Organic Syntheses, Vol. 78, pp. 202-211
Checked by Sivaraman Dandapani and Dennis P. Curran.
1. Procedure
2. Notes
1.
2-Furoyl chloride
was purchased from Aldrich Chemical Company, Inc.,
and used without further purification.
3.
Sodium azide (99%)
was purchased from Aldrich Chemical Company, Inc.; a
Teflon spatula was
used when handling this reagent.
Caution: avoid contact with metal
and heat when using sodium azide.
4. The protective shield was purchased from Lab-Line, Inc. and was used for
protection when heating at high temperatures.
5. The product has the following spectralcharacteristics: IR (neat) cm
−1: 3267,
2980, 1700, and 1546;
1H NMR (CDCl
3,
300 MHz) δ: 1.50 (s, 9 H), 6.04 (brs, 1 H), 6.34
(m, 1 H), 6.63 (brs, 1 H), and 7.06 (m, 1 H);
13C NMR (CDCl
3,
75 MHz) δ: 28.2, 81.3, 95.1, 111.2,
136.0, 145.4, 151.9. Anal. Calcd
for C
9H
13NO
3: C, 59.00; H, 7.15; N, 7.64. Found:
C, 59.09; H, 7.13; N, 7.67.
6.
3-Methyl-3-buten-1-ol
was purchased from Aldrich Chemical Company, Inc.,
and used without further purification.
8.
Triethylamine was
purchased from Aldrich Chemical Company, Inc., and
used without further purification.
10. The product has the following spectral characteristics: IR (neat) cm
−1: 3075,
1652, 1445, and 890;
1H NMR (CDCl
3, 400 MHz) δ:
1.75 (s, 3 H), 2.58 (t, 2 H, J = 7.4), 3.47 (t, 2
H, J = 7.4), 4.77 (s, 1 H), and 4.86 (s, 1 H);
13C NMR (CDCl
3,
100 MHz) δ: 22.1, 31.0, 41.1, 112.9,
and 142.6
13. The product has the following spectral characteristics: IR (neat) cm
−1: 2975,
1711, 1606, and 1369;
1H NMR (CDCl
3,
400 MHz) δ: 1.45 (s, 9 H), 1.74 (s, 3 H), 2.27
(t, 2 H, J = 7.2), 3.67 (dd, 2 H, J = 9.2 and 6.0), 4.71
(s, 1 H), 4.76 (s, 1 H), 6.33 (brs, 1 H), 7.14
(t, 1 H, J = 1.2), and 6.0 (brs, 1 H);
13C NMR (CDCl
3, 100 MHz) δ:
22.2, 28.0, 36.6, 46.9, 80.7,
100.9, 110.7, 111.8, 137.8, 142.3,
148.3, and 153.5. Anal. Calcd for C
14H
21NO
3:
C, 66.91; H, 8.42; N, 5.57. Found: C, 66.93; H, 8.38; N, 5.60. The broad resonance
at δ 6.0 in the
1H NMR spectrum merges into a sharp multiplet when
the spectrum is recorded at 50°C.
14. The 35-mL heavy-wall high pressure tube, Teflon plug, and O-ring
were purchased from Ace Glass and were oven dried prior to use.
15. The product has the following spectral characteristics: IR (KBr) cm
−1: 2961, 1709,
and 1388;
1H
NMR (DMSO-d
6, 400 MHz) δ: 0.94 (s, 3 H), 1.42
(s, 9 H), 1.72 (m, 2 H), 2.35 (d, 1 H, J = 14.6),
2.49 (d, 1 H, J = 14.6), 2.63 (dd, 1 H, J = 14.6 and 2.8),
2.89 (dd, 1 H, J = 14.6 and 4.8), 3.51 (m, 1 H), 3.66
(m, 1 H), and 5.78 (brs, 1 H);
13C NMR (DMSO-d
6, 100 MHz) δ:
22.8, 27.7, 35.2, 36.7, 42.5,
46.1, 51.6, 79.6, 96.4, 143.7,
151.5, and 208.3. Anal. Calcd for C
14H
21NO
3:
C, 66.91; H, 8.42; N, 5.57. Found: C, 66.99; H, 8.38; N, 5.49.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Heterocycles such as
furan,
thiophene,
and
pyrrole undergo Diels-Alder reactions despite their stabilized
6p-aromatic electronic configuration.
2 By far the
most extensively studied five-ring heteroaromatic system for Diels-Alder cycloaddition
is furan and its substituted derivatives.
3
The resultant 7-oxabicyco[2.2.1]heptanes are valuable synthetic intermediates that
have been further elaborated to substituted arenes, carbohydrate derivatives, and
various natural products.
4
5 6 A crucial
synthetic transformation employing these intermediates involves the cleavage of the
oxygen bridge to produce functionalized cyclohexene derivatives.
7,8
While the bimolecular Diels-Alder reaction of alkyl-substituted furans has been the
subject of many reports in the literature,
9
much less is known regarding the cycloaddition behavior of furans that contain heteroatoms
attached directly to the aromatic ring.
10 In this regard, we have become
interested in the Diels-Alder reaction of 2-aminofurans as a method for preparing substituted
aniline derivatives since these compounds are important starting materials for the
preparation of various pharmaceuticals.
11 Many furan Diels-Alder reactions
require high pressure or Lewis acid catalysts to give satisfactory yields of cycloadduct.
12
In contrast to this situation,
2-amino-5-carbomethoxyfuran readily
reacted with several monoactivated olefins by simply heating in
benzene
at 80°C. The initially formed cyclohexadienol underwent a subsequent dehydration when
treated with 1 equiv of
boron trifluoride etherate (BF
3·OEt
2)
to give the substituted aniline derivative.
13 In each case, the cycloaddition proceeded with complete
regioselectivity, with the electron-withdrawing group being located ortho to the amino
group. The regiochemical results are perfectly consistent with FMO theory.
14 The most favorable FMO
interaction is between the HOMO of the furanamine and the LUMO of the dienophile.
The atomic coefficient at the ester carbon of the furan is larger than at the amino
center, and this nicely accommodates the observed regioselectivity.
The intramolecular Diels-Alder reaction of furans, often designated as IMDAF,
15 helps
to overcome the sluggishness of this heteroaromatic ring system toward [4+2]-cycloaddition.
Not only do IMDAF reactions allow for the preparation of complex oxygenated polycyclic
compounds, but they also often proceed at lower temperatures than their intermolecular
counterparts.
9 Even more significantly, unactivated
p-bonds are often suitable dienophiles for the internal cycloaddition. Indeed, the
submitters discovered that the IMDAF reaction of a series of furanamide derivatives
occurred smoothly to furnish cyclized aromatic carbamates as the only isolable products
in high yield.
16
When the alkenyl group possesses a substituent at the 2-position of the p-bond, the
thermal reaction furnishes a rearranged hexahydroindolinone.
17
With this system, the initially formed cycloadduct cannot aromatize. Instead, ring
opening of the oxabicyclic intermediate occurs to generate a zwitterion that undergoes
hydride transfer to give the rearranged ketone. The procedure described here provides
a simple and general approach for the construction of various hexahydroindolinones.
This strategy can be cleanly applied toward the synthesis of more complex octahydroindole-based
alkaloids.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
tert-Butyl 3a-methyl-5-oxo-2,3,3a,4,5,6-hexahydroindole-1-carboxylate:
1H-Indole-1-carboxylic acid, 2,3,3a,4,5,6-hexahydro-3a-methyl-5-oxo-, 1,1-dimethylethyl
ester (14); (212560-98-0)
Furan-2-ylcarbamic acid tert-butyl ester: Carbamic
acid, 2-furanyl-, 1,1-dimethylethyl ester (9); (56267-47-1)
2-Furoyl chloride (8): 2-Furancarbonyl chloride
(9); (527-69-5)
tert-Butyl alcohol (8): 2-Propanol, 2-methyl-
(9); (75-65-0)
Sodium azide (8,9); (26628-22-8)
4-Bromo-2-methyl-1-butene: 1-Butene, 4-bromo-2-methyl-
(8,9); (20038-12-4)
3-Methyl-3-buten-1-ol: 3-Buten-1-ol, 3-methyl-
(8,9); (763-32-6)
Methanesulfonyl chloride (8,9); (124-63-0)
Lithium bromide (8,9); (7550-35-8)
tert-Butyl N-(3-methyl-3-butenyl)-N-(2-furyl)carbamate:
Carbamic acid, 2-furanyl(3-methyl-3-butenyl)-, 1,1-dimethylethyl ester
(14); (212560-95-7)
Toluene (8); Benzene, methyl-
(9); (108-88-3)
Tetrabutylammonium hydrogen sulfate: Ammonium,
tetrabutyl-, sulfate (1:1) (8); 1-Butanaminium, N,N,N-tributyl-,
sulfate (1:1) (9); (32503-27-8)
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