An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• Knoevenagel adduct 2.12 and methyl butynoate 2.13 (Scheme 25) [68]. The reaction is reported to progress in high regioselectivity (>50:1) albeit in moderate isolated yield. Following debenzylation of the Diels–Alder product a selective allylic bromination was achieved again in good selectivity (>80:20

• in xylenes undergoes ring-closure yielding the desired pyrimidine 3.22 but unfortunately only in modest yield. However, this key intermediate could be readily N-methylated, and in a simple extension to the sequence subjected to direct amide formation, debenzylation and finally coupled with the

Practical synthesis of indoles and benzofurans in water using a heterogeneous bimetallic catalyst

• Cybille Rossy,
• Eric Fouquet and
• François-Xavier Felpin

Beilstein J. Org. Chem. 2013, 9, 1426–1431, doi:10.3762/bjoc.9.160

• , activated-charcoal-supported palladium catalyst for hydrogenation and debenzylation [33]. This homemade Pd/C catalyst was prepared by impregnation of activated charcoal by the reduction of Pd(OAc)2 in MeOH under an atmosphere of H2 (1 atm). With these previous results in mind, we reasoned that the

Selective copper(II) acetate and potassium iodide catalyzed oxidation of aminals to dihydroquinazoline and quinazolinone alkaloids

• Matthew T. Richers,
• Chenfei Zhao and
• Daniel Seidel

Beilstein J. Org. Chem. 2013, 9, 1194–1201, doi:10.3762/bjoc.9.135

• , which contains two tertiary amines and is readily obtainable by an acid-promoted hydride shift process [52][53][54], was also exposed to oxidative conditions (Scheme 1, reaction 2). We had hypothesized that quinazolinone 32 might be formed in this reaction by the debenzylation of an intermediate iminium

Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

• Brad M. Loertscher,
• Yu Zhang and
• Steven L. Castle

Beilstein J. Org. Chem. 2013, 9, 1179–1184, doi:10.3762/bjoc.9.132

• mass balance. Although not investigated in detail, analysis of these reactions by 1H NMR and mass spectrometry indicated that partial debenzylation was occurring. Accordingly, we decided to replace the benzyl ether with a 2-naphthylmethyl (NAP) ether [28]. Unfortunately, attempted protection of alcohol

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

• Ping-An Wang,
• Sheng-Yong Zhang and
• Henri B. Kagan

Beilstein J. Org. Chem. 2013, 9, 265–269, doi:10.3762/bjoc.9.32

• ][13][14] from compounds 4 through three steps, including reduction, debenzylation and cyclization (Scheme 1), but this failed. However, we have found a novel one-pot tandem cyclization of these enantiopure asymmetric cis-2,5-disubstituted pyrrolidines to produce chiral trisubstituted 10

• process, both N-debenzylation and a ring-opening reaction occurred. Diamino-alcohols 6a and 6b are enantiomers, and they can serve as precursors for the synthesis of hydroxy N-heterocyclic carbenes. Following the reported procedure for the preparation of N-heterocyclic carbenes [19][20], the enantiopure

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT₂ receptor family

• Adam Pigott,
• Stewart Frescas,
• John D. McCorvy,
• Xi-Ping Huang,
• Bryan L. Roth and
• David E. Nichols

Beilstein J. Org. Chem. 2012, 8, 1705–1709, doi:10.3762/bjoc.8.194

• to the amine by a Curtius type rearrangement (Scheme 2). In our previous synthesis [2] we had employed an N-carbobenzoxy intermediate, followed by catalytic debenzylation over Pd(C); but those conditions would lead to dehalogenation in the present series, so we instead employed acid-catalyzed removal

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• . Similarly, the related iodides 14 and 15 performed well in this sequence yielding 33 and 34. The first step in the synthesis of the mimics of papulacandin D was debenzylation of 32, since these groups cannot be removed in the presence of olefines in the final product side chain (Scheme 4). The liberated

Chemistry of polyhalogenated nitrobutadienes, 10: Synthesis of highly functionalized heterocycles with a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Armin de Meijere and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2012, 8, 621–628, doi:10.3762/bjoc.8.69

• from 21 by means of surplus trifluoroacetic acid under mild conditions, the corresponding free amine 29 was obtained in 83% yield, without any further optimization. However, accurately tailored conditions seemed to be necessary for the N-debenzylation of the protected amino compounds 12 and 28. The

A new phenylethyl alkyl amide from the Ambrostoma quadriimpressum Motschulsky

• Guolei Zhao,
• Chao Yang,
• Bing Li and
• Wujiong Xia

Beilstein J. Org. Chem. 2011, 7, 1342–1346, doi:10.3762/bjoc.7.158

• compound 6 in quantitative yield. The following debenzylation and reduction with BH3·THF afforded alcohol 7 in 95% isolated yield. Then primary alcohol 7 was protected again with TBDMSCl to give compound 8 in 100% yield. An initial attempt to synthesize compound 9 by reduction of 8 with LiAlH4, however

Evaluation of a commercial packed bed flow hydrogenator for reaction screening, optimization, and synthesis

• Marian C. Bryan,
• David Wernick,
• Christopher D. Hein,
• James V. Petersen,
• John W. Eschelbach and
• Elizabeth M. Doherty

Beilstein J. Org. Chem. 2011, 7, 1141–1149, doi:10.3762/bjoc.7.132

• ® systems have been used successfully for a variety of reductions; some of the more notable applications including O-debenzylation, CBz-hydrogenolysis, aromatic ring saturation, imine reduction, and enantioselective carbonyl reductions [8][10][11][12][13]. In our hands, the ThalesNano H-Cube® and the H-Cube

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• starts from α-(trifluoromethyl)acrylic acid (2). Conjugate addition of α-(p-methoxyphenyl)ethylamine ((S)-3b), generated an addition adduct 4b which was cyclised to β-lactam 5b. Separation of the diastereoisomers by chromatography gave ((αS,3S)-5b). N-Debenzylation afforded the desired α-(trifluoromethyl

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• on carbon gave the core triazolopiperazine 280. This was then coupled with carboxylic acid unit 281 under standard peptide bond forming conditions and subjected to palladium catalysed debenzylation to liberate the free amine functionality of sitagliptin (275) (Scheme 55). An inherent problem with

Synthesis of 5-(6-hydroxy-7H-purine-8-ylthio)- 2-(N-hydroxyformamido)pentanoic acid

• Yanmei Zhang,
• Greg Elliot,
• Adrian Saldanha,
• Igor Tsigelny,
• Dennis Carson and
• Wolf Wrasidlo

Beilstein J. Org. Chem. 2010, 6, 742–747, doi:10.3762/bjoc.6.93

• -formylation produced 12. Finally, debenzylation with boron tribromide afforded the hybrid molecule 13 as a slightly tan powder [9][10][11][12]. All compounds were fully characterized and their structures confirmed by 1H NMR and mass spectroscopy. The purity of the final product was determined by HPLC and

Synthesis of imidazol- 1-yl-acetic acid hydrochloride: A key intermediate for zoledronic acid

• Santosh Kumar Singh,
• Narendra Manne,
• Purna Chandra Ray and
• Manojit Pal

Beilstein J. Org. Chem. 2008, 4, No. 42, doi:10.3762/bjoc.4.42

• . The ester 4 was then converted to compound 3 either by debenzylation using 10% Pd/C (50% wet) or by acidic hydrolysis using 10% hydrochloric acid (Method b, Scheme 1). The third process [9] involved the reaction of methyl chloroacetate with 1 in a mixture of solvents followed by hydrolysis to afford

A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine

• Jian-Feng Zheng,
• Wen Chen,
• Su-Yu Huang,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2007, 3, No. 41, doi:10.1186/1860-5397-3-41

• procedure, namely, N-debenzylation/O-mesylation/Boc-cleavage/cyclization, and O-debenzylation. Alternatively, amino alcohol 8 was mesylated and the resultant mesylate 12 was subjected to hydrogenolytic conditions, which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8. Conclusion By

• derivative 8 in 95% yield. Compound 8 was then converted to (1S,8aR)-1-hydroxyindolizidine (ent-3) {[α]D 27 +50 (c 0.90, EtOH); lit.[29] [α]D +51.0 (c 0.54, EtOH); lit.[32] −49.7 (c 0.95, EtOH) for the antipode} via a four-step procedure, namely, one-pot N-debenzylation-N-Boc formation/O-mesylation/Boc

• -cleavage/cyclication, and O-debenzylation. In searching for a more concise method, amino alcohol 8 was mesylated (MsCl, NEt3, 0 °C) and the resultant labile mesylate 12 was subjected to catalytic hydrogenolysis (H2, l atm, 10% Pd/C, r.t.), which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall

The enantiospecific synthesis of (+)-monomorine I using a 5-endo- trig cyclisation strategy

• Malcolm B. Berry,
• Donald Craig,
• Philip S. Jones and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2007, 3, No. 39, doi:10.1186/1860-5397-3-39

• of 28 under Wacker conditions proved highly capricious and was ultimately abandoned in favour of a more reliable oxymercuration protocol. [24] Under these conditions the methyl ketone 29 was isolated in 70% yield (Scheme 9). Catalytic transfer hydrogenation led to sequential debenzylation and

Diastereoselective synthesis of some novel benzopyranopyridine derivatives

• Pradeep K. Mohakhud,
• Sujeet M. R. Kumar,
• Vasanth M. R. Kumar,
• Ravi M. R. Kumar,
• Moses D. R. Babu,
• Vyas D. R. K and
• Om D. R. Reddy

Beilstein J. Org. Chem. 2006, 2, No. 25, doi:10.1186/1860-5397-2-25

• reported synthesis [5] for the trans compound involved reaction of ethyl 2-methoxy-6-methoxymethyl cinnamate with ethyl N-benzylamidomalonate followed by reduction with LiAlH4. Subsequent conversion of the hydroxymethyl to a leaving group and then intramolecular cyclization, followed by debenzylation