A New Entry to Benzo[4,5]furo[3,2-b]pyridines via N-(Benzofuran-3-yl)iminophosphorane

Abstract

Mild thermal reaction of enones with N-(benzofuran-3-yl)iminophosphorane, newly prepared by Staudinger reaction of 3-azidobenzofuran with triphenylphosphine, provides a synthetic entry to virtually unknown benzo[4,5]furo[3,2-b]pyridines via a tandem aza-Wittig-electrocyclization process.

Key words

iminophosphoranes - azides - aza-Wittig - electrocyclization - benzofuropyridines

References and Notes

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• 7 Tricycle 3a was originally reported in low yield via a troublesome six-step sequence from an N-(aryloxy)-pyridinium salt, see: Abramovitch RA. Inbasekaran MN. Kato S. Radzikowska TA. Tomask P. J. Org. Chem.  1983,  48:  690 
• For leading reviews on the chemistry of iminophosphoranes and their use in aza-Wittig electrocyclization reactions, see:
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• 14a

  Unlike aryl azides, the (electron-rich) five-membered heteroaryl counterparts are usually hardly available from corresponding amines via diazonium salts.

• 14b For the first report of azido-group-transfer reaction with thiophenes and benzothiophenes, see: Spagnolo P. Zanirato P. J. Org. Chem.  1978,  43:  3539 
• 14c For original general information on the synthesis of five-membered heteroaromatic azides, see: Funicello M. Spagnolo P. Zanirato P. Acta Chem. Scand.  1993,  47:  231 

6

The 2- and 3-amines derived from electron-rich, five-membered heteroaromatic compounds usually are highly unstable compounds, unless electron-withdrawing substituents are present, and therefore find uncommon
use in synthetic annulation processes.

15

Synthesis of 3-Azidobenzofuran (4) via Azido-Group-Transfer Reaction To a solution of 3-bromobenzofuran (1.07 mmol) in dry Et₂O (6 mL) n-BuLi (1.6 M in hexane, 1.07 mmol) was added at -70 ˚C under a stream of nitrogen. After 1 h, tosyl azide (1.07 mmol in 4 mL of dry Et₂O) was added dropwise, and the mixture was stirred for 5 h at -70 ˚C. The resulting yellow mixture was slowly led to r.t. and then treated with an aq solution of sodium pyrophosphate (5 mL, 1.07 mmol). After stirring for 30 min, the eventual reaction mixture was extracted with Et₂O and then with EtOAc; the collected organic layers were dried over Na₂SO₄ and finally evapo-rated in vacuo. Column chromatography of the crude on a Florisil column using PE as eluant isolated the title azide (0.71 mmol, 66%) as yellow thick oil. Physical and IR and NMR spectral data were fully consistent with those originally reported.

16

Synthesis of Triphenyliminophosphorane 5
3-Azidobenzofuran (4, 1 mmol) in dry Et₂O (3 mL) was slowly added to a solution of Ph₃P (1 mmol) in dry Et₂O (3 mL) at 0 ˚C under a stream of nitrogen. The mixture was stirred at 0 ˚C for 3 h and then at r.t. for an additional 1 h. Removal of the solvent in vacuo afforded the title imino-phosphorane as yellow thick oil in 95% yield. ^¹H NMR (500 MHz, CDCl₃): δ = 7.23-7.70 (m, 16 H), 7.20 (t, J = 10.5 Hz, 2 H), 7.03 (d, J = 9.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 132.78, 132.71, 132.59, 132.51, 131.99, 131.75, 128.77, 128.67, 128.53, 128.44, 123.57, 121.18, 120.05, 119.84, 110.88, 110.67.

17

Synthesis of Benzofuropyridines 3a-f: Typical Procedure A mixture of iminotriphenylphosphorane 5 (1 mmol) and methyl trans-4-oxo-2-pentenoate (6e, 1 mmol) in dry toluene (5 mL) was stirred at 90 ˚C for ca. 20 h under a stream of nitrogen. After cooling, the solvent was removed in vacuo, and the resultant crude was purified on a silica gel column by progressive elution with PE-EtOAc mixtures to give the benzofuropyridine 3e in 80% yield as a dark-yellow thick oil. ^¹H NMR (500 MHz, CDCl₃): δ = 8.27 (d, J = 7.0 Hz, 1 H), 7.76 (s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.62 (t, J = 7.0 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 4.10 (s, 3 H), 2.81 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 165.7, 164.3, 156.2, 153.6, 133.5, 130.2, 126.2, 124.2, 121.7, 118.6, 114.1, 113.2, 52.7, 29.7. MS (EI): m/z = 241 [M]. The parent benzofuropyridine 3a had spectral data consistent with those previously reported.^4b The hitherto unknown benzofuro-pyridines 3b-d,f were identified on the basis of ^¹H NMR, ^¹³C NMR, and MS spectral data.

18

Reactions of enones with (benzothien-3-yl)iminophos-phoranes bearing methyl substituent(s) on phosphorus were shown to form b-fused pyridines due to aza-Wittig electrocyclization along with those due to opposite regiochemistry, see ref. 10b,c.

19

Replacement of phenyl with electron-donating methyl group(s) on phosphorus could enhance the reactivity of previous (benzothien-2-yl)- and, especially, (benzothien-3-yl)imino-­phosphoranes with enones, see ref. 10b,c.