Synthesis of Isoindolines

Recently, Kim and coworkers developed an efficient strategy for the construction of isoindolines 10 via Rh(III)-catalyzed oxidative alkenylation and subsequent intramolecular cyclization ofAf-benzyltriflamides with olefins. Under these reaction conditions, various substituted electron-deficient alkenes were successfully employed in good product yields [8]. The authors proposed a mechanism to account for the catalytic reaction (Eq. (5.10)). 

Miura et cd. also demonstrated a Rh-catalyzed room-temperature dehydro-genative coupling of a,a-disubstituted benzylamines with alkenes. The reaction proceeded via an ort/ro-alkenylation directed by the free amino group and subsequent cyclization to produce isoindole-l-yl derivatives 11 (Eq. (5.11)). It is rare for catalytic processes to use an amino group as a directing group [9]. The reaction was unsuccessful when styrene was used as the coupling partner. 

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The latter process must play a key role in the recently reported Pd-catalyzed alternative copolymerization of ethene and CO in water. It is also involved as a mechanistic step in a new synthesis of isoindolin-l-ones 40 by Pd-catalyzed intermolecular coupling and heteroannelation between 2-iodobenzoyl chloride (37) and imines 38 (Scheme 11). In this case, however, a /3-hydride elimination in the intermediate 39 would not be possible at all. 

Scheme 77 Synthesis of isoindolines fused with azoles...

Scheme 1.20 (a-d) Palladium-catalyzed carbonylative synthesis of isoindolin-l-ones. 

Scheme 10.18 Synthesis of isoindolines through domino aza-Morita-Baylis-Hillman/aza-...

Scheme 11.17 Conjugate addition/Mannich reaction for the synthesis of isoindoline 71...

The practical and convenient solvent-free iridium-catalyzed [2 + 2 + 2] cycloaddition of a,(D-diynes and alkynes was explored as an efficient route for the synthesis of isoindolines, dihydrobenzo[c]frirans, and indanes (13S2003).The asymmetric synthesis of C2-symmetric axially chiral biaryls was achieved by the cationic rhodium(I)/l,3-bis(diphenylphosphino)pro-pane (dppp)-catalyzed diastereoselective double [2 + 2 + 2] cycloaddition of (R)-3-butyn-2-ol-derived tetraynes with functionalized monoynes (13EJOC6774). 

Scheme 6.17. Synthesis of isoindolines and related structures via solid-supported [2 + 2 + 2] cyclotrimerization reactions. R = H, Bu, Ph, CH2OH, CH20Bn, CH2NHB0C, (CH2)3CN, SiMes, (CH2)4CI, C02Me, Et, CH20Me R = H, Et, CH20Me R = H, CH2OH R = H, Me, TMS Trt=trityl linker.

The preferred starting material for the industrial synthesis of isoindoline pigments is diiminoisoindohne (10a) or its tautomeric form aminoiminoisoindoline (10b), which can be produced from o-phthalodinitrile (9) and gaseous ammonia in ethylene glycol or other suitable solvents. Suitable starting materials further include l,l-dialkoxy-3-iminoisomdolines, synthesized from 9 and C1-C4 alcohols . ... 

Cho, C.S., Shim, S.C., Choi, H.-J., Kim, T.-J., Shim, S.C. and Kim, M.C. (2000) Synthesis of isoindolin-l-ones via palladium-catalyzed intermolecular coupling and heteroannulation between 2-iodobenzoyl chloride and imines. Tetrahedron Letters, 41, 3891-3893. 

Sato, Y., Nishimata, T. and Mori, M. (1994) asymmetric synthesis of isoindoline and isoquinoline derivatives using nickel (O)-catalyzed [2-1-2- -2]-cocyclization. Journal of Organic Chemistry, 59(21), 6133-6135. 

Isoindolines comprise a group of well-characterized and easily synthesized substances, and being at the next stable reduction state below that of isoindoles, they constitute suitable precursors for synthesis of the latter. In principle, either oxidation or elimination from isoindolines should lead to isoindoles however, in view of the susceptibility of isoindoles to further oxidation, elimination has been preferred, and in all cases reported the leaving group has been placed on nitrogen rather than carbon. 

Elimination from A -oxides of substituted isoindolines provides an exceptionally facile synthesis of the isoindole sy.stem. Kreher and Seubert found that treatment of the oxides of both 2-alkyl- and 2-arylisoindolines with acetic anhydride at 0° to —10° afforded... 

In contrast to isoindoliiiium salts and A-oxides of isoindolines, successful elimination from simple 2-substituted isoindolines has been realized in only two cases. One of these, however, was the synthesis of isoindole itself, and it seems likely that this method is particularly well suited to the preparation of other sensitive isoindoles. 

In contrast to phthalocyanines (tetra- or octasubstituted) in which the isoindoline units carry all the same substituents, reports of phthalocyanines with lower symmetry, which have been prepared by using two different phthalonitriles, have rarely appeared. This is due to the problems which are associated with their preparation and separation. For the preparation of unsymmetrical phthalocyanines with two different isoindoline units four methods are known the polymer support route,300 " 303 via enlargement of subphthalocyanines,304 " 308 via reaction ofl,3,3-trichloroisoindoline and isoindolinediimine309,310 and the statistical condensation followed by a separation of the products.111,311 319 Using the first two methods, only one product, formed by three identical and one other isoindoline unit, should be produced. The third method can be used to prepare a linear product with D2h symmetry formed by two identical isoindoline units. For the synthesis of the other type of unsymmetrical phthalocyanine the method of statistical condensation must be chosen. In such a condensation of two phthalonitriles the formation of six different phthalocyanines320 is possible. 

Recently, the use of flash vacuum pyrolysis, at 420°C and at pressure less than 0.5 mm Hg has been described for the synthesis of isoindolyl nitrone 1,1,3-tri-methylisoindole A-oxide (TMINO) from isoindoline nitroxide 1,1,3,3-tetra-methylisoindolin-2-yloxy (TMIO), with yields up to 73% (Scheme 2.71) (354). 

This paper traces in some detail the path which led to the discovery of a new class of herbicides, the 2-(5-oxo-2-imidazolin-2-yl)arylcarboxylates. The journey started when it was found that a phthalimide, a-isopropyl-a-methyl-l,3-dioxo-2-isoindoline-acetamide, had sufficient herbicidal activity to warrant further synthesis effort. This work led to a series of analogs essentially devoid of herbicidal activity yet possessing interesting plant growth regulating effects. Further chemical modifications resulted in the synthesis of two new groups of compounds, imidazoisoindolediones and dihydro-imidazoisoindolediones, and the return of herbicidal activity. The imidazoisoindolediones were in turn transformed into o-(5-oxo-imidazo-lin-2-yl)benzoates, the first members of a very interesting new class of herbicides. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

Synthesis of 4-(l//-tetrazol-l-yl)butylamine 453 from 2-[4-(l//-tetrazol-l-yl)butyl]isoindoline-l,3-dione 452 has been reported <2006S1504>. In a subsequent reaction, butylamine 453 was converted in low yield into 1 -[4 (4//-l,2,4-triazol-4-yl)butyl]-l //-tctrazole 454 (Scheme 56) <2006S1504>. 

Lamblin M, Couture A, Deniau E, Grandclaudon P (2008) Alternative and complementary approaches to the asymmetric synthesis of C3 substituted NH free or N-substituted isoindolin-1-ones. Tetrahedron Asymmetry 19 111-123... 

Figure 7.9 Validation in solution for the synthetic scheme to the isoindoline SP pool library L2 synthesis of 7.7.

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