Iodination of Phenols in Water using Easy to Handle Amine-Iodine Complexes

A reação entre o iodo e a N-metil-piperazina ou a tiomorfolina em água, na presença de KI, levou a formação de complexos amina-iodo estáveis e de fácil manipulação, tal qual o complexo morfolina-iodo, previamente descrito na literatura. Entretanto, o complexo formado entre o iodo e a N,N-tetrametiletilenodiamina mostrou-se pouco estável, enquanto que nenhum complexo foi isolado quando a piperidina foi usada como base. Estes resultados mostram que a presença do segundo heteroátomo na estrutura das aminas é fundamental para a formação e estabilidade desses complexos. Neste trabalho descrevemos, pela primeira vez, o emprego dos complexos morfolina-iodo, N-metil-piperazina-iodo e tiomorfolina-iodo como agentes de iodação de vários fenóis substituídos, conduzindo a uma série de produtos iodados em rendimentos variando de bons a excelentes.


Introduction
Aryl iodophenols and other aryl iodides are versatile intermediates in organic synthesis, being used as precursors of new carbon-carbon bonds.2][3][4][5][6][7][8][9] In particular, the palladium catalyzed oxyarylation of chromens by orthoiodophenols have been used to synthesize pterocarpans and its derivatives. 10,11On the other hand, coumarins were formed through a tandem Heck-lactonization reaction when these species were allowed to react with enoates and cinnamates. 12,135][26][27][28][29][30][31][32][33][34] Recently, Esteves and Mattos 35 described the scope of the triiodoisocyanuric (TICA) acid as iodinating agent.The reaction of TICA with activated arenes in acetonitrile led to an efficient and highly regioselective formation of the corresponding iodoarenes.Aniline and phenol were monoiodinated regioselectively using MeOH and CH 2 Cl 2 as solvents, respectively.Vol. 20, No. 10, 2009   Amines can also be used to increase the reactivity of I 2 and Hinman and Giza 36 used iodine in the presence of morpholine as iodinating agent to synthesize thyroxine analogs from 3-carbethoxy-5-hydroxy-2methylbenzofuran.Iodine in the presence of amines react readily with benzophenone, cinnamates and chalcones leading to α,β-diamino-benzylacetophenones and α,β-diamino-benzylacetones derivatives. 37While in most cases complexes of I 2 with amines are generated and used in situ, 13,14 a stable and easily to handle complex 1a (Figure 1) was prepared by Rice 38 just mixing of morpholine, KI and I 2 in water.Recently Perez et al. 39 described the use of this complex as iodinating reagent to prepare 2-hydroxy-3iodo-naphthoquinone from lawsone in 87% yield, but did not evaluate the scope of this new iodinating agent using other phenols as substrates.
In this paper we describe the synthesis of new amineiodine complexes (1b-d), structurally related to complex 1a.The scope of these complexes (1a-d) as iodinating agents was evaluated for the first time using a series of phenols (2-5) as substrates (Figure 1).

Results and Discussion
A series of secondary amines (7, 8 and 10) and a tertiary amine (9) were allowed to react with I 2 in water in the presence of KI, under the conditions described by Rice 38 to prepare 1a.Stable complexes (1b and 1c) were formed when N-methyl-piperazine (7) and thiomorpholine (8)  were used (Scheme 1).In contrast, complex 1d, obtained from N,N-tetrametylethylenediamine (9), was unstable and completely decomposes at room temperature after 1 h.In contrast, no complex could be isolated from the reaction of I 2 with piperidine (10).
Complexes 1a, 1b, 1c and 1d were used as iodinating agents of phenols 2-5.The reactions are shown in Schemes 2, 3, 4 and 5 and yields obtained are shown in Table 1.
Using the complexes 1a or 1b, vanillin 5b and isovanillin 5c (entries 18-21), having activating and deactivating groups at the aromatic ring, also led to the corresponding ortho-iodophenol derivatives 14b 27 and 14c, 28 although the para position in 2h is not substituted.A mixture of non-identified products was obtained when the m-hydroxy-benzaldehyde (5d) was treated with the complex 1a (entry 22).Unfortunately, sesamol 5e, a very activated phenol, furnished only products of degradation when allowed to react with 1a (entry 23).α-Naphthol 3 led to 12 in 60% and 63% yield, respectively (entries 24-25), by reaction with complexes 1a or 1b. 244][45][46] According to Manoharan and Ananthavel, 47 a suitable interaction exist between σ*-orbital in the interhalogen (LUMO) and lone electron pair of donor (HOMO).][50][51][52] Amine-iodine complexes have been studied by UV and IR spectroscopy and a dipolar structure has been suggested (Figure 2). 53,54Based on our results, the presence of the second hetero-atom in the structure of 1a, 1b and 1c, respectively, is essential for the stability of the complexes, but do not influence the reactivity, and consequently the yields of products.Studies toward the structural elucidation of these complexes are underway in our laboratories.
In conclusion, in this paper we report the synthesis of new stable in easy to handle amine-iodine complexes 1b and 1c from of N-methyl-piparazine (7) and thiomorpholine (8), respectively.These complexes were evaluated for the first time as iodinating reagents of phenols, leading to iodinated products in similar yields to those observed for complex 1a.The soft conditions used make them useful iodinating agents.

General
Melting points were measured with a Fisher-Johns (Fisher Scientific Co) apparatus. 1H NMR was recorded on a Varian Gemini-200 instrument.

Synthesis of the compounds 11-14
Typical procedure for 13c: To a mixture of methyl 4-hydroxybenzoate 4c (4.56 g, 30 mmol) and K 2 CO 3 (12.6 g, 90 mmol) in an erlenmeyer flask was added distilled water (300 mL).The dark red solution was stirred at room temperature while the complex 1a or 1b or 1c or 1d (37.5 mmol) or was added in small portions every 15 min during 2 h.The mixture was cooled in an ice bath and then acidified with 25% H 3 PO 4 until the pH was approximately 2. At this point, the mixture was allowed to age (24 h) and a bright yellow precipitate was formed.The solid was filtered off and washed with cold H 2 O.The product was dried under vacuum to provide the desired methyl-3-iodo-4-hydroxybenzoate product 13c (7.92 g, 95%), or (7.50 g, 90%) or (7.96 g, 96%) or (6.67 g, 80%), respectively.mp 156-158 °C (mp 155-159 °C); 55