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Synthesis 2009(12): 2029-2034  
DOI: 10.1055/s-0028-1088061
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Anionic Cyclization of (N,N-Dimethylamino)[2-(prop-2-yn-1-yloxy)aryl]acetonitriles

Tadeusz Zdrojewski, Joanna Musielak, Andrzej Jończyk*
Warsaw University of Technology, Faculty of Chemistry, Koszykowa St. 75, 00-662 Warszawa, Poland
Fax: +48(22)6282741; e-Mail: anjon@ch.pw.edu.pl;

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Publication History

Received 6 February 2009
Publication Date:
27 April 2009 (online)

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Abstract

The cyclization of (N,N-dimethylamino)[2-(prop-2-yn-1-yloxy)aryl]acetonitriles is carried out under phase-transfer conditions using powdered sodium hydroxide and benzyltriethylammonium chloride as catalyst in dimethyl sulfoxide to afford mixtures of a methylenechromane and a methylchromene via favored 6-exo-dig and 6-endo-dig processes, respectively. Several of the chromenes rearranged into benzofuranone derivatives during column chromatography on alumina and the formation of these is rationalized.

Key words

phase-transfer catalysis - carbanions - cyclizations - heterocycles - intramolecular vinylation

Compounds which possess both an acidic site and a suitably located carbon-carbon triple bond, on treatment with a base, generate anions which can undergo intramolecular addition to the triple bond via exo- and/or endo-dig cyclization [¹] leading to the formation of carbo- or heterocyclic products.

There are several examples in the literature of such carbanionic cyclizations. These include cyclizations of substituted derivatives of malonic [²-5] and acetoacetic acid esters, [²] [5-7] α-substituted methyl acetate derivatives, [5] alkynyl ketones, [7-9] o-alkynyl- [¹0] and o-propargyloxyacetophenones, [¹¹] propargyl ethyl malonates, [¹²] ethyl N-(2-ethynyloxyphenyl)malonamate [¹³] and nitro-substituted compounds. [¹4] The one-pot reaction of dimethyl 2-oxo-cycloalkane-1,3-dicarboxylates with 1,4-dibromobut-2-yne produced substituted dihydrofurans in 92-100% yield. [¹5] Cyclizations of α-cyanocarbanions generated from suitably substituted α-aminonitriles using lithium diisopropylamide (followed by oxidation of the crude intermediates with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone), [¹6] or from phenylacetonitrile, or ω-ethynylalkyl-α-substituted-benzylsulfones, using catalytic amounts of cesium hydroxide, [¹7] produced either mixtures of substituted pyrroles and azetidines, [¹6] or 2-exo-methylenecyclopentanes or hexanes, [¹7] respectively.

It has been reported that 2-(dialkylamino)phenylacetonitriles can be alkylated in the presence of a mixture of concentrated aqueous and solid sodium hydroxide and benzyltriethylammonium chloride (TEBAC) as a phase-transfer catalyst (PTC system [¹8-²0] ), at elevated temperature. [²¹] On the other hand, efficient intermolecular addition of 2-phenylalkanenitriles to ethynes occurred on treatment with solid sodium hydroxide, benzyltriethylammonium chloride as the catalyst and dimethyl sulfoxide [²²] or cesium tert-butoxide in N-methyl-2-pyrrolidinone. [¹7] The former conditions were also suitable for intermolecular vinylation of 2-(dialkylamino)arylacetonitriles [²³-²5] and 2-substituted N-(benzylidene)glycinonitriles. [²6] Based on the above, [²¹-²6] we have investigated the phase-transfer-catalyzed intramolecular addition reactions of aminonitriles 3, which are easily prepared from salicylic aldehydes 1a-e (Scheme 1 and Table 1).

Scheme 1  Reagents and conditions: (i) 10% aq NaOH, toluene, TEBAC, 60 ˚C, 3-10 h; (ii) powdered NaOH, DMSO, TEBAC, 35 ˚C, 2 h.

Table 1 2-Propargyloxyarylcarbaldehydes 2, Aminonitriles 3, and the Anionic Cyclization Products 4 and 5
Compd X, Y Time (h)a Yield (%) of 2 Yield (%) of 3 Yield (%) of 4 Yield (%) of 5 Ratio of 4:5 b
1a H, H  3 88 80 32 44 1:2
1b 5-Cl, H  4 83 82 48 30 2:1
1c 5-Br, H  5 79 77 36 -c 5:1
1d H, 3-MeO  4 85 48 21d 1:0
1e 5,6-(CH)4 10 55 73 30 -c 5:1
a Reaction time for the conversion of 1 into 2.
b Determined on the basis of ¹H NMR spectroscopy.
c Decomposed with the formation of 9 during column chromatography.
d Competitive oxidation of 3d - decreased the yield of the cyclization product.

Aldehydes 1 were O-alkylated with propargyl bromide under phase-transfer conditions (10% aqueous sodium hydroxide, benzyltriethylammonium chloride, toluene) to give alkynes 2 which were converted into the required aminonitriles 3 via the Strecker reaction. Subsequent anionic cyclization of compounds 3 was carried out in the presence of powdered sodium hydroxide, benzyltriethyl­ammonium chloride as the catalyst and dimethyl sulfoxide (solid-liquid system), under mild conditions, to give chromanes 4 or mixtures of 4 and chromenes 5 (Scheme 1).

According to Baldwin’s rules, [¹] formation of exo products 4 should occur by way of favored 6-exo-dig cyclization, while endo products 5 are formed by a favored 6-endo-dig process (Scheme 2). Production of exo-4 occurs through straightforward carbanion attack on the carbon-carbon triple bond of 3 to generate 4 - , yet a similar process leading to endo-5 requires propargyl to allenyl ether rearrangement in 3, prior to cyclization. Alternatively, the highly basic vinyl anion 4 - may undergo a [1,3]-proton shift to yield allyl anion 5 - which gives 5 on protonation.

Scheme 2 Intramolecular cyclization leading to chromanes 4 and chromenes 5

The compositions of the crude reaction mixtures of 4 and 5, after cyclization, were determined by integration of the signals of the dimethylamino groups in the ¹H NMR spectra.

Attempted isolation of cyclic products 4 and 5 by column chromatography on alumina led to pure exo-4 while endo-5 was transformed into heterocycle 9. Two possible routes ‘a’ and ‘b’ leading from 5 to 9 are shown in Scheme 3.

Scheme 3 Possible routes leading to the formation of heterocycle 9

According to route ‘a’, the latent carbonyl group in aminonitrile 5 is unmasked during column chromatography giving chromone 6 which undergoes addition of cyanide to form 7 - . The latter affords the heterocyclic product 9 via a ring-opening/ring-closing process. The base-induced­ ring-opening of chromenes has been described previously. [²7] [²8] In route ‘b’, aminonitrile 5 can exist in equilibrium with the strongly electrophilic immonium salt 10 which can easily add a cyanide anion to form enamine 11. Hydrolysis of the latter gives a β-cyanoketone which after deprotonation produces 7 - , which is further transformed into 9 via the processes described above. Some of the steps presented in route ‘b’ have already been reported in the reactions of vinylaminonitriles. [²4]

Products 4 and 5 contain a masked carbonyl group and hence are precursors of the corresponding 3-methylene-chroman-4-ones and 3-methylchromone derivatives 6. However, attempted unmasking of the carbonyl groups [²³] in 4 and 5 under typical conditions (benzene-aqueous copper sulfate solution, or water-ethanolic copper sulfate solution) failed; a complex mixture of products was obtained instead.

In conclusion, we have demonstrated that a phase-transfer catalytic system can be used to achieve anionic cyclization of aminonitriles 3. Some of the chromenes 5 proved to be unstable during column chromatography on alumina and underwent rearrangement into benzofuranones 9.

Column chromatography was carried out on Fluka 5016A aluminum oxide (basic) using EtOAc-hexane (1:5 v/v) as eluent. Gas chromatography (GC) was performed using an Agilent 6850 Series GC System fitted with a HP-50+ (30 m) column. ¹H NMR (400 MHz, CDCl3) and ¹³C NMR (100 MHz, CDCl3) spectra were recorded on a Varian Mercury 400BB spectrometer; chemical shifts (δ) are given in ppm relative to tetramethylsilane (TMS); coupling constants (J) are given in Hz. MS and HRMS spectra were obtained using an AMD 604 (Intectra) apparatus. Elemental analyses were performed on a Perkin Elmer 2400 Series II CHNS/O microanalyzer. Melting points were measured on a capillary apparatus and are uncorrected. Aldehydes 1 and propargyl bromide (80 wt% solution in toluene) were commercial grade (Aldrich).

(Prop-2-yn-1-yloxy)benzaldehydes and (Prop-2-yn-1-yloxy)naphthaldehyde 2; General Procedure

To a stirred solution of aldehyde 1 (50 mmol) and TEBAC (0.11 g, 0.5 mmol) in toluene (70 mL) was added a solution of NaOH (2.4 g, 0.06 mol) in H2O (22 mL). The mixture was stirred (ca. 0.5 h) and then propargyl bromide (55 mmol, 80 wt% in toluene) was added dropwise. Stirring was continued at 60 ˚C until aldehyde 1 was no longer detected by GC (3-10 h, Table 1). The reaction mixture was allowed to cool and the organic phase was separated. The aq phase was extracted with toluene (3 × 20 mL) and the combined organic phase was washed with H2O (30 mL) and dried (MgSO4). Following evaporation of the solvent, the crude product was crystallized from C6H6 or from a mixture of C6H6-cyclohexane.

2-(Prop-2-yn-1-yloxy)benzaldehyde (2a)

Mp 66-69 ˚C (Lit. [²9] 66-68 ˚C).

¹H NMR: δ = 2.56 (t, J = 2.4 Hz, 1 H, CCH), 4.80 (d, J = 2.4 Hz, 2 H, CH2), 6.94-7.89 (m, 4 H, ArH), 10.46 (s, 1 H, CHO).

¹³C NMR: δ = 56.0, 76.4, 77.5, 113.1, 121.5, 125.3, 128.3, 135.7, 159.7, 189.5.

Anal. Calcd for C10H8O2: C, 74.99; H, 5.03. Found: C, 75.13; H, 4.99.

5-Chloro-2-(prop-2-yn-1-yloxy)benzaldehyde (2b)

Mp 75-76 ˚C.

¹H NMR: δ = 2.59 (t, J = 2.4 Hz, 1 H, CCH), 4.81 (d, J = 2.4 Hz, 2 H, CH2), 7.07 (d, J = 9.2 Hz, 1 H, ArH), 7.49 (dd, J = 9.2, 2.8 Hz, 1 H, ArH), 7.78 (d, J = 2.8 Hz, 1 H, ArH), 10.38 (s, 1 H, CHO).

¹³C NMR: δ = 56.6, 76.9, 77.1, 114.9, 126.3, 127.3, 128.0, 135.1, 158.0, 188.1.

Anal. Calcd for C10H7ClO2: C, 61.72; H, 3.63; Cl, 18.22. Found: C, 61.54; H, 3.60; Cl, 18.13.

5-Bromo-2-(prop-2-yn-1-yloxy)benzaldehyde (2c)

Mp 93-95 ˚C (Lit. [²9] 89-91 ˚C).

¹H NMR: δ = 2.59 (t, J = 2.4 Hz, 1 H, CCH), 4.82 (d, J = 2.4 Hz, 2 H, CH2), 7.02 (d, J = 9.2 Hz, 1 H, ArH), 7.63 (dd, J = 9.2, 2.4 Hz, 1 H, ArH), 7.93 (d, J = 2.4 Hz, 1 H, ArH), 10.38 (s, 1 H, CHO).

¹³C NMR: δ = 56.6, 76.7, 77.3, 114.6, 115.3, 126.7, 131.1, 138.0, 158.5, 188.1.

Anal. Calcd for C10H7BrO2: C, 50.24; H, 2.95; Br, 33.42. Found: C, 50.09; H, 2.99; Br, 33.60.

3-Methoxy-2-(prop-2-yn-1-yloxy)benzaldehyde (2d)

Mp 43-44 ˚C.

¹H NMR: δ = 2.48 (t, J = 2.4 Hz, 1 H, CCH), 3.91 (s, 3 H, OCH3), 4.89 (d, J = 2.4 Hz, 2 H, CH2), 7.16-7.20 (m, 2 H, ArH), 7.44-7.49 (m, 1 H, ArH), 10.50 (s, 1 H, CHO).

¹³C NMR: δ = 56.0, 60.8, 76.9, 78.2, 117.7, 118.8, 124.9, 131.0, 149.4, 152.8, 190.6.

Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.50; H, 5.38.

2-(Prop-2-yn-1-yloxy)-1-naphthaldehyde (2e)

Mp 107-110 ˚C.

¹H NMR: δ = 2.58 (t, J = 2.4 Hz, 1 H, CCH), 4.95 (d, J = 2.4 Hz, 2 H, CH2), 7.36-7.49 (m, 2 H, ArH), 7.59-7.68 (m, 1 H, ArH), 7.79 (d, J = 8.0 Hz, 1 H, ArH), 8.07 (d, J = 9.2 Hz, 1 H, ArH), 9.27 (d, J = 8.0 Hz, 1 H, ArH), 10.91 (s, 1 H, CHO).

¹³C NMR: δ = 57.0, 76.5, 79.4, 108.3, 124.5, 126.5, 127.7, 127.9, 129.0, 129.8, 130.6, 138.9, 157.8, 190.0.

Anal. Calcd for C14H10O2: C, 79.98; H, 4.79. Found: C, 79.90; H, 4.82.

( N , N -Dimethylamino)[2-(prop-2-yn-1-yloxy)aryl]acetonitriles 3; General Procedure

To a stirred, chilled (ca. 5 ˚C) suspension of aldehyde 2 (25 mmol) and dimethylamine hydrochloride (3.1 g, 38 mmol) in MeCN (25 mL), a solution of NaCN (1.9 g, 38 mmol) in H2O (2 mL) was added dropwise whilst maintaining the temperature of the reaction mixture below 10 ˚C. The mixture was stirred for ca. 24 h at 30 ˚C until aldehyde 2 could no longer be detected by GC. The reaction mixture was cooled, diluted with H2O (25 mL) and extracted with C6H6 (5 × 20 mL). The combined extracts were washed with H2O (10 mL) and dried (MgSO4). After evaporation of the solvent the crude residue was distilled and/or crystallized from Et2O or a mixture of C6H6-cyclohexane.

( N , N -Dimethylamino)[2-(prop-2-yn-1-yloxy)phenyl]acetonitrile (3a)

Bp 107-108 ˚C (0.1 Torr); mp 35-36 ˚C.

¹H NMR: δ = 2.35 [s, 6 H, N(CH3)2], 2.52 (X of ABX, J AX = J BX = 2.4 Hz, 1 H, CCH), 4.75, 4.81 (AB of ABX, J AB = 16 Hz, 2 H, CH2), 5.16 (s, 1 H, CH), 7.03-7.50 (m, 4 H, ArH).

¹³C NMR: δ = 41.6 (2C), 56.4, 56.8, 75.9, 77.9, 113.0, 115.2, 121.2, 122.5, 129.5, 130.2, 154.7.

Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.81; H, 6.52; N 13.14.

[5-Chloro-2-(prop-2-yn-1-yloxy)phenyl]( N , N -dimethylamino)acetonitrile (3b)

Mp 68-70 ˚C.

¹H NMR: δ = 2.35 [s, 6 H, N(CH3)2], 2.53 (X of ABX, J AX = J BX = 2.4 Hz, 1 H, CCH), 4.72, 4.78 (AB of ABX, J AB = 16 Hz, 2 H, CH2), 5.08 (s, 1 H, CH), 7.00 (d, J = 8.8 Hz, 1 H, ArH), 7.33 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.46 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 41.6 (2C), 56.4, 56.8, 75.9, 77.9, 113.0, 115.2, 121.2, 122.5, 129.5, 130.2, 154.7.

Anal. Calcd for C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26; Cl, 14.25. Found: C, 62.79; H, 5.25; N, 11.23; Cl, 14.31.

[5-Bromo-2-(prop-2-yn-1-yloxy)phenyl]( N , N -dimethylamino)acetonitrile (3c)

Mp 66-69 ˚C.

¹H NMR: δ = 2.36 [s, 6 H, N(CH3)2], 2.53 (X of ABX, J AX = J BX = 2.4 Hz, 1 H, CCH), 4.72, 4.79 (AB of ABX, J AB = 16 Hz, 2 H, CH2), 5.08 (s, 1 H, CH), 6.95 (d, J = 8.8 Hz, 1 H, ArH), 7.45 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.60 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 41.8 (2C), 56.6, 56.8, 76.4, 77.3, 113.8, 114.8, 115.0, 124.9, 133.0, 154.0.

Anal. Calcd for C13H13BrN2O: C, 53.26; H, 4.47; N, 9.56; Br, 27.26. Found: C, 53.21; H, 4.40; N, 9.54; Br, 27.36.

( N , N -Dimethylamino)[3-methoxy-2-(prop-2-yn-1-yloxy)phenyl]acetonitrile (3d)

Mp 64-67 ˚C.

¹H NMR: δ = 2.34 [s, 6 H, N(CH3)2], 2.51 (X of ABX, J AX = J BX = 2.4 Hz, 1 H, CCH), 3.87 (s, 3 H, OCH3), 4.71, 4.83 (AB of ABX, J AB = 16 Hz, 2 H, CH2), 5.23 (s, 1 H, CH), 6.95 (d, J = 8.8 Hz, 1 H, ArH), 6.94-7.14 (m, 2 H, ArH).

¹³C NMR: δ = 41.6 (2C), 55.8, 57.5, 60.4, 75.4, 79.1, 113.3, 115.4, 120.7, 124.3, 128.5, 144.6, 152.7.

Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.72; H, 6.52; N, 11.43.

( N , N -Dimethylamino)[2-(prop-2-yn-1-yloxy)-1-naphthyl]acetonitrile (3e)

Mp 72-73 ˚C.

¹H NMR: δ = 2.42 [s, 6 H, N(CH3)2], 2.55 (X of ABX, J AX = J BX = 2.4 Hz, 1 H, CCH), 4.85, 4.94 (AB of ABX, J AB = 16 Hz, 2 H, CH2), 5.32 (s, 1 H, CH), 7.37-7.67 (m, 3 H, ArH), 7.82 (d, J = 8.4 Hz, 1 H, ArH), 7.89 (d, J = 9.2 Hz, 1 H, ArH), 8.33 (d, J = 8.4 Hz, 1 H, ArH).

¹³C NMR: δ = 43.5 (2C), 53.2, 56.8, 76.5, 79.4, 109.9, 113.5, 118.6, 122.9, 125.5, 125.7, 129.3, 130.1, 130.3, 137.2, 153.0.

Anal. Calcd for C17H16N2O: C, 75.25; H, 6.10; N, 10.60. Found: C, 77.29; H, 6.12; N, 10.68.

Intramolecular Vinylation of Aminonitriles 3; General Procedure

To a stirred (under nitrogen) solution of aminonitrile 3 (10 mmol) and TEBAC (50 mg, 0.2 mmol) in DMSO (15 mL), powdered NaOH (2.4 g, 60 mmol) was added in one portion, at r.t. A slight exotherm was observed and the temperature of the mixture increased to ca. 30 ˚C. Stirring was continued at 35 ˚C until aminonitrile 3 was no longer detected by GC (usually 2 h). The mixture was quenched with H2O (50 mL) and extracted with C6H6 (5 × 10 mL). The combined organic extract was washed with H2O (20 mL) and brine (20 mL), and then dried (MgSO4). After removing the solvent, the resulting residue consisting of 4 and 5 was treated as described below.

Residue from 3a

The mixture of products 4a and 5a was distilled (Kugelrohr, 115-125 ˚C/0.2 Torr) to afford a yellowish oil which partially crystallized. The crystals were separated and were identified as being predominantly chromene 5a. The oil containing mostly chromane 4a was chromatographed on alumina to give pure 4a; residual 5a in the oil rearranged into 9a.

4-( N , N -Dimethylamino)-3-methylenechromane-4-carbonitrile (4a)

Yellowish oil.

¹H NMR: δ = 2.27 [s, 6 H, N(CH3)2], 4.59, 4.96 (AB of ABMX, J AB  = 12 Hz, J AX = J BX = 0.8 Hz, J BM = 1.6 Hz, 2 H, CH2), 5.39 (M of ABMX, J BM = 1.6 Hz, 1 H, CH), 5.74 (X of ABMX, J AX = J BX = 0.8 Hz, 1 H, CH), 6.84-6.97 (m, 2 H, ArH), 7.24-7.44 (m, 2 H, ArH).

¹³C NMR: δ = 39.7 (2C), 66.6, 68.1, 114.1, 116.0, 117.5, 119.5, 119.8, 129.2, 131.0, 137.5, 153.1.

Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.77; H, 6.46; N, 12.86.

4-( N , N -Dimethylamino)-3-methyl-4 H -chromene-4-carbonitrile (5a)

Yellowish crystals; mp 68-70 ˚C (cyclohexane).

¹H NMR: δ = 1.99 (d, J = 1.4 Hz, 3 H, CH3), 2.21 [s, 6 H, N(CH3)2], 6.77 (q, J = 1.4 Hz, 1 H, CH), 7.03-7.54 (m, 4 H, ArH).

¹³C NMR: δ = 14.9, 38.9 (2C), 61.2, 106.9, 114.0, 116.7, 118.0, 123.3, 128.9, 129.8, 139.8, 151.1.

Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.63; H, 6.55; N, 12.95.

(2-Methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetonitrile (9a)

White powder; yield: 6%; mp 54-55 ˚C (C6H6).

¹H NMR: δ = 1.58 (s, 3 H, CH3), 2.72, 2.87 (AB, J AB  = 16.8 Hz, 2 H, CH2), 7.10-7.18 (m, 2 H, ArH), 7.64-7.73 (m, 2 H, ArH).

¹³C NMR: δ = 21.0, 26.7, 84.6, 113.8, 115.0, 118.8, 122.8, 125.1, 139.1, 170.9, 200.3.

Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.52; H, 4.99; N, 7.29.

Residue from 3b

The sticky oil partially solidified and was triturated with cyclohexane (5 mL) to give pure isomer 5b. The organic layer containing 4b was filtered through alumina to remove tars.

6-Chloro-4-( N , N -dimethylamino)-3-methylenechromane-4-carbonitrile (4b)

White crystals; mp 69-71 ˚C (cyclohexane).

¹H NMR: δ = 2.27 [s, 6 H, N(CH3)2], 4.59, 4.95 (AB of ABMX, J AB  = 12 Hz, J AX  = J BX  = 0.8 Hz, J BM  = 1.6 Hz, 2 H, CH2), 5.42 (M of ABMX, J BM  = 1.6 Hz, 1 H, CH), 5.76 (X of ABMX, J AX = J BX  = 0.8 Hz, 1 H, CH), 6.80 (d, J = 8.8 Hz, 1 H, ArH), 7.23 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.39 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 39.7 (2C), 66.8, 67.9, 113.7 116.8, 119.0, 120.9, 124.7, 128.6, 131.0, 136.9, 151.8.

Anal. Calcd for C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26. Found: C, 62.71; H, 5.29; N, 11.33.

6-Chloro-4-( N , N -dimethylamino)-3-methyl-4 H -chromene-4-carbonitrile (5b)

Yellowish crystals; mp 120-124 ˚C (dec.; cyclohexane-C6H6).

¹H NMR: δ = 1.97 (d, J = 1.6 Hz, 3 H, CH3), 2.21 [s, 6 H, N(CH3)2], 6.77 (q, J = 1.6 Hz, 1 H, CH), 7.00 (d, J = 8.8 Hz, 1 H, ArH), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.49 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 14.7, 38.8 (2C), 60.9, 106.7, 115.5, 117.6, 118.1, 128.3, 128.4, 129.9, 139.6, 149.6.

Anal. Calcd for C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26. Found: C, 62.74; H, 5.33; N, 11.20.

Residue from 3c

Column chromatography gave pure 4c and 9c. The NMR data for chromene 5c are taken from the proton and carbon spectra of the mixture of crude 4c/5c (5:1). No other data are presented for 5c.

6-Bromo-4-( N , N -dimethylamino)-3-methylenechromane-4-carbonitrile (4c)

Yellow oil.

¹H NMR: δ = 2.24 [s, 6 H, N(CH3)2], 4.59, 4.94 (AB of ABMX, J AB  = 12 Hz, J AX  = J BX  = 0.8 Hz, J BM  = 1.6 Hz, 2 H, CH2), 5.42 (M of ABMX, J BM  = 1.6 Hz, 1 H, CH), 5.76 (X of ABMX, J AX  = J BX  = 0.8 Hz, 1 H, CH), 6.75 (d, J = 8.8 Hz, 1 H, ArH), 7.36 (dd, J = 8.8, J = 2.4 Hz, 1 H, ArH), 7.51 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 39.6 (2C), 66.6, 67.7, 111.6, 113.5, 116.7, 119.4, 121.3, 131.3, 133.8, 136.6, 152.2.

Anal. Calcd for C13H13BrN2O: C, 53.26; H, 4.47; N, 9.56. Found: C, 52.89; H, 4.21; N, 9.39.

6-Bromo-4-( N , N -dimethylamino)-3-methyl-4 H -chromene-4-carbonitrile (5c)

¹H NMR: δ = 1.97 [d, J = 1.6 Hz, 3 H, CH3), 2.21 (s, 6 H, N(CH3)2], 6.75 (q, J = 1.6 Hz, 1 H, CH), 6.94 (d, J = 8.8 Hz, 1 H, ArH), 7.43 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.63 (d, J = 2.4 Hz, 1 H, ArH).

¹³C NMR: δ = 14.7, 38.7 (2C), 60.7, 106.6, 115.4, 115.8, 117.5, 118.4, 131.1, 132.7, 139.5, 149.9.

(6-Bromo-2-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetonitrile (9c)

Yellow oil; yield: 15%.

¹H NMR: δ = 1.59 (s, 3 H, CH3), 2.74, 2.88 (AB, J AB  = 16.8 Hz, 2 H, CH2), 7.08 (dd, J = 8.8, 0.8 Hz, 1 H, ArH), 7.73-7.82 (m, 2 H, ArH).

¹³C NMR: δ = 21.1, 25.7, 85.6, 114.7, 115.4, 115.6, 120.6, 127.6, 141.7, 169.8, 198.8.

Anal. Calcd for C11H8BrNO2: C, 49.65; H, 3.03; N, 5.26. Found: C, 49.71; H, 2.93; N, 5.02.

Residue from 3d

Column chromatography afforded pure 4d and the product of oxidation of carbanion 3d - : 3-methoxy-N,N-dimethyl-2-(prop-2-yn-1-yloxy)benzamide 3d′.

4-( N , N -Dimethylamino)-8-methoxy-3-methylenechromane-4-carbonitrile (4d)

Yellow oil.

¹H NMR: δ = 2.27 [s, 6 H, N(CH3)2], 3.87 (s, 3 H, OCH3), 4.72, 5.03 (AB of ABMX, J AB  = 12 Hz, J AX  = J BX  = 0.8 Hz, J BM  = 1.6 Hz, 2 H, CH2), 5.41 (M of ABMX, J BM  = 1.6 Hz, 1 H, CH), 5.74 (X of ABMX, J AX  = J BX  = 0.8 Hz, 1 H, CH), 6.88-6.93 (m, 2 H, ArH), 7.01-7.07 (m, 1 H, ArH).

¹³C NMR: δ = 39.8 (2C), 56.0, 67.0, 68.0, 112.4 114.2, 116.2, 119.5, 120.1, 121.0, 137.4, 142.8, 148.7.

Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.69; H, 6.64; N, 7.01.

3-Methoxy- N , N -dimethyl-2-(prop-2-yn-1-yloxy)benzamide 3d′

White crystals; yield: 44%; mp 54-55 ˚C (C6H6).

¹H NMR: δ = 2.48 (t, J = 2.5 Hz, 1 H, CCH), 2.87 (s, 3 H, NCH3), 3.11 (s, 3 H, NCH3), 3.87 (s, 3 H, OCH3), 4.69 (s, 2 H, CH2), 6.84 (dd, J = 7.6, 1.6 Hz, 1 H, ArH), 6.92 (dd, J = 8.2, 1.6 Hz, 1 H, ArH), 7.11 (dd, J = 8.2, 7.6 Hz, 1 H, ArH).

¹³C NMR: δ = 34.8, 38.4, 55.8, 60.9, 75.1, 79.1, 112.8, 119.2, 125.2, 132.2, 142.7, 152.5, 168.5.

Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.97; H, 6.42; N, 5.90.

Residue from 3e

Column chromatography afforded pure compounds 4e and 9e. The NMR data for chromene 5e are taken from the proton and carbon spectra of the mixture of crude 4e/5e (5:1). No other data are presented for 5e.

1-( N , N -Dimethylamino)-2-methylene-2,3-dihydro-1 H -benzo[ f ]chromene-1-carbonitrile (4e)

White crystals; mp 86-92 ˚C (C6H6).

¹H NMR: δ = 2.41 [s, 6 H, N(CH3)2], 4.60, 4.68 (AB of ABMX, J AB  = 12 Hz, J AM  = 1.2 Hz, J BM  = 0.6 Hz, 2 H, CH2), 5.65 (M of ABMX, J AM  = 1.2 Hz, J BM  = 0.6 Hz, 1 H, CH), 5.80 (s, X of ABMX, 1 H, CH), 7.06 (d, J = 9.2 Hz, 1 H, ArH), 7.37-7.80 (m, 4 H, ArH), 8.86 (d, J = 8.8 Hz, 1 H, ArH).

¹³C NMR: δ = 39.4 (2C), 62.8, 68.7, 109.7, 118.5, 118.9, 124.1, 124.5, 127.1, 128.6, 129.8, 132.1, 132.3, 133.8, 153.7.

Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.22; H, 6.32; N, 10.51.

1-( N , N -Dimethylamino)-2-methyl-1 H -benzo[ f ]chromene-1-carbonitrile (5e)

¹H NMR: δ = 2.01 (d, J = 1.6 Hz, 3 H, CH3), 2.46 [s, 6 H, N(CH3)2], 6.80 (q, J = 1.6 Hz, 1 H, CH), the aromatic signals overlapped with those of 4e.

(2-Methyl-1-oxo-1,2-dihydronaphtho[2,1- b ]furan-2-yl)acetonitrile (9e)

White crystals; yield: 13%; mp 97-99 ˚C (C6H6).

¹H NMR: δ = 1.68 (s, 3 H, CH3), 2.79, 2.96 (AB, J AB  = 16.8 Hz, 2 H, CH2), 7.29 (d, J = 9.2 Hz, 1 H, ArH), 7.47-7.56 (m, 1 H, ArH), 7.66-7.71 (m, 1 H, ArH), 7.87 (d, J = 8.2 Hz, 1 H, ArH), 8.15 (d, J = 9.2 Hz, 1 H, ArH), 8.70 (d, J = 8.2 Hz, 1 H, ArH).

¹³C NMR: δ = 21.1, 25.8, 85.6, 111.1, 113.8, 115.1, 123.1, 125.8, 128.7, 129.2, 129.5, 130.2, 141.1, 173.8, 199.6.

MS (EI, 70 eV): m/z (%) = 237 (80, M+), 197 (100), 154 (20), 126 (25).

HRMS (EI): m/z calcd for C15H11NO2: 237.07898; found: 237.07929.

Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.90; H, 4.63; N, 5.96.

Acknowledgment

This work was financially supported by Warsaw University of Technology.

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Scheme 1  Reagents and conditions: (i) 10% aq NaOH, toluene, TEBAC, 60 ˚C, 3-10 h; (ii) powdered NaOH, DMSO, TEBAC, 35 ˚C, 2 h.

Scheme 2 Intramolecular cyclization leading to chromanes 4 and chromenes 5

Scheme 3 Possible routes leading to the formation of heterocycle 9