Tetrahedron Letters,Vol.28,No.l9,pp 2103-2106,1987 oo40-4039/87 $3.00 + .OO Printed in Great Britain Pergamon Journals Ltd.
`
`ENHANCED REACTIVITY OF IMINIUM IONS AS HETERODIENOPHILES
`
`IN LEWIS ACID MEDIATED 4+2 CYCLOADDITION REACTIONS
`
`K.M. RYAN, R.A. REAMER, R.P. VOLANTE AND I. SHINKAI
`
`MERCK SHARP AND DOHME RESEARCH LABORATORIES
`
`DIVISION OF MERCK AND CO., INC.
`
`RAHWAY, NEW JERSEY 07065
`
`Summary: The use of a Lewis acid-proton acid combination was found to be highly
`effective
`for the activation
`of imines
`as heterodienophiles
`in Diels-Alder
`cycloaddition reactions.
`
`The ability of an imine group to function as a heterodienophile
`
`in an apparent
`
`Diels-Alder cycloaddition reaction with a conjugated diene has been shown to possess a
`
`vast potential for the synthesis of a variety of nitrogen containing heterocyc1es.I
`
`However, not all imino compounds are effective dienophiles
`
`in 4+2 cycloaddition
`
`reactions unless exceptionally reactive dienes are employed.
`
`This unreactivity has
`
`been traditionally overcome by activation of the imine function by substitution with
`one or more electron withdrawing groups and/or the use of Lewis acid catalysis. 's3
`
`addition there have been several recent reports concerning the cycloaddition of Mannich
`
`generated iminium ions with conjugated dienes.4
`
`We now wish to report our findings
`
`concerning the enhanced reactivity of iminium ions as heterodienophiles in the presence
`
`of Lewis acids.
`
`7 ~yqygyyi; la OTMS OTMS - - -_ 2103
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`In
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`treated with trifluoroacetic
`
`acid in methylene chloride or chloroform to give the
`
`iminium trifluoroacetate 5. Subsequent addition of 1.0 equivalent of boron trifluoride
`-
`etherate resulted in the quantitative production of the more reactive BF3 mediated
`
`iminium species 5. 'H NMR indicated that the nitrogen of imine 2 was protonated with
`
`the N-H broadened and in rapid exchange at ambient temperature; however, at -20°C a 9.0
`
`Hz vicinal coupling between the imine N-H proton and the methine C-H was observed.
`
`Treatment of 2 with diene 2 led to a quantitative conversion to the desired enol silyl
`
`ether 3*.
`-
`presence of diene 2.
`
`Iminium trifluoroacetate
`
`species 2 did not undergo cycloaddition
`
`in the
`
`The reactive species is believed to be the protonated iminium ion 2 with the boron
`
`trifluoride associated with the trifluoroacetate counterion.
`
`This association should
`
`make iminium ion 6 more naked and hence more reactive.
`-19
`is supported by
`
`F NMR studies showing both an associated
`
`The BF3-counterion association
`
`and non-associated
`
`trifluoroacetate
`
`species
`
`This hypothesis is further supported by the clean,
`
`quantitative conversion of the iminium tetrafluoroborate salt to the enol silyl ether 2
`
`in the absence of a Lewis acid.
`
`HBF4
`
`a
`
`lb
`--
`
`7
`-
`
`Procedure:
`
`dichloromethane
`
`To a stirred solution of imine trimer lb (855 mg, 5.0 mmol) in 15 ml of dry
`-
`at ambient temperature was added trifluoroacetic
`
`acid (385 uL, 5.0
`
`mmol). The solution was stirred for 5 min and boron trifluoride etherate (615 pL, 5.0
`
`nunol) was added. After 5 min the solution was treated with diene 1 (1.32 mL, 7.5 mmol)
`and stirred an additional 30 min at 22-24". The reaction was quenched by washing with
`
`two portions of saturated sodium bicarbonate solution (30 mL each). The organic phase
`
`was separated, dried (Na2S04), and concentrated to give enol silyl ether 3 as a yellow
`-
`oillo.
`_ The oil 3 was dissovled in methanol (20 mL) and stirred over anhydrous sodium
`
`
`partitioned between dichloromethane and water.
`
`carbonate (0.5 g) at 22-24" for 1 hr. The solution was filtered, concentrated, and
`The organic phase was dried (Na2S04)
`10
`and concentrated to give 1.10 g (91%) of ketone 4
`-
`
`as a yellow oil which slowly
`
`crystallized on standing.
`
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`2104
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`2105
`
`The Lewis acid catalyzed
`
`(BF3-OEt2 or ZnC12) cycloaddition
`
`of 3,4-dihydro-
`
`benzofuro[2,3-clpyridine
`
`(la)5 with 2-(trimethylsilyloxy)-1,3-butadiene
`-
`silyl enol ether 2 was recently reported by Vacca as a general methodology for the
`
`(2) to give the
`
`synthesis of aryl[2,3-alquinolizin-2-ones
`
`(i).6 This finding and our interest in the
`
`quinolizinone system has led us to further investigate this cycloaddition.
`
`We found
`
`lb
`-
`
`A
`--
`
`B
`-
`
`that treatment of benzofuropyridine trimer lb with BF3.0Et2 gave rise to two distinct
`-
`monomeric imine species, 4 (H-C=N, 6=8.9) and i (H-C=N, 6=8.6), of which only species A
`
`was converted to silyl enol ether 3 upon addition of diene 2.
`-
`-
`relative amounts of imine species A and B produced were found to be dependent on the
`-
`purity of both the reagents and the solvents used in the reaction.
`Species i and B -
`were characterized by multinuclear NMR studies and the results are discussed below.
`
`Furthermore, the
`
`Species E was prepared quantitatively from trimer lb by treatment with freshly
`-
`distilled BF3*0Et2 in anhydrous methylene chloride and could be isolated as a solid.
`
`The l3 C NMR for imine 1 shows a 3-bond coupling (J=3.5 Hz) between the sp2 imine carbon
`Furthermore "B and "F NMR show a "F_"B
`
`and the boron fluorines (-C=N-B-F).
`
`splitting indicative of an almost symmetrical tetrahedral boron species.
`
`These facts
`
`imply a strong B-N interaction7.
`
`However, the 'H NMR of reactive species A showed a
`
`broad, rapidly exchanging N-H signal indicating the presence of an adventitious proton
`
`source. An analogous iminimum species was prepared as follows. Trimer lb was first
`-
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`

`Acknowledgment:
`
`Helpful discussions with Dr. A.W. Douglas and FT-IR experiments with
`
`Dr. S.M. Riseman are gratefully acknowledged.
`
`References:
`
`1.
`
`Weinreb, S.M.; Staib, R.R. Tetrahedron 1982, 38, 3087; Weinreb, S.M.; Levin,
`
`Heterocycles 1979, 12, 949.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`a.
`
`9.
`
`10.
`
`Kerwin, J.F.; Danishefsky, S. Tetrahedron Lett. 1982, 23, 3739.
`--
`Oppolzer, W. Agnew Chem. Int. Ed. Engl. 1972, 11, 1031; Titov, Y.A. Russ. Chem.
`Rev. 1962, 31, 267.
`--
`Larsen, S.D,; Grieco, P.A. J. Am. Chem. Sot. 1985, 107, 1768.
`
`Monomeric species la exists in equilibrium with the corresponding trimer lb with
`-
`-
`the latter predominating under neutral or basic conditions.
`
`Vacca, J.P. Tetrahedron Lett. 1985, 26, 1277.
`Selected NMR data for B and 6. F-19 and
`"B spectra were obtained in CDC13 on a
`-
`-
`Bruker WM-250 referenced as follows:
`"F, C6F6, 6F=-163.0 ppm; "B, BF3*Et20,
`B: N+BF3,
`6B=-0.45
`6B=0.0 ppm. Negative chemical shifts are to higher field.
`
`ppm, 6F=-155.2, 'JBF=12Hz.
`
`6: CF3C02-BF3, 6B=-0.54 ppm,
`
`6,-76.7 (-CF3),
`
`SF=-149.7 (BF3); excess free CF3C02H, 6F=-76.2.
`
`Other acid/Lewis acid combinations were found to be less effective.
`and FT-IR studies with triethylammonium
`
`"B
`
`"F)
`
`Multinuclear
`
`NMR (13C
`
`trifluoroacetate and boron trifluoride etherate show completely analogous results.
`
`NMR data for 3 and 4. Hydrogen and
`-
`Bruker WM-250 and AM-300 spectrometers.
`
`13C NMR experiments were run in CDC13 on
`
`Assignments were made using homo- and
`
`hetero nuclear 2-D experiments (COSY-45, HETCOR).
`
`were used to assign the quaternary carbons in 4.
`-
`primarily of overlapped multiplets the more informative 13C data are reported.
`
`Fully 'H coupled 13C spectra
`1
`H spectra consist
`
`Since
`
`13C NMR 3: (CDC13, 6C=77.0ppm) 0.33(OSi(CH3)3), 21.0(C7), 34.2(C1), 51.2(C6), 52.9
`
`(C,), 55.9(C12b), 101.4(C3), lll.0(C7,), 111.2(Cll), 118.8(Ca), 122.4(Cg), 123.4
`
`(Cl,), 128.1(C7,), 14B.1(C2), 153.3(C12a), 154.9(Clla).
`
`4: (CDC13, 6c=77.0 ppm)
`
`20.9(C7), 41.2(C3), 43.7(C1), 51.0(C6), 53.6(C4), 58.1 (C12b), lll.0(C7b, Cl&
`
`118.6(Ca),
`
`122.3(Cg),
`
`123.5(Clo),
`
`127.5(C7a),
`
`151.5
`
`(C12a),
`
`154.4(Clla),
`
`206.7(C2).
`
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`2106
`J.I.
`-
`,
`,
`(Received in USA 26 February 1987)
`