Nonplanar cyclobutane. Steric product control in the deamination of cis- and trans-3-methylcyclobutylamine

Lillien, Irving; Handloser, L.

doi:10.1021/jo01262a059

Cited by 9 publications

(3 citation statements)

References 5 publications

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“…(±)-a-2-(2-Hydroxyethylamino)-5-[l-(indol-3-yl)ethyl]-A2-thiazolin-4-one (24). Evaporation of the solvent gave an oil which, after chromatography on silica gel eluted with 10% methanol in ethyl acetate and trituration with hot chloroform, yielded 13% of the crystalline thiazolinone 24: mp 195-197 °C; TLC RfO.03; iw (KBr) 1670 (C=0), 1580 cm"1 (C=N); NMR (Me2SO-d6) 1.20 (d, 3, J = 7 Hz, CHCH3), 3.1-3.7 (m, 4, CH2CH2), 3.85 (m, 1, CHCH3), 4.75 (d, 1, J = 3 Hz, CHS), 4.80 (s, 1, D20 exchangeable, OH), 6.8-7.7 (m, 5, aromatic), 9.27 (s, br, 1, D20 exchangeable, N/íCH2), 10.86 (s, 1, D20 exchangeable, (±)-a-2-(2-JV,lV-Dimethylaminoethylamino)-5-[l-(indol-3-yl)ethyl]-A2-thiazolin-4-one Hydrochloride (25). The white solid which separated from the original reaction mixture was collected and recrystallized from ethanol to yield 22% (0.40 g) of crystalline thiazolinone hydrochloride 25: mp 208-209 °C; TLC /0.11; iw (KBr) 3400, (br, NH), 1700 (0=0), 1620 cm"1 (C=N); NMR (Me2SO-d6) 1.27 (d, 3, J = 7.0 Hz, CHCH3), 2.75 [s, 6, N(CH3)2], 3.23 (m, 2, NHCHj), 3.97 (m, 3, CH2N+ and CHCH3), 4.92 (d, 1, J = 4.0 Hz, CH-S), 6.8-7.7 (m, 5, aromatic), 9.5 (s, br, 1, D20 exchangeable, NfíCH2), 11.05 (s, 1, D20 exchangeable, indole NH).…”

Section: Methodsmentioning

confidence: 99%

Thiazolinone analogs of indolmycin with antiviral and antibacterial activity

Harnden¹,

Bailey²,

Boyd³

et al. 1978

J. Med. Chem.

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Total synthesis of a series of thiazolinone and thiazolidinone analogues of the antibacterial oxazolinone antibiotic indolmycin is described. The synthetic route involves nucleophilic displacement of mesyloxy and chloro groups from methyl 2-substituted-3-(indol-3-yl)propionates 3 and 4 and butyrate 19 with N-substituted thioureas. The formation of the rearranged chloro esters 29, 43, and 44 from beta(RS,RS)-methyl indolmycenate (27), alpha(RS,SR)-methyl 2-hydroxy-3-(2-methylindol-3-yl)butyrate (39), and alpha-methyl 2-hydroxy-3-(indol-3-yl)valerate (41) supports a reaction mechanism involving neighboring group participation by the indole C-3 carbon during nucleophilic displacement on the beta-carbon of a C-3 substituent. Structure-activity relationships are discussed. Although neither indolmycin nor its diastereoisomer isoindolmycin is antiviral, 2-monoalkylaminothiazolinone analogues have in vitro activity against both RNA viruses and bacteria. The most active compound is the sulfur isostere of indolmycin, and only the levorotatory enantiomer 46, with the same absolute stereochemistry as natural indolmycin, has antimicrobial activity.

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Section: Methodsmentioning

confidence: 99%

Thiazolinone analogs of indolmycin with antiviral and antibacterial activity

Harnden¹,

Bailey²,

Boyd³

et al. 1978

J. Med. Chem.

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“…Cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) cations (C 4 H 7 + ) have been of great scientific interest since Roberts’ 1951 report that cyclobutyl and cyclopropylcarbinyl electrophiles solvolyze quickly to the same mixture of cyclobutyl, cyclopropylcarbinyl, and homoallyl products, hinting at a common, stabilized intermediate . After many years of scientific debate, the C 4 H 7 + intermediates are now understood as a mixture of triply degenerate σπ-bisected cyclopropylcarbinyl (CPC) I and nonclassical bicyclobutonium (BCB) II cations (Figure A), − the latter being the more stable structure (by 1.8 kcal/mol from MP2 calculations). − Solvolysis experiments of substituted cyclobutyl or cyclopropylcarbinyl electrophiles provide complex product mixtures in which the major component seems difficult to predict, even for simple substitution patterns (Figure B). − Nevertheless, over the years multiple synthetic approaches have reported CPC/BCB and cyclobutyl (CB) cations as intermediates toward cyclopropylcarbinyl, − cyclobutyl, , and homoallyl (HA) products. ,, Such cations have also been proposed as intermediates in the biosynthesis of various terpenes, using Density Functional Theory (DFT) calculations as support. − …”

Section: Introductionmentioning

confidence: 99%

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations

Larmore,

Champagne

2024

J. Org. Chem.

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The cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) structures of the C 4 H 7 + cation have been proposed as intermediates in various reactions forming cyclopropylcarbinyl, cyclobutyl, or homoallyl products. While these cations can react with nucleophiles stereospecifically, in each system there are usually multiple BCB/CPC cations in equilibrium with related cyclobutyl (CB) and homoallyl (HA) cations, from which stereospecificity is jeopardized. Using density functional theory (DFT) and DLPNO−CCSD(T) calculations, we studied the electronic and steric effects on the equilibria between mono-and polysubstituted C 4 H 7 + cations. We find that the shapes of the potential energy surfaces (PESs) vary significantly, with structures that are minima for a given substituent becoming high-energy transition structures for another. Electron-donating groups at C1, C2, or C3/C4 positions favor CPC, BCB/CB, and HA structures, respectively. Electron-withdrawing groups yield shallower PESs where multiple related structures are energetically accessible. Strong Hammett correlations (σ + ) are observed for the substituent effects, which appear to be additive. In addition, BCB cations with more substituents are energetically destabilized compared to CPC cations, except with donating substituents at the C2 position. This work allows predictions of the major structures expected in mixtures of CPC/BCB/ CB/HA cations for given substituent patterns, and of the major products produced from such cations.

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“…[5][6][7] Solvolysis experiments of substituted cyclobutyl or cyclopropylcarbinyl electrophiles provided complex product mixtures in which the major component seems unpredictable, even for simple substitution patterns (Figure 1B). [8][9][10][11][12][13][14][15][16][17][18][19][20] Nevertheless, over the years multiple synthetic approaches have reported CPC/BCB and cyclobutyl (CB) cations as intermediates toward cyclopropylcarbinyl, [21][22][23][24][25] cyclobutyl, 26,27 and homoallyl (HA) products. 22,28,29 Such cations have also been proposed as intermediates in the biosynthesis of various terpenes, using DFT calculations as support.…”

mentioning

confidence: 99%

Substituent effects on the equilibria between cyclopropylcarbinyl, bicyclobutonium, homoallyl, and cyclobutyl cations

Larmore,

Champagne

2023

Preprint

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The cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) structures of the C4H7+ cation have been proposed as intermediates in various synthetic transformations forming cyclopropylcarbinyl, cyclobutyl, or homoallyl products. It has recently been recognized that such cations, when generated from chiral electrophiles, are themselves chiral and can react with nucleophiles stereospecifically. However, the CPC and BCB cations are in equilibrium with each other and with other related structures such as the cyclobutyl (CB) and homoallyl (HA) cations, from which stereospecificity is not guaranteed. Currently, the effect of substitution on the composition of cation mixtures containing CPC/BCB/CB/HA cations is not understood, precluding the prediction and control of the major products generated from such cations. Using Density Functional Theory and DLPNO-CCSD(T) calculations, we have studied the electronic and steric effects on the equilibria between mono- and polysubstituted C4H7+ cations. Our results indicate that electron-donating groups at the C1 position favor CPC structures, while BCB/CB structures are favored for the C2 position and HA structures for the C3/C4 positions. Electron-withdrawing groups yield shallower potential energy surfaces where many related structures are energetically accessible. Strong Hammett correlations (σ+) are observed for the various substituent effects, which appear to be additive in nature. In addition, BCB cations with more substituents are energetically destabilized compared to CPC cations, except with donating substituents at the C2 position. This work provides a predictive model for the major structures observed in mixtures of CPC/BCB/CB/HA cations, for given substituent patterns.

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Nonplanar cyclobutane. Steric product control in the deamination of cis- and trans-3-methylcyclobutylamine

Cited by 9 publications

References 5 publications

Thiazolinone analogs of indolmycin with antiviral and antibacterial activity

Thiazolinone analogs of indolmycin with antiviral and antibacterial activity

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations

Substituent effects on the equilibria between cyclopropylcarbinyl, bicyclobutonium, homoallyl, and cyclobutyl cations

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