A practical and general ipso iodination of arylboronic acids using N-iodomorpholinium iodide (NIMI) as a novel iodinating agent: mild and regioselective synthesis of aryliodides

Abstract

A mild and efficient protocol for the ipso-iodination of aryl boronic acids using N-iodomorpholinium iodide (NIMI) generated in situ from morpholine and molecular iodine as a novel iodinating agent has been developed. The addition of a catalytic amount of copper iodide found to promote rate enhancement of the iodination reaction and dramatic increase in the yield depending upon the nature of the boronic acid was observed. The mechanistic study revealed that depending upon the nature of the substrate, either the classical ipso substitution or copper catalysed iododeborylation pathway overall dominates the present iodination reaction. The features such as mild reaction conditions, operational simplicity, high to excellent yields, excellent functional group compatibility and low catalyst loading make this method potentially useful in organic synthesis.

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Introduction

Development of an efficient, mild and regioselective protocol for the synthesis of aryl halides, in particular aryl iodides is much sought after as they are highly versatile synthetic intermediates widely used in transition metal catalyzed carbon–carbon and carbon–heteroatom bond formation.¹ Aryl iodides are also used as precursors for the synthesis of various hypervalent iodine reagents.² Another important utility of iodoarenes is in the area of labeling of biological targets with short lived radioisotopes for nuclear imaging by positron emission tomography. For instance, Kim et al.³ investigated the possibility of using iodine labeled hypericin derivatives for imaging malignant gliomas with PET and SPECT. Moreover, mild and regioselective iodination of arenes is of particular importance from the perspective of iodine labelled diagnostic and therapeutic agents.⁴

Due to the low reactivity of iodine and related iodinating agents than the corresponding chloro and bromo analogues, synthesis of functionalized aryl iodides is more challenging.⁵ Generally, iodoarenes are synthesized by the oxidative iodination of arenes with variety of oxidizing agents⁶ and using classical Sandmeyer reaction⁷ involving regioselective iodination of arenediazonium salts under acidic conditions.

However, these methods suffer from the limitations such a use of hazardous oxidizing agents, harsh reaction conditions, poor yields, and regioselectivity. Consequently, many alternative methods for the synthesis of aryl iodides have been developed. These include organocatalytic variants of Sandmeyer reaction,⁸ the use of mercury⁹ and thallium¹⁰ compounds etc., however, these methods also involve the use of toxic reagents. The copper catalyzed synthesis of iodoarenes directly from arenes or aryl bromides as an attractive alternative for the above methods has been reported by Buchwald and co-workers.¹¹

In contrast to many air-sensitive, tend to be easily hydrolysed organoboron compounds,¹² boronic acids [R–B(OH)₂], are usually crystalline solids, stable to air and moisture and are relatively of low toxicity [benzene boronic acid:¹³ LD₅₀, oral-rat = 740 mg kg⁻¹] and environmental impact. Apart from being versatile building blocks in organic synthesis, boronic acids find numerous applications such as in the field of material science, biotechnology, medicinal chemistry and supramolecular chemistry.¹⁴ The recent advancement in the transition metal catalyzed Miyaura borylation¹⁵ and iridium catalysed C–H activation strategies,¹⁶ the large number of boronic acids could be readily synthesized without using haloarenes, an unacclaimed perception among scientific community, has advance the field of organoboron chemistry further.

In recent years, ipso substitution of organoboron compounds, in particular, of arylboronic acids/esters/tetrafluoroborate, in which boronic or related group is replaced by entering functional group has emerged a as powerful tool for the regioselective functionalization of arenes. This strategy has been successfully employed for the synthesis of arylazides,¹⁷ phenols,^17a,18 arylsulfones,^17a,19 aryl halides,^17a,20,21 nitroarenes^17a,22 and amines.^17a,23 Based on similar strategy, very recently, we have reported an efficient and green protocol for the ipso iodination of arylboronic acids using CTAB/I₂ in aqueous media.²⁴ As compared to other ipso substitutions (ipso nitration, azidation, hydroxylation and amination), relatively the reports on the ipso iodination of arylboronic acids are scares. Moreover, many reported methods for the ipso iodination in the literature^17a,19a,f,24 are either performed at high temperature or required large excess of additives/special ligand and high catalyst loading and some of them are having limited substrate scope.²⁴ Therefore, the general, milder and inexpensive alternative is highly desired.

The guiding principle of ipso substitution is that it generally requires the concomitant activation of both the organoboron compounds (via Lewis acid–base type interaction) and electrophilic species (for instance, iodinating agents) which help ipso substitution to occur readily. We reasoned that the activation of I₂ with mild base such as morpholine at room temperature would generate in situ N-iodomorpholinium iodide (NIMI). The activation of boronic acid by iodide (I⁻) ion giving more nucleophilic boron species and its subsequent ipso attack with highly electrophilic N-iodomorpholinium ion could lead to the mild and efficient protocol for ipso iodination of boronic acids at room temperature.

In the present paper, in continuation of our interest in exploring boronic acids as green catalysts or reagents in organic synthesis,^24,25 we report herein the copper catalysed an efficient, mild, and general approach for the regioselective synthesis of iodoarenes via ipso iodination of boronic acids using N-iodomorpholinium iodide as iodinating agent at low catalyst loading.

Results and discussion

The iodinating agent used here, N-iodomorpholinium iodide²⁶ was generated in situ from I₂ and morpholine. Initially, the ipso iodination of 4-ethylphenyl boronic acid using morpholine and I₂ in methanol was considered as a model reaction. A series of experiments were carried to optimize various reaction parameters such as effect of morpholine: I₂ ratio, catalyst loading, temperature, solvent and reaction time (Scheme 1).

Scheme 1

The results are summarized in Table 1. As can be seen from our results, in the absence of morpholine and using I₂ alone, the reaction hardly proceeded despite of continuing the reaction for 24 h at room temperature, (Table 1, and entry 1) and use of even higher temperature did not facilitate the reaction (Table 1, entry 2). However, using stoichiometric amount of morpholine and little excess of I₂, the above reaction proceeded smoothly but to give low yield, (Table 1, entry 3). In order to improve the product yield, we decided to probe the effect of copper catalyst on this reaction. Thus using catalytic amount (5 mol%) of CuI, considerable increase in the yield of the above reaction was observed (Table 1, entries 3 vs. 4). Under same reaction conditions but using higher temperature, a good yield of corresponding iodoproduct could be obtained within short reaction time (Table 1, entry 5). Use of equimolar amount of morpholine to I₂ did not give much favorable result even in the presence of 10 mol% of the catalyst. On the other hand, using 1 : 2.4 equiv. of morpholine and I₂ and in the presence of 10 mol% of catalyst, 68% yield was obtained at 40 °C within 24 h.

Table 1 Optimising the reaction conditions for the ipso iodination of 4-ethylphenyl boronic acid^a

Entry	Morpholine (equiv.)	I2 (equiv.)	CuI (mol%)	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 0.2 mmol of 4-ethylphenyl boronic acid in 1.5 ml of methanol for the time indicated in table.b Isolate yields by column chromatography.c Under N2 atmosphere.d The boronic acid was completely consumed but no iodoproduct was detected.e 2.0 equiv. of KI or NaI was used as iodinating agent.
1	None	1.2	None	rt	24	0
2	None	1.2	None	65	10	Trace
3	1.0	1.2	None	rt	24	32
4	1.0	1.2	5	rt	24	40
5	1.0	1.2	5	65	10	68
6	1.0	1.0	10	65	4	39
7	1.0	2.4	10	40	24	68
8	1.0	2.4	5	65	4	50
9	2.0	2.4	None	rt	24	67
10	2.0	2.4	5	rt	24	75
11	2.0	2.4	5	65	4	74
12	2.0	2.4	5	rt	24	62^c
13	2.0	2.4	100	rt	1	65
14	0.2	1.0	None	40	24	12
15	0.2	2.4	None	40	24	28
16	0.2	2.4	5	40	24	30
17	None	2.4	5	40	24	29
18	None	None	100	rt	5	nd^d
19	None	None	5	rt	24	0^e

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Despite of several attempts, the yield was still not as good as the process to be called practical. Therefore, to improve the yield further, we decided to use further higher amount of morpholine and iodine. We were delighted to see that using twofold amount of these reagents, more than two fold increases in the yield was observed, (Table 1, entries 3 vs. 9). In the presence of catalytic amount of copper iodide, however, the same reaction furnished 75% yield of the corresponding iodoproduct, (Table 1, and entry 10). Almost similar result was obtained when above reaction was performed at 65 °C but within short reaction time (Table 1, entries 10 vs. 11). These results clearly indicate the striking effect of temperature on the present iodination reaction. Use of inert (N₂) atmosphere found to be detrimental for the present reaction as it gave less favourable result, (Table 1, compare entries 11 and 12). As anticipated, using stoichiometric amount of copper catalyst, reaction reached to completion within less than hour but with lower yield even than the uncatalyzed reaction (Table 1, compare entries 9 and 13).

To check whether the reaction can be proceeded even using catalytic amount of morpholine, the model reaction was performed again but this time using catalytic amount of morpholine. As can be seen from our results that the use of catalytic amount of morpholine and little excess of I₂ could promote the ipso iodination but to give very low yield, (Table 1, entry 14). Use of twofold excess of I₂, however, resulted into more than twofold increase in the yield under same reaction conditions (Table 1, entry 15). We also checked the effect of catalytic amount of morpholine and CuI in the model reaction. Unfortunately, under these conditions the reaction furnished very low yield of the iodoproduct (Table 1, entry 16). Thus the use of catalytic amount of morpholine alone or in combination with CuI did not provide the acceptable results and hence no further attempts of optimizing the catalytic study were made.

Also to check whether the CuI alone or CuI/I₂ system could facilitate the ipso iodination of boronic acid, two independent experiments were carried out. One involving copper iodide alone and another one involving catalytic CuI and excess of I₂. While CuI/I₂ as an iodinating agent found to facilitate the ipso iodination albeit in low yield (Table 1, entry 17), the use of CuI alone did not give any ipso product even in the presence of stoichiometric amount of former (Table 1, entry 18). Finally, the use of alternative iodinating agents such as KI and NaI did not furnish any ipso product (Table 1, entry 19). Thus 2 : 2.4 equiv. of morpholine to I₂ ratio was found to be optimal for the success of the reaction.

We also investigated the effect of different copper salts such as CuCl, CuCN, Cu(OAc)₂, CuSO₄, and CuO on model reaction using optimized reaction conditions as described above (Table 1, entry 10). The results are summarised in Table 2.

Table 2 Effect of copper salts on the ipso iodination of 4-ethylphenyl boronic acid^a

Entry	Copper salt	Yield^b (%)
a Reaction conditions: 0.2 mmol of 4-ethylphenyl boronic acid, 0.4 mmol of morpholine, 0.48 mmol of I2 in the presence of 5 mol% of copper salt in 1.5 ml of methanol at room temperature for 24 h.b Isolated yield by column chromatography.
1	None	67
2	CuI	75
3	CuCl	71
4	CuCN	72
5	Cu(OAc)2	65
6	CuSO4·5H2O	55
7	Cu2O	71

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Among various copper salts screened, CuI was found to be the most effective catalyst giving highest yield of the iodoproduct (Table 2, entry 2). The copper salts such as CuCl (Table 2, entry 3), CuCN (Table 2, entry 4) and CuO (Table 2, entry 7) were also found to be effective catalysts, however they furnished lower yields as compared to CuI under same reaction conditions. The other catalysts such as CuSO₄ and Cu(OAc)₂ found to have no effect on the iodination reaction as they furnished lower yields even than the uncatalyzed reaction (Table 2, compare entries 1, 5 & 6). The reactions involving these two copper salts resulted into relatively complex reaction mixture as compared to other catalysts which probably might be reason behind the low yields obtained using them.

Initially, the methanol was deliberately chosen as a solvent due to high solubility of the salt, N-iodomorpholinium iodide in methanol.²⁶ We also investigated the effect of various solvents such as DCM, acetonitrile, acetone, DMF and THF on the model reaction.

The results are shown in Table 3. As can be seen from our results, amongst all the solvent tested, the methanol was found to be best solvent (Table 3, entry 1). The DCM was found to be another effective solvent for the present reaction but gave little lower yield than methanol (Table 3, entry 2). The acetonitrile (Table 3, entry 3) and DMF (Table 3, entry 4) furnished moderate and low yield respectively and thus proved to be less effective solvents than methanol and DCM. Acetone (Table 3, entry 5) on the other hand found to be fruitless solvent for the present reaction giving only 5% yield. Finally, THF was found to have detrimental effect on the reaction as it gave complex reaction mixture, though the starting material was found to be completely consumed as indicated by TLC (Table 3, entry 6).

Table 3 Effect of solvent on ipso iodination of 4-ethylphenyl boronic acid^a

Entry	Solvent	Yield^b (%)
a Reaction conditions: 0.2 mmol of 4-ethylphenyl boronic acid, 0.4 mmol of morpholine, 0.48 mmol of I2 in the presence of 5 mol% of CuI in 1.5 ml of solvent at room temperature for 24 h.b Isolated yields by column chromatography.c A complex reaction mixture was formed.
1	MeOH	75
2	DCM	72
3	MeCN	58
4	DMF	36
5	Acetone	5
6	THF	—^c

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From the detail optimization study, it was found that the CuI had little effect on the present iodination reaction. The other catalysts found to have either lower effect that CuI or less effective even than uncatalyzed reaction. Thus, initial study could not provide the clear information as to the exact role of copper catalyst in the reaction.

In order to have the clear insight into the role of the copper catalyst, solvent effect and reaction conditions on the ipso iodination reaction, we thought it is worthwhile to have the optimization study with the electron deficient substrate. To probe the effect of above parameters on the iodination reaction, this time the ipso iodination of 3-nitrophenylboronic acid was considered as model reaction, Scheme 2.

Scheme 2

The results are summaries in Table 4.

Table 4 Optimising the reaction conditions for the ipso iodination of 3-nitrophenyl boronic acid^a

Entry	Morpholine (equiv.)	I2 (equiv.)	CuI (mol%)	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 0.2 mmol of 3-nitrophenyl boronic acid in 1.5 ml of methanol for the time indicated in table.b Isolate yields by column chromatography.c Reaction time was not optimised and continued for 24 h.
1	0.2	2.4	5	rt	24	21
2	0.2	2.4	5	40	24	26
3	2.0	2.4	None	rt	24	20
4	2.0	2.4	None	40	24	41
5	1.0	2.4	5.0	40	24	63
6	2.0	2.0	5.0	65	4	92
7	2.0	2.4	5.0	rt	24	94
8	2.0	2.4	5.0	40	24	>99^c
9	None	2.4	5.0	40	24	15

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As shown in Table 4, reaction can be proceeded using catalytic amount of morpholine to give 21 and 26% yield of the iodoproduct at room temperature and 40 °C respectively (Table 4, entries 1 and 2). To our surprise, however, using 2 : 2.4 equiv. of morpholine to I₂ ratio but without copper catalyst, the reaction gave only 20% yield of the corresponding iodoproduct at room temperature. Thus in contrast to the results obtained with 4-ethylphenylboronic acid, the significant effect of copper catalyst on the ipso iodination of 3-nitrobenzeneboronic acid could be observed even at catalytic level of morpholine (Table 4, compare entries 1 and 3). Interestingly, using 1 : 2.4 equiv. of morpholine to I₂ ratio and 5 mol% of CuI, 63% yield (Table 4, entry 5) of the corresponding iodoproduct was obtained. This result is much closer to the yield obtained with 4-ethylphenylboronic acid when 10 mol% of CuI was used (compare Table 1, entry 7 with Table 4, entry 5). Furthermore, using stoichiometric amount of morpholine and I₂, but at higher temperature, the reaction reached to completion rapidly to give 92% yield which is much greater than the yield obtained with 4-ethylphenylboronic acid but using 2 : 2.4 equiv. of morpholine and I₂ ratio under almost similar conditions (compare Table 1, entry 11 with Table 4, entry 6). To our delight, using 2 : 2.4 equiv. morpholine to I₂ ratio and 5 mol% of CuI, excellent and almost quantitative yield of the 3-nitro-1-iodobenzene were obtained at room temperature and 40 °C respectively. All these findings clearly indicates the pronounced effect of copper iodide on the iodination of 3-nitrophenylboronic acid as compared to the 4-ethylphenylboronic acid. Surprisingly, in the absence of morpholine but using CuI/I₂ as iodinating agent, much lower yield than that of 4-ethylphenylboronic acid was obtained under exactly same reaction conditions (compare Table 1, entry 15 with Table 4, entry 9). The above results clearly indicates the crucial role of morpholine in the present iodination reaction.

It's worth mentioning here that with electron rich 4-ethylphenylboronic acid only 10% increment in the yield while in case of electron deficient 3-nitophenylboronic acid dramatic increment in the yield (94% vs. 20 mol%) in copper catalysed reaction as compared to the catalyst free reaction was observed, (Table 1, entries 6 and 7 vs. Table 4, entries 2 and 6). Explicitly, present iodination reaction is strongly dependence upon the electronic nature of the substituent. It can be concluded that the copper catalyst has little effect on the ipso iodination of electron rich substrate but at the same time it dramatically accelerates the reaction when electron withdrawing substituent is present in the boronic acid.

Similar to 4-ethylphenylboronic acid, we also investigated the effect of different copper salts and solvents on the model reaction in this case also. The results are summarized in Table 5. As can be seen from our results, CuI and CuCl (Table 5, entries 2 and 3) were found to be equally effective catalysts giving near quantitative yield of the corresponding iodoproduct under optimized reaction conditions. In contrast to the results obtained with 4-ethylphenylboronic acid, all the copper salts screened here shown pronounced catalytic effect on the present iodination reaction as compared to the uncatalyzed one giving high to near quantitative yield of the corresponding iodoproduct.

Table 5 Effect of different solvents and copper salts on ipso iodination of 3-nitrophenylboronic acid^a

Entry	Solvent	Copper salt (CuX)	Yield^b (%)
a Reaction conditions: 0.2 mmol of 3-nitrolphenyl boronic acid, 0.4 mmol of morpholine, 0.48 mmol of I2 in the presence of 5 mol% of CuX in 1.5 ml of solvent at 40 °C for 24 h.b Isolated yields by column chromatography.
1	MeOH	CuI	>99
2	MeOH	CuCl	99
3	MeOH	Cu2O	80
4	MeOH	CuSO4·H2O	94
5	MeOH	Cu(OAc)2	89
6	DCM	CuI	10
7	MeCN	CuI	59
8	DMF	CuI	Trace
9	Acetone	CuI	6

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In sharp contrast, the copper salts, Cu(OAc)₂ and CuSO₄·H₂O which were found to be less effective catalysts even than uncatalyzed reaction in case of 4-ethylphenylboronic acid, proved to be highly effective catalysts for iodination of 3-nitophenylboronic acid giving very high and excellent yield respectively (Table 5, entries 4 and 5).

Next, the effect of all the solvents investigated previously also tested here. Once again, methanol found to be the best solvent giving highest yield among all the solvent tested. However, the DCM, acetonitrile, and DMF which were proved to be the effective solvents in earlier study, in the present case, except acetonitrile, they found to be fruitless solvents giving very low or poor yield.

Thus the CuI and methanol were found to be most suitable catalyst and solvent respectively for the substrates, 4-ethyl and 3-nitrophenylboronic acid. It's worth mentioning here that the reaction parameters such as nature of copper catalyst, catalyst loading, morpholine: I₂ ratio, temperature and solvent all have strikingly different effect on the ipso iodination of electronically contrasting substrates.

The ipso iodination of both, 4-ethyl and 3-nitobenzeneboronic acid can be proceeded very rapidly with good and excellent yields respectively but at the expense of high catalyst loading and temperature, (Table 1, entry 11 and Table 4, entry 8). However, without necessarily relying on such a drastic conditions, excellent results could be obtained using low catalyst loading and under mild conditions. Thus 1.0 equiv. of boronic acid, 2.0 equiv. morpholine, and 2.4 equiv. of I₂ in the presence of 5 mol% CuI in methanol at room temperature for 24 h were considered to be the best reaction conditions and used for further study (Scheme 3).

Scheme 3

With optimized reaction conditions at hand, next the scope and generality of the reaction was explored using diverse arylboronic acids. The results are summarized in Table 6. As can be seen from our results, the reaction is general as the structurally diverse boronic acids reacted smoothly under present reaction conditions giving high to excellent yields of the corresponding aryliodides.²⁷ Though electron neutral phenylboronic acid provided moderate yield (∼39%) of the iodoproduct, (Table 6, entry 1), the electron rich and electron deficient boronic acids invariably shown much higher reactivity under optimized conditions as described previously.

Table 6 Scope of boronic acids in copper catalysed ipso iodination^a

Entry	Boronic acid	Product	Yield^b (%)
a Reaction conditions: 0.2 mmol of boronic acid, 0.4 mmol of morpholine, 0.48 mmol of I2 in the presence of CuI (5 mol%) in methanol (1.5 ml) at room temperature for 24 h.b Isolated yields by column chromatography.c A complex mixture was obtained.
1			39
2			75
3			90
4			87
5			95
6			—^c
7			85
8			53
9			82
10			92
11			85
12			93
13			90
14			78
15			96
16			95
17			81
18			94
19			83
20			28

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The arylboronic acids bearing alkyl- (Table 6, entries 2 and 3), alkylthio- (Table 6, entries 4, and 5), carbonyl- (Table 6, entries 7 and 8), alkoxy- (Table 6, entry 12), alkoxycarbonyl- (Table 6, entries 9 & 10), amide- (Table 6, entry 11), halide- (Table 6, entries 12–16), cyano- (Table 6, entry 17), nitro- (Table 6, entry 18), sulfonyl- (Table 6, entry 19) etc. participated successfully in the ipso iodination process. Notably, one of the most electron deficient boronic acids, for instance, 3-nitrobenzeneboronic acid had shown exceptionally high reactivity giving near quantitative yield of the iodoproduct using these conditions.

Of particular importance, ortho substituted, sterically hindered boronic acids such as 2-chloro-4-methoxy- (Table 6, entry 12) and 2-bromophenylboronic acid (Table 6, entry 14) also found to be the suitable substrates in the present reaction giving excellent and good yield of the corresponding iodoproducts respectively.

The representative heteroarylboronic acids such pyridine-4-boronic acid and 5-trifluoromethyl-pyridine-3-boronic acid were also investigate under present reaction conditions. The corresponding 3-iodo-5-trifluoromethyl-pyridine was obtained in 28% yield (Table 6, entry 20) and unfortunately, the isolation of product from the reaction of pyridine-4-boronic acid by column chromatography was almost become impossible probably due to rapid formation of corresponding N-oxide and other side products (result not shown). The low yield in case of 5-trifluoromethyl-pyridine-3-boronic acid was mainly due to the complications arised during column chromatography (despite of using triethylamine treated silica) as TLC indicated complete consumption of starting material. For similar reason, highly electron rich, (4-N,N-dimethylamino)phenyl boronic acid (Table 6, entry 6) failed to furnish any ipso product.

Its worth mentioning here that very recently we reported the green protocol for the ipso iodination of arylboronic acids using CTAB/I₂ in aqueous media.²⁴ Though the method provides the green alternative for the synthesis of aryl iodides, however, it required high temperature (80 °C) and has limited substrate scope as only electron rich boronic acids were found to be the suitable substrates. As compared to our previous work, the present method involving novel NIMI as iodinating agent is highly versatile as both electron rich as well as electron deficient arylboronic acids and heteroarylboronic acids reacted efficiently to give good to excellent yield of the aryliodides. Furthermore, the method is mild, operationally simple and could be carried out in open atmosphere without the need for special ligand or additives using very low catalyst loading. Thus these two methods have significant differences and the present method provides alternative ipso iodination tool for synthetic applications.

As alkylboronic acids such as methyl- and indanylboronic acids (results not shown) did not react at all under present reaction conditions, it was clear that the presence of aryl group was the prerequisite for the success of the iodination reaction. In general, the reaction was highly regioselective and invariably no formation of other side products was observed.

Finally, we sought to determine the plausible mechanism(s) for the present ipso iodination process. Regarding mechanistic aspect of the present reaction, we carefully noted many crucial facts during our optimization study: (1) the reaction can be proceeded using catalytic amount of morpholine (Table 1, entries 2 and 3 and Table 4, entries 1 and 2) indicates that morpholine might be regenerated during the catalytic cycle, (2) the iodination does not proceed at all even using stoichiometric amount of CuI or more than twofold excess of I₂ alone, but using catalytic amount of CuI and excess I₂ the ipso iodination proceeded smoothly even at room temperature. We believe that that I₂ oxidizes CuI to copper(II) species which must acts as a true catalyst, (3) there is little effect of CuI on the reaction with 4-ethylphenylboronic acid but the effect is pronounced in case of electron deficient 3-nitrophenylboronic acid indicates that CuI plays pivotal role in the catalysis of iodination of 3-nitrophenylboronic acid and related substrates, (4) under inert atmosphere, the yield obtained was more or less similar to that of uncatalyzed reaction (Table 1, entries 15 vs. 10) justifying the need for air atmosphere to facilitate the copper catalysed pathway, (5) the fact that in the absence of morpholine but using CuI and I₂ very low yield was obtained (Table 1, entries 15 vs. 17) and using other iodinating agents such as KI or NaI, the reaction did not proceed at all even in the presence of stoichiometric amount of CuI evident the key role of NIMI for the success of the reaction, (6) the transmetallation of organoboron compound to organocopper is not a general reaction. Due to their similar bond energies and electronegativities such a transmetallation of organoboron to organocopper reagents is limited to the preparation of alkenylcopper and to some extent to unfunctionalized alkylcopper compounds.²⁸ This is why the popular Chan–Lam coupling requires either stoichiometric copper catalyst or catalytic copper strictly under oxygen atmosphere or other primary oxidant in the presence of 2–3 equivalent of amine base and special ligand. In case of 3-nitrophenylboronic acid the use of excess morpholine can only proceed the reaction successfully. Therefore, we believe that in the present CuI catalysis such a transmetallation of 3-nitrophenylboronic acid and other electron deficient substrates to the corresponding organocopper reagents must be a slow process and the use of excess morpholine must compensate for the same ultimately giving satisfactory result.

All these findings lead us to speculate that the present ipso iodination reaction can be attributed to the multiple underlying mechanisms such as concomitant metal free ipso-iodination and NIMI/morpholine assisted copper-catalyzed deiodoborylation pathway and depending upon the nature of substrate either of them overall dominates the reaction. On this basis, we proposed the plausible mechanism(s) for the ipso iodination of the boronic acid as outline in Scheme 4.

Scheme 4 Proposed mechanism(s) for the ipso iodination of boronic acid: (a) classical ipso-iodination pathway and, (b) and (c) NIMI and morpholine assisted copper-catalysed deiodoborylation pathways respectively.

The N-iodomorpholinium iodide 2 generated from morpholine 1 and I₂ acts as actual iodinating agent. The iodide ion activates the boronic acid 3 via Lewis acid–base type interaction leading to the formation of ionic species 4. The ipso attack involving N-iodomorpholinium ion lead to the formation of iodocompound 5 and morpholine is regenerated and reused again. As regard to the copper catalysed deiodoborylation pathway, we believe that the oxidation of CuI 6 with I₂ generates Cu(II) species 7 which supposed to be the actual copper catalyst. The transmetallation between 7 and 4 forms the organocuprate 8 which on air oxidation or oxidation with equilibrated O₂ in methanol²⁹ results into the formation of aryl copper(III) intermediate 9. The reductive elimination of 9 yield the aryliodides 5 and Cu(I) species is regenerated and reused again. Alternatively, the improvement of the yield in correlation to the added morpholine can also be explained on the basis of participation of morpholine–boronic acid “ate complex” 10 in copper catalysed deiodoborylation pathway (Scheme 4, path C). This also strongly support the need for excess morpholine for the smooth proceeding of the reaction. However, the possibility of stabilization of unstable CuI₂ by morpholine as a ligand cannot be ruled out at this point of time.

Experimental section

General information

All the solvents were redistilled before used. Analytical TLCs were performed on Merck silica gel 60F254 plates. The boronic acids were purchased from Johnson Matthey Chem. Ltd and other chemicals were purchased from Sigma Aldrich Chem. Ltd. The IR spectra (ATR mode) were recorded on Brucker IR spectrometer. The ¹H and ¹³C NMR spectra (in CDCl₃) were recorded on Agilent 400 or Bruker Avance-II 400 MHz spectrometer. The chemical shift values are on a δ scale and TMS was used as an internal standard. The ¹⁹F NMR spectra were recorded in DMSO-d6 on Bruker Avance II 400 MHz spectrometer using CFCl₃ as internal standard. Abbreviations used are: s (singlet), d (doublet), t (triplet), dd (double doublet), dt (doublet triplet), m (multiplet). The high-resolution mass spectral analysis was performed on Micromass Q-Tof (ESI-HRMS) and GCMS were recorded on Shimadzu gas chromatograph.

General procedure for the synthesis of aryl iodides

To a 10 ml round bottomed flask charged with morpholine (0.4 mmol, 2 equiv.) and I₂ (0.48 mmol, 2.4 equiv.) was added methanol (1.5 ml) and the reaction mixture was stirred for 30 minutes at room temperature. Then the appropriate arylboronic acid (0.2 mmol) and CuI (2 mg, 0.01 mmol) was added to it and the mixture was stirred vigorously at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 10% sodium thiosulphate solution (to remove excess of iodine) and extracted with ethyl acetate (3 × 10 ml) and the combined organic extract was washed with water and brine. The evaporation of solvent under vacuum after drying over anhy. Na₂SO₄ followed by column chromatography (petroleum ether (100%) or petroleum ether : ethyl acetate, 9 : 1) gave the analytically pure product. (Note: direct column chromatography of crude product adsorbed on silica followed by washing the effluent with Na₂S₂O₃ solution, drying and evaporation of the solvent gave exactly similar results).

Conclusions

In conclusion, we have developed the general and efficient protocol for the regioselective synthesis of aryl iodides via ipso-iodination of arylboronic acids using N-iodomorpholinium iodide as iodinating agent under mild conditions. The method utilizes the readily accessible and cheap reagents, morpholine & I₂, copper iodide as catalyst, nonhazardous methanol as a solvent and could be performed in open atmosphere without the need for any special ligand or additives. The mild reaction conditions, operational simplicity, high to excellent yields, excellent functional group compatibility and low catalyst loading are the noteworthy features of the present method which makes it an attractive alternative for the synthesis of valuable aryl iodides. The present method would attract much attention of chemical community at large.

Acknowledgements

RHT thanks Department of Science and Technology (DST) Ministry of Science, India for financial support of this project (SR/FT/CS-85/2011), GVB and TGK thank UGC India, for Rajiv Gandhi National Fellowship.

Notes and references

1. (a) Metal catalyzed cross coupling reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinheim, 1997; (b) Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize J. Seechurn, C. C. Carin, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062; (c) Palladium Catalysed Cross Coupling Reactions of Organoboron Compounds N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
2. (a) T. Wirth, M. Ochiai, A. Varvgolis, V. V. Zhdankin, G. F. Koser, H. Tohma and Y. Kita, Topics in Current Chemistry: Hypervalent Iodine Chemistry/Modern Developments in Organic Synthesis, Springer-Verlag, Berlin, 2002, pp. 1–248; (b) A. Varvoglis, Hypervalent Iodine in Organic Synthesis, Academic Press, London, 1997, pp. 1–223; (c) P. Stang and V. V. Zhadankin, Chem. Rev., 1996, 96, 1123; (d) A. Parra and S. Reboredo, Chem.–Eur. J., 2013, 19, 17244.
3. S. W. Kim, J. H. Park, S. D. Yang, M. G. Hur, Y.-S. Kim, J.-S. Chai, Y. S. Kim and K. H. Yu, Bull. Korean Chem. Soc., 2004, 25, 1147–1150.
4. (a) M. K. Dewanjee, Radioiodination : Theory, Practice and Biomedical Applications, Kluwer Academic Publishers, Bosten, 1992; (b) R. Weissleder, Science, 2006, 312, 1168–1171.
5. J. March, Advance Organic Chemistry, Wiley-Interscience, 4th edn, New York, 2000.
6. (a) J. Iskra, S. Stavber and M. Zupan, Synthesis, 2004, 1869–1873; (b) N. C. Ganguly, S. K. Barik and S. Dutta, Synthesis, 2010, 1467–1472; (c) K. M. Sosnowski and L. Skulski, Synthesis, 2006, 1195–1199; (d) A.-S. Castanet, F. Colobert and P.-E. Broutin, Tetrahedron Lett., 2002, 43, 5047–5048; (e) P. Lulinski and L. Skulski, Bull. Chem. Soc. Jpn., 1997, 70, 1665; (f) P. Lulinski, A. Kryska, M. Sosnowski and L. Skulski, Synthesis, 2004, 441–445; (g) B. Krassowska-Swiebocka, P. Lulinkski and L. Skulski, Synthesis, 1995, 926; (h) H. O. Wirth, O. Konigstein and W. Kern, Liebigs Ann.Chem., 1977, 42, 4049; (i) S. Ahmed and S. Razaq, Tetrahedron, 1976, 32, 503; (j) H. Suzuki, K. Nakamura and R. Goto, Bull. Chem. Soc. Jpn., 1966, 39, 128; (k) H. Suzuki, Bull. Chem. Soc. Jpn., 1970, 43, 481; (l) A. Shimizu, K. Yamataka and T. Isoya, Bull. Chem. Soc. Jpn., 1985, 58, 1611; (m) A. Bachki, F. Foabelo and M. Yus, Tetrahedron, 1994, 50, 5139; (n) W.-W. Sy, B. A. Lodge and A. W. By, Synth. Commun., 1990, 20, 877.
7. T. Sandmeyer, Chem. Ber., 1884, 1633.
8. (a) V. D. Filimonov, N. I. Semenischeva, E. A. Krasnokutskaya, A. N. Tretyakov, H. Y. Hwang and K.-W. Chi, Synthesis, 2008, 185–187; (b) V. D. Filimonov and P. Knochel, Synthesis, 2007, 81–84; (c) A. Hubbard, T. Okazaki and K. K. Laali, J. Org. Chem., 2008, 73, 316–319.
9. R. W. Fish and M. Rosenblum, J. Org. Chem., 1965, 1253.
10. A. McKillop, J. D. Hunt, M. J. Zelesko, J. S. Fowler, E. C. Taylor, G. Mc-Gillivray and F. Kienzle, J. Am. Chem. Soc., 1971, 93, 484.
11. A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844–14845.
12. A. Pelter, K. Smith and H. C. Brown, Borane Reagents, Academic Press, London, 1998; K. Smith, Organoboron Chemistry, in Organometallic in Synthesis, ed. M. Schlosser, Wilet Chinchester, 1994.
13. Boron, Metallo-Boron, Compounds and Boranes, ed. R. M. Adams, Wiley, New York, 1964, p. 693, data quoted in Registry of Toxic Effect of Chemicals Substances, NIOSH, 2002.
14. (a) D. G. Hall, Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2011, and references cited therein; (b) D. G. Hall, Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, Wiley-VCH, 2nd edn, Weinheim, 2011, and references cited therein; (c) Y. Guan and Y. Zhang, Chem. Soc. Rev., 2013, 42, 8106; (d) J. N. Cambre and B. S. Sumerlin, Polymer, 2011, 52, 4631.
15. For metal catalyzed borylation reactions: see (a) W. K. Chow, Y. O. Yuen, P. Y. Choy, C. M. So, C. P. Lau, K. W. Wong and F. Y. Kwong, RSC. Adv., 2013, 3, 12518–12539; (b) T. Ishiyama, M. Murata and N. Miyura, J. Org. Chem., 1995, 60, 7508–7510; (c) A. L. S. Thomson, G. Kabalka, M. R. Akula and J. W. Huffman, Synthesis, 2005, 547–550; (d) A. Molander, L. N. Cavalcanti and C. Garcia-Garcia, J. Org. Chem., 2013, 78, 6427–6439; (e) G. A. Molander, S. L. J. Trice and S. M. Kennedy, Org. Chem., 2012, 77, 8678–8688; (f) W. Tang, S. Keshipeddy, Y. Zhang, X. Wei, J. Savoie, N. D. Patel, N. K. Yee and C. H. Senanayake, Org. Lett., 2011, 13, 1366–1369; (g) S. Dundik and G. C. Fu, J. Am. Chem. Soc., 2012, 134, 10693–10697; (h) J. Takagi, A. Kamon, T. Ishiyama and N. Miyaura, Synlett, 2002, 1880–1882; (i) J. Takagi, K. Takahashi, T. Ishiyama and N. Miaura, J. Am. Chem. Soc., 2002, 124, 8001–8006; (j) D. G. Hall, Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2011, and references cited therein.
16. For borylation of arenes via C–H activation see: (a) J. M. Murphy, X. Liao and J. F. Hartwig, J. Am. Chem. Soc., 2007, 129, 15434–15435; (b) B. Partridge and J. F. Hartwig, Org. Lett., 2013, 15, 140–143; (c) S. Sebelius, J. Olsson and K. J. Szabo, J. Am. Chem. Soc., 2005, 127, 10478; (d) V. J. Olsson and K. J. Szabo, Angew. Chem., Int. Ed., 2007, 46, 689; (e) V. J. Olsson, S. Sebelius, N. Selander and K. J. Szabo, J. Am. Chem. Soc., 2006, 128, 4588; (f) V. J. Olsson and K. J. Szabo, Org. Lett., 2008, 10, 3129; (g) D. Hall, Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2011, and references cited therein; (h) M. Murata, S. Watanabe and Y. Masuda, J. Org. Chem., 1997, 62, 6458; (i) M. Murata, T. Oyama, S. Watanabe and Y. Masuda, J. Org. Chem., 2000, 65, 164; (j) C. Kleeberg, L. Dang, Z. Lin and T. B. Marder, Angew. Chem., Int. Ed., 2009, 48, 5350.
17. (a) C.-Z. Tao, X. Cui, A.-X. Liu, L. Liu and Q.-X. Guo, Tetrahedron Lett., 2007, 48, 3525–3529; (b) S. Mohammed, A. K. Padala, A. Dar, B. Singh, B. Sreedhar, R. A. Vishwakarma and S. B. Bharate, Tetrahedron, 2012, 68, 8156–8162.
18. A. Kar, I. A. Sayeed, W. F. Low, H. M. Kaiser, M. Beller and M. K. Tse, Org. Lett., 2007, 9, 3405.
19. (a) S. Guo, L. Lu and H. Cai, Synlett, 2013, 24, 1712–1714; (b) J. Xu, X. Wang, C. Shao, D. Su, G. Cheng and Y. Hu, Org. Lett., 2010, 12, 1964–1967; (c) C. Zhu, R. Wang and J. R. Falck, Org. Lett., 2012, 14, 3494–3497; (d) G. A. Molander and L. N. Cavalcanti, J. Org. Chem., 2011, 76, 623–630; (e) A. Gogoi and U. Bora, Synlett, 2012, 23, 1079–1081; (f) H.-L. Qi, D.-S. Chen, J.-S. Ye and J.-M. Huang, J. Org. Chem., 2013, 78, 7482–7487; (g) D.-S. Chen and J.-M. Huang, Synlett, 2013, 24, 499–501; (h) G. K. S. Prakash, S. Chacko, C. Panja, T. E. Thomas, L. Gurung, G. Rasul, T. Mathew and G. A. Olah, Adv. Synth. Catal., 2009, 351, 1567–1574.
20. (a) C. Thiebes, G. K. S. Prakash, N. A. Petasis and G. A. Olah, Synlett, 1998, 141–142; (b) L. Niu, H. Zhang, H. Yang and H. Fu, Synlett, 2014, 25, 995–1000; (c) M. P. Akula, M. L. Yao and G. W. Kabalka, Tetrahedron Lett., 2010, 51, 1170–1171; (d) F. Tramutola, L. Chiummiento, M. Funicello and P. Lupatteli, Tetrahedron Lett., 2015, 56, 1122–1123; (e) G. Y. Zhang, G. L. Lv, L. P. Li, F. Chen and J. Cheng, Tetrahedron Lett., 2011, 52, 1993–1995.
21. For the synthesis of aryl halides from organoboron compounds see (a) B. M. Partridge and J. F. Hartwig, Org. Lett., 2013, 15, 140–143; (b) G. A. Molander and L. N. Cavalcanti, J. Org. Chem., 2011, 76, 7195–7203; (c) T. Furuya, H. M. Kaiser and T. Ritter, Angew. Chem., Int. Ed., 2008, 47, 5993–5996; (d) T. Furuya, D. Benitez, E. Tkatchouk, A. E. Strom, P. P. Tang, W. A. Goddard and T. Ritter, J. Am. Chem. Soc., 2010, 132, 3793–3807; (e) T. Furuya and T. Ritter, Org. Lett., 2009, 11, 2860–2863; (f) G. W. Kabalka and E. E. Gooch, J. Org. Chem., 1980, 45, 3578; (g) G. W. Kabalka and E. E. Gooch, J. Org. Chem., 1981, 46, 2582; (h) G. W. Kabalka, V. Namboodiri and M. R. Akula, J. Labelled Compd. Radiopharm., 2001, 44, 921; (i) G. W. Kabalka and A. R. Mereddy, Organometallics, 2004, 23, 4519; (j) R. H. Szumigala, P. N. Devine, D. R. Gauthier and R. P. Volante, J. Org. Chem., 2004, 69, 566; (k) A. L. S. Thompson, G. W. Kabalka, M. R. Alkula and J. W. Huffman, Synthesis, 2005, 547.
22. (a) G. K. S. Prakash, C. Panja, T. Mathew, V. Surampudi, N. A. Petasis and G. A. Olah, Org. Lett., 2004, 6, 2205–2207; (b) S. Salzbrunn, J. Simon, G. K. S. Prakash, N. A. Petasis and G. A. Olah, Synlett, 2000, 1485–1487; (c) S. Manna, S. Maity, S. Rana, S. Agasti and D. Maiti, Org. Lett., 2012, 14, 1736–1739; (d) X. F. Wu, J. Schranck, H. Neumann and M. Beller, Chem. Commun., 2011, 47, 12462–12463; (e) S. B. Bharate, R. R. Singh and R. A. Vishwakarma, Tetrahedron Lett., 2012, 53, 5958–5960.
23. (a) S. Voth, J. W. Hollet and J. McCubbin, J. Org. Chem., 2015, 80, 2545–2553; (b) Q. Xiao, L. Tian, T. Renchang, Y. Xia, D. Qiu, Y. Zhang and J. Wang, Org. Lett., 2012, 14, 4230–4233; (c) V. Coeffard, X. Moreau, C. Thomassigny and C. Greck, Angew. Chem., Int. Ed., 2013, 52, 5684–5686; (d) K. W. Anderson, P. M. Mendez, J. Priego and S. L. Buchwald, J. Org. Chem., 2003, 68, 9563–9573; (e) C. Zhu, G. Li, D. H. Ess, J. R. Falck and L. Kurti, J. Am. Chem. Soc., 2012, 134, 18253–18256.
24. R. H. Tale, G. K. Toradmal, V. B. Gopula, A. H. Rodge, R. P. Pawar and K. M. Patil, Tetrahedron Lett., 2015, 56, 2699–2703.
25. (a) R. H. Tale and R. N. Adude, Tetrahedron Lett., 2006, 47, 7263–7265; (b) R. H. Tale, A. D. Sagar, H. D. Santan and R. N. Adude, Synlett, 2006, 3, 415–418; (c) A. D. Sagar, R. H. Tale and R. N. Adude, Tetrahedron Lett., 2003, 44, 7061–7063.
26. (a) R. V. Rice and G. D. Beal, US Pat. 2,290,710, July 21, 1943; (b) M. Koyama, N. Ohtani, F. Kai, I. Moriguchi and S. Inouye, J. Med. Chem., 1987, 30, 552.
27. The analytical data for representative compounds are provided below: 4-ethyliodobenzene 2b: yellow liquid, 75% ¹H NMR: δ 1.20 (t, 3H), 2.57 (q, 2H), 6.93 (dd, 2H), 7.57 (dd, H). EI-MS [M]⁺ = 232. 4-Isopropyl iodobenzene 2c: yellow liquid, 90% ¹H NMR: (CDCl₃, 400 MHz) δ 1.25 (d, 6H), 2.68 (septet, 1H), 6.98 (dd, 2H), 7.61 (dd, H); EI-MS [M]⁺ = 246. Isopropyl-4-iodophenyl sulphide 2e: yellow liquid, yield 95% ¹H NMR (CDCl₃, 400 MHz): δ 1.27 (d, 6H), 3.35 (septet, 1H), 7.10 (dd, 2H), 7.58 (dd, H). ¹³NMR (CDCl₃, 400 MHz): δ 23.00, 36.1, 91.7, 133.2, 135.7, 137.7; GC-MS RT= 11.01[m/z] = 278. HRMS; calcd for: C₉H₁₁IS, 277.9626; found 277.962, 4-carboethoxyiodobenzene 2j: yellow liquid, yield 92% ¹H NMR (CDCl₃, 400 MHz): δ 1.38 (t, 3H), 4.35 (q, 2H), 7.73 (dt, 2H), 7.78 (dt, 2H). ¹³C NMR (CDCl₃, 400 MHz): δ 14.5, 61.2, 100.6, 129.9, 131, 137.6, 166. 2-Chloro-1-iodo-4-methoxybenzene 2l: faint yellow oil, yield 93% ¹H NMR (CDCl₃, 400 MHz): δ 3.78 (s, 3H), 6.55 (dd, J = 2.97 Hz, 1H), 7.02 (d, J = 2.88 Hz, 1H), 7.67 (d, J = 8.78 Hz, 1H). 1-Bromo-3-iodo-5-methylbenzene 2o: light yellow liquid, yield 96% ¹H NMR (CDCl₃, 400 MHz): δ 2.28 (s, 3H), 7.29 (s, 1H), 7.46 (s, 1H), 7.65 (s, 1H). HRMS; calcd for: C₇H₆BrI, 295.8698; found 295.8698. 1-Iodo-4-(methylsulfonyl)benzene 2s: while solid, yield 83% ¹H NMR (CDCl₃, 400 MHz): δ 3.03 (s, 3H), 7.63 (m, 2H), 7.91 (m, 2H), ¹³C NMR (CDCl₃, 400 MHz): δ 44.4, 101.6, 128.7, 138.6, 140.1. 3-(Trifluoromethyl)-5-iodopyridine 2t: white solid, yield 28% (isolated by column chromatography using trimethyl amine pretreated silica gel) ¹H NMR (CDCl₃, 400 MHz): δ 8.24 (m, 1H), 8.83 (s, 1H), 9.03 (s, 1H), HRMS (calculated for C₆H₃NIH = 272.9271); found = 273.9341 (M + H)⁺.
28. (a) Modern Organocopper Chemistry, ed. N. Krause, Wiley-VCH Verlag GmbH, 2002; (b) N. Miyaura, N. Sasaki, M. Itoh and A. Suzuki, Tetrahedron Lett., 1977, 18, 173.
29. F. Alonso, Y. Moglie, G. Radivoy and M. Yus, Synlett, 2012, 23, 2179–2182.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, analytical data and copies of ¹H, ¹³C, ¹⁹F NMR; and, HRMS/mass spectra of newly synthesized compounds. See DOI: 10.1039/c5ra18820b

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