum mechanical calculations. The success of these reactions is attributed to increases in reaction exothermicities; this both decreases activation enthalpies and increases barriers to retrocycloadditions. Halogen substitution on furan increases reactant energy and stabilizes the product, which is attributed to the preference of electronegative halogens to be attached to a more highly alkylated and therefore more electropositive framework.

Full text of DOI:10.1021/jo0602322

Halo Substituent Effects on Intramolecular Cycloadditions Involving
Furanyl Amides
Albert Padwa,* Kenneth R. Crawford, and Christopher S. Straub
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Susan N. Pieniazek and K. N. Houk*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
houk@chem.ucla.edu
ReceiVed February 5, 2006
Intramolecular Diels-Alder reactions involving a series of N-alkenyl-substituted furanyl amides were
investigated. Stable functionalized oxanorbornenes were formed in high yield upon heating at 80-110
°C. The cycloaddition reactions include several bromo-substituted furanyl amides, and these systems
were found to proceed at a much faster rate and in higher yield than without substitution. This effect was
observed by incorporating a halogen in the 3- or 5-position of the furan ring and appears to be general.
The origin of increased cycloaddition rates for halo-substituted furans has been investigated with quantum
mechanical calculations. The success of these reactions is attributed to increases in reaction exothermicities;
this both decreases activation enthalpies and increases barriers to retrocycloadditions. Halogen substitution
on furan increases reactant energy and stabilizes the product, which is attributed to the preference of
electronegative halogens to be attached to a more highly alkylated and therefore more electropositive
framework.
SCHEME 1
Introduction
Diels-Alder reactions involving furan as a diene form
oxanorbornenes that have been used in the syntheses of
numerous complex targets.1 Rh(II)-catalyzed cyclizations2 rep-
resent useful methods for preparing furan substrates (Scheme
1).3 We have relied on this and other methods for the strategic
incorporation of various functional groups into the furan moiety
that allow for facile subsequent transformations.4
The preparation of N-alkenyl-substituted furanyl amides for
intramolecular Diels-Alder reactions has also been achieved.5
Certain systems of this type, however, gave low yields of [4+2]-
cycloadducts. A survey of the literature reveals similar examples
of seemingly well-designed substrates for intramolecular cy-
cloaddition that fail, usually due to substrate inertness6 or the
tendency of the products to undergo retrocycloadditions.7,8
The yields of intramolecular Diels-Alder reactions involving
furan are highly sensitive to both diene and dienophile substitu-
(2) (a) Padwa, A.; Krumpe, K. E.; Gareau, Y.; Chiacchio, U. J. Org.
Chem. 1991, 56, 2523-2530. (b) Padwa, A.; Xu, S. L. J. Am. Chem. Soc.
1992, 114, 5881-5882. (c) Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org.
Chem. 1991, 56, 6971-6972. (d) Baird, M. S.; Buxton, S. R.; Whitley, J.
S. Tetrahedron Lett. 1984, 25, 1509-1512. (e) Padwa, A.; Fryxell, G. E.;
Zhi, L. J. Org. Chem. 1988, 53, 2875-2877. (f) Padwa, A.; Krumpe, K.
E.; Zhi, L. Tetrahedron Lett. 1989, 30, 2633-2636. (g) Padwa, A.;
Chiacchio, U.; Garreau, Y.; Kassir, J. M.; Krumpe, K. E.; Schoffstall, A.
M. J. Org. Chem. 1990, 55, 414-416. (h) Padwa, A.; Austin, J. A.; Xu, S.
L. J. Org. Chem. 1992, 57, 1330-1331. (i) Padwa, A.; Krumpe, K. E.;
Kassir, J. M. J. Org. Chem. 1992, 57, 4940-4948. (j) Padwa, A.; Austin,
D. J.; Xu, S. L. Tetrahedron Lett. 1991, 32, 4103-4106. (k) Padwa, A.;
Chiacchio, U.; Fairfax, D. J.; Kassir, J. M.; Litrico, A.; Semones, M. A.;
Xu, S. L. J. Org. Chem. 1993, 58, 6429-6437. (l) Padwa, A.; Kassir, J.
M.; Semones, M. A.; Weingarten, M. D. J. Org. Chem. 1995, 60, 53-62.
(m) Padwa, A.; Austin, D. J.; Chiacchio, U.; Kassir, J. M.; Rescifina, A.;
Xu, S. L. Tetrahedron Lett. 1991, 32, 5923-5926. (n) For a mini review,
see: Padwa, A. J. Organomet. Chem. 2001, 617, 3-16.
(1) (a) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999,
55, 13521-13642. (b) Kappe, C. O.; Murphree, S. S.; Padwa, A.
Tetrahedron 1997, 53, 14179-14233. (c) Lipshutz, B. H. Chem. ReV. 1986,
86, 795-819. (d) Ashton, P. R.; Brown, G. R.; Isaacs, N. S.; Giuffrida, D.;
Kohnke, F. H.; Mathias, J. P.; Slawin, A. M. Z.; Smith, D. R.; Stoddart, J.
F.; Williams, D. J. J. Am. Chem. Soc. 1992, 114, 6330-6353. (e) Lo¨ffler,
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10.1021/jo0602322 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/28/2006
5432
J. Org. Chem. 2006, 71, 5432-5439

Halo Substituent Effects on Intramolecular Cycloadditions
tion, as well as to the nature and length of the tether.1b In
particular, substitution on furan greatly affects the chemical
reactivity of these reactions. The group of Jakopcic found that
chlorine, bromine, or iodine substituents on furan increase
cycloaddition yields and cycloadduct stability (see yields for
conversion of 5 to 6).9 Our group also reported increased rates
and yields of reactions with halogen substitution (see conversion
of 7 to 9).5 The possibility that simple halogen substitution might
turn previous failures into successes led us to explore the origins
of this halogen effect.10
Results and Discussion
A series of intramolecular cycloaddition reactions leading to
the syntheses of oxanorbornenes were undertaken, and these
results are summarized in Table 1. Cycloadduct 9c was prepared
by one-pot N-allylation and intramolecular cycloaddition of
secondary amide 7c under phase-transfer conditions. Alterna-
tively, heating a sample of N-allyl furanylamide 8c at 110 °C
for 90 min provided the stable oxatricycle 9c as a single
diastereomer. The stereochemistry of 9c is consistent with the
preferred exo orientation of the tether in the Diels-Alder
cycloaddition reaction and is analogous to that reported for
related furanyl systems possessing short tethers.11 In contrast,
the unsubstituted furan amide 8a (X ) H) was heated for one
week at 110 °C to complete its transformation into 9a.
Conducting the N-allylation at reflux temperatures, furans 7a
and 7c allowed the direct conversion into cycloadducts 9a and
9c. After 48 h, bromofuran 7c was completely transformed to
cycloadduct 9c, whereas the unsubstituted variant 7a gave a
mixture of 8a (40%) and cycloadduct 9a (48%) at 110 °C.
Incorporation of a halogen at the 5-position of furan provides
a significant rate enhancement. This effect appears to be
general,9 and when the analogous 5-chloro- and 5-iodofurans,
7b and 7d, were subjected to the allylation conditions in benzene
at reflux, cycloadducts 9b and 9d were isolated in 92% and
94% yield, respectively.
Cycloadditions involving dihalogenated furans were also
investigated. The substrates 3-bromo-, 10, and 4,5-dibromo-,
12, substituted furanyl amides yielded the expected intramo-
lecular Diels-Alder cycloadducts 11 (92%) and 13 (74%) under
allylation conditions for 48 h.
Bromine substitution also dramatically influenced the rate of
cycloadditions involving substituted dienophiles (systems 15 and
17). For example, although the cycloaddition of 14a was only
40% complete after 6 days of constant heating at 80 °C, bromo-
furan 14b was completely converted to 15b after only 36 h.12
A rate enhancement over the unsubstituted furan was observed
for the more highly activated bromo furanyl amides obtained
by N-alkylation of 7c with 16a and 16b, which afforded 17a
(85%) and 17b (70%) upon refluxing in benzene for 90 min.
Theoretical Calculations. Our experimental studies demon-
strate that halogen substitution can increase rates and yields of
intramolecular Diels-Alder cycloaddition reactions (Table 1).
In a recent communication,10 we computationally explored the
origin of this halogen effect with the high-accuracy CBS-QB3
method. Halogen substitution (fluorine, chlorine, and bromine)
on furan increases exothermicities by 4-9 kcal/mol, which
causes smaller decreases in activation barriers (2-3 kcal/mol),
and creates larger barriers to retrocycloadditions. This indicates
that the stabilizing effect of halogens increases as bond forming
between diene and dienophile proceeds. Several other repre-
sentative substituents and hydrocarbon dienes were investigated
for comparison. The origin of these substituent effects is the
In this study, we report the generality of the furan halogen
effect by experimental and computational studies. Reactions
yielding intramolecular cycloadducts substituted on different
positions of furan have been explored experimentally. The origin
of the increased rates and yields for halo-substituted intra-
molecular Diels-Alder reactions has been investigated with
quantum mechanical calculations. Synthetic versatility provided
by halogen substitution, which allows for several derivatizations
of the oxanorbornene cycloadducts, is also described herein.
(3) (a) Kinder, F. R.; Padwa, A. Tetrahedron Lett. 1990, 31, 6835-
6838. (b) Padwa, A.; Kinder, F. R. J. Org. Chem. 1993, 58, 21-28. (c)
Padwa, A.; Straub, C. S. Org. Lett. 2000, 2, 2093-2095.
(4) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J.
Org. Chem. 2002, 67, 3412-3424.
(5) Crawford, K. R.; Bur, S. K.; Straub, C. S.; Padwa, A. Org. Lett.
2003, 5, 3337-3340.
(6) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc. 1988,
110, 7188-7194.
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Gschwend, H. W.; Hillman, M. J.; Kisis, B. J. Org. Chem. 1976, 41, 104-
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Tetrahedron Lett. 1988, 29, 2493-2496. (e) McNelis, B. J.; Sternbach,
D. D.; MacPhail, A. T. Tetrahedron 1994, 50, 6767-6782. (f) Hudlicky,
T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Persichini, P. J., III; Stabile,
M. R.; Merola, J. S. J. Chem. Soc., Perkin Trans. 1 1995, 2393-2398.
(g) Heiner, T.; Kozhushkov, S. I.; Noltemeyer, M.; Haumann, T.; Boese,
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(c) Rogers, C.; Keay, B. A. Synlett 1991, 353-355. (d) Rogers, C.; Keay,
B. A. Can. J. Chem. 1992, 70, 2929-2947. (e) DeClercq, P. J.; Van Royen,
L. A. Synth. Commun. 1979, 9, 771-780. (f) Van Royen, L. A.; Mijngher,
R.; DeClercq, P. J. Bull. Soc. Chim. Belg. 1984, 93, 1019-1036. (g) Fischer,
K.; Hunig, S. J. Org. Chem. 1987, 52, 564-569. (h) Padwa, A.; Brodney,
M. A.; Satake, K.; Straub, C. S. J. Org. Chem. 1999, 64, 4617-4626.
(12) The slow conversion of furan 14a to oxabicyclo 15a (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.
(8) Jung, M. E.; Min, S.-J. J. Am. Chem. Soc. 2005, 127, 10834-10835.
(9) Klepo, Z.; Jakopcic, K. J. Heterocycl. Chem. 1987, 1787-1791.
(10) Pieniazek, S. N.; Houk, K. N. Angew. Chem., Int. Ed. 2006, 45,
1442-1445.
J. Org. Chem, Vol. 71, No. 15, 2006 5433

Padwa et al.
TABLE 1. Experimental Results for Furanyl Amide Intramolecular Cycloadditions
a Reaction Conditions: (i) (a) NaOH, K2CO3, n-Bu4NHSO4, toluene, room temperature, (b) allyl bromide, toluene, 110 °C; (ii) (a) NaOH, K2CO3,
n-Bu4NHSO4, benzene, room temperature, (b) allyl bromide, benzene, 80 °C; (iii) toluene, 110 °C; (iV) benzene, 80 °C; (V) (a) NaOH, K2CO3, n-Bu4NHSO4,
benzene, room temperature, (b) 16a, benzene, 80 °C; (Vi) (a) NaOH, K2CO3, n-Bu4NHSO4, benzene, room temperature, (b) 16b, benzene, 80 °C.
energetic preference for electronegative halogens to be attached
to the saturated and more highly alkylated carbon.10 This is more
electropositive than the alkene carbon of furan, and the
electronegative halogen forms a stronger bond to the more
electropositive carbon. Electropositive groups stabilize both
carbocations and carbon centers carrying electronegative sub-
stituents by means of hyperconjugative and σ-inductive effects.13
lecular cycloadditions has been investigated using B3LYP/6-
31G(d). The effect of bromination on two different positions
of furan has been considered. Furanyl amides C (Table 2) have
been chosen as computational models for the experimental
systems in Table 1. The corresponding parent intermolecular
reaction (A, Table 2) and an intramolecular system involving a
tether with three methylene units (B, Table 2) were also explored
computationally to test the generality of this halogen effect.
In this work, the initial studies are extended to intramolecular
systems. The kinetic and thermodynamic facilitation of intramo-
Activation and reaction enthalpies for model reactions A-C
are given in Table 2. In comparison with our previous CBS-
QB3 calculations,10 B3LYP/6-31G(d) performs well in repro-
ducing the effect of bromine substitution on activation and
reaction enthalpies. For the intermolecular case (A), B3LYP/
6-31G(d) enthalpies show an overestimation of reactant stability
with respect to the TS and product. However, the relative
changes in activation and reaction enthalpies upon bromination
(13) (a) Dill, J. D.; Schleyer, P. v. R.; Pople, J. A. J. Am. Chem. Soc.
1976, 98, 1663-1668. (b) Clark, T.; Spitznagel, G. W.; Klose, R.; Schleyer,
P. v. R. J. Am. Chem. Soc. 1984, 106, 4412-4419. (c) Schleyer, P. v. R.
Pure Appl. Chem. 1987, 59, 1647-1660. (d) Luo, Y.-R.; Benson, S. W. J.
Phys. Chem. 1988, 92, 5255-5257. (e) Dorigo, A. E.; Houk, K. N.; Cohen,
T. J. Am. Chem. Soc. 1989, 111, 8976-8978. (f) Wiberg, K. B. J. Org.
Chem. 1991, 56, 544-550. (g) Harvey, J. N.; Viehe, H. G. J. Prakt. Chem.
1995, 337, 253-256.
5434 J. Org. Chem., Vol. 71, No. 15, 2006

Halo Substituent Effects on Intramolecular Cycloadditions
TABLE 2. Activation and Reaction Enthalpies (kcal/mol) for Cycloadditions Involving Furan or Bromofuransa
a Bond lengths are given in Å.
are very close to the CBS-QB3 numbers. In general, bromine
substitution on furan decreases activation enthalpies (∆∆H‡ )
1.4-2.0 kcal/mol) and increases exothermicities (∆∆H ) 3.1-
4.6 kcal/mol). This trend is common for both intermolecular,
A, and intramolecular reactions, B and C. In comparison with
the more than 3 kcal/mol absolute increases in reaction
exothermicities, reaction enthalpy differences of 2- vs 3-bromo
(intermolecular) and 5- vs 3-bromofurans (intramolecular) are
less than 1.5 kcal/mol. The position of the halogen on the ring
has only minor consequences.
The type of tether influences the absolute activation and
reaction enthalpies, the amide linker showing slightly lower
activation enthalpies and higher exothermicities than the alkyl
tether. However, the relative energies of brominated vs unsub-
stituted systems are conserved for all reactions A-C. TS9, the
3-bromo furanyl amide, is the only case that deviates from the
general trend. The effect of bromine substitution on activation
and reaction enthalpies is ∼1.5 kcal/mol larger than those
expected from this trend. In this case, the observed deviation
can be explained by an additional stereoelectronic effect
introduced by substitution at position 3 of furan. Repulsion
FIGURE 1. Tether conformations relative to the furan ring.
between the amide carbonyl oxygen and the bromine substituent
causes a deviation of 22° in the dihedral angle around the C-C
bond connecting the furan ring and the amide group (Figure
1). This deviation from coplanarity between the two moieties
is ∼10° larger than that observed in the unsubstituted (TS7)
and 5-bromo-substituted (TS8) cases. The decrease in conjuga-
tion causes a destabilization of the reactant with respect to the
J. Org. Chem, Vol. 71, No. 15, 2006 5435

Padwa et al.
SCHEME 2. Approaches to the ACDE Core of Morphine
SCHEME 3
SCHEME 4
prompted us to examine possible synthetic applications of these
reactions.16 Ciganek had previously reported the intramolecular
Diels-Alder reaction of 18 to provide the ACDE core of
morphine 19, albeit in only 10% yield (Scheme 2).17 R-Pyrone
derivative 20, on the other hand, produced 21 in 53% yield.17
Inspired by this report, we envisioned an alternative approach
involving intramolecular Diels-Alder reaction of furanyl amide
22 to furnish the cycloadduct 23.
Acylation of tert-butylamine 24 with acyl chloride 25, derived
from commercially available 5-bromo-2-furoic acid, gave the
desired tertiary amide 27 in good yield (Scheme 3). Unfortu-
nately, all of our attempts to effect the cycloaddition of 27 only
resulted in the removal of the labile tert-butyl group to give
28. Thermal conditions (heating at 180 °C in xylene), microwave
assistance, and the addition of several Lewis acids (i.e., SnCl4,
TiCl4, ZnCl2‚OEt2, BF3‚OEt, TMSOTf) failed to promote the
desired cycloaddition. Similarly, our attempts to add across the
benzofuran ring using the related t-Boc furanyl amide 29 also
failed to produce a cycloadduct. Extended heating of 29
furnished the unsubstituted amide 28 in 92% yield.
TS and product, providing both a further decrease in activation
enthalpy and an additional increase in reaction exothermicity.
Similar steric effects caused by bulky substituents at the vicinal
position with respect to the tether have been reported by Klein.14
Since bromine is not a bulky substituent, this steric effect is
only significant for the amide tether type due to the coplanarity
requirement. As shown in Figure 1, bromine has a minor effect
in the conformation of the alkyl linker. This agrees with TS6
fitting in the general trends expected for halogen substitution
on furan.
Finally, it was originally suggested that rate acceleration with
brominated systems may result from transition state stabilization
due to the polarizability of the substituent.5 If the electronic
structure of a transition state is altered due to this substituent
effect, changes in forming bond distances and/or synchronicity
would be expected. However, all transition structures located
in Table 2 involving furan and nonactivated alkenes are
concerted and rather synchronous. Intramolecular reactions are
slightly more asynchronous than intermolecular ones (cf. TS4-
TS9 with TS1-TS3), and halogen substitution has a minimal
effect on the synchronicity. These results support the rationale
of the origin of the halogen effect, as do the parallel effects on
activation barriers and reaction enthalpies.10
The N-allyl-substituted furanyl amide 31 readily reacted at
80 °C, furnishing cycloadduct 32 in 89% yield. The more
encumbered N-prenyl-substituted amide 33 also underwent the
(16) (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.
Morphine. The remarkable rate enhancements in the cy-
cloadditions involving bromofurans, combined with our recent
success with cycloadditions across heteroaromatic π-systems,15
(14) Klein, L. L. J. Org. Chem. 1985, 50, 1770-1773.
(15) (a) Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643-
4645. (b) Meija-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241-3244.
(17) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261-6262.
5436 J. Org. Chem., Vol. 71, No. 15, 2006

Halo Substituent Effects on Intramolecular Cycloadditions
SCHEME 5
FIGURE 2. Activation and reaction enthalpies (kcal/mol) of Diels-
Alder reactions involving isobutene (35) and benzofuran (36) with
2-bromofuran.
SCHEME 6
cycloaddition, although heating at 180 °C (24 h) was required
for the cycloaddition to proceed (Scheme 4). As in the case of
amides 27, 29, and 30, amides 31 and 33 failed to undergo
cycloaddition across the π-bond of benzofuran. In the latter two
compounds, cycloaddition takes place with the competing alkene
dienophile (Scheme 4).
Model Diels-Alder reactions (Figure 2) involving 2-bromo-
furan with isobutene (35) or benzofuran (36) have been
calculated at the B3LYP/6-31G(d) level of theory. The activation
enthalpy of TS36 is higher (∆∆H‡ ∼ 3 kcal/mol) and the
reaction enthalpy is significantly more endothermic (∆∆H ∼
11 kcal/mol) than those of the same reaction involving isobutene
(TS35). These examples reveal the limitations of the halogen
activation of furan. This activation is not strong enough to allow
the cycloaddition with the highly unreactive and aromatic
dienophile, benzofuran.
Versatility of Halo-Furanyl Amide Cycloadducts. Oxan-
orbornenes are known to be valuable synthetic intermediates
used to construct substituted arenes, carbohydrate derivatives,
and various natural products.18 An important synthetic trans-
formation employing these intermediates involves cleavage of
the oxygen bridge to produce functionalized cyclohexene
derivatives.19 We have examined possible cleavage reactions
of bromo-oxatricyclonorbornenes 9c and 15b. These transfor-
mations open the possibility for the syntheses of various highly
functionalized nitrogen heterocycles.
simple reduction product 9a in 60% yield (Scheme 5). Heatinga
sample of 9c in the presence of p-TsOH in xylene afforded the
phenol 37 in 95% yield. The Lewis acid TiCl4 was used to
promote ring opening at temperatures as low as 0 °C to
R-hydroxylactam 38 in 98% yield as a single diastereomer.
Changing the Lewis acid to Me2AlCl allowed for the synthesis
of the epimer hydroxylactam 39 in 95% yield. Similarly,
cycloadduct 15b afforded the corresponding hydroxylactams 40
and 41 with TiCl4 and Me2AlCl, respectively. The stereochem-
ical assignments of compounds 40 and 41 were unequivocally
established on the basis of X-ray crystallography.
In the case of TiCl4, cycloadduct 9c (or 15b) may undergo
an eventual ring opening to give intermediate 42, which then
delivers a chloride from the same face as the neighboring oxygen
to furnish 38 (or 40), where the chloro and hydroxy groups are
cis disposed (Scheme 6).
The preferred chloride attack, when Me2AlCl is used as the
Lewis acid, occurs on the side opposite to the hydroxy
functionality, which corresponds to the less-congested face of
the π-bond.
Our initial efforts focused on the bridgehead oxabicyclic
radical derived from 9c because very little is known about such
intermediates. Exposure of 9c to n-Bu3SnH under standard
radical initiation conditions failed to give any products derived
from oxabicyclic ring opening and instead gave largely the
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1984, 106, 8327-8329. (l) Mirsadeghi, S.; Rickborn, B. J. Org. Chem.
1985, 50, 4340-5919. (m) Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J. J.
Am. Chem. Soc. 1986, 108, 5908-5919. (n) Takayama, H.; Hayashi, K.;
Koizumi, T. Tetrahedron Lett. 1986, 27, 5509-5512. (o) Hanessian, S.;
Beaulieu, P.; Dube, D. Tetrahedron Lett. 1986, 27, 5071-5074. (p) Arjona,
O.; Dios, A.; Pradilla, R. F.; Plumet, J.; Viso, A. J. Org. Chem. 1994, 59,
3906-3916.
(18) (a) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
173-185. (b) Reymond, J. L.; Pinkerton, A. A.; Vogel, P. J. Org. Chem.
1991, 56, 2128-2135. (c) Renaud, P.; Vionnet, J. P. J. Org. Chem. 1993,
58, 5895-5896. (d) Eggette, T. A.; de Koning, H.; Huisman, H. O. J. Chem.
Soc., Perkin Trans. 1 1978, 980-989. (e) Ogawa, A.; Iwasawa, Y.; Nose,
T.; Suami, T.; Ohba, S.; Ito, M.; Saito, Y. J. Chem. Soc., Perkin Trans. 1
1985, 903-906. (f) Just, G.; Kim, S. Tetrahedron Lett. 1976, 1063-1066.
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J. Org. Chem, Vol. 71, No. 15, 2006 5437

Padwa et al.
(MgSO4), filtered, and concentrated under reduced pressure. The
yellow oil obtained was subjected to silica gel flash chromatography
to give furanyl amide 7c (15 g, 100%) as a white solid. All of its
spectroscopic properties were identical to those reported previ-
ously.24
Conclusion
The generality of halogen substitution on furan increasing
reaction rates and yields of Diels-Alder reactions has been
explored. This effect is beneficial because several reactions
involving poor tethers or dienophiles have been known to fail
or be low yielding. This effect is general for inter- and
intramolecular cycloadditions, regardless of halogen position
or tether type. These substituent effects are a manifestation of
the energetic preference for electronegative halogens to be
attached to a more highly alkylated and therefore more elec-
tropositive carbon. Halo substitution on furan is not enough to
allow cycloadditions with aromatic benzofuran, a limitation to
this method. We have further demonstrated the importance of
the halo-substituted furanyl amide cycloadducts by using simple
reagents to produce synthetically interesting polycycles.
5-Bromofuran-2-carboxylic Acid Allyl-benzylamide (8c). A
mixture of furan 7c (1.0 g, 3.6 mmol), powdered NaOH (0.6 g, 14
mmol), K2CO3 (0.5 g, 3.6 mmol), and n-Bu4NHSO4 (0.01 g, 0.01
mmol) in benzene (20 mL) was stirred for 1 h at room temperature.
Allyl bromide (0.6 mL, 7.2 mmol) was added, and the reaction
mixture was stirred at room temperature for 22 h. The mixture was
diluted with water, and the layers were separated. The aqueous layer
was extracted with EtOAc, and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The
resulting crude oil was subjected to silica gel flash chromatography
to give 1.1 g (99%) of 8c as a colorless oil: IR (neat) 1711, 1624,
1572, 1478, 1414, 1261, 1013 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.08 (brs, 2H), 4.59-4.88 (m, 2H), 5.08-5.35 (m, 2H), 5.79-
5.95 (m, 1H), 6.39 (brs, 1H), 6.83-7.10 (m, 1H), and 7.16-7.45
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 48.8, 49.7, 113.2, 117.8,
118.7, 124.5, 127.5, 128.6, 132.9 (br), 134.2, 136.7, 149.2, 159.1;
HRMS calcd for C15H14BrNO2 319.0208, found 319.0208.
3-Benzyl-10-oxa-3-aza-tricyclo[5.2.1.0]dec-8-en-2-one (9a). A
0.16 g sample of 8a (0.66 mmol) in toluene (7 mL) was heated at
125 °C for 7 days. The mixture was concentrated under reduced
pressure, and the residue was subjected to silica gel flash chroma-
tography to give 0.16 g (98%) of 9a as a white solid: mp 140-
Computational Methods
All structures were fully optimized at B3LYP/6-31G(d)20 in
Gaussian 03.21 The nature of stationary points was confirmed by
frequency analysis, with the minima and TS having zero and one
imaginary frequency, respectively. We have shown that B3LYP/
6-31G(d) calculations are accurate for many hydrocarbon pericyclic
reactions.22 This method gives a trend similar to the high-accuracy
(mean absolute error ∼ 1 kcal/mol) CBS-QB3 level of theory23
when comparing the energetics of brominated to unsubstituted
Diels-Alder reactions involving furan.
1
141 °C; IR (film) 1690, 1446, 1282, 1158, 1020 cm-1; H NMR
(300 MHz, CDCl3) δ 1.47 (dd, 1H, J ) 11.7 and 7.5 Hz), 1.75-
1.90 (m, 1H), 2.21 (ddd, 1H, J ) 16.1, 8.1, and 3.0 Hz), 3.11 (dd,
1H, J ) 9.5 and 8.5 Hz), 3.40 (dd, 1H, J ) 9.5 and 8.5 Hz), 4.48
(s, 2H), 5.10-5.20 (m, 1H), 6.37-6.45 (m, 1H), 6.54-6.62 (m,
1H), 7.16-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 31.0, 38.7,
46.7, 51.4, 81.4, 91.8, 127.4, 127.8, 128.6, 133.0, 135.8, 137.1,
168.1. Anal. calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81.
Found: C, 74.51; H, 6.11; N, 5.74.
Experimental Section
5-Bromofuran-2-carboxylic Acid Benzylamide (7c). To a
solution of 5-bromo-2-furoic acid (10 g, 52 mmol) in CH2Cl2 (65
mL) at 0 °C was added (COCl)2 (6.8 mL, 79 mmol) and DMF (50
µL). The flask was fitted with a drying tube containing CaSO4,
and the resulting solution was warmed to room temperature for
1.5 h. Concentration under reduced pressure afforded the crude acid
chloride as a yellow solid that was used directly in the next step
without further purification. A solution of this acid chloride in THF
(20 mL) was added slowly to a solution of benzylamine (6.2 mL,
57 mmol) and Et3N (15 mL, 100 mmol) in THF (20 mL) at 0 °C.
The solution was warmed to room temperature over 1 h, and then
H2O was added. The layers were separated, and the aqueous layer
was extracted with ether. The combined organic layer was dried
5-Bromofuran-2-carboxylic Acid (2-Benzofuran-3-yl-ethyl)-
tert-butylamide (27). To a solution of 2-benzofuran-3-yl-ethanol25
(6.2 g, 38 mmol) in CH2Cl2 (200 mL) at 0 °C was added Et3N (8.0
mL, 57 mmol) and TsCl (8.4 g, 44 mmol). The resulting solution
was allowed to warm slowly to room temperature and was then
stirred for 12 h. At the end of this time, the reaction mixture was
washed with H2O, dried (Na2SO4), and concentrated under reduced
pressure to afford the crude tosylate (10.1 g, 84%) that was
immediately carried forward in the next step. The crude tosylate
(10.1 g) was dissolved in MeCN (160 mL) and was treated
sequentially with NaHCO3 (8.1 g, 96 mmol) and tert-butylamine
(8.4 mL, 80 mmol). The resulting suspension was warmed to 50-
55 °C for 2 h. The mixture was cooled to room temperature and
was treated with additional NaHCO3 (8.1 g, 96 mmol) and tert-
butylamine (8.4 mL, 80 mmol). After heating for an additional 8 h
at 50-55 °C, the suspension was cooled to room temperature,
filtered through a pad of Celite, and concentrated under reduced
pressure to give a tan oil. The crude (2-benzofuran-3-yl-ethyl)-
tert-butylamine (24) solidified upon standing in the freezer (5.0 g,
72%) and was used directly in the next step without further
purification.
(20) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
To a solution of 24 (0.44 g, 2.0 mmol) and Et3N (0.5 mL, 3.6
mmol) in CH2Cl2 (15 mL) at 0 °C was added a cooled solution of
5-bromo-2-furoyl chloride (25) (0.4 g, 2.0 mmol) in CH2Cl2 (5 mL)
dropwise. After warming to room temperature over 1 h, the reaction
mixture was subjected to normal aqueous workup. The crude
product was purified by silica gel flash chromatography to give 27
(0.84 g, 73%) as a pale yellow oil: IR (neat) 1639, 1476, 1452,
(22) (a) Guner, V. A.; Khuong, K. S.; Houk, K. N.; Chuma, A.; Pulay,
P. J. Phys. Chem. A 2004, 108, 2959-2965. (b) Guner, V.; Khuong, K. S.;
Leach, A. G.; Lee, P. S.; Bartberger, M. D.; Houk, K. N. J. Phys. Chem.
A 2003, 107, 11445-11459.
(23) (a) Nyden, M. R.; Petersson, G. A. J. Chem. Phys. 1981, 75, 1843-
1862. (b) Petersson, G. A.; Al-Laham, M. A. J. Chem. Phys. 1991, 94,
6081-6090. (c) Petersson, G. A.; Tensfeldt, T.; Montgomery, J. A. J. Chem.
Phys. 1991, 94, 6091-6101. (d) Montgomery, J. A.; Ochterski, J. W.;
Petersson, G. A. J. Chem. Phys. 1994, 101, 5900-5909.
(24) Rai, U. K.; Shanker, B.; Singh, S.; Rao, R. B. Indian J. Chem.,
Sect. B 1988, 27, 674-675.
(25) Albanez-Walker, J.; Rossen, K.; Reamer, R. A.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1999, 40, 4917-4920.
5438 J. Org. Chem., Vol. 71, No. 15, 2006

Halo Substituent Effects on Intramolecular Cycloadditions
1012, 744 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.61 (s, 9H), 3.07
(t, 2H, J ) 8.1 Hz), 3.83 (t, 2H, J ) 8.1 Hz), 6.32 (d, 1H, J ) 3.4
Hz), 6.86 (d, 1H, J ) 3.4 Hz), 7.17-7.34 (m, 2H), 7.40 (d, 1H, J
) 8.1 Hz), 7.46 (d, 1H, J ) 7.5 Hz), 7.51 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 26.8, 28.7, 45.7, 58.2, 111.5, 113.2, 116.8, 118.0,
119.2, 122.4, 123.0, 124.3, 127.6, 141.8, 151.7, 155.2, 160.7; HRMS
calcd for C19H20BrNO3 389.0627, found 389.0625.
5.94-5.95 (m, 1H), 7.21-7.36 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 33.2, 41.2, 46.6, 47.3, 59.5, 71.4, 124.7, 128.0, 128.2,
128.2, 129.0, 136.0, 171.7. Anal. calcd for C15H15BrClNO2: C,
50.70; H, 4.26; N, 3.94. Found: C, 50.58; H, 4.15; N, 3.97.
2-Benzyl-5-bromo-7-chloro-7a-hydroxy-2,3,3a,4,7,7a-hexahy-
droisoindol-1-one (39). To a solution of 0.15 g (0.5 mmol) of
3-benzyl-7-bromo-10-oxa-3-aza-tricyclo[5.2.1.0]dec-8-en-2-one (9c)
in 8 mL of CH2Cl2 cooled in an ice bath was slowly added dropwise
a 1.0 M solution of Me2AlCl in hexane (0.6 mmol). The reaction
mixture was stirred at 0 °C for 2 h, poured into 10 mL of ice water,
and extracted with EtOAc. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel chromatography to give
0.14 g (95%) of 39 as a white solid: mp 187-189 °C; IR (film)
(2-Benzofuran-3-yl-ethyl)-(5-bromofuran-2-carbonyl)carbam-
ic Acid tert-Butyl Ester (29). To a solution of amide 28 (0.75 g,
2.2 mmol) in MeCN (5 mL) was added DMAP (0.014 g, 0.11
mmol) and (Boc)2O (0.64 g, 2.9 mmol), and the resulting solution
was allowed to stir for 12 h. The reaction mixture was partitioned
between Et2O and H2O, and the ether layer was separated. The
aqueous layer was washed with Et2O, and the combined Et2O layer
was dried over MgSO4, filtered, concentrated, and purified by silica
gel column chromatography to give compound 29 (0.94 g, 97%)
1
1674, 1446, 1425 cm-1; H NMR (400 MHz, CDCl3) δ 2.52 (dd,
1H, J ) 15.2 and 3.6 Hz), 2.81-2.92 (m, 2H), 3.23 (dd, 1H, J )
9.2 and 6.8 Hz), 3.30 (t, 1H, J ) 9.2 Hz), 4.50 (s, 2H), 4.72 (d,
1H, J ) 5.2 Hz), 5.74 (d, 1H, J ) 1.6 Hz), 6.11 (dd, 1H, J ) 5.2
and 1.6 Hz), 7.20-7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
34.5, 35.2, 46.8, 48.2, 54.2, 75.5, 126.8, 127.2, 127.8, 128.0, 129.1,
135.6, 173.0. Anal. calcd for C15H15BrClNO2: C, 50.70; H, 4.26;
N, 3.94. Found: C, 50.81; H, 4.23; N, 3.68.
1
as a clear oil: H NMR (300 MHz, CDCl3) δ 1.32 (s, 9H), 3.00-
3.12 (m, 2H), 3.95-4.07 (m, 2H), 6.44 (d, 1H, J ) 3.6 Hz), 7.01
(d, 1H, J ) 3.6 Hz), 7.19-7.33 (m, 2H), 7.39-7.51 (m, 2H), 7.65-
7.74 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 23.2, 27.5, 45.5, 83.4,
111.3, 116.7, 118.7, 119.7, 122.4, 124.2, 125.0, 127.9, 142.0, 150.3,
152.5, 155.2, 161.0.
2-Benzyl-5-hydroxy-2,3-dihydroisoindol-1-one (37). A solution
of 0.1 g (0.3 mmol) of 3-benzyl-7-bromo-10-oxa-3-aza-tricyclo-
[5.2.1.0]dec-8-en-2-one (9c), 5 mg of p-TsOH, and 5 mL of xylene
was heated at 150 °C for 5 h. The solvent was removed under
reduced pressure, and the residue was subjected to silica gel
chromatography to give 0.07 g (95%) of 37 as a beige solid: mp
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant No. CHE-
0132651 and CHE-0450779), the National Institutes of Health
(GM 059384-24), and the Partnerships for Advanced Compu-
tational Infrastructure (PACI). We thank our colleague, Dr.
Kenneth Hardcastle, for his assistance with the X-ray crystal-
lographic studies and the University Research Committee of
Emory University for funds to acquire a microwave reactor.
The computations were performed on the National Science
Foundation Terascale Computing System at the Pittsburgh
Supercomputing Center (PSC) and on the UCLA Academic
Technology Services (ATS) Hoffman Beowulf cluster.
1
222-224 °C; IR (film) 1636, 1592, 1453, 1420, 1251 cm-1; H
NMR (400 MHz, CDCl3) δ 3.54 (brs, 1H), 4.20 (s, 2H), 4.75 (s,
2H), 6.82 (d, 1H, J ) 2.0 Hz), 6.91 (dd, 1H, J ) 8.4 and 2.0 Hz),
7.27-7.36 (m, 5H), 7.69 (d, 1H, J ) 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 46.4, 49.5, 109.5, 115.9, 123.6, 125.2, 127.8, 128.7, 128.9,
136.9, 143.9, 160.9, 169.5. Anal. calcd for C15H13NO2: C, 75.30;
H, 5.48; N, 5.85. Found: C, 73.51; H, 5.44; N, 5.60.
2-Benzyl-5-bromo-7-chloro-7a-hydroxy-2,3,3a,4,7,7a-hexahy-
droisoindol-1-one (38). To a solution of 0.15 g (0.5 mmol) of
3-benzyl-7-bromo-10-oxa-3-aza-tricyclo[5.2.1.0]dec-8-en-2-one (9c)
in 8 mL of CH2Cl2 cooled in an ice bath was added 0.18 g (0.9
mmol) of TiCl4 dropwise. The reaction mixture was stirred at 0 °C
for 2 h, poured into 10 mL of ice water, and extracted with EtOAc.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed under reduced pressure. The residue was
subjected to silica gel chromatography to give 0.15 g (98%) of 38
as a white solid: mp 159-161 °C; IR (film) 1673, 1432, 1426
Supporting Information Available: Information concerning the
preparation and characterization of compounds using general
1
procedures, H or 13C NMR spectra for new compounds lacking
elemental analyses, CIF files with crystallographic data (and ORTEP
drawings) for compounds 40 and 41, and Cartesian coordinates of
all of the computed structures together with their total energies.
The authors have deposited atomic coordinates for the structures
of 40 and 41 with the Cambridge Crystallographic Data Centre.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.26-2.34 (m, 1H), 2.40-
2.45 (m, 1H), 2.79-2.88 (m, 1H), 3.13 (dd, 1H, J ) 9.2 and 7.2
Hz), 3.27 (d, 1H, J ) 2.0 Hz), 3.31 (t, 1H, J ) 9.2 Hz), 4.45 (d,
1H, J ) 16.0 Hz), 4.49 (d, 1H, J ) 16 Hz), 4.83-4.85 (m, 1H),
JO0602322
J. Org. Chem, Vol. 71, No. 15, 2006 5439