Si può desiderare di provare un trattamento naturale disfunzione erettile come un diverso per i problemi di costruzione. Al giorno d oggi ci sono diverse terapie sul mercato, ma un trattamento naturale disfunzione erettile è stato confermato qualche ora e ora di nuovo per dare risultati efficienti e permanenti. Cos è la disfunzione sessuale? L incapacità di sviluppare o sostenere una costruzione abbastanza lungo per fare l amore è chiamato disfunzione erettile, ED https://farmacia-senzaricetta.it/ o (maschio) problemi di erezione. Tutti gli uomini possono avere problemi di costruzione di volta in volta e gli scienziati considerano ED essere presenti se si verificano problemi di costruzione almeno il 25% del tempo. Alcuni fatti duri: ED Può essere dovuto a problemi emotivi. Stress, pressione, giltiness, depressione, bassa autostima e ansia prestazioni può essere la causa dei vostri problemi di costruzione. La ricerca ha confermato che il 90 per cento della disfunzione erettile è fisica in origine, non emotiva. L impotenza colpisce la maggior parte degli uomini durante la loro vita e può essere dovuto a troppo colesterolo, problemi cardiaci, diabete, ipertensione, fumo o alcol. Alcuni rimedi possono essere la ragione. Le questioni legate al movimento sono collegate. Se ti occupi dei tuoi problemi di movimento, hai piu possibilita di risolvere questo problema. Qui ci sono 5 consigli facili su come aumentare la circolazione: 1. Mangia i pasti giusti. Questo ti rendera il flusso sanguigno ovvio. Una grande parte di rimanere sani e anche mantenere il flusso sanguigno ovvio è legato al vostro piano di alimentazione quotidiana e quello che si mangia. Una buona cura per la disfunzione erettile è mangiare un piano a basso contenuto di grassi e grande alimentazione di fibre. Mangiare fibre tutti i giorni e questo viene scoperto in prodotti cerealicoli cereali integrali, frutta e verdura. Evitare il più possibile pasti pronti o pasti non sani. 2. Wonder herbal rimedi. Molti rimedi vegetali per ED eseguire bene come possono migliorare il movimento. Hanno molto meno reazioni avverse rispetto ai farmaci convenzionali e si svolgono in modo efficiente per migliorare hardons e la forza, troppo. Erbe naturali come Ginkgo Biloba sono utilizzati come una strategia per ED. Gli specialisti di erboristeria credono anche che le spezie o le erbe come noce moscata, portano al movimento intorno al corpo, tra cui il pene. 3. Vitamine naturali vitali. Gli scienziati sanitari hanno scoperto che una mancanza di supplemento è tipico tra gli uomini con ED in particolare vitamina A. Se si ha una mancanza del nutriente ossido di zinco, Questo è stato confermato per portare alla disfunzione erettile. Queste inadeguatezze derivano dal fatto che molti valori nutrizionali in quello che mangiamo piano non sono sufficienti. Aggiungere al vostro fabbisogno di nutrienti aumenterà la circolazione del sistema e migliorare questa condizione. Gli integratori alimentari sono completamente naturali, quindi non dovrete preoccuparvi dei rischi di reazioni avverse. Inoltre, queste vitamine naturali sono utili per il vostro benessere over-all. Oltre a questi vantaggi benessere, disfunzione erettile vitamine naturali e integratori costano molto meno di farmaci rimedi. 4. Esercitare. Fai una mossa e non un tablet vibrante. Camminare farà di più per migliorare e sostenere hardons di qualsiasi altra compressa chimica nel lungo periodo. Il fitness fisico manterrà bassi livelli di pressione e mantenere grandi stadi di movimento. Andando per un 20-30 minuti di movimento rapido ogni giorno, può affrontare questo problema e può sostenere la vostra libido senza l uso di qualsiasi farmaco. 5. Sottolineare. Questo è il peggior attaccante per problemi di erezione. Scopri diversi metodi per riposare. Alcuni metodi tipici per riposare includono la lettura di un libro, la meditazione, un bagno rilassante o allenamenti di respirazione. Sto solo imparando alcuni semplici allenamenti di respirazione che possono migliorare significativamente il movimento nel reparto pantaloni. Una naturale disfunzione erettile soluzioni di trattamento stanno diventando sempre più popolare con gli uomini. Questi rimedi a base di erbe sono preferiti perché non hanno reazioni avverse e sono confermati essere efficiente come il farmaco. La maggior parte degli uomini combattere parlano dei loro problemi, in particolare la disfunzione erettile come c è poca discussione sui problemi di erezione. La verita e che ED ha un impatto su piu di dieci milioni di uomini solo negli Stati Uniti. Non siete soli e l aiuto è disponibile.

Tmsch₂li and tmsch₂lilidmae: efficient reagents for noncryogenic halogenlithium exchange in bromopyridines

TMSCH2Li and TMSCH2Li-LiDMAE: Efficient
SCHEME 1.
Metal-Halogen Exchanges Reported in the
Reagents for Noncryogenic Halogen-Lithium
Literature
Exchange in Bromopyridines
Abdelatif Doudouh,† Christopher Woltermann,‡ and Synthe`se Organome´tallique et Re´actiVite´, UMR CNRS 7565, Nancy UniVersite´, UniVersite´ Henri Poincare´, BouleVard des Aiguillettes, 54506 VandoeuVre-le`s-Nancy, France, and FMC Corporation, Lithium DiVision, Highway 161, Box 795, Bessemer City, North Carolina 28016 SCHEME 2.
Metalation of Electrophilic Halogenopyridines
with TMSCH2Li-LiDMAE
or -78 °C), solvent (toluene), as well as dilution was neededto avoid C-2 to C-5 isomerization and degradation (Scheme 1,eq 2).
An alternative to this sensitive lithiation process has been reported recently by Song,6 who realized the magnesium halogenexchange at C-2 under noncryogenic conditions (0 °C) using TMSCH2Li and TMSCH2Li-LiDMAE have been used i-PrMgCl in THF. The reaction proceeded smoothly allowing efficiently for bromine-lithium exchange in 2-bromo-, the preparation of a range of C-2-substituted derivatives.
3-bromo-, and 2,5-dibromopyridines under noncryogenic However, since the magnesation of 2,5-dibromopyridine was conditions, while low temperatures (-78 to -100 °C) are known to occur mainly at C-5,7 the authors had to exchange always needed with n-BuLi. The aminoalkoxide LiDMAE bromine at C-2 for iodine to direct the reaction toward the induced a remarkable C-2 selectivity with 2,5-dibromopyr- desired position, thus implying an additional step and added idines in toluene at 0 °C, which was unprecedented at such expense to the transformation (Scheme 1, eq 3).
a temperature. The lithiopyridines were successfully reacted Thus, the search for new reagents able to promote the clean with electrophiles also under noncryogenic conditions giving bromine-lithium exchange in pyridines under easily applicable the expected adducts in good yields.
Recently, we have reported a new lithiating agent TMSCH2- Li-LiDMAE (with LiDMAE ) Me2N(CH2)2OLi)8-10 which Metal-halogen exchange in 2,5-dibromopyridine 3 has been
promoted the clean C-6 deprotonation of chloropyridines and the subject of much attention motivated by the usefulness of even of the highly sensitive fluoropyridines at 0 °C when used this doubly reactive intermediate for the synthesis of ligands1,2 in hexane (Scheme 2).8 This unprecedented reactivity contrasted and biologically active compounds.3 First studies by Parham4 with those of our previous reagent BuLi-LiDMAE for which and further developments by other groups1,2 clearly established low temperatures (-78 to -100 °C) were needed to prevent that the C-5 position could be lithiated selectively with n-BuLi in THF at -78 or -100 °C (Scheme 1, eq 1).
This high level of functional tolerance at 0 °C led us to In contrast, Wang5 reported the control of the C-2 lithiation consider TMSCH2Li for the selective bromine-lithium ex- to be more problematic. Due to the instability of 2-lithio-5- change in 2,5-dibromopyridine under noncryogenic condi- bromopyridine, careful attention to reaction temperature (-50 (6) Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake, C. H. Org. Lett. 2004, 6, 4905.
(1) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber. 1992,
(7) Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G. Tetrahedron Lett. 1999, 40, 4339.
(2) Romero-Salguero, F. J.; Lehn, J.-M. Tetrahedron Lett. 1999, 40, 859.
(8) Doudouh, A.; Gros, P. C.; Fort, Y.; Woltermann, C. Tetrahedron (3) Nicolaou, K. C.; Sasmal, P. K.; Rassias, G.; Reddy, M. V.; Altmann, 2006, 62, 6166.
K.-H.; Wartmann, M.; O’Brate, A.; Giannakakou, P. Angew. Chem., Int. (9) Gros, P. C.; Doudouh, A.; Woltermann, C. Chem. Commun. 2006,
Ed. 2003, 42, 3515.
(4) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257.
(10) Gros, P. C.; Doudouh, A.; Woltermann, C. Org. Biomol. Chem. (5) Wang, X.; Rabbat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J. J.; 2006, 4, 4331.
Reider, P. J. Tetrahedron Lett. 2000, 41, 4335.
(11) Choppin, S.; Gros, P. C.; Fort, Y. Org. Lett. 2000, 2, 803.
10.1021/jo070620j CCC: $37.00 2007 American Chemical Society J. Org. Chem. 2007, 72, 4978-4980
TABLE 1. Bromine-Lithium Exchange in 1 and 2 with
TABLE 2. Metalation of 3 with TMSCH2Li-Based Reagentsa
TMSCH2Lia
1b
2b
1a, 94c
1a, 70d
1a, 47d
2a, 88c
Reaction performed on 1.84 mmol of 3. b GC yields. S.M.: starting
1b, 86c
2b, 88c
a Reaction performed on 1.84 mmol of 1 or 2. b Isolated yield. c The
SCHEME 4.
Proposed Intermediate for Stabilization of
GC analysis revealed conversions >98%. d The remainder was unreacted 5-Bromo-2-lithiopyridine
SCHEME 3.
Proposed Pathway for TMSCH2Li
Consumption
Since no data was available about the reactivity of TMSCH effects. The metalation mixtures were quenched with MeOH Li in such halogen-metal exchange reaction, we first investi- gated its behavior at 0 °C toward 2- and 3-bromopyridine in As shown, in toluene, which was the best solvent reported hexane (Table 1). Bromine-lithium exchange in such substrates for selective C-2 lithiation with n-BuLi at -78 °C,5 TMSCH2- was known to need very low temperature (-78 to -100 °C) Li led to a mixture of 1 and 2 at 0 °C. Extended reaction time
with n-BuLi in THF to avoid dimerization, side deprotonation led to C-2 to C-5 isomerization and degradation of 3 (entries 1
and subsequent aryne formation with the latter.12 exchange at 0 °C very cleanly with the two substrates. The lation with a small amount of C-5 metalation (entry 3). The exchange product was obtained exclusively in high yield. In effect of TMSCH2Li-LiDMAE on the reaction outcome was particular, no product resulting from side deprotonation of 2
also examined. In hexane, the aminoalkoxide induced a complete was detected. The yields decreased proportionally to the amount conversion but a loss in selectivity was noted. The effect of incorporating LiDMAE was remarkable in toluene leading to 2Li, and 2 equiv of TMSCH2Li were necessary for completion of the exchange. An explanation is the formation the C-2 metalation in 95% yield with only 4% of the other isomer after 30 min at 0 °C. Extended reaction time did not produce notable isomerization of the lithiated species (entries present in NMR spectra and GC analysis of the crude mixtures The effect of coordinating solvents was also examined (entries The metalation and the electrophilic condensation step were 8 and 9) to attempt the metalation of the C-5 position. In THF, realized in the same solvent and at similar temperatures. Large only degradation was observed while diethyl ether led to the excesses of electrophiles were not necessary despite the use of expected C-5 lithiation in 65% yield.
2Li-LiDMAE was, to our knowledge, the first reagent to regioselectively lithiate 2,5-dibromopyridine at 0 °C.
The selectivity could be explained by chelation of 2-lithio intermediate by LiDMAE ensuring stabilization and preventing 2Li was found to be practical and selective for the bromine-lithium exchange in monobromopyridines at 0 °C.
the C-2 to C-5 isomerization (Scheme 4). The reason for a lower This result was strongly encouraging for trying it in the selective selectivity in hexane remains unclear but could be due to a C-2 lithiation of 2,5-dibromopyridine 3. The reaction was
slower formation of the 2-lithiopyridine in this less polar solvent.
investigated under various conditions with focus on solvent The synthetic usefulness of this new lithiation process was then finally illustrated by reaction with a set of electrophilicreagents (Table 3). All of the electrophiles reacted efficiently (12) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43,
providing the expected products in good yields comparable with J. Org. Chem, Vol. 72, No. 13, 2007 4979
TABLE 3. Reaction with Electrophilic Reagentsa
reasonable amounts of electrophiles (20-50% excess compared
to 3) despite the use of 2 equiv of TMSCH2Li, and the
condensation step could be realized efficiently at 0 or -20 °C
in toluene.
In summary, we have discovered a new reactivity of TMSCH2Li and TMSCH2Li-LiDMAE reagents. These reagentsare suitable for selective bromine-lithium exchange and subse-quent functionalization of several bromopyridines in apolarsolvents. The effect of LiDMAE on the selectivity in bromine-lithium exchange of 2,5-dibromopyridine is remarkable. Thetransformation proceeds under noncryogenic conditions con-suming only small excesses of electrophiles opening access toa potentially scalable process.
Experimental Section
Procedure for Bromine-Lithium Exchange in 2,5-Dibro-
mopyridine. To a solution of 2-dimethylaminoethanol (164 mg,
1.84 mmoles) in toluene (6 mL) cooled at 0 °C was added dropwise
(trimethylsilyl)methyllithium (5.52 mmol, 6 mL of a 0.92 M
solution in hexane) under a nitrogen atmosphere. After being stirred
for 30 min at the same temperature, a solution of 2,5-dibromopyr-
idine (436 mg, 1.84 mmoles) in toluene (2 mL) was added dropwise.
The obtained red solution was then stirred for 30 min at 0 °C and
treated dropwise with a solution of the appropriate electrophile (2.2
or 2.76 mmol) in toluene (2 mL) at 0 or -20 °C. After 1 h of
stirring, the mixture was hydrolyzed with water (10 mL). The
organic layer was then extracted with diethyl ether (10 mL) and
dried over MgSO4, and the solvents were evaporated. The crude
product was subjected to GC analysis and finally purified by column
chromatography using hexane-AcOEt mixtures as eluent.
Acknowledgment. We thank the FMC Corporation (Lithium
a Reaction performed on 1.84 mmol of 3. b Isolated yield after column
chromatography. The conversions were >97% in each case.
Supporting Information Available: Experimental details and
characterization data for all compounds. This material is availablefree of charge via the Internet at http://pubs.acs.org.
those obtained using BuLi at low temperatures (-78 °C)5 orby the magnesation process.6 The quenching step consumed 4980 J. Org. Chem., Vol. 72, No. 13, 2007

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