Ortho -iodination of aromatic carboxylic acids in aqueous media

Introduction

The important role of aryl halides is quite obvious to the researchers in the field of organic synthesis. The significant presence of these compounds in preparation of natural products and heterocyclic compounds doubles this importance.^1–8 Furthermore, aryl halides are valuable precursors for preparation of reagents such as organolithium compounds ⁹ and Grignard reagents ¹⁰ which are the key substrates in various cross-coupling reactions. ¹¹ Hence, synthetic methods toward the production of aryl halides are of great interest. Traditional methods for the synthesis of aryl halides—such as Sandmeyer reactions, ¹² directed-orthometallation (DoM), ¹³ and electrophilic aromatic substitution ¹⁴ —are often faced with different limitations.

In the last decade, transition metal-catalyzed direct halogenation of C–H bonds has been a method of choice to obtain haloarenes. ¹⁵ However, finding a suitable adjacent functional group to control regioselectivity in molecules containing diverse C–H groups remains a challenge for these methods. ¹⁶ Aromatic carboxylic acids are cheap and readily available compounds and the carboxyl group can easily be converted into other functional groups. However, the carboxyl group is less studied as the directing group due to the weak complexion ability to the metal center.

As far as we know, only two systems have been reported for transition metal-catalyzed iodination of aromatic compounds directed by carboxyl functionality. In 2008, a method was reported for ortho-iodination of benzoic acid derivatives under palladium-catalyzed conditions (Scheme 1). ¹⁷ In the conditions employed by this group, poor selectivity was observed for derivatives having no ortho- or meta-substitution. In 2018, an excellent method for the synthesis of ortho-iodobenzoic acids under iridium catalysis was presented. This method failed to reach the high selectivity for the substrates with no ortho- or meta-substitution (Scheme 1(a)). ¹⁸

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Scheme 1.

History of ortho-iodination of benzoic acid derivatives at a glance: (a) previous works and (b) this work.

Due to the challenges of using carboxyl as a directing group and a few reports in this field, we were interested in studying the mono-selective iodination of benzoic acids in aqueous media (Scheme 1(b)).

Results and discussion

Initially, we were looking for a suitable system for production of I⁺ under green conditions in aqueous media. In 2009, Firouzabadi et al. ¹⁹ presented a novel method for highly regioselective mono-iodination and bromination of arenes. Inspired by this method, we used NaI as the source of I⁺, a catalytic amount of Ce(III), and H₂O₂ (35% aq.) as the terminal oxidant in aqueous media under reflux conditions. We started our investigations using benzoic acid as the substrate in the presence of Pd(OAc)₂ as the catalyst. Under the employed conditions, the desired mono-iodinated product was isolated in 11% yield (Table 1, entry 1). The use of other oxidants such as oxone, benzoquinone (BQ), AgNO₃, K₂S₂O₈, Cu(OAc)₂.H₂O, ^tBuOOH, or H₂O₂ were not successful (Table 1, entries 2–8). The reaction failed using CuI or FeCl₃ instead of CeCl₃.7H₂O (Table 1, entries 9 and 10). CoCl₂, NiCl₂, or Cu(OAc)₂.H₂O were not effective catalysts for this reaction (Table 1, entries 11–13). In contrary to the Yu observations, ¹⁷ the basic additives were detrimental in this reaction (Table 1, entries 14–16). However, trifluoroacetic acid (TFA) and acetic acid did not affect the reaction significantly (Table 1, entries 17 and 18). Increasing the amounts of each of the starting materials did not improve the reaction process (Table 1, entries 19–21). Increasing the amount of Pd(OAc)₂ to 0.2 mmol did not change the reaction efficiency and the side products were observed (Table 1, entry 22). Next, we switched the catalyst to PdCl₂(PhCN)₂ as another source of Pd(II) (Table 1, entries 23–27). Under the standard conditions, the desired product was not formed (Table 1, entry 23). To increase the solubility of benzoic acid in water, we used a combination of organic solvents such as dimethylformamide (DMF) and polyethylene glycol (PEG) with the phase transfer catalyst tetrabutylammonium iodide (TBAI) (Table 1, entries 24 and 25). Under these conditions, the starting materials remained intact and the desired product was not formed. When we increased the amount of the catalyst to 30 mol%, trace amount of the product was formed (Table 1, entry 26) and further increase in the amount of catalyst up to 50 mol% significantly increased the product yield up to 54% and no side product (e.g. 2,6-diiodobenzoic acid) was observed in this reaction (Table 1, entry 27).

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Table 1.

Optimization of the reaction conditions.

Entry	Catalyst	Oxidant	Additive	Solvent	Temperature (°C)	Yield (%)
1	Pd(OAc)2	H2O2/CeCl3.7H2O	–	H2O	110	11
2	Pd(OAc)2	Oxone	–	H2O	110	–
3	Pd(OAc)2	BQ	–	H2O	110	–
4	Pd(OAc)2	AgNO3	–	H2O	110	–
5	Pd(OAc)2	K2S2O8	–	H2O	110	–
6	Pd(OAc)2	Cu(OAc)2.H2O	–	H2O	110	–
7	Pd(OAc)2	tBuOOH	–	H2O	110	–
8	Pd(OAc)2	H2O2	–	H2O	110	–
9	Pd(OAc)2	H2O2/CuI	–	H2O	110	–
10	Pd(OAc)2	H2O2/FeCl3	–	H2O	110	–
11	CoCl2	H2O2/CeCl3.7H2O	–	H2O	110	–
12	NiCl2	H2O2/CeCl3.7H2O	–	H2O	110	–
13	Cu(OAc)2.H2O	H2O2/CeCl3.7H2O	–	H2O	110	–
14	Pd(OAc)2	H2O2/CeCl3.7H2O	K2CO3	H2O	110	–
15	Pd(OAc)2	H2O2/CeCl3.7H2O	NaOAc	H2O	110	–
16	Pd(OAc)2	H2O2/CeCl3.7H2O	Et3N	H2O	110	–
17	Pd(OAc)2	H2O2/CeCl3.7H2O	TFA	H2O	110	8
18	Pd(OAc)2	H2O2/CeCl3.7H2O	AcOH	H2O	110	10
19 a	Pd(OAc)2	H2O2/CeCl3.7H2O	–	H2O	110	–
20 b	Pd(OAc)2	H2O2/CeCl3.7H2O	–	H2O	110	–
21 c	Pd(OAc)2	H2O2/CeCl3.7H2O	–	H2O	110	11
22 d	Pd(OAc)2	H2O2/CeCl3.7H2O	–	H2O	110	11
23	PdCl2(PhCN)2	H2O2/CeCl3.7H2O	–	H2O	110	–
24 e	PdCl2(PhCN)2	H2O2/CeCl3.7H2O	TBAI	H2O/PEG	110	–
25 f	PdCl2(PhCN)2	H2O2/CeCl3.7H2O	TBAI	H2O/DMF	110	–
26 g	PdCl2(PhCN)2	H2O2/CeCl3.7H2O	–	H2O	110	Trace
27 h	PdCl2(PhCN)2	H2O2/CeCl3.7H2O	–	H2O	110	54%

TFA: trifluoroacetic acid; BQ: benzoquinone; DMF: dimethylformamide; PEG: polyethylene glycol.

Reaction conditions: benzoic acid (1 mmol), KI (1.5 mmol), catalyst (0.05 mmol), CeCl₃.7H₂O (0.5 mmol), oxidant (H₂O₂:1 mL, others: 0.5 mmol), additive (0.5 mmol), and solvent (3 mL).

a

KI (2 mmol).

b

CeCl₃.7H₂O (1 mmol).

c

H₂O₂ (3 mL).

d

Pd(OAc)₂ (0.2 mmol).

e

TBAI (0.1 mmol), PEG (1 mL), H₂O (2 mL).

f

TBAI (0.1 mmol), DMF (1 mL), H₂O (2 mL).

g

PdCl₂(PhCN)₂ (0.3 mmol).

h

PdCl₂(PhCN)₂ (0.5 mmol).

Based on the optimization studies, the scope of the reaction was investigated. 3-Methyl benzoic acid was subjected to the standard reaction conditions giving the desired product in 60% yield. 3-Bromobenzoic acid was also active in this reaction and the corresponding bromo-iodo-derivative was isolated in 65% yield. The nitro substitution in the meta or para positions to the carboxyl group caused the significant decrease in the activity of the substrate (Scheme 2). In order to clarify the mechanism of the reaction, we investigated the model reaction in the absence of palladium catalyst. No product was formed under these conditions indicating the probable progress of the reaction via C–H bond activation pathway. The reaction failed in the absence of CeCl₃ and H₂O₂, showing that the in situ production of I⁺ via this oxidation system is a key step for this iodination reaction.

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Scheme 2.

Ortho-iodination of aromatic carboxylic acids via Pd-catalyzed directed C–H activation.

Based on our observations and also the reports in the literature, the proposed mechanism for ortho-iodination of benzoic acid derivatives is presented in Scheme 3. First, Pd(II) is oxidized to cationic palladium(IV) in the presence of CeCl₃.7H₂O/H₂O₂ oxidation system. ²⁰ This cationic palladium(IV) is reported to be an effective catalyst for C–H bond activation. ²¹ Second, the carboxyl group coordinates to Pd(IV) directing C–H activation to generate a palladacycle intermediate. Finally, C–I bond formation is achieved in the presence of iodonium ion.

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Scheme 3.

Plausible mechanism for o-iodination of aromatic carboxylic acids via the in situ generated Pd(IV) catalyst.

Conclusion

In summary, we reported the palladium(II)-catalyzed mono-iodization of benzoic acid derivatives in aqueous media using potassium iodide as the iodinium source. Mechanistic studies support palladacycle intermediate for C–H bond activation that can be a spark to expand the regioselective C–H bond functionalization in the presence of adjacent functional groups in aqueous media.

Supplemental Material