Bicyclic allyltin derivatives through selective “one pot” hydrostannation - Diels-Alder reaction

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Introduction
The Diels-Alder reaction is one of the most commonly used organic reactions to construct, in a regio-and stereocontrolled way, a six membered ring with up to four stereogenic centers. 1 The widespread utility of the reaction rests on its ability to form otherwise difficult to access molecules such as bridged bicyclic compounds and also more complex structures due to its potential to form carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds.The synthesis of stereodefined conjugated dienylstannanes is an area of interest as they are very useful synthetic intermediates.We are interested in developing a fast route to obtain these types of precursors in order to study them as dienes in a "one pot" Diels-Alder reaction.Furthermore, allyltin reagents are very important in organic and asymmetric synthesis, 2 as shown, for instance, in reactions of allystannanes with aldehydes in the presence of chiral non-racemic ligands coordinated with Lewis acids. 3 We now report the synthesis of a variety of functionalized compounds containing allyltin structures via a "one pot" hydrostannation Diels-Alder reaction.These compounds could be suitable building blocks of non-steroidal compounds which are selective modulators (i.e., agonists and antagonists) of a steroid receptor, specifically, the glucocorticoid receptor.Such receptors are useful to treat diseases such as obesity, diabetes, inflammation and others. 4Thus, the possibility of synthesizing such precursors through a "one pot" protocol was the main target of this study.The allyltin compounds obtained are being tested in palladium catalyzed C-C Stille coupling reactions with the aim to obtain tin free non-steroidal analogs.

Results and Discussion
Initially the hydrostannation of 1-ethynylcyclohexene (1) was performed with the easy to handle and commercially available tri-n-butyltin hydride under three different reaction conditions: Method A: free radical conditions and photochemical initiation, nitrogen atmosphere, azobisisobutyronitrile (AIBN) (0.01 equiv), without solvent, at 75 °C; Method B: free radical conditions using ultrasound, 5 nitrogen atmosphere, r.t., AIBN (0.01 equiv), without solvent and Method C: under catalyzed conditions bis(triphenylphosphine)palladium (II) chloride (2 mol%), r.t. in THF (Scheme 1).The 119 Sn NMR spectra of the crude products resulting from these additions clearly showed that mixtures of at least three dienyltin adducts were obtained.In previous studies with monoand disubstituted alkynes, 6 we demonstrated that it was possible to improve the selectivity of this reaction using organotin hydrides with bulky organic ligands.In view of the poor regio-and stereoselectivity of the present hydrostannylation (Scheme 1), we considered the alternative addition of the more sterically demanding trineophyltin hydride 2 (neophyl -Nephis 2-methyl-2-phenylpropyl) to enyne 1 under similar reaction conditions.As shown in Scheme 2, the results obtained were substantially different.In the case of Methods A and B under free radical conditions, [(1Z)-2-cyclohexenylvinyl]trineophylstannane 3 resulting from an anti attack, was the only product obtained in quantitative yield after 1 h (Method A) and 40 min (Method B) of reaction, respectively.The geometry of compound 3 was assigned on the basis of the large 3 J(Sn,H) coupling constant of 151. 3 Hz that indicated the existence of trans H-C-C-Sn linkages.The absence of the signal corresponding to a terminal vinyl methylene in the 13 C NMR spectra supported that the tin atom was not attached to the cyclohexenyl moiety.The structure was confirmed by other 1 H, 13 C and 119 Sn NMR data (see Experimental Section).When the reaction was performed under palladium catalyzed conditions and after 45 min (Method C), a mixture of [(1E)-2-cyclohexenylvinyl]trineophylstannane 4 and (1-cyclohexenylvinyl)trineophylstannane 5 (4:5, 2.3:1) was obtained.The ratio of isomers was determined through the corresponding 119 Sn NMR spectrum of the crude product.These adducts were the result of the corresponding syn addition of the trineophyltin hydride.No addition to the double bond of enyne 1 was observed in any case.Although the mixture of regioisomers 4 and 5 could not be separated, we were able to obtain enriched mixtures from which useful NMR data could be obtained.The stereochemistry of 4 and 5 was assigned taking into account that the 3 J(Sn,H) coupling constant value of 69.8 Hz extracted from the 1 H NMR spectrum lies in the range 65-85 Hz, and indicated a cis arrangement between the proton attached to the same vinyl carbon as the cyclohexenyl moiety and the stannyl group in stereoisomer 4. Furthermore, the 3 J(H,H) of 19.1 Hz indicated trans H-C-C-H linkages around the vinyl group in the same adduct.In the case of compound 5, the 2 J(Sn,C) coupling constant of 28.2 Hz corresponded to a CH2 at 123.41 ppm in the 13 C NMR spectra together with 2 J(H,H) and 3 J(Sn,H) coupling constants values of 2.3 Hz and 67.5 Hz, respectively, confirmed both the existence of a terminal sp 2 carbon and cyclohexenyl-and trineophyltin groups attached to the same vinyl carbon.Other 1 H, 13 C and 119 Sn NMR data also confirmed the assigned structures (see Experimental Section).
As we were looking for the best conditions for a "one pot" hydrostannation Diels-Alder reaction, we selected the addition of Neph3SnH 2 to 1 using Method B (Scheme 3).Since the trialkylstannyl group was known to have a small electron-donating inductive effect 7 when attached to a dienic sp 2 carbon atom, it could react readily with electron-poor dienophiles.The adducts obtained in these reactions should reflect the stereochemistry of the starting compounds.So, without further purification, the dienylstannane 3 was used as the conjugated diene precursor for the Diels-Alder reaction performed under three different experimental conditions with several activated dienophiles: Method D: methylene dichloride, aluminum trichloride, -78 °C; Method E: benzene, hydroquinone (as polymerization inhibitor), 80 °C and Method F: benzene, hydroquinone, 40 °C, ultrasound (Table 1).
The formation of the "ortho or meta" adducts in the Diels-Alder reaction in most cases can be explained in terms of Frontier Orbital Theory and it was possible to predict the regiochemistry of these [4n + 2] cycloadditions.Thus, the strongest interaction will be between the centers on the frontier orbitals having the largest orbital coefficients, which are, in this case, the HOMO of the diene with an electron releasing group (ERG) at C1 that reacts with the LUMO of the dienophile with an electron withdrawing group (EWG).The most favored regioisomer that should be expected is the "ortho" adduct (Scheme 4, a).
However, when the diene was substituted at C1 with a weak ERG such as the trineophylstannyl group, its contribution to the distortion effect on the size of the orbital was very small so the coefficients of C1 and C4 were expected to be very similar.Because of this, in the determination of the regiochemistry, the predominant effect was steric and as such the preferred product was expected be the "meta" adduct (Scheme 4, b).This structural hypothesis was confirmed through the spectroscopic analyses of the products obtained in the corresponding "one pot" reactions.Thus, the reaction of diene 3 and methyl acrylate 6 (entry 1, Table 1), gave exclusively methyl-4-trineophylstannylbicyclo[4.4.0]dec-5-ene-2-carboxylate 14 in 92% yield (Method E) and 75% yield in the presence of Lewis acid at -78 °C (Method D).Only starting material was recovered when the ultrasound was used (Method F).The absence of Sn, C coupling constants between the tin atom and the carbonyl group and the signals at δ 24.41 [ 2 J(Sn,C) = 15. 2 Hz]  corresponding to a methylene group (C3), clearly showed that 14 was the "meta" adduct together with the observed 3 J(Sn-C4-C3-C2) = 11.2Hz, that, according to previous work and the graph of the Karplus equation, 8  corresponded to a dihedral angle close to 110º which supported a trans relation between the methoxycarbonyl group and the tin moiety.As expected, 4-trineophylstannyl-1,3,3a,4,6,7,8,9,9a,9b-decahydrobenzo[e]isobenzofuran-1,3-dione 15 was the only cycloaddition product in the reaction between 3 and the symmetric maleic anhydride 7 (entry 2, Table 1).The trans geometric relationship between the tin atom and the nearest carbonyl group (C3) was determined through the 3 J(Sn-C4-C3a-C3=O) coupling constant value of 64.6 Hz extracted from 13  C NMR spectra that gave a 150-180° dihedral angle between C4-Sn bond and C3=O group.This hypothesis was confirmed by considering the observed 3 J(H,H) coupling constant value between H-3a and H-9b which was about 2.3 Hz consistent with a cis conformation.Once again, the highest yield of 95% for adduct 15 occurred under the experimental conditions given by Method E. A similar analysis allowed us to determine the structure of 8-trineophylstannyltricyclo[8.4.0.0 2,7  ]tetradeca-4,9-diene-3,6-dione 16, obtained from the reaction between 3 and pbenzoquinone 8 (entry 3, Table 1).The value of 3 J(Sn,C) = 53.8Hz among the trineophyltin group attached to C8 and the carbonyl group (C6) indicated a dihedral angle close to 150º.Following the same analysis as before, 3 J(H,H) coupling constant value between H2 and H7 of 3.0 Hz supported a cis conformation.
In this case, both Methods E and F gave 16 in 91 and 87% yield, respectively.When the reaction was performed using acrylonitrile as the starting dienophile 9 (entry 4, Table 1), and benzene and hydroquinone were used (Method E) the formation of two adducts was observed in a 7.3:1 ratio, respectively according to 119 Sn spectra of the crude product.Only starting material was recovered under the other two reaction conditions.Column chromatography purification was very difficult because of the very similar interaction of both adducts with silica gel or alumina.
However, 4-trineophylstannylbicyclo[4.4.0]dec-5-en-2-yl cyanide 17 could be isolated and for 17´ characterization of an enriched mixture was used.Analysis of the 1 H and 13 C NMR spectra showed that the "meta" adduct 17 was the predominant regioisomer and the "ortho" adduct, 4-trineophylstannylbicyclo[4.4.0]dec-5-en-3-yl cyanide 17´ was the minor one.The conclusions about each structure were based on the fact that there was a CH2 signal at 34.13 ppm with 2 J(Sn,C) of 10.3 Hz coupling constant value in the case of 17 and a CH signal at 39.26 ppm with 2 J(Sn,C) of 11.2 Hz for 17´.Furthermore, there was a 3 J(Sn-C-C-CN) of 24.7 Hz that was consistent with a dihedral angle of about 120º indicating a trans relation between the nitrile group and the tin moiety in compound 17´.The absence of any coupling constant between the same groups in 17, supported the meta arrangement proposed for this adduct.Nevertheless, αsubstituted dienophiles gave very different results.Only a 20% yield was observed in the cycloaddition reaction when methyl 2-methylacrilate was used 10 (entry 5, Table 1).Under the conditions fixed by Method E (benzene/hydroquinone), a mixture of two regioisomers, methyl 2methyl-4-trineophylstannylbicyclo [4.4.0]dec-5-ene-2-carboxylate 18 and methyl 3-methyl-4trineophylstannylbicyclo[4.4.0]dec-5-ene-3-carboxylate 18´ were obtained in a 3 : 1 ratio, respectively according to the 119 Sn NMR spectrum of the crude product.No reaction was detected in other cases (Method D and F, see Table 1).Purification by column chromatography on silica-gel 60 only gave enriched fractions of each adduct and according to their spectral data ( 1 H and 13 C) we were able to analyze their possible structures.The absence of the 3 J coupling constant between the trineophyltin group and the carbonyl group in 18 possibly indicated that, once again, the major product was the "meta" adduct.While, the observed 3 J(Sn,C=O) = 12.3 Hz, corresponding to a dihedral angle close to 110º, supported a trans relation between the carboximethyl group and the tin moiety in the "ortho" adduct 18´.
Comparing methyl acrylate 6 with methyl-2-methylacrylate 10, the methyl group in C2 seems to change dramatically the yield of the reaction (entries 1 and 5, Table 1) probably due to both steric hindrance and the weak electron-releasing capacity of this group that diminished the electron-withdrawing effect of the carbonyl moiety.It is important to note that no cycloaddition product at all was obtained in the reactions conducted with dienophiles 11 and 12 (entry 6 and 7, Table 1).Presumably and in spite of the conjugating effect of the phenyl group, there was an important steric factor that prevented the reaction.
Taking into account that allyltin compounds can be used as Stille coupling substrates, 9 we tested the cited reaction with compound 14 and 16 and three substituted aryl halides: 4-iodoanisole, 2-bromopyridine and 2-bromo-6-methylquinoline (Scheme 5) according to previous experimental reaction conditions. 10New compounds 19-24 were purified by column chromatography and obtained in moderate to good yields (48-85%).The stationary phase (neutral alumina) was previously treated with with 10% KF to retain the trineophyltinhalides formed in the reaction.From the NMR spectra of these compounds, it seemed that there was absolute retention of configuration in the carbon attached to the new aryl moiety.Scheme 5. Stille coupling between 14 and 16 with some substituted aryl halides.
From these studies, we showed that, in the presence of suitably activated dienophiles, it was possible to carry out "one-pot hydrostannation Diels-Alder" reactions to obtain allylstannyl compounds in very high yields that were easily purified by column chromatography.These allylstannyl substrates are important precursor intermediates for Stille coupling reactions leading to bicyclic aryl compounds.In view of these preliminary results, we intend to optimize the method (improve yields and reaction time) with the aim of generalizing the Stille coupling for substrates 14 and 16.

Experimental Section
General.All reactions were carried out under argon or nitrogen atmosphere. 1 H, 13 C, COSY and 119 Sn NMR spectra were recorded on a Bruker ARX 300 Multinuclear instrument and calibrated by using signals from solvents referenced to SiMe4 ( 1 H, 13 C, COSY) and with respect to Me4Sn in the case of 119 Sn-NMR spectra and chemical shifts are reported in ppm.Infrared spectra were recorded with a Nicolet Nexus FT spectrometer.The reactions under ultrasonic conditions were performed in an ULTRASONIC 104X bath.Elemental analyses (C, H) were performed in an EXETER CE-440 instrument at UMYMFOR (Argentina).High-resolution mass spectra (HRMS) were recorded on a BRUKER micrOTOF-Q II spectrometer (HR-ESI-MS) at UMYMFOR (Argentina).Melting points were determined with a Koefler Hot-Stage apparatus and are uncorrected.All the solvents and reagents were analytical grade.Solvents were dried using standard procedures.Trineophyltin hydride was prepared as described previously. 11