- Synthesis of electron-rich sterically hindered P1 phosphazene bases by the staudinger reaction
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The synthesis of electron-rich P1 phosphazene bases with a sterically protected basic center by a Staudinger reaction is reported. The initial products of the reaction between peralkylated triaminophosphanes and bulky alkyl azides, phosphazides 1a-f, were isolated in all cases in good to quantitative yield. The structures of 1d and 1e were confirmed by single-crystal X-ray diffraction. Acidic hydrolysis of pyrrolidino-substituted phosphazide (pyrr)3PN3tBu 1d led to the quantitative formation of aminophosphonium salt (pyrr)3PNH2+· BF4- 8, a direct precursor to a Schwesinger's "building block" synthetic unit. Thermally induced denitrogenation of the phosphazides, which is the second step performed in most cases under solvent-free conditions gave P1 phosphazene bases 2a-f in moderate to excellent yields. A "one-pot" two-step synthesis of phosphazene bases from commercially available triaminophosphanes was discovered. Most of the syntheses were performed on a large laboratory scale. The basicities of the newly synthesized bases 2e and 2f were determined. X-ray crystal structures were obtained for base 2e and for protonated species 2d·HBF4, 2e·HBF4, and 2f·HOTs, which provided the crucial geometrical parameters around the basic center. A rationale for the higher basicity of the pyrrolidino- (pyrr)3P=NR than the piperidino- (pip)3P=NR phosphazenes is presented. A Staudinger reaction was successfully used for the synthesis of a number of sterically congested electron-rich P1 phosphazene bases in moderate to quantitative yield. The intermediate phosphazides were isolated and characterized in all cases; their application in the preparation of higher-order phosphazenes is described. Copyright
- Alexandrova, Anastasia V.,Masek, Tomas,Polyakova, Svetlana M.,Cisarova, Ivana,Saame, Jaan,Leito, Ivo,Lyapkalo, Ilya M.
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p. 1811 - 1823
(2013/04/10)
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- Convenient synthesis of non-conjugated alkynyl ketones from keto aldehydes by a chemoselective one-pot nonaflation - Base catalyzed elimination sequence
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Keto aldehydes were selectively converted to non-conjugated alkynyl ketones possessing an unsubstituted alkyne terminus using one-pot nonaflation - base catalyzed elimination reaction sequences. Consecutive one-pot nonaflation of keto aldehydes with perfluorobutane-1-sulfonyl fluoride and elimination of the nonaflyl group using the P1 phosphazene base resulted in the formation of a terminal CC triple bond with the keto group remaining intact. Careful optimization of the reaction conditions enabled a highly chemoselective conversion of the aldehyde function in the presence of unprotected keto groups exploiting a minor difference in acidity of their α-hydrogen atoms. Scope and limitations of the protocol as well as possible implementation of these substrates in Sonogashira coupling were explored.
- Boltukhina, Ekaterina V.,Sheshenev, Andrey E.,Lyapkalo, Ilya M.
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experimental part
p. 5382 - 5388
(2011/08/06)
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- Solid-phase chemical synthesis of phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides
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Phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides were prepared via a solid-phase synthesis strategy. Under Reformatsky reaction conditions, novel esterified acetic acid phosphinodiamidites were synthesized and condensed with appropriately protected 5′-O-(4, 4′-dimethoxytrityl)-2′-deoxynucleosides to yield 3′-O-phosphinoamidite reactive monomers. These synthons when activated with tetrazole were used with an automated DNA synthesizer to prepare phosphonoacetic acid modified internucleotide linkages on controlled pore glass. The phosphinoacetate coupling products were quantitatively oxidized at each step with (1S)-(+)-(10-camphorsulfonyl)oxaziridine or 3H-1,2-benzodithiol-3-one-1,1-dioxide to produce mixed sequence phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides with an average per cycle coupling efficiency of greater than 97%. Completely deprotected, modified oligodeoxynucleotides were purified by reverse-phase HPLC and characterized by ion exchange HPLC, 31P NMR, and MALDI/TOF mass spectroscopy. Both analogues were stable toward hydrolysis with snake venom phosphodiesterase and stimulated RNase H1 activity.
- Dellinger, Douglas J.,Sheehan, David M.,Christensen, Nanna K.,Lindberg, James G.,Caruthers, Marvin H.
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p. 940 - 950
(2007/10/03)
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- Synthesis of phosphorodithioate DNA via sulfur-linked, base-labile protecting groups
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Phosphorodithioate DNA, a new and potentially useful DNA analog with a deoxynucleoside-OPS2O-deoxynucleoside internucleotide linkage, was synthesized from deoxynucleoside 3'-phosphorothioamidites having a variety of thioesters and thiocarbonates as base-labile phosphorus protecting groups. The major challenge in the synthesis of this DNA analog was to derive a reaction pathway whereby activation of deoxynucleoside 3'-phosphorothioamidites occurred rapidly and in high yield under conditions that minimize Arbuzov rearrangements, exchange reactions, unwanted oxidation to phosphorothioates, and several other side reactions. Of the various phosphorus protecting groups examined for this purpose, a thorough evaluation of these parameters led to the conclusion that β-(benzoylmercapto)ethyl was preferred. Synthesis of phosphorodithioate DNA began by preparing deoxynucleoside 3'-phosphorothioamidites from the appropriately protected deoxynucleoside, tris(pyrrolidino)phosphine, and ethanedithiol monobenzoate via a one-flask synthesis procedure. These synthons were activated with tetrazole and condensed with a deoxynucleoside on a polymer support to yield the deoxynucleoside thiophosphite. Subsequent steps involved oxidation with sulfur to generate the completely protected phosphorodithioate triester, acylation of unreacted deoxynucleoside, and removal of the 5'-protecting group. Yields per cycle were usually 97-98% with 2-5% phosphorothioate contamination as determined by 31P NMR. By using deoxynucleoside 3'-phosphorothioamidites and deoxynucleoside 3'-phosphoroamidites, deoxyoligonucleotides having phosphorodithioate and the natural phosphate internucleotide linkages in any predetermined order can also be synthesized.
- Wiesler,Caruthers
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p. 4272 - 4281
(2007/10/03)
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- N-pyrrolyl phosphines: An unexploited class of phosphine ligands with exceptional π-acceptor character
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The coordination chemistry of N-pyrrolyl phosphines (P-NC4H4) is described. These ligands are prepared in excellent yield from pyrrole, a phosphorus halide, and base, and this synthesis has been applied to the series PPhx(pyrrolyl)3-x (x = 0-2) and the chelate (pyrrolyl)2P(CH2)2P(pyrrolyl)2. These ligands readily form coordination complexes, and the complexes trans-RhCl(CO)[PPhx(pyrrolyl)3-x]2 (x = 0-2) and Mo(CO)4[(pyrrolyl)2P(CH2) 2-P(pyrrolyl)2] are described. The carbonyl stretching frequencies of these complexes are shifted to significantly higher energy relative to "traditional" phosphine ligands, indicating that N-pyrrolyl phosphines are poor σ-donors, exceeding phosphites and approaching fluoroalkylphosphines with respect to this property. For example, νCO for trans-RhCl(CO)-[P(pyrrolyl)3]2 exceeds that of the PPh3 analogue by 59 cm-1. That these ligands are π-acceptors is suggested by the single crystal X-ray structure of trans-RhCl(CO)[P(pyrrolyl)3]2 which shows shortened Rh-P distances and a lengthened Rh-C distance, consistent with enhanced Rh to P back-bonding. The X-ray structure of trans-RhCl(CO)-[P(pyrrolidinyl)3]2 is also reported; this complex possesses longer Rh-P distances which more closely resemble those found for other complexes of this type. The exceptional π-acceptor character of these ligands is convincingly demonstrated by their substitution chemistry with electron rich [PPN][Rh(CO)4]. P(pyrrolyl)3 is found to displace CO in a stepwise manner to give the entire series [PPN][Rh(CO)4-x{P(pyrrolyl)3}xr] (x = 1-4). Similar results are obtained with (pyrrolyl)2P(CH2)2P(pyrrolyl)2, and the anions [PPN][Rh(CO)x{(pyrrolyl)2P(CH2) 2P(pyrrolyl)2}y] (x = 2, y = 1; x = 0, y = 2) are reported. An X-ray structure analysis of [PPN][Rh(CO){P(pyrrolyl)3}3] shows that the Rh-P bonds in this tetrahedral anion are shorter than those found in the Rh(I) complex, consistent with significantly greater π back-bonding in this more electron rich system. The infrared spectra of these anions again show a substantial shift in νCO to higher frequency relative to other phosphine ligands. The structural results further indicate that PPhx(pyrrolyl)3-x (x = 0-2), PPh3, and P(pyrrolidinyl)3 possess nearly identical steric properties (cone angles). The wide range of electronic properties (π-acceptor/σ-donor) exhibited by this isosteric series, together with their ready availability, suggests that they, and N-pyrrolyl phosphines in particular, may find utility in physical inorganic and organometallic chemistry.
- Moloy, Kenneth G.,Petersen, Jeffrey L.
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p. 7696 - 7710
(2007/10/02)
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- Thioacylation Achieved by Activation of a Monothiocarboxylic Acid with Phosphorus Reagents
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A selection of phosphorus-based coupling reagents have been tested for their ability to activate the ambident nuceophilic monothio acid group as a thiocarbonyl functionality, suitable for use in thioacylations for the formation of thioamides.For these studies the reaction between thioacetic acid and cyclohexylamine to give the corresponding thioamide was chosen as a model.The obtained O/S-selectivities were monitored by the use of 31P NMR and were found to be dependent on the nature of the phosphorus functinality and on the kind of leaving group involved.Several new analogues of the widely used peptide coupling reagent (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP, 1a) were prepared and investigated.Best results were obtained with two new analogues of PyBOP: tris(pyrrolidino)phosphonium hexafluorophosphate (PyNOP, 1b) and oxy>tris(pyrrolidino)phosphonium hexafluorophosphate (PyFOP, 1c).Both reagents, containing electron-withdrawing substituents at the benzotriazole ring, secured fast activation of the monothio acid.Other phosphorus reagents, such as bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP, 1d), gave an undesired O/S-selectivity, leading to the formation of oxoamides and phosphorus sulfides.
- Hoeg-Jensen, Thomas,Olsen, Carl Erik,Holm, Arne
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p. 1257 - 1263
(2007/10/02)
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- A CONVENIENT AND HIGH YIELD SYNTHESIS OF TERTIARY (AMINO) PHOSPHINES BY TRANSAMINATION ROUTE
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Tris(diethylamino)phosphine affords tertiary (amino) phosphines of pyrrolidine, piperidine, hexamethyleneimine, morpholine and N-methylpiperazine in nearly quantitative yields by transamination route - an easy and convenient synthesis occuring under mild conditions.
- Hussain, L. Altaf,Elias, Anil J.,Rao, M. N. Sudheendra
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p. 5983 - 5986
(2007/10/02)
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