Conformational Analysis of Marine Polyhalogenated β-Chamigrenes Through Temperature-Dependent NMR Spectra

Temperature-dependent ¹H- and ¹³C-NMR spectra reveal that polyhalogenated marine β-chamigrenes or synthetic derivatives thereof which are trans-diequatorially, substituted at C(8) and C(9), such as rogiolol ((?)- 2 ), obtusol ((+)- 3 ), and their acetates (+)- 1 and (?)- 4 , undergo slow ring- A chair-chair inversion. Conformational equilibria and kinetics are investigated with the aid of synthetic model compounds and molecular-mechanics calculations. Thus, steric repulsions between Br_ax–C(2) and H_eq–C(7) are seen to disfavour thermodynamically conformers 1b , 2b , 3b , and 4b , which can only be detected through cross-saturation transfer, while additional steric repulsions between Me_ax–C(1) and OH_ax–C(3) make conformer 8b of obtusol epimer so scarcely populated that it can not be detected. In agreement, with (+)- 9 and (+)- 10 , which have a trigonal C(2), two conformers can be directly observed by NMR. The kinetic barriers, which are seen to arise mainly from steric repulsions between H_ax–C(14) and the axial H or halogen atoms at C(8) and C(10), are calculated and discussed with respect to well documented exocycliemethylidene-substituted cyclohexane(ene) systems. This helps to rationalize why in rogiolol acetate ((+)- 1 ) ring B is unusually inert towards Zn/Et₂O/AcOH which causes bromohydrine-group elimination from ring A.     

Ab initio molecular orbital study of energies and conformers of 3,4-dihydro-1,2-dithiin, 3,6-dihydro-1,2-dithiin, 4H-1,3-dithiin,and 2,3-dihydro-1,4-dithiin

Optimized geometries and energies for 3,4-dihydro-1,2-dithiin ( 1 ), 3,6-dihydro-1,2-dithiin ( 2 ), 4H-1,3-dithiin ( 3 ), and 2,3-dihydro-1,4-dithiin ( 4 ) were calculated using ab initio 6-31G* and MP2/6-31G*//6-31G* methods. At the MP2/6-31G*//6-31G* level, the half-chair conformer of 4 is more stable than those of 1 , 2 , and 3 by 2.5, 3.5, and 3.6 kcal/mol, respectively. The half-chair conformers of 1 , 2 , 3 , and 4 are 2.9, 7.1, 2.0, and 5.6 kcal/mol, respectively, more stable than their boat conformers. The calculated half-chair structures of 1 – 4 are compared with the calculated chair conformer of cyclohexane and the half-chair structures for cyclohexene, 3,4-dihydro-1,2-dioxin ( 5 ), 3,6-dihydro-1,2-dioxin ( 6 ), 4H-1,3-dioxin ( 7 ), and 2,3-dihydro-1,4-dioxin ( 8 ). © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1064–1071, 1998     

Conformational studies of aliphatic secondary ozonides (propene, 1-butene and 1-heptene) by means of FTIR spectroscopy

Ozonization reaction of simple alkenes was studied by means of FT infrared absorption gas spectroscopy. The reaction was performed at 95 K in neat films of the reactants. IR absorption spectra of the gaseous products were recorded. The spectra were analyzed combining experimental results with theoretical calculations performed at B3LYP 6-311++G (3df, 3pd) level. We found that among all theoretically predicted conformers of propene secondary ozonide, only one which has the O-O half-chair configuration for the five membered ring and the radical attached in the equatorial position was present in the sample. Samples of 1-butene and 1-heptene secondary ozonides consist from two conformers of very similar energy (ΔH=0.3 kJ/mol). The most stable conformer for both ozonides is the one with O-O half-chair configuration of the five membered ring and the radical attached in equatorial position and the aliphatic chain in gauche position. The second stable conformer has the aliphatic chain in anti position.     

Conformational analysis of 1,2,3,4-tetrahydroisoquinolines

Ring and nitrogen inversion account for the conformational equilibria of 3-phenyl-1, 2,3, 4-tetrahydroiso-quinolines. In order to quantitate the relative contribution of each conformer to the equilibrium, we undertook a molecular mechanics study on several substituted 3-phenyl-1, 2, 3, 4-tetrahydroisoquinolines. Predictions from calculations were checked against cmr chemical shift data. No boat conformation contributed significantly to the equilibrium. A general result of our calculations is that in all cases the 3-phenyl group in the equatorial position is strongly favored (by at least 2.50 kcal/mole). For 3-phenyl-1, 2, 3, 4-tetrahydroisoquinolines without substitution at nitrogen, N-H in equatorial position is preferred over the axial conformer, although the energy difference between both is always small (0.30–1.10 kcal/mole). For the cis-1,3-disubstituted compounds the le'3e conformers are the only species present (at least 99.8%). The calculated energy differences between the la′3a conformer and the le′3e conformer are always large (3.80–6.10 kcal/mole for the NHe conformers and 3.60–3.80 kcal/mole for the NHa conformers). The lack of a γ_1a upfield shift at C3 also points to the preference for the pseudoequatorial-equatorial conformer. For N-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline a preference for the NMe group in the equatorial position is predicted (0.60–2.00 kcal/mole). The small downfield shift at C4 (γ_Na = 0.5 ppm) is consistent with the equatorial NMe preference. For the cis-1,2,3-trisubstituted compounds no significant γ_1a effect at C3 (γ_1a = -0.2 and 1.0 ppm) or γ_Na effect at C4 (γ_Na = 0.1 and 0.4 ppm) is observed. For these compounds, deformations due to steric congestion are evidenced by the deviation from the values of the C4a-C8a-Cl-N and C4a-C4-C3-N torsional angles, as compared to less crowded 3-phenyl-1,2,3,4-tetrahydroisoquinolines. Here the heterocyclic ring adopts a distorted half-chair conformation.     

Furopyridines. XXIII. Synthesis and reactions of chloropyridine derivatives of furo[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine

Chlorination of the N-oxides of furo[2,3-b]- 1a , -[2,3-c]- 1b and -[3,2-c]pyridine 1c with phosphorus oxychloride afforded compounds substituted normally at the α- or λ-position to the ring nitrogen, 2a, 2′a, 2b, 2c, 2′c and 2′c , and in addition, in the case of 1b , compounds substituted on the furan ring, 2′b and 2″b . The structures of these compounds were confirmed from their ir, nmr and mass spectra. The major chlorinated products 2a, 2b and 2c were converted to methoxy- 5a, 5b and 5c , N-pyrrolidyl- 7a, 7b and 7c , and phenylthiofuropyridines 8a, 8b , and 8c .     

Theoretical Studies on S-Phenyl-thiabenzene,S-Phenyl-thianaphthalene,and S-Phenyl-thiaanthracene

The molecular structures of S-phenyl-thiabenzene 1, S-phenyl-1-thianaphthalene 2, S-phenyl-2-thianaphthalene 3, and S-phenyl-9-thiaanthracene 4 are studied by ab initio calculations using HF as well as DFT methods at the 6–311+G? level of theory. The non-planar boat conformers of 1–4 with 6π electrons in the heterocyclic ring appear to be more stable than the corresponding planar conformers with 8π electrons in the ring. The activation energy for the inversion at the sulfur atom is compared for 1–4. Conformational flexibility of 1–4 is studied.     

Furopyridines. XIX. Reaction of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine with acetic anhydride

Acetoxylation of N-oxide of furo[2,3-b]- 2a , -[3,2-b]- 2b , -[2,3-c]- 2c and -[3,2-c]pyridine 2d with acetic anhydride afforded compounds substituted normally at the α- or γ-position to the ring nitrogen, 3a, 4a, 4b, 3d, 4d, 8 and 9 , and in addition compounds substituted on the furan ring, 5a, 6a, 5b, 6b, 7b, 5c and 7c which were unexpected compounds. The structures of these compounds were established from the ir, nmr and mass spectra, and x-ray crystal analysis of 5b .     

Conformational Studies of Marine Polyhalogenated α-Chamigrenes Using Temperature-Dependent NMR Spectra. Cyclohexene-ring flipping and rigid-chair cyclohexane ring in the presence of equatorial halogen atoms at C(8) and C(9)

Temperature-dependent NMR spectra indicate that the α-chamigren-3-ones (?) -11 , (+) -12 , (+) -14 (?) -15 , (+) -16, 18 , and 19 bearing equatorial halogen atoms at C(8) and C(9) undergo slow conformational flipping of the envelope-shaped enone ring, while the cyclohexane ring is maintained in the chair conformation. The α-chamigren-3-ols (+) -20 and (+) -21 , obtained by hydride reduction of (+) -12 , behave similarly, with slow half-chair inversion of the cyclohexenol ring. In each case, both conformers are about equally populated and detectable by NMR, except in the case of (+) -15 , where repulsive interactions between Br? C(2) and H_eq?C(7) make the population of the conformer 15b with Me—C(5) faced to H_ax?C(10) so low that it escapes direct ¹H-NMR detection. The energy barriers to these conformational motions are viewed to arise mainly from repulsive interactions between Me—C(5) and the axial H-atoms at C(8) and C(10), while, contrary to previous beliefs, no twist-boat conformations of the cyclohexane ring intervene. Similar conclusions hold for the 4,5-epoxides of both (?) -6 and (+) -7 . Clean Jones oxidatio of (?) -2 to 17 , where the CH₂?C(5) bond is maintained, and acid dehydration-isomerization of the α-chamigrene (+) -21 to the β-chamigrene (+) -24 , reflect the special stability of β-chamigrenes, providing a reason for their frequent occurrence in nature.     

New guaianolides from Berlandiera Pumila and B. Texana,and the X-ray crystal structure of pumilin

The isolation and structure determination of two new guaianolides, pumilin and its 2,3-epoxide, from Berlandiera pumila and B. texana are reported. The structure of pumilin was determined from nmr and mass spectral data, and from an X-ray single crystal study; the structure of the epoxide was found by comparison of nmr spectra. Pumilin is shown to be a Δ¹⁽¹⁰⁾-cis-guaianolide with a cyclopentenone ring attached to C1 and C5, and an α-methylene-γ-lactone ring trans-fused to C6 and C7. The absolute configuration was inferred from spectral considerations and knowledge of previous structural determinations. The cd spectrum of pumilin exhibits a negative Cotton effect, and the lactone chromophore has left-handed chirality. The cyclo-heptene ring is in the chair configuration, with the lactone a half-chair and the cyclopentenone essentially planar. Crystals are orthorhombic, a = 7.065, b = 13.652, c = 19.586 Å, space group P2₁2₁2₁, Z = 4, and the final R value is 3.9%. The crystal structure is strengthened by an O···O hydrogen bond linking the molecules into infinite chains.     

Conformational analysis and steric effects of substituents in derivatives of 3-oxo-, 3-imino-, and 3-methylenecyclohexene

The equilibrium conformations and the inversion barriers of the rings in 3-oxo-, 3-imino-, 3-methylenecyclohexenes and in their methyl,tert-butyl, and phenyl derivatives were calculated by molecular mechanics. The unsubstituted molecules adopt a sofa conformation. The nonbonded interactions between substituents at positions 2 and 4 and the exocyclic double bond lead to a change in the conformation of the ring to a half-chair. The effect is enhanced as the volume of the substituent increases in the series of the oxo, imino, and methylene derivatives. Substituents at other positions of the ring affect only slightly the equilibrium conformation. The results of calculations were confirmed by X-ray structural analysis of 2-(4-benzoyloxybenzyl)-6-isopropyl-3-methylcyclohex-2-enone. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1995–2000, November, 1997.     

Synthesis and studies on spectral behaviour and molecular dynamics of 7-Aryl-4,5-Dihydro-2-Oxo-3H,8H-Furo[3,4-b] [1,4]diazepines

A new series of 7-aryl-4,5-dmydro-2-oxo-3H,8H-furo[3,4-b][1,4] diazepines were prepared. Their ^lH nmr spectra have been interpreted in terms of the interconversion of two pseudo-boat conformers. Molecular-dynamics simulations at different temperatures on this type of compounds revealed a very small energy difference between these two conformers.     

Chemistry of thienopyridines. XXXI. A new synthesis of thieno[3,2-b]pyridine and studies on direct substitution into its thiophene ring

Thieno[3,2-b]pyridine ( 1 ) is synthesized in 65% overall yield for two steps which consist of addition of toluene-α-thiol to 2-ethynylpyridine plus vacuum pyrolysis of the addend ( 7 ). Cis and trans forms of 7 are described. Compound 1 undergoes (a) electrophilic substitution at C-3 to give chloro, bromo, and iodo derivatives (44–57% yields) and (b) lithiation at C-2 (to give 1a ). Intermediate 1a is converted into derivatives of 1 with halo (19–48%), formyl (54%), acetyl, and hydroxymethyl (40%) substituents at C-2. Also described are 2-cyano and 2,3-dibromo derivatives of 1 . Structural assignments are based on chemical transformations plus ¹H and ¹³C nmr spectral data. The substitution pattern of 1 is compared with predictions made on the bases of analogous ring systems and molecular orbital calculations.     

Conformational Composition of Stereoisomers of 2-Alkyl-5-isopropyl-4-methyl-1,3,2-dioxaborinanes

¹H and ¹³C NMR spectroscopy was used to assign the configuration of a mixture of stereoisomers of 2-alkyl-5-isopropyl-4-methyl-1,3,2-dioxaborinanes with different ratios of the cis and trans forms. These forms differ in the configuration of C⁽⁴⁾ in the ring. The results of MM+ and AM1 calculations for the optimal geometry indicate high conformational flexibility of both isomers, which exist in an equilibrium mixture of sofa and half-chair conformers.     

Novel tricyclic heterocycles (benzopyrrocolines) arising via carbanion attack on a nitrile function

A new reaction of 2-n-alkanoyl-1,2-dihydroisoquinaldonitriles 1 (isoquinoline Reissert compounds) has been discovered. As previously reported reaction of the conjugate bases of Reissert compounds with alkyl halides yields the corresponding 1-alkyl derivatives 2 . However, compounds 2 , R = n-alkyl, with only a catalytic amount of bases form the enolate ion, which attacks the neighboring nitrile functionality to produce directly in the same reaction vessel excellent yields of benzopyrrocoline derivatives 5-10 . The nmr spectrum reveals a solvent dependent tautomeric equilibrium between ketoeneamine ( a ) and ketoimine ( b ) forms. Unlike compounds 2 the double bonds of the pyridine ring of compounds 7 and 8 were readily reduced with hydrogen. Thus, n-alkanoyl Reissert compounds afford a convenient route to the corresponding benzopyrroco-lines.     

Ab initio molecular orbital calculations of 3,4-dihydro-1,2-dioxin, 3,6-dihydro-1,2-dioxin, 4H-1,3-dioxin (1,3-diox-4-ene), and 2,3-dihydro-1,4-dioxin (1,4-dioxene)

Optimized geometries and total energies for 3,4-dihydro-1,2-dioxin ( 1 ), 3,6-dihydro-1,2-dioxin ( 2 ), 4H-1,3-dioxin (1,3-diox-4-ene, 3 ), and 2,3-dihydro-1,4-dioxin (1,4-dioxene, 4 ) were calculated using ab initio 3-21G, 6-31G*, and MP2/6-31G*//6-31G* methods. The half-chair conformers of 1 (C₁), 2 (C₂), 3 (C₁), and 4 (C₂) are more stable than their respective planar structures [ 1 (C_s), 2 (C_2v), 3 (C_s), and 4 (C_2v)]. Among the four isomers 1 – 4 , the half-chair conformer of 3 is the most stable. It is 53.1, 54.6, and 3.4 kcal mol⁻¹ more stable than 1 , 2 , and 4 , respectively. The largest energy difference (19.0 kcal mol⁻¹) is observed between the half-chair and planar conformers of 2 . The boat conformers of 2 and 4 are less stable than their respective half-chair conformers, but are more stable than their planar structures. Hyperconjugative orbital interactions (anomeric effects) contribute to the greater stability of 3 (n_O(3) →σ*_C(2)—O(1), n_O(3)→σ*,n _O(3)→σ*) and of 4 (n_O(1)→ σ*). The ab initio calculated structural features of the half-chair conformations of the dihydrodioxins 1 – 4 are compared with the half-chair conformations of cyclohexene and the chair conformations of cyclohexane, oxacyclohexane (tetrahydropyran), 1,2-dioxacyclohexane (1,2-dioxane), 1,3-dioxacyclohexane (1,3-dioxane), and 1,4-dioxacyclohexane (1,4-dioxane) © 1997 by John Wiley & Sons, Inc. J Comput Chem 18 : 1392–1406, 1997     

Synthesis of quinazolino-1,3-benzothiazine derivatives

The ring-closure reactions of N-(3,4-dimethoxyphenylthiomethyl)-2-nitrobenzamide derivatives 5a,b with phosphoryl chloride gave 4-(2-nitrophenyl)-2H1,3-benzothiazine derivatives 7a,b , which on reduction yielded 4-(2′-aminophenyl)-3,4-dihydro-2H-1,3-benzothiazines 8a,b. Reaction of these compounds with phosgene led to a new heterocyclic ring system, 6H,8H-quinazolino[3,4-c][1,3]benzothiazine derivatives 9a,b. The structures of the title compounds were proved via their ir and nmr (¹H, ¹³C) spectra.     

Controlling the Conformational Changes in Donor–Acceptor [4]‐Dendralenes through Intramolecular Charge‐Transfer Processes

The synthesis of two [4]‐dendralene compounds incorporating thiophene‐(p‐nitrophenyl) donor–acceptor units is presented. The dendralenes adopt two different conformers in solution and solid state and the transformation between the structures can be controlled by light and heat. The electron‐donating components of the dendralenes are represented by bromothienyl (in 13 ) and ethylenedioxythiophene(EDOT)‐thienyl (in 15 ) end‐groups. The most facile transformation involves the isomerisation of donor–acceptor conjugated systems ( a conformers) into structures in which only the thiophenes are conjugated ( b conformers), and this process is driven by ambient light. The structures of the two conformers of compound 13 are confirmed by single‐crystal X‐ray diffraction studies and the structural changes in both compounds have been monitored by ¹H NMR spectroscopy and absorption studies. The transformations were found to be first‐order processes with rate constants of k=0.0027 s^?1 and k=0.00022 s^?1 for 13 and 15 , respectively. Density functional theory calculations at the B3LYP/6‐31G* level give credence to the proposed mechanism for the a → b conversion, which involves photoinduced intramolecular charge transfer (ICT) as the key step. The EDOT derivative ( 15 ) can be polymerised by electrochemical oxidation and a combination of cyclic voltammetry and UV/Vis spectroelectrochemical experiments indicate that the a conformer can be trapped and stabilised in the solid state.     

Structure and Reactivity of Five- and Six-Ring N,N-, N,O-, and O,O-acetals: A lesson in allylic 1, 3-strain (A1, 3 strain)

The X-ray structures of fifteen 1, 3-imidazolidine, 1, 3-oxazolidine, 1, 3-dioxan-4-one, and hydropyrimidine-4(1H)-one derivatives are described (Table 2) and compared with known structures of similar compounds (Figs. 1–20). The differences between structures containing exocyclic N-acyl groups and those lacking this structural element arise from the A^1,3 effect of the amide moieties. Even t-Bu groups are forced into axial positions of six-ring half-chair or into flag-pole positions of six-ring twist-boat conformers by this effect (Figs. 16–20). In the N-acylated five-membered heterocycles, a combination of ring strain and A^{1, 3} strain leads to strong pyramidalizations of the amide N-atoms (Table 1) such that the acyl groups wind up on one side and the other substituents on the opposite side of the rings (Figs. 4–9 and Scheme 3). Thus, the acyl (protecting!) groups strongly contribute to the steric bias between the two faces of the rings. Observed, at first glance surprizing stereoselectivities of reactions of these heterocycles (Schemes 1 and 2) are interpreted (Scheme 3) as an indirect consequence of the amide A^{1, 3} strain effect. The conclusions drawn are considered relvant for a better understanding of the ever increasing role which amide groups play in stereoselective syntheses.     

CASSCF and CASPT2 calculations on the cleavage and ring inversion of bicyclo[2.2.0]hexane find that these reactions involve formation of a common twist-boat diradical intermediate.

(6/6)CASSCF and CASPT2/6-31G calculations have been performed to understand the experimental finding of Goldstein and Benzon (J. Am. Chem. Soc. 1972, 94, 5119) that exo-bicyclo[2.2.0]hexane-d(4) (1b) undergoes ring inversion to form endo-bicyclo[2.2.0]hexane-d(4) (4b) faster than it undergoes cleavage to form cis,trans-1,5-hexadiene-d(4) (3b). Goldstein and Benzon also found that the latter reaction, which must occur via a chairlike transition structure (TS), is much faster than cleavage of 1b to trans,trans-1,5-hexadiene-d(4) (2b) via a boatlike TS. Our calculations reveal that all three of these reactions involve ring opening of 1, through a boat diradical TS (BDTS), to form a twist-boat diradical intermediate (TBDI). TBDI can reclose to 4 via a stereoisomeric boat diradical TS (BDTS'), or TBDI can cleave, either via a half-chair diradical TS (HCDTS) to form 3 or via a boat TS (BTS) to form 2. The calculated values of DeltaH(++) = 34.6 kcal/mol, DeltaS(++) = -1.6 eu, and DeltaH(++) = 35.2 kcal/mol, DeltaS(++) = 2.0 eu for ring inversion of 1 to 4 and cleavage of 1 to 3, respectively, are in excellent agreement with the values measured by Goldstein and Benzon. The higher value of DeltaH(++) = 37.6 kcal/mol, computed for cleavage of TBDI to 2, is consistent with the experimental finding that very little 2b is formed when 1b is pyrolyzed. The relationships between BDTS, HCDTS, and BTS and the chair and boat Cope rearrangement TSs (CCTS and BCTS) are discussed.     

Nitrogen bridgehead compounds,Part 31 1H and 13C NMR study of tetra- and octahydro-11H-pyrido[2,1-b]quinazolin-11-ones

Conformational analysis of some tetra-and octahydro-11H-pyrido[2,1-b]quinazolin-11-ones 1-3 by ¹H and ¹³C nmr revealed that the 9-methyl-6,7,8,9-tetrahydro derivative exists mainly in the conformation containing the methyl group in a quasi-axial orientation. Of the 1,2,3,4,5,6,7,8-octahydro compounds, the 9-methyl derivative 3e contains the methyl group in a quasi-axial position, while that in the 7-methyl and the 8-methyl derivatives 3c,d is in the equatorial position, and the 6-methyl derivative 3b is a mixture of the two conformers.