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Synlett 2012(6): 925-929  
DOI: 10.1055/s-0031-1290607
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 2-Aryl-Substituted Chromans by Intramolecular C-O Bond Formation

Yu Wang, Robert Franzén*
Department of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland
Fax: +358(3)31152108; e-Mail: robert.franzen@tut.fi;

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Publication History

Received 30 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

A synthetic route for the preparation of 2-aryl-substituted chromans from commercially available starting materials and utilizing either a palladium- or copper-catalyzed intramolecular cyclization of aryl bromides is described. Chromans with stereocontrol at C-2 can thus be obtained via a palladium-catalyzed asymmetric allylic etherification procedure utilizing a chiral indole-phosphine oxazoline (IndPHOX) ligand.

Key words

intramolecular cyclization - chromans - chalcones - palladium - copper

Synthetic approaches towards 2-substituted chromans (tetrahydrobenzopyrans) have attracted considerable attention continuously due to the formation of a core that exhibits biological activities in numerous natural products. [¹] A well-known example is α-tocopherol (1), a member of the vitamin E family that serves as a radical scavenger and lipophilic antioxidant. Moreover, the compound 4′,6-dichloroflavan (BW683C; 2) is a potent inhibitor of rhinovirus replication in vitro, [²] and 2-(2-piperidyl)chroman 3 and 2-(2-pyrrolidyl)chroman 4 have shown to be promising new types of nicotine agonists (Figure  [¹] ). [³]

Figure 1 Examples of biologically active chroman compounds

There are several synthetic studies on the construction of the chroman core utilizing many strategies. [4-6] The process of Pd- [7] or Cu-catalyzed [8] intramolecular C-O bond formation using aryl halides has been successfully established for the preparation of diverse oxygen-containing heterocyclic compounds. On the other hand, there are only a few examples to synthesize 2-alkyl chromans, [7b] [d] [9] and especially 2-aryl chromans [9a] via this approach. In this paper we report a new synthetic route for 2-aryl-substituted chromans with the intramolecular cyclization of aryl bromides as the key step (Scheme  [¹] ), which also enables access to enantiomerically enriched chromans.

Chalcones 7a-d, prepared from commercially available 2-bromoaldehyde (5) and ketones 6a-d, were readily converted to the corresponding alcohols 8a-d in quantitative yields using sodium borohydride (Scheme  [¹] ). The following reduction of the allylic double bond with para-toluenesulfonyl hydrazide and sodium acetate trihydrate led to the desired ortho-bromophenylpropanols 9a-d in high yields without notable cleavage of the aryl-bromide bond. [¹0]

Scheme 1 Synthesis of 3-(2-bromophenyl)propan-1-ol derivatives 9a-d

With compounds 9a-d in hand, the intramolecular C-O bond formation was studied. We first studied the palladium-catalyzed cyclization procedure reported by Buchwald, [7b] employing the biaryl ligand 11 (Table  [¹] ). [¹¹] The reactions with phenyl- and methyl-substituted aryl propanols 9a and 9b proceeded smoothly to provide chromans 10a and 10b in good yields (71% and 79%, respectively; entry 1 and entry 2), whereas the results for 2-heteroaryl-substituted chromans (10c and 10d) were poor. Due to the formation of the β-hydride elimination by-product, [¹²] the 2-furylchroman (10c) was obtained in moderate yield (43%, entry3). After 96 hours at 90 ˚C we noticed that substrate 9d reacted poorly and gave a very low yield (16%, entry 4) of the product probably because of the palladium catalyst deactivation caused by the pyridinyl group.

Because of the limitation of the palladium-catalyzed method for the cyclization, we started to investigate the possibility to use an intramolecular Ullmann alkoxylation reaction for the cyclization of 9 instead.

Table 1 Palladium-Catalyzed Intramolecular Cyclizationa

Entry Temp (˚C) Time (h) Product Isolated yield (%)
1 90 24 10a 71
2b 65 24 10b 79
3 90 24 10c 43
4 90 96 10d 16
a See Supporting Information for details.
b See reference 7b.
Table 2 Copper-Catalyzed Intramolecular Cyclization of Compounds 9a-d a

Entry NaOMe (equiv) Time (h) Product Isolated yield (%)
1 1.5 24 10a 78
2 2.1b 24 10b 44
3 1.5 48 10c 74
4 1.5 24 10d 88
a See Supporting Information for details. b No reaction was observed using NaOMe (1.5 equiv).

After a preliminary screening, we noticed that a previously reported approach using CuI and 2-aminopyridine with sodium methoxide as base in diglyme was suitable for our purposes (Table  [²] ). [¹³] Although 2-alkyl chroman 10b was only obtained in moderate yield (44%, entry 2), the method worked well to afford 2-aryl chromans 10a, 10c and 10d in high yields (78%, 74% and 88%, respectively, entries 1, 3 and 4). [¹4]

After establishing the synthetic route for racemic 2-monosubstituted chromans, we next turned our attention to the asymmetric synthesis of chiral chromans. Based on our previous work with the Pd-catalyzed asymmetric allylic substitutions using indole-phosphine oxazoline (IndPHOX) ligands, [¹5] we designed a new route for the synthesis of chromans with stereocontrol at C-2 via the preparation of a chiral alcohol 8 obtained by an asymmetric allylic etherification procedure.

Preliminary experiments were carried out for the synthesis of chiral 2-phenylchroman (10a; Scheme  [²] ). Starting from acetate 12, the catalytic reaction was performed utilizing our IndPHOX ligand 13 with (E)-benzaldehyde oxime and cesium carbonate as base in THF at 0 ˚C, yielding a mixture of oximes 14a and 14b. After treatment with zinc powder in AcOH-H2O, [¹6] the linear alcohol 8a was isolated in 43% yield with moderate enantioselectivity (41%); [¹7] while the branched product 15, derived from the attack of the nucleophile to the more sterically hindered position by SN2′ mechanism, was obtained in good ee value (82%). [¹7] After reduction of the double bond of alcohol 8a, followed by cyclization using CuI, the chiral chroman 10a was obtained with 44% enantioselectivity (Scheme  [²] ).

Scheme 2 Synthesis of chiral chroman 10a

Encouraged by these promising results, we continued the investigation with (E)-1,3-bis(2-bromophenyl)allyl acetate (16), which was chosen based on the following aspects: (i) to suppress regioselectivity issue in Pd-catalyzed allylic substitution; (ii) to enhance the enantioselectivity; and to (iii) afford diversity to further chroman derivatives. When starting material 16 was reacted with (E)-benzaldehyde oxime using IndPHOX ligand 13 and cesium carbonate as base in THF at 0 ˚C for 24 hours, oxime 17 was obtained with good enantioselectivity (89%) [¹7] and 70% yield (Scheme  [³] ). The subsequent cleavage of the N-O bond, the reduction of the double bond and the intramolecular cyclization proceeded smoothly to afford chroman 20, [¹8] maintaining original enantiopurity.

Scheme 3 Synthesis of chiral chroman 20

The absolute configuration of compound 18 was determined by transforming it into known chiral compound 21 (Scheme  [4] ). The reduction of 18 was performed in methanol using NaBH4 in the presence of nickel(II) chloride hexahydrate, providing chiral 21 without remarkable racemization. Comparison of the optical rotation value [¹9] of 21 with the literature data [²0] revealed that the absolute stereochemistry of 18 was R.

Scheme 4 Determination of the absolute configuration of compound 18

The adjacent 2-bromophenyl group in the structure of chroman 20 offered various possibilities for further applications via catalytic transformations. [²¹] As an example, we carried out a Suzuki coupling reaction. [²¹c-e] Chroman 20 with 89% ee was reacted with phenylboronic acid (22) using Pd(PPh3)4 with sodium carbonate as base in toluene-H2O-EtOH for 20 hours at 80 ˚C.

The Suzuki reaction proceeded well to afford product 22 [²²] in high yield (88%) and without loss of ee (Scheme  [5] ).

Scheme 5 Suzuki coupling reaction with chroman 20 and phenylboronic acid 22

In conclusion, we have developed a preparation route to 2-aryl-substituted chromans from readily available starting materials. The route gives access to enantiomerically enriched chromans as well. Chiral 2-phenylchroman (10a) and 2-(2-bromophenyl)chroman (20) were obtained in moderate and high ee values when utilizing IndPHOX ligand 13. The further modification of 20 was investigated by Suzuki cross-coupling affording 2-([1,1′-biphenyl]-2-yl)chroman (23) with preserved enantioselectivity.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

Financial support of this work was provided by the National Technology Agency of Finland (TEKES). The authors thank Matti ­Vaismaa, PhD, for preliminary work performed in this paper, Mrs Päivi Joensuu for the mass analyses, and Prof. Petri Pihko and Mr Antti Neuvonen for the optical rotation measurements.

11

General Procedure for Palladium-Catalyzed Intramolecular Cyclization: To a mixture of Pd(OAc)2 (2.4 mg, 0.0105 mmol), ligand 11 (3.1 mg, 0.0105 mmol) and Cs2CO3 (0.17 g, 0.525 mmol), compound 9 (0.35 mmol) in toluene (1.2 mL) was added. After stirring under 90 ˚C for reported time, the reaction mixture was cooled to r.t., diluted with Et2O, and filtered through a pad of celite. The resulting solution was purified by silica gel chromatography (n-hexane-EtOAc, 30:1).

12

The by-product was 1-(furan-2-yl)-3-phenylpropan-1-one, isolated in 22% yield. For the reaction mechanism, see reference 7b.

14

General Procedure for Copper-Catalyzed Intramolecular Cyclization: To a mixture of CuI (2.8 mg, 0.015 mmol), 2-aminopyridine (2.8 mg, 0.03 mmol) and NaOMe (12 mg, 0.225 mmol), compound 9 (0.15 mmol) in diglyme (0.7 mL) was added. After stirring under 100 ˚C for reported time, the reaction mixture was cooled to r.t., quenched with H2O, and extracted with Et2O. The extracts were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (n-hexane-EtOAc, 30:1).

17

The reported ee is the average value of three entries.

18

2-(2-Bromophenyl)chroman (20): [α]D ²0 +71.2 (c = 0.95, CHCl3, 89% ee). ¹H NMR (300 MHz, CDCl3): δ = 7.54-7.61 (m, 2 H), 7.36 (td, J = 7.7, 1.2 Hz, 1 H), 7.10-7.19 (m, 3 H), 6.86-6.93 (m, 2 H), 5.38 (td, J = 10.2, 2.2 Hz, 1 H), 3.00-3.10 (m, 1 H), 2.75-2.83 (m, 1 H), 2.31-2.39 (m, 1 H), 1.85-1.94 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 155.4, 141.3, 133.0, 130.0, 129.4, 128.1, 127.8, 127.7, 122.3, 121.8, 120.8, 117.2, 77.3, 29.1, 25.5. HRMS (ESI+): m/z [M + Na]+ calcd for C15H13ONaBr: 311.0047; found: 311.0015.

19

[α]D ²0 +27.7 (c = 0.5, CH2Cl2, 87% ee).

22

2-([1,1′-Biphenyl]-2-yl)chroman (22): [α]D ²0 -36.5 (c = 0.40, CHCl3, 89% ee). ¹H NMR (300 MHz, CDCl3): δ = 7.64-7.67 (m, 1 H), 7.25-7.46 (m, 8 H), 7.00-7.11 (m, 2 H), 6.80-6.88 (m, 2 H), 5.05-5.10 (m, 1 H), 2.71-2.78 (m, 2 H), 2.01-2.09 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 155.8, 141.2, 141.0, 139.3, 130.4, 129.8, 129.6, 128.5, 128.2, 128.0, 127.5, 127.4, 126.7, 122.2, 120.5, 117.3, 75.2, 30.1, 25.9. HRMS (ESI+): m/z [M + Na]+ calcd for C21H18ONa: 309.1255; found: 309.1263.

11

General Procedure for Palladium-Catalyzed Intramolecular Cyclization: To a mixture of Pd(OAc)2 (2.4 mg, 0.0105 mmol), ligand 11 (3.1 mg, 0.0105 mmol) and Cs2CO3 (0.17 g, 0.525 mmol), compound 9 (0.35 mmol) in toluene (1.2 mL) was added. After stirring under 90 ˚C for reported time, the reaction mixture was cooled to r.t., diluted with Et2O, and filtered through a pad of celite. The resulting solution was purified by silica gel chromatography (n-hexane-EtOAc, 30:1).

12

The by-product was 1-(furan-2-yl)-3-phenylpropan-1-one, isolated in 22% yield. For the reaction mechanism, see reference 7b.

14

General Procedure for Copper-Catalyzed Intramolecular Cyclization: To a mixture of CuI (2.8 mg, 0.015 mmol), 2-aminopyridine (2.8 mg, 0.03 mmol) and NaOMe (12 mg, 0.225 mmol), compound 9 (0.15 mmol) in diglyme (0.7 mL) was added. After stirring under 100 ˚C for reported time, the reaction mixture was cooled to r.t., quenched with H2O, and extracted with Et2O. The extracts were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (n-hexane-EtOAc, 30:1).

17

The reported ee is the average value of three entries.

18

2-(2-Bromophenyl)chroman (20): [α]D ²0 +71.2 (c = 0.95, CHCl3, 89% ee). ¹H NMR (300 MHz, CDCl3): δ = 7.54-7.61 (m, 2 H), 7.36 (td, J = 7.7, 1.2 Hz, 1 H), 7.10-7.19 (m, 3 H), 6.86-6.93 (m, 2 H), 5.38 (td, J = 10.2, 2.2 Hz, 1 H), 3.00-3.10 (m, 1 H), 2.75-2.83 (m, 1 H), 2.31-2.39 (m, 1 H), 1.85-1.94 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 155.4, 141.3, 133.0, 130.0, 129.4, 128.1, 127.8, 127.7, 122.3, 121.8, 120.8, 117.2, 77.3, 29.1, 25.5. HRMS (ESI+): m/z [M + Na]+ calcd for C15H13ONaBr: 311.0047; found: 311.0015.

19

[α]D ²0 +27.7 (c = 0.5, CH2Cl2, 87% ee).

22

2-([1,1′-Biphenyl]-2-yl)chroman (22): [α]D ²0 -36.5 (c = 0.40, CHCl3, 89% ee). ¹H NMR (300 MHz, CDCl3): δ = 7.64-7.67 (m, 1 H), 7.25-7.46 (m, 8 H), 7.00-7.11 (m, 2 H), 6.80-6.88 (m, 2 H), 5.05-5.10 (m, 1 H), 2.71-2.78 (m, 2 H), 2.01-2.09 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 155.8, 141.2, 141.0, 139.3, 130.4, 129.8, 129.6, 128.5, 128.2, 128.0, 127.5, 127.4, 126.7, 122.2, 120.5, 117.3, 75.2, 30.1, 25.9. HRMS (ESI+): m/z [M + Na]+ calcd for C21H18ONa: 309.1255; found: 309.1263.

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Figure 1 Examples of biologically active chroman compounds

Scheme 1 Synthesis of 3-(2-bromophenyl)propan-1-ol derivatives 9a-d

Scheme 2 Synthesis of chiral chroman 10a

Scheme 3 Synthesis of chiral chroman 20

Scheme 4 Determination of the absolute configuration of compound 18

Scheme 5 Suzuki coupling reaction with chroman 20 and phenylboronic acid 22