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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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Subsequent reduction of the nitro group with SnCl2-2H20 in DMF afforded the corresponding di-anilines 37, along with varying amounts of the cyclic intermediates 38, depending on the nature of the substituents derived from the (3-amino acids (R1). The partial formation of the seven-membered ring was then driven to completion using DECP and DIEA in DMF. Notably, all other cyclization conditions examined failed, including heating 37 in the absence of reducing agent or treatment with the carbodi-imide-type reagents previously found successful in the benzothiazepine series (see Section 3.2.1).
Alkylation at N(5) of the cyclic intermediates 38 was accomplished using concentrated solutions of alkyl halides in DMF at 50C. Addition of a base proved not only unnecessary but even counterproductive in terms of the purity of the resulting 7V(5)-substituted benzodiazepinones 39. Alkyl halides producing good results in this reaction include more than 40 benzyl bromides, allyl bromide, various esters of bromoacetic acid, as well as methyl and ethyl iodide. Other alkyl iodides, along with benzyl chlorides and a-bromo acetophenones, however, did not give satisfactory results.
The final alkylation at N(\) of 39 was accomplished using alkyl halides and lithiated 4-benzyl-2-oxazolidinone as a base.30,31 The halides used for 7V(5)-alkylation were also found suitable for yV(l)-alkylation, with the notable expansion to include other alkyl iodides beyond methyl and ethyl iodide. From the spectroscopic data of the final products 4, and in agreement with literature data in similar systems,30,31 no evidence was found for C-
94
BENZOFUSED HETEROCYCLES VIA SOLID-PHASE S/y/AR REACTIONS
()
h2n^
COOH
35
1a
(Resin is ArgoGel/Rink)
0.5M NaHC03 (aq)/ acetone 1:1, 709C
(ii) SnCI2*2H20, DMF
A
COOH
36 (R,R' = O)
37 (R,R' = H)
DECP, DIEA, DMF, 25 8C
() 0.25M X-CH2-R3, Lithiated 4-benzyl-2-oxazolidinone THF/DMF 1:1, 25 SC
(ii) TFA, CH2CI2

Scheme 6.
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS 95
and/or O-alkylation. Full compatibility of this 1,5-benzodiazepinone synthesis with our dialkylamine encoding method has been established through model studies analogous to those performed with the benzothiazepine compounds.4 Figure 3.2 displays a selection of structures, compounds 40-45, accessible from this first synthetic approach.
Lee and co-workers have developed a complementary approach to 1,5-benzodiazepinones in which la was reacted with a variety of a- and/or (-substituted p-amino acid esters 46 (Scheme 7).7 Many of these building
OPh
40
41 ()
42 ()
F
43 ()
44 ()
45
Figure 3.2. Selection of 1,5-benzodiazepin-2-ones synthesized from 1a and commercially available p-amino acids 35.
96 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SWAR REACTIONS
1a
(i)
HoN
46
COOEt
DIEA, DMF, 25
(ii) SnCI2*2H20, DMF
RR'N H COOEt
47 (R,R' = 0)
48 (R,R = H)
(i) 1N NaOH/THF 1:1 reflux >
(ii) DIC, HOBt, DMF, 25
(i) XCH2R , K2C03, acetone ____________reflux__________
(ii) TFA, CH2CI2
Scheme 7.
blocks were prepared in advance by an expedient solution-phase synthesis involving a Knoevenagel condensation of ethyl cyanoacetate with aldehydes, followed by reduction of the resulting acrylic nitriles.
The SyyAr reaction was performed in DMF using DIEA as an auxiliary base and allowed to proceed for three days at room temperature. Subsequent reduction of the aromatic nitro group of 47 with SnCl2*2H20 in DMF was followed by hydrolysis of the ester moiety using a heterogeneous mixture of 1 N NaOH and THF at reflux for 24 h. Closure of the seven-membered ring using DIC and HOBt afforded the benzodiazepin-2-ones 49 in good
3.3. FORMATION OF [6,6J-FUSED SYSTEMS 97

OMe
51 ()
52 ()
53 ()
Figure 3.3. Selection of 1,5-benzodiazepin-2-ones synthesized from 1a and P-amino acid esters 46.
overall yields. Additional diversity was introduced at the penultimate step by alkylating the 7V(5)-position with five different benzyl bromides using K2C03 as a base in refluxing acetone (see also Section 3.3.2).8 Figure 3.3 shows a selection of benzodiazepinone structures (51-53) shown to be accessible from this second synthetic approach.
3.3. FORMATION OF [6,6]-FUSED SYSTEMS
3.3.1 4-Alkoxy-1,4-thiazin-3-ones (5)
A logical extension of the synthetic strategy underlying our solid-phase approach toward 1,5-benzothiazepinones was to replace the P-mercapto acids (cysteine, penicillamine) by a-mercapto acids, such as mercaptoacetic acid 54a or thiolactic acid 54b. This change would facilitate access to the corresponding [6,6]-fused systems, i.e. l,4-benzothiazin-3-ones57. As with the benzothiazepines, no solid-phase synthesis of benzothiazines has been reported to date.
To test our proposed synthesis of [6,6]-fused systems, 4-fluoro-3-nitrobenzamide la was reacted with solutions of 54a or 54b in DMF, with DIEA as base (Scheme 8). The solid-phase S^Ar reaction again proved reliable and afforded the corresponding onitrothioethers 55a or 55b, re-
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