Convergent Synthesis of 2H-Chromenes – a Formal [3+3] Cycloaddition by a One-pot, Three-Step Cascade

Abstract

In cases in which the palladium-catalyzed coupling of a bromoquinone with a vinyl stannane affords a vinyl quinone that enolizes, the resulting ortho-quinone methide undergoes an oxa-6π electrocyclization. Enolization is promoted by the presence of a polar additive. The net conversion is a formal [3+3] cycloaddition that gives 2H-chromenes. Because the first two steps of the cascade are catalyzed, the overall conversion is an example of multicatalysis. Yields for the optimized, one-pot protocol are dramatically improved over the conventional stepwise process.

1. Introduction

In the course of our research directed toward the synthesis of aryl C-glycoside natural products,¹ we discovered that the coupling reaction of bromobenzoquinone (1) with vinyl stannane 2² did not provide the desired vinyl quinone 3. Instead, 2H-chromene 4 and hydroquinone 5 were isolated, each in modest yield (20-30%), along with small amounts of benzofuran 6 (approx. 5%, Scheme 1).³

Scheme 1.

Unexpected Products from Stille Coupling. (a) 5 mol% (Ph₃P)₄Pd, toluene (10 mM), reflux.

We had not originally set out to prepare chromene compounds;^{4, 5} nonetheless, we were aware of the incidence of this structural feature among biologically active natural products.⁶ Therefore we set out to elucidate the mechanism of the chromene synthesis and to examine its generality and practicality.

We soon discovered that vinyl quinone 3, prepared by an independent route (see below), underwent conversion to chromene along with previously observed byproducts when exposed to the Pd(PPh₃)₄ coupling conditions We concluded that quinone 3 was, as expected, the initial product of the Pd(0) catalyzed reaction and that the conversion of quinone 1 to 2H-chromene 4 took place by transformations of this intermediate under the coupling conditions.

In further experiments with quinone 3, we took the precaution of excluding light from the reaction vessel. Both overhead fluorescent fixtures and sunlight can initiate photochemistry with quinones.⁷ In fact, the photochemical isomerization of vinyl quinones to benzofurans is known. ⁸ We ourselves have seen efficient isomerization of a vinyl quinone imine to the isomeric indole in a sunlight induced reaction. ⁹

Although the presence of catalytic amounts of Pd(PPh₃)₄ converted quinone 3 to chromene 4, heating the substrate in toluene alone or in the presence of Pd₂(dba)₃ did not effect this change. Further experimentation revealed that the presence of 0.2 - 5 equivalents of a phosphine or a phosphine oxide in the reaction medium was sufficient to lead to the formation of product mixtures. (It is likely that the phosphines are being converted to phosphine oxides in the reaction medium). We also found that DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) had the same effect. All of this indicated that a polar additive or Lewis base was essential for effecting the observed transformation (3 → 4).

A particularly convenient protocol involved the addition of traces of hexamethylphosphoramide (HMPA) to a toluene solution of vinyl quinone 3 before heating. In these experiments, we observed the appearance of a dark red color immediately upon the mixing of the HMPA with the solution of substrate. This color was maintained during the course of the reflux, gradually being replaced by a brown color as the reaction went to completion. Under these conditions,¹⁰ the reaction was complete in a matter of hours. These improvements, when applied to quinone 3 gave chromene 4 as a single clean product.

We suspected that the red color represented quinone methide 7 (presumably both 7a and 7b), the enol form of the vinyl quinone. In fact, we could observe the appearance of a new species corresponding to approximately 80% of the substrate in solution in the nmr spectrum of quinone 3 in THF-d8 as soon as traces of hexamethylphosphoramide (HMPA) were added. This intermediate was stable in the nmr solution at 10 °C for several hours. An oxa-6π electrocyclization would convert enol 7a to the observed product 4. Enol 7b, if present, must undergo isomerization to enol 7a before the electrocyclization; it is reasonable to believe that low energy proton transfers, facilitated by HMPA, effect this change.¹¹ The oxa-6π electrocyclization then would complete the 2-step transformation of vinyl quinone 3 or the 3-step transformation of bromoquinone 1 to chromene 4 (Scheme 2).^{12, 13}

Scheme 2.

Mechanism of the Formation of 2H-Chromene from Vinyl Quinone.

It is clear that the conversion of quinone 3 to a reactive intermediate requires the presence of a polar organic additive that promotes the enolization step by changing the polarity of the reaction medium, by acting as a Lewis base, or by both mechanisms. The additive accelerates the conversion to chromene and is not, itself, changed in the process. Therefore, it fits the classical definition of a catalyst.

The approach to chromenes in which the Stille coupling and enolization/electrocyclization conversions are effected in separate steps can be considered relatively efficient by today's standards. We applied this strategy (Scheme 3) to the synthesis of five additional chromenes and utilized one of these in a short synthesis of the purported structure of the juvenile hormone from Ageratum conyzoides. This preliminary work has been reported.³

Scheme 3.

Multistep Synthesis of 2H-Chromenes. (a) triethylsilyl triflate (TESOTf), imidazole, DMF, rt; (b) 10 mol% (Ph₃P)₄Pd, toluene, cat. amounts of 2,6-di-tert.-butyl-4-methyl phenol (radical scavenger), reflux; (c) THF, 50% aq. AcOH, rt; (d) Ag₂O, O₂, MgSO₄, THF, rt; (e) toluene, HMPA (0.5% v/v), reflux in the dark.

Nevertheless, we recognized the potential advantages of a one-pot transformation as suggested by the original observation of the direct production of chromene 4 from bromoquinone 1. Multicatalysis and other cascade procedures¹⁴ offer opportunities to optimize yields and to minimize the time, effort, and waste incurred in multistep transformations. Here we complete the survey of the stepwise convergent chromene synthesis and we also describe the development of a three-step cascade sequence that effects the equivalent conversion in a single reaction vessel (Scheme 4). This formal [3+3] cycloaddition has three steps, the Pd(0) catalyzed coupling, the HMPA-promoted enolization, and the thermal electrocyclization. However, no change in reaction conditions is required from one step to the next. We suggest that this is a case of “tandem catalysis” or, more generally, multicatalysis and we utilize the relevant notation for the first two steps in Scheme 4. ¹⁵ Finally, we demonstrate the superiority of this protocol to the stepwise approach for the preparation of selected annulated chromene products.

Scheme 4.

One-Pot Synthesis of 2H-Chromenes by a Tandem Catalysis Cascade

2. Results and Discussions

2.1 Scope of the stepwise synthesis

We tested the generality of the stepwise procedure (Scheme 3) by extending it to a series of bromohydroquinone substrates that bear one or more methyl or methoxy substituents, structural features frequently found in naturally occurring benzo- and naphthopyrans (Table 1).¹⁶ Thus each of the hydroquinones 8, 8a, and 8c-8e was converted to its bis TES ether 9. Coupling with the known tin reagent 2 was followed by deprotection and oxidation of intermediates 10 to the corresponding quinones 3. Quinone 3b was most conveniently prepared by the AgO oxidation of the 1,3,4-trimethoxyphenyl butenoate 12 derived from the known 2-bromo-1,3,4-trimethoxybenzene (11; Scheme 5).³² Heating vinyl quinone substrate 3-3e in toluene in the presence of small amounts of HMPA gave, as expected, the corresponding chromene in each case. Yields for each step and the overall yields for the stepwise preparative sequence are shown in Table 1.

Table 1.

Multistep Synthesis of Chromenes via Protected Hydroquinones

Example		yield 9 [%]	yield 10 [%]	yield 5 [%]	yield 3 [%]	yield 4 [%]	overall yield [%]
8 R3= R5= R6= H		9: 98	10: 70	5: 92a	3: quant. (trans)	4: 76	4: 48b
					3: quant. (cis)	4: 86	4: 54b
8ac R3= H, R5= R6= CH3		9a: 98	10a: 69	5a: 80	3a: quant.	4a: 70	4a: 38
8b R3= OMe, R5= H, R6= H		-	-	-	3b: 98	4b: 58	4b: 30d
8ce R3= H, R5= OMe, R6= H		9c: 99	10c: 53	5c: 81	3c: 97	4c: 70	4c: 29b
8df R3= R5= H, R6= OMe		9d: 85	10d: 42	5d: 75	3d: 98	4d: 63	4d: 17
8eg R3= H, R5= R6=		9e: 89	10e: 83	5e: 86	3e: 94	4e: 59	4e: 35b

^a65% trans compound and 25% cis compound isolated by chromatography;

^bExperimental procedures and compound characterization data for this entry are reported in the Supporting Information for reference 3;

^cHydroquinone 8a was prepared by bromination of 2,3-dimethyl-1,4-hydroquinone according to Takanashi and Mori, reference 17;

^d30% yield from 2-bromo-1,3,4-trimethoxybenzene; see text;

^eHydroqinone 8c was prepared by bromination of methoxyhydroquinone according to Guzikowski et al, reference 18;

^fHydroquinone 8d was prepared according to Zhu et al, reference 19;

^gHydroquinone 8e was prepared by reduction of the corresponding quinone and used immediately; see the Supporting Information for reference 3.

Scheme 5.

(a) 10 mol% (Ph₃P)₄Pd, toluene, cat. amounts of 2,6-di-tert.-butyl-4-methyl phenol (radical scavenger), reflux; (b) AgO, HNO₃, THF, rt.

The low to modest overall yields of the multistep syntheses of 2H-chromenes reflect, in part, the losses affiliated with the manipulation and the isolation procedures of up-to five sequential reactions. The yields of the coupling reactions of TES-protected bromo hydroquinones with stannane 2 and, in some cases, the enolization/electrocyclization steps are especially unsatisfying. In an effort to improve the efficiency of the chromene synthesis, we therefore focused attention again on the original one-pot protocol. In this approach, enolization/electrocyclization occurs in situ, offering the possibility that vinyl quinones 3 could be converted to chromene products 4 as soon as they are formed.²⁰ The one pot protocol avoids the Stille coupling of the relatively unreactive, ²¹ electron rich benzene derivative 9 entirely.

2.2 Development of the one-pot synthesis

The development of one pot multi-reaction cascades requires not only the careful optimization of each step but also the establishment of conditions under which the reagents and intermediates do not interfere with each other in counterproductive phenomena. For the transformation discussed herein, particular attention had to be paid to eliminating photochemical transformations of the quinone intermediates. Thus, light was excluded from the reaction mixtures in all attempts to develop the one pot procedure. Also, we needed to minimize the redox chemistry of the bromoquinones and vinylquinones along the reaction pathway and promote the conversion of the delicate ortho-quinone methide intermediates to stable chromene products.

Optimization studies were performed with the parent bromobenzoquinone system. Reaction of substrate 1 with stannane 2 in toluene (10 mM) containing traces of HMPA (0.5% v/v) and (Ph₃P)₄Pd (10-20 mol%) at reflux in the dark gave a 1:1 mixture of desired 2H-chromene 4 and vinyl hydroquinone 5 in combined yields of approximately 70%. Thus, the formation of benzofuran 6 was prevented.

Vinyl hydroquinone 5, arises from a redox reaction, most likely between the phosphine ligand of the palladium catalysts and the quinone starting material and/or vinyl quinone intermediate.²² Since vinyl hydroquinone 5 does not undergo the enolization/electrocyclic ring closure transformation, its formation helps to explain the moderate yield of 2H-chromene 4. To overcome the problems encountered with phosphine ligands of the palladium catalyst we attempted to make use of “ligand-free” (or phosphine-free) conditions²³ reported for the successful Stille coupling of delicate substrates.²⁴ However, employment of Pd(OAc)₂, Pd₂(dba)₃ or (CH₃CN)₂PdCl₂ in the absence of phosphine ligands gave complex product mixtures, in some cases even at room temperature. Experiments in which the quantity of catalyst was reduced (1-2 mol% instead of 10-20 mol% (Ph₃P)₄Pd were slow; complete conversion to chromene products could not be achieved within reasonable times.

Although only traces (0.5%v/v) of HMPA are adequate for catalyzing the conversion of quinone 3 to dihydrochromene 4,³ increasing the amount of HMPA in the reaction medium of the one-pot reaction (1 → 4) was advantageous. When only 1-2% of (Ph₃P)₄Pd was used, concentrations of 2- 5% v/v, HMPA accelerated the overall conversion so that it was complete within a convenient timeframe. Furthermore, we found that more dilute reaction solutions (3 mM instead of 10 mM) gave cleaner products. Presumably, the presence of HMPA increases the rate of enolization, if not the rates of coupling and electrocyclization, and lowering the concentration of substrate decelerates bimolecular redox reactions.

Thus we developed suitable conditions for the one-pot, three-step procedure. Heating of a dilute toluene solution (3 mM) of equimolar amounts of bromobenzoquinone (1) and vinyl stannane 2 in the dark, in the presence 2-5 % v/v HMPA and 1-2 mol% catalyst ((Ph₃P)₄Pd) for 30 min provided 2H-chromene 4 cleanly and in good yields (Table 2; entry 1).

Table 2.

Synthesis of Substituted Benzo- and Naphthopyrans by Multicatalysis.

Entry	Bromoquinone substrates		Product (yield)b
1	1: R3 = R5 = R6= H		4 (66%)
2	1a: R3= H, R5= R6= CH3		4a (71%)
3	1b: R3= OMe, R5= R6= H		4b (70%)
4	1c: R3= H, R5= OMe, R6= H		4c (64%)
5	1d: R3= R5= H, R6= OMe		4d (66%)
6	1e: c R3= H, R5=R6=		4e (70%)

^aStoichiometric amounts of the bromoquinones and vinylstannane 2 (scale: 0.1-0.15 mmol) in toluene (30-45 mL; approx. 3 mM), 2-5% v/v HMPA, 1-2 mol% (Ph₃P)₄Pd, 1-5 h reflux in the dark.

^bYields of isolated products.

^c1e = 2-bromo-5-methoxynaphthoquinone (2-bromojuglone methyl ether).

With these optimized reaction conditions, we set out to investigate the general utility of the one-pot procedure and compare it to the stepwise synthesis. Except for the known 1b,²⁵ each of the bromoquinone starting materials was prepared according to the literature. 2-Bromo-5,6-dimethylbenzoquinone (1a)²⁶ was prepared by oxidation of the known hydroquinone.¹⁷ 2-Bromo-5-methoxybenzoquinone (1c) and 2-bromo-6-methoxybenzoquinone (1d), were prepared according to Blatchly et al.²⁵ and 2-bromojuglone methylether 1e was prepared according to Jung.²⁷ Quinone 1b was prepared by AgO oxidation of known compound 11. Each was subjected to reaction with vinylstannane 2 under the optimized multicatalysis conditions (Table 2). The yields of isolated products 4-4e were uniformly good and in all cases superior to the overall yields achieved by the alternative multistep procedure (Table 1). It can therefore be concluded that neither methyl (entry 2) nor methoxy (entries 3-5) substituents on the bromoquinone substrate interfere with the reaction cascade. In addition, the methodology can be applied to extended aromatic systems (e.g., naphthopyrans; entry 6). It is noteworthy that the multicatalysis method provides crude materials uncontaminated with by-products; only extractive removal of the polar additive and filtration through a short pad of silica gel is required for purification.

3. Conclusions

A one-pot, three step cascade that consists of a Stille-coupling/enolization/oxa-6π electrocyclization cascade effects the conversion of bromoquinones and vinyl stannanes to annulated 2H-chromenes. Although the yields for these transformations (1 → 4) could be termed modest, each represents three individual reactions and compares favorably with the corresponding stepwise sequences. This suggests – as is sometimes the case with cascade reactions – that unstable intermediates may be forwarded in the direction of the desired product before they can partition along undesired pathways.

A key feature of the method is the use of HMPA to promote the formation of the quinone methide that undergoes the oxa-6π electrocyclization. It is reasonable to believe that HMPA acts catalytically as a proton shuttle.²⁸ Similar enolizations of allyl quinones that preface oxa-6π electrocyclizations are promoted by basic alumina,²⁹ pyridine,³⁰ and triethyl amine.³¹ In any case, the conversion of vinylquinone to chromene requires the presence of a polar additive, leading us to apply the term “multicatalytic” to the three step cascade. Furthermore, we suggest that, as the field of multicatalysis develops, there will be additional examples of sequences in which an additive such as HMPA plays a critical role in one of the steps.

This new synthetic methodology enhances the portfolio of synthetic approaches by which structurally diverse benzo- and naphthopyrans can be prepared. Because it tolerates structural variants of the bromoquinone substrate, this attractive approach appears well suited for general applications in natural product total synthesis and compound library design.

4. Experimental Section

4.1 General Information

Reagents and solvents from Sigma-Aldrich, and TCI and catalysts from Strem Chemicals were used as supplied. Flash chromatography was performed with Fisher brand silica gel (170-400 mesh) and preparative tlc on Analtech precoated silica gel GF, 1000-microns glass plates (20 × 20 cm). All experiments were monitored by thin layer chromatography performed on EM Science precoated silica gel 60 F-254 glass supported plates. Reactions in the dark were performed by covering the reaction flask in aluminum foil.

Nuclear magnetic resonance spectra were recorded with a Bruker 300 or 400 MHz spectrometer with the corresponding solvent signal as an internal standard. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane (0.00 ppm). Values of coupling constants, J, are given in Hertz (Hz). The following abbreviations are used in the experimental section for the description of ¹H-NMR spectra: singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublets of triplets (dt), and broad singlet (bs). Low-resolution mass spectra were meassured with a Kratos MS80RFA (LRFAB, NBA / NaI) or with a HPGCD (LRGC-MS). Infrared spectra were recorded with a Perkin-Elmer 1600 Series FT-IR. Melting points were taken on a Thomas-Hoover apparatus and are uncorrected.

4.2 General Synthetic Procedures

4.2.1 General Procedure 1: Synthesis of TES-protected hydroquinones

Bromo hydroquinones (1.5-3.2 mmol) were dissolved in DMF (1 mL/mmol) and imidazole (5 equiv.) and TESOTf (3 equiv.) were added at 0 °C. The resulting solution was warmed to rt, stirred for 30-60 min and poured into water (10-20 mL). The mixture was extracted 3 times with ether. The organic phases were combined and the resulting solution was washed twice with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel with hexane to afford the TES-protected product.

4.2.2 General Procedure 2: Stille coupling of protected bromohydroquinones with vinylstannane 2

Protected bromohydroquinones (0.6-2 mmol) and vinylstannane 2 (1.2 equiv.) were dissolved in toluene (10-100 mL/mmol) and (Ph₃P)₄Pd (10 mol%) and a few crystals of 2,6-di-tert.-butyl-4-methylphenol (radical scavenger) were added. The mixture was stirred at reflux until tlc indicated complete conversion of the bromohydroquinone substrate (7-20 h). The reaction mixture was filtered through Celite^® and concentrated under reduced pressure. The crude product was purified by flash chromatography or preparative tlc on silica gel with mixtures of ethyl acetate and hexane to afford the final product.

4.2.3 General Procedure 3: Removal of TES-protective groups from vinylhydroquinones

Protected vinylhydroquinones (0.1-1 mmol) were dissolved in THF (12 mL/mmol) and 50% aq. AcOH (12 mL/mmol) was added. The mixture was stirred at rt until tlc indicated complete conversion of the protected vinylhydroquinone substrate (18-48 h). The reaction mixture was poured into 5% aq. NaHCO₃ and extracted with ether (3 times). The organic phases were combined and the resulting solution was washed twice with water, dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by flash chromatography or preparative tlc on silica gel with mixtures of ethyl acetate and hexane to afford the final product.

4.2.4 General Procedure 4: Oxidation of vinylhydroquinones

Vinylhydroquinones (0.05-0.2 mmol) were dissolved in THF (20-200 mL/mmol) and Ag₂O (5-10 equiv.) and MgSO₄ (ca. 50-100 mg, ca. 10 equiv.) were added. The suspension was stirred at rt under an oxygen atmosphere (O₂-balloon) until tlc indicated complete conversion of the vinylhydroquinone substrate (30-45 min). The reaction mixture was filtered through Celite^® and concentrated under reduced pressure to afford the final product.

4.2.5 General Procedure 5: Synthesis of 2H-chromenes from vinylquinones

Vinylquinones (0.05-0.1 mmol) were dissolved in toluene (5 mM) and HMPA (0.5% v/v) was added. The mixture was stirred at reflux in the dark until tlc indicated complete conversion of the vinylquinone substrate (0.25-36 h). The reaction mixture was diluted with toluene and washed with water (twice). The organic phase was dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography or preparative tlc on silica gel with mixtures of ethyl acetate and hexane to afford the final product.

4.2.6 General Procedure 6: One-pot synthesis of 2H-chromenes

Bromoquinone substrates and vinylstannane 2 were dissolved in equimolar amounts (0.1-0.25 mmol) in toluene (30-80 mL; approx. 3 mM) and HMPA (2-5 %v/v) and (Ph₃P)₄Pd (1-2 mol%) were added. The solution was stirred at reflux in the dark for 0.5-1.5 h after which time tlc indicated complete conversion of the substrates. The reaction mixture was diluted with toluene and washed twice with water. The water phases were extracted two more times with toluene. The organic phases were then combined and the resulting solution was dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified either by flash chromatography on silica gel or by filtration through a short pad of silica gel using mixtures of ethyl acetate and hexane.

4.3 Synthesis and Characterization of Compounds

For additional characterization of compounds 4, 4c and 4e and their respective precursors, see the Supporting Information for reference 3.

4.3.1 Synthesis of Bromoquinone 1a²⁶

From 5-bromo-2,3-dimethylbenzene-1,4-diol¹⁷ (44 mg, 0.2 mmol) according to general procedure 4; reaction time: 15 min. Orange crystals (42 mg, 98%); mp 47-49 °C.

4.3.2 Synthesis of Vinyl Quinone 3a

From vinyl hydroquinone 5a (cis/trans 1:7; 12 mg, 0.05 mmol) according to the general procedure 3; reaction time: 30 min. Brown oil (12 mg, quant.; mixture of trans/cis isomers 7:1): IR (neat) ν 2954, 1739, 1650, 1252, 1165 cm^-1; ¹H-NMR (THF-d8) δ 6.79-6.65 (m, 1.87H, trans isomer), 6.57-6.46 (m, 1H), 6.20 (dt, 0.13H, ³J = 12.0 Hz, 7.2 Hz, cis-isomer), 3.65 and 3.64 (each s, total 3H, cis/trans 1:7 in the order given), 3.33 and 3.26 (each dd, total 2H, ³J = 7.2 Hz, ⁴J = 1.9 Hz and ³J = 7.1 Hz, ⁴J = 1.2 Hz respectively, cis/trans 1:7 in the order given), 2.00, 1.99, 1.98 and 1.97 (each s, total 6H) ppm; ¹³C-NMR (THF-d8) (dominant signals of the major trans-isomer) δ 187.8, 187.2, 171.3, 142.2, 141.5, 141.3, 132.6, 129.3, 125.9, 52.0, 39.1, 12.4, 12.1 ppm; LRFAB-MS: [M+Na]⁺ = 257 (calc. for C₁₃H₁₄O₄Na: 257).

4.3.3 Synthesis of vinyl quinone 3b

1,3,4-Trimethoxy butenoate 12 (cis/trans 1:3, 19 mg, 0.07 mmol) was dissolved THF (1.5 mL) and AgO (69 mg, 0.28 mmol) was added. The suspension was sonicated for 1 min and 6 N HNO₃ (71 μL, 0.43 mmol) was added to the homogenous suspension. The reaction mixture was stirred at rt for 10 min during which the precipitate was dissolved. The solution was poured into water (5 mL) and the resulting mixture was extracted with ether (3 × 5 mL). The organic layers were washed with water (2 × 5 mL) and then combined, dried over MgSO₄ and concentrated under reduced pressure affording a cis/trans-mixture (1:3) of pure quinone 3b as a brown oil (16 mg, 98 %): IR (neat) ν 2953, 1737, 1658, 1572, 1443, 1323, 1208, 1165, 1057, 847 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.97 (dt, 0.75H, ³J = 16.2, 7.3 Hz, trans-isomer), 6.68-6.59 (m, 2H), 6.49 (dt, 0.75H, ³J = 16.2 Hz, ⁴J = 1.5 Hz, trans-isomer), 6.20 (d, 0.25H, ³J = 11.7 Hz, cis-isomer), 6.11 (dt, 0.25H, ³J = 11.7 Hz, 5.9 Hz, cis-isomer), 4.06 and 3.96 (each s, total 3H, trans/cis 3:1 in the order given), 3.68 and 3.66 (each s, total 3H, trans/cis 3:1 in the order given), 3.26 (dd, 1.5H, ³J = 7.3 Hz, ⁴J = 1.5 Hz, trans-isomer), 2.98 (bd, 0.5H, ³J = 5.9 Hz, cis-isomer) ppm; ¹³C-NMR (CD₂Cl₂) δ 188.0, 187.8, 184.0, 183.8, 171.94, 171.85, 155.1, 155.0, 137.04, 137.02, 135.5, 135.4, 134.1, 130.7, 125.6, 125.5, 122.2, 121.1, 61.5, 61.4, 52.4, 52.2, 40.3, 36.0 ppm; LRFAB-MS: [M+Na]⁺ = 259 (calc. for C₁₂H₁₂O₅Na: 259).

4.3.4 Synthesis of Vinyl Quinone 3d

From hydroquinone 5d (trans isomer; 24 mg, 0.10 mmol) according to the general procedure 4; reaction time: 30 min. Yellow solid (23 mg, 98%; trans isomer): mp 113-116 °C; IR (KBr) ν 2953, 1733, 1676, 1635, 1603, 1239, 1176 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.71-6.59 (m, 2H), 6.47 (bd, 1H, ³J = 16.1 Hz), 5.90 (d, 1H, ⁴J = 2.2 Hz), 3.80 and 3.69 (each s, each 3H), 3.28 (dd, 2H, ³J = 7.1 Hz, ⁴J = 1.2 Hz) ppm; ¹³C-NMR (CD₂Cl₂) δ 187.8, 181.7, 171.4, 159.2, 140.4, 132.1, 130.1, 124.9, 108.0, 57.0, 52.5, 39.0 ppm; LRFAB-MS: [M+Na]⁺ = 259 (calc. for C₁₂H₁₂O₅Na: 259).

4.3.5 Chromene 4³

Multistep procedure: From vinyl quinone 3 (12.4 mg, 0.06 mmol; trans- or cis-isomer) according to procedure 5 (in the case of the trans isomer in the presence of 3.5 equiv. of FeCl₃); reaction time: 45 min (trans-isomer) and 2 h (cis-isomer): Yields: 10 mg, 76% (trans-isomer) and 11mg, 86% (cis-isomer). One-pot procedure: From the reaction of bromo benzoquinone (1, 19 mg, 0.10 mmol) and vinylstannane 2 (40 mg, 0.10 mmol) according to general procedure 6; reaction time 30 min. Yellow solid (13.5 mg, 66%).

4.3.6 Chromene 4a

Multistep procedure: From vinyl quinone 3a (24 mg, 0.10 mmol) according to the general procedure 5; reaction time: 10 h (16.5 mg, 70%). One-Pot procedure: From 2-bromo-5,6-dimethylquinone 3a (24 mg, 0.10 mmol)²⁶ and vinyl stannane 2 (40 mg, 0.10 mmol) by general procedure 6; reaction time: 1 h (16.6 mg, 71%). Beige solid: mp 130-133 °C (decomposition); IR (KBr) ν 3468, 2928, 1738, 1434, 1206, 1086 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.40 (dd, 1H, ³J = 9.6 Hz, ⁴J = 1.7 Hz), 6.32 (s, 1H), 5.82 (dd, ³J = 9.6 Hz, 4.6 Hz), 5.34 (dd, 1H, ³J = 4.6 Hz, ⁴J = 1.7 Hz), 3.71 (s, 3H), 2.17 and 2.14 (each s, each 3H) ppm; ¹³C-NMR (CD₂Cl₂) δ 170.9, 148.40, 148.37, 145.1, 126.0, 125.1, 120.0, 118.8, 110.7, 73.7, 52.7, 12.4, 12.0 ppm; LRFAB-MS: [M+Na]⁺ = 257 (calc. for C₁₃H₁₄O₄Na: 257).

4.3.7 Chromene 4b

Multistep procedure: From vinyl quinone 3b (cis/trans isomer 1:3, 12 mg, 0.05 mmol) according to the general procedure 5; reaction time: 36 h (7 mg, 58%). One-Pot procedure: From 2-bromo-3-methoxyquinone (3b²⁵, 32.5 mg, 0.15 mmol) and vinyl stannane 2 (59 mg, 0.15 mmol) by the one-pot procedure by general procedure 6; reaction tim: 1 h (24.8 mg, 70%). Yellow oil: IR (neat) ν 3436, 2953, 1739, 1479, 1437, 1240, 1097, 1042, 800 cm^-1; ¹H-NMR (acetone-d6) δ 7.78 (bs, 1H), 6.71 (dd, 1H, ³J = 9.9 Hz, ⁴J = 1.8 Hz), 6.78 and 6.49 (each d, each 1H, ³J = 8.7 Hz), 5.91 (dd, 1H, ³J = 9.9 Hz, 4.6 Hz), 5.36 (dd, 1H, ³J = 4.6 Hz, ⁴J = 1.8 Hz) 3.78 and 3.70 (each s, each 3H) ppm; ¹³C-NMR (acetone-d6) δ 170.6, 147.0, 145.2, 144.4, 121.0, 120.9, 117.4, 115.8, 112.0, 73.5, 61.7, 52.5 ppm; LRFAB-MS: [M+Na]⁺ = 259 (calc. for C₁₂H₁₂O₅Na: 259).

4.3.8 Chromene 4c³

Multistep procedure: From vinyl quinone 3c (cis/trans isomer 1:3, 40 mg, 0.17 mmol) according to the general procedure 5; reaction time: 8h (28 mg, 70%). One-pot procedure: From the reaction of 2-bromo-5-methoxybenzoquinone (1c,²⁵ 32.5 mg, 0.15 mmol) and vinylstannane 2 (59 mg, 0.15 mmol) according to general procedure 6; reaction time: 1.5 h. Yellow oil (22.5 mg, 64%).

4.3.9 Chromene 4d

Multistep procedure. From vinyl quinone 3d (14 mg, 0.06 mmol; trans-isomer) according to the general procedure 5; reaction time: 15 min (9 mg, 63%). One-pot procedure. From the reaction of 2-bromo-6-methoxybenzoquinone (1d,²⁵ 24 mg, 0.10 mmol) and vinylstannane 2 (40 mg, 0.10 mmol) by general procedure 6; reaction time: 1 h (15.6 mg, 66%). Brown oil: IR (neat) ν 3413, 2923, 1739, 1591, 1475, 1200, 1066, 995 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.41 (dd, 1H, ³J = 9.7 Hz, ⁴J = 1.9 Hz), 6.38 and 6.12 (each d, each 1H, ⁴J = 2.8 Hz), 5.88 (dd, 1H, ³J = 9.7 Hz, 4.4 Hz), 5.35 (dd, 1H, ³J = 4.4 Hz, ⁴J = 1.9 Hz), 4.79 (bs, 1H), 3.83 and 3.73 (each s, each 3H) ppm; ¹³C-NMR (CD₂Cl₂) δ 170.6, 151.8, 148.9, 148.8, 126.0, 122.0, 121.0, 105.3, 102.1, 73.8, 56.7, and 52.8 ppm; LRFAB-MS: [M+Na]⁺ = 259 (calc. for C₁₂H₁₂O₅Na: 259).

4.3.10 Chromene 4e³

Multistep procedure: From vinyl naphtoquinone 3e (cis/trans isomer 1:2, 23 mg, 0.08 mmol) according to procedure 5; reaction time: 8 h (13.5 mg, 59%). One-pot procedure: From the reaction of 2-bromojuglone methylether 3e²⁷ (27 mg, 0.10 mmol) and vinylstannane 2 (40 mg, 0.1 mmol) by general procedure 6; reaction time: 1 h; pink solid (20 mg, 70%).

4.3.11 Vinyl hydroquinone 5a

From protected hydroquinone 10a (cis/trans 1:7; 240 mg, 0.52 mmol) according to the general procedure 3; reaction time: 48 h. Pale orange solid (97 mg, 80 %): mp 66-71 °C; IR (KBr) ν 3405, 2953, 1715, 1438, 1213, 1079 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.66 and 6.41 (each s, total 1H, trans/cis 7:1 in the order given), 6.64 and 6.54 (each dt, total 1H, ³J = 15.9 Hz, ⁴J = 1.4 Hz and ³J = 11.1 Hz, ⁴J = 1.5 Hz respectively, trans/cis 7:1 in the order given), 6.12 and 5.96 (each dt, total 1H, ³J = 15.9 Hz, 7.2 Hz and ³J = 11.1 Hz, 7.5 Hz, respectively, trans/cis 7:1 in the order given), 4.95 and 4.83 (each bs, total 2H), 3.70 and 3.68 (each s, total 3H, trans/cis 7:1 in the order given), 3.24 and 3.14 (each dd, total 2H, ³J = 7.2 Hz, ⁴J = 1.4 Hz and ³J = 7.5 Hz, ⁴J = 1.5 Hz respectively, trans/cis 7:1 in the order given), 2.16 and 2.14 (each s, total 6H, cis/trans 1:7 in the order given) ppm; ¹³C-NMR (CD₂Cl₂) δ 173.1, 173.0, 148.1, 147.5, 145.4, 128.7, 128.1, 127.3, 125.1, 124.3, 123.4, 122.4, 113.0, 110.6, 52.6, 52.5, 38.8, 34.6, 12.64, 12.56, 12.4 ppm; LRFAB-MS: [M+Na]⁺ = 259 (calc. for C₁₃H₁₆O₄Na: 259).

4.3.12 Vinyl hydroquinone 5d

From protected hydroquinone 10d (cis/trans 1:5; 131 mg, 0.28 mmol) according to the general procedure 3; reaction time: 36 h. Pale brown solid (50 mg, 75 %; mixture of cis/trans isomers with the trans isomer as the major product): mp 146-149 °C; IR (KBr) ν 3475, 3392, 2957, 1710, 1598, 1489, 1442, 1284, 1148, 966 cm^-1; ¹H-NMR (acetone-d6; dominant signals of the major trans-isomer) δ 7.71 and 7.01 (each bs, each 1H), 6.77 (dt, 1H, ³J = 16.0 Hz, ⁴J = 1.4 Hz), 6.52 and 6.41 (each d, each 1H, ⁴J = 2.7 Hz), 6.26 (dt, 1H, ³J = 16.0 Hz, 7.2 Hz), 3.79 and 3.65 (each s, each 3H), 3.25 (dd, 2H, ³J = 7.2 Hz, ⁴J = 1.4 Hz) ppm; ¹³C-NMR (acetone-d6; dominant signals of the major trans-isomer) δ 172.5, 151.0, 149.0, 138.1, 128.8, 124.3, 122.8, 104.3, 100.3, 56.4, 51.9, 38.9 ppm; LRFAB-MS: [M+Na]⁺ = 261 (calc. for C₁₂H₁₄O₅Na: 261).

4.3.13 TES-protected bromo hydroquinone 9a

Obtained from 2-bromo-5,6-dimethyl hydroquinone 8a¹⁷ (326 mg, 1.50 mmol) according to general procedure 1; reaction time: 1 h. Pale yellow oil (660 mg, 98 %): IR (neat) ν 2956, 2879, 1460, 1410, 1231, 1095, 928, 735 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.84 (s, 1H), 2.18 and 2.09 (each s, each 3H), 1.05-0.85 (m, 18H), 0.83-0.70 (m, 12H) ppm; ¹³C-NMR (CD₂Cl₂) δ 148.8, 146.6, 130.5, 128.5, 120.5, 111.6, 15.2, 13.6, 7.2, 7.0, 6.3, 5.7 ppm; LRFAB-MS: [M]⁺ = 446 (calc. for C₂₀H₃₇O₂BrSi₂: 446).

4.3.14 TES-protected bromo hydroquinone 9d

Obtained from 2-bromo-6-methoxy hydroquinone 8d¹⁹ (701 mg, 3.20 mmol) according to general procedure 1; reaction time: 30 min. Colorless oil (1.22 g, 85 %): IR (neat) ν 2956, 2878, 1597, 1566, 1489, 1454, 1411, 1242, 1207, 1147, 998, 908, 730 cm^-1; ¹H-NMR (CDCl₃) δ 6.64 (d, 1H, ⁴J = 2.8 Hz), 6.37 (d, 1H, ⁴J = 2.8 Hz), 3.76 (s, 3H), 1.10-0.93 (m, 18H), 0.83-0.69 (m, 12H) ppm; ¹³C-NMR (CDCl₃) δ 151.6, 150.0, 138.0, 115.3, 115.1, 104.0, 55.5, 6.9, 6.7, 5.7, 5.1 ppm; LRFAB-MS: [M]⁺ = 448 (calc. for C₁₉H₃₅O₃Si₂Br: 448).

4.3.15 TES-protected vinylhydroquinone 10a

From TES-protected 2-bromo-5,6-dimethyl hydroquinone 9a (446 mg, 1.00 mmol) and vinyl stannane 2 (mixture of cis/trans isomers) according to the general procedure 2; reaction time: 7 h. Pale yellow oil (320 mg, 69 %, mixture of 7:1 trans/cis isomers): IR (neat) ν 2955, 2877, 1745, 1469, 1415, 1223, 1092, 925, 741 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.75 and 6.52 (each s, total 1H, trans/cis 7:1 in the order given), 6.71 and 6.65 (each bd, total 1H, ³J = 15.9 Hz and 11.8 Hz respectively, trans/cis 7:1 in the order given), 6.05 and 5.81 (each dt, total 1H, ³J = 15.9 Hz, 7.1 Hz and ³J = 11.8 Hz, 7.4 Hz respectively, trans/cis 7:1 in the order given), 3.70 and 3.69 (each s, total 3H, trans/cis 7:1 in the order given), 3.28 and 3.24 (each dd, total 2H, ³J = 7.4 Hz, ⁴J = 1.8 Hz and ³J = 7.1 Hz, ⁴J = 1.3 Hz respectively, cis/trans 1:7 in the order given), 2.14, 2.13 and 2.12 (each s, total 6H, trans/cis isomers), 1.07-0.88 (m, 18H), 0.84-0.65 (m, 12H) ppm; ¹³C-NMR (CD₂Cl₂) δ 172.6, 172.5, 148.6, 148.0, 147.0, 146.5, 140.5, 133.7, 130.4, 129.3, 128.8, 128.5, 126.4, 125.5, 123.3, 121.3, 117.1, 113.4, 52.2, 52.1, 39.0, 34.6, 14.4, 14.3, 14.1, 13.6, 7.09, 7.08 6.2, 6.0, 5.84, 5.78, ppm; LRFAB-MS: [M]⁺ = 464 (calc. for C₂₅H₄₄O₄Si₂: 464).

4.3.16 TES-protected vinylhydroquinone 10d

From TES-protected bromo-hydroquinone 9d (448 mg, 1.00 mmol) and vinyl stannane 2 (mixture of cis/trans isomers) according to the general procedure 2; reaction time: 20 h. Pale yellow oil (195 mg, 42 %; mixture of trans/cis isomers 5:1): IR (neat) ν 2956, 2878, 1743, 1477, 1227, 1192, 1160, 1007, 908, 732 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.79 and 6.67 (each dt, total 1H, ³J = 16.2 Hz, ⁴J = 1.4 Hz and ³J = 11.5 Hz, ⁴J = 1.5 Hz respectively, trans/cis 5:1 in the order given), 6.56 and 6.40 (each d, total 1H, ⁴J = 2.7 Hz and ⁴J = 2.8 Hz respectively, trans/cis 5:1 in the order given), 6.35 and 6.33 (each d, total 1H, ⁴J = 2.7 Hz and ⁴J = 2.8 Hz respectively, trans/cis 5:1 in the order given), 6.17 and 5.85 (each dt, total 1H, ³J = 16.2 Hz, 7.1 Hz and ³J = 11.5 Hz, 7.4 Hz, trans/cis 5:1 in the order given), 3.77 and 3.76 (each s, total 3H, cis/trans 1:5 in the order given), 3.71 and 3.69 (each s, total 3H, trans/cis 5:1 in the order given), 3.28 and 3.26 (each dd, total 2H, ³J = 7.4 Hz, ⁴J = 1.5 Hz and ³J = 7.1 Hz, ⁴J = 1.4 Hz respectively, cis/trans 1:5 in the order given), 1.09-0.91 (m, 18H), 0.83-0.65 (m, 12H) ppm; ¹³C-NMR (CD₂Cl₂) δ 172.6, 172.4, 151.8, 150.2, 149.8, 148.9, 138.2, 137.9, 129.3, 129.2, 129.1, 128.9, 124.0, 122.6, 112.3, 108.4, 104.5, 104.4, 56.5, 55.7, 52.2, 52.0, 39.0, 34.7, 7.2, 7.1, 6.1, 5.6 ppm; LRFAB-MS: [M+Na]⁺ = 489 (calc. for C₂₄H₄₂O₅Si₂Na: 489).

4.3.17 1,3,4-Trimethoxyphenyl butenoate 12

From 2-bromo-1,3,4-trimethoxybenzene (11)³² (151 mg, 0.61 mmol) and vinyl stannane 2 (mixture of cis/trans isomers) according to general procedure 2; reaction time: 18 h. Pale yellow oil (84 mg, 52 %, mixture of trans/cis isomers 3:1): IR (neat) ν 2951, 2837, 1738, 1483, 1257, 1164, 1100, 796 cm^-1; ¹H-NMR (CD₂Cl₂) δ 6.82 and 6.78 (each d, total 1H, ³J = 9.0 Hz, cis/trans 1:3 in the order given), 6.79-6.64 (m, 1.75H), 6.59 (d, 0.75H, ³J = 9.0 Hz, trans-isomer), 6.40 (dt, 0.25H, ³J = 11.3 Hz, ⁴J = 1.6 Hz, cis-isomer), 5.97 (dt, 0.25H, ³J = 11.3 Hz, 7.2 Hz, cis-isomer), 3.80, 3.79, 3.78, 3.76, 3.72, 3.69, 3.66 and 3.65 (each s, total 12H), 3.26 (d, 1.5H, ³J = 6.2 Hz, trans-isomer), 3.01 (dd, 0.5H, ³J = 7.2 Hz, ⁴J = 1.6 Hz, cis-isomer) ppm; ¹³C-NMR (CD₂Cl₂) δ 172.8, 172.7, 152.8, 151.9, 148.6, 148.1, 147.8, 147.7, 120.6, 127.5, 126.6, 124.6, 123.5, 120.4, 112.3, 111.9, 106.4, 106.1. 40.3, 35.5, 60.6, 56.72, 56.70, 56.4, 56.2, 52.2, 52.0 ppm; LRFAB-MS: [M+Na]⁺ = 289 (calc. for C₁₄H₁₈O₅Na: 289).