Pd(II)-catalyzed C-H Iodination Using Molecular I₂ as the Sole Oxidant

Abstract

Pd-catalyzed ortho-C–H iodination directed by a weakly coordinating amide auxiliary using I₂ as the sole oxidant was developed. This reaction is compatible with a wide range of heterocycles including pyridines, imidazoles, oxazoles, thiazoles, isoxazoles and pyrazoles.

Aryl halides (Ar-X, X = Cl, Br and I) are extensively used in Grignard¹ and cross-coupling² reactions. Directed lithiation followed by reaction with a halogen-containing electrophile has been a major method for the regioselective preparation of aryl halides.³ In the past decade, Pd(II)-catalyzed C–H halogenation utilizing electrophilic halogenating reagents has been extensively studied^4-10 and these collective efforts have significantly improved the synthetic utility of this potentially powerful transformation. Notably, the diastereoselective iodination of both prochiral sp³ and sp² C–H bonds was demonstrated.⁸ Protocols to iodinate broadly useful substrates such as carboxylic acids and protected amines have also been developed.¹⁰ Unfortunately, the use of the Suárez reagent IOAc¹¹ generated by reacting I₂ with AgOAc or PhI(OAc)₂ is not practical. Furthermore, non-catalyzed electrophilic iodination of electron-rich arenes can occur with this highly reactive iodinating reagent, leading to scrambling of regioselectivity.¹² Recently, Kakiuchi^9d has demonstrated the C–H chlorination of 2-phenylpyridine using a chloronium species generated in situ via electro-oxidation of HCl. Alternatively, the use of a combination of metal chlorides,^{9b, 9e} NCS^10d or NIS^9f and strong co-oxidants to achieve halogenation is also an improvement in terms of catalysis. A rare example of Rh(III)-catalyzed iodination of benzamides using NIS reported by Glorius is also an important advance.¹³ We envision that development of a simple catalytic system, using cheaper and milder molecular I₂ as the sole oxidant, will greatly improve the practicality of Pd-catalyzed C–H iodination reactions.

Herein we report an efficient and operationally simple Pd-catalyzed C–H iodination reaction that uses I₂ as the sole oxidant (Scheme 1). For the first time, directed C–H iodination was successfully applied to a wide range of heterocycles, which typically inhibit directed C–H activation. The success of this development hinges upon the combination of an amide auxiliary for promoting C-H activation and CsOAc as iodide scavenger to close the catalytic cycle.

Scheme 1.

A Practical C–H Iodination Reaction

We commenced our study by revisiting our earlier diastereoselective C–H iodination chemistry using a chiral auxiliary.⁸ Therein we observed two turnovers in iodination with I₂ which can be explained by the extensively studied Pd(II)/Pd(IV) or Pt(II)/Pt(IV) redox chemistry with IX reagents including I₂ (Figure 1).¹⁴ As expected from the redox chemistry shown in Figure 1, unreactive crystalline PdI₂ was formed following two turnovers of iodination when I₂ is used.⁸ We have previously used IOAc to regenerate Pd(OAc)₂ and close the catalytic cycle.^8,10

Figure 1.

Redox Chemistry of C–H Iodination with IX.

A single example of Pd-catalyzed iodination of azobenzene using I₂ as the halogen source and CuCl₂ as a co-oxidant indicated the possibility of using molecular I₂ as the halogenation reagent for C-H iodination.^5b We envision that an efficient anionic ligand exchange of PdI(OAc) or PdI₂ with other added metal salts MXn could provide a practical solution to regenerate PdXn as reactive catalysts. To ensure that the C–H activation step can proceed under various conditions and with additives that may be beneficial for the anionic ligand exchange, we attached one of the most efficient auxiliaries to phenylacetic acid to give amide 1a (Table 1) as the substrate,¹⁵ and began to test conditions for catalytic C–H iodination with I₂.

Table 1. Screening of Iodination Conditions^a.

entry	Pd (II)b	basec	solventd	yield (%)e
1	Pd(OAc)2	–	DMF	15
2	Pd(OAc)2	CsOAc	DMF	62
3	Pd(OAc)2	CsOAc	t-AmylOH	<5
4	Pd(OAc)2	CsOAc	DMF/t-AmylOH	80
5	Pd(OAc)2	CsOAc/NaHCO3f	DMF/t-AmylOH	99
6	Pd(OAc)2	NaHCO3f	DMF/t-AmylOH	35
7g	Pd(OAc)2	CsOAc/NaHCO3f	DMF/t-AmylOH	98 (95%h)
8	–	CsOAc/NaHCO3f	DMF/t-AmylOH	0
9	PdCl2	CsOAc/NaHCO3f	DMF/t-AmylOH	83
10	PdI2	CsOAc/NaHCO3f	DMF/t-AmylOH	75
11	PdI2	–	DMF/t-AmylOH	<5

^aThe reactions were run on 0.10 mmol scale in a 25 mL-sealed tube under aira.

^b5 mol % of the Pd(II) catalyst was used unless otherwise stated.

^c1.2 eq of CsOAc was used.

^dSolvent volume = 2.0 mL; DMF/t-AmylOH = 1:1.

^e% yield was determined e by the 1H NMR spectroscopy using CH₂Br₂ as the internal standard.

^f1.0 eq of NaHCO₃ was added.

^gThe reaction was run on 0.30 mmol scale with 2 mol % Pd(OAc)₂ in 5.0 mL of solvent.

^hYield of the isolated product.

Considering the poor solubility of PdI₂ in organic solvents, we anticipated that the use of a coordinative solvent could help solubilize PdI₂ and facilitate subsequent anionic exchange. After a short screening of inorganic salts (see the supporting information), we found that addition of cesium acetate (CsOAc) effectively improved catalytic turnovers (Table 1, entries 1, 2). Treatment of 1a with 2.5 equiv of I₂ at 65 °C in the presence of 5 mol % of Pd(OAc)₂ and 1.2 equiv of CsOAc in DMF produced the ortho-iodinated product 2a in 62% yield after 20 h (entry 2). 4 Å molecular sieves were added to prevent the hydrolysis of the amide. While t-amyl alcohol alone is a poor solvent for this reaction (entry 3), a mixture of DMF and t-amyl alcohol in a 1:1 ratio was found to improve the yield to 80% (entry 4). The use of NaHCO₃ as a co-additive improved yield to 99% (entry 5). The enhanced reactivity can be attributed to the N-H deprotonation of the amide to form imidate structure by using NaHCO₃ as a co-additive as established previously.^15g We were pleased to find that these conditions allowed us to reduce the Pd loading to 2 mol % while maintaining the yield as high as 98% (entry 7). Both PdCl₂ and PdI₂ are effective catalysts in the presence of CsOAc, albeit less effective than Pd(OAc)₂ (entries 9, 10). The loss of reactivity of PdI₂ in the absence of CsOAc suggests that the formation of Pd(OAc)₂ or PdI(OAc) via anionic ligand exchange is essential for catalysis (entry 11). Notably, treatment of 1a with NIS under these conditions led to full recovery of the starting material.

With our newly developed iodination method in hand, the substrate scope of this reaction was investigated. As shown in Table 2, both electron-donating methyl and methoxy groups (2a-d) and electron-withdrawing chloro, fluoro and trifluoromethyl groups (2e-h) were well tolerated as demonstrated by the excellent yields of the iodinated products. Naphthalene was iodinated at the β-position selectively (2i). Typically only 2 mol% Pd(OAc)₂ was used except for substrates bearing strong electron-withdrawing groups which required 5 mol% Pd for obtaining high yields (2g and 2h). When the ortho-positions of substrates were unsubstituted, di-iodinated products were formed exclusively (product 2j-n). With substrates bearing meta-substituents, the hindered ortho-position can still be iodinated to give the di-iodinated products (2o, 2p) in very high yields. To secure high conversions of these di-iodinations, 5 mol % of Pd(OAc)₂ was used. Interestingly, the α-methyl group in the arene substrates derived from Ibuprofen and Naproxen hampered the di-iodination (2q, 2r), presumably due to the steric buttress. The iodination of the latter substrate afforded the mono-iodinated product exclusively in 89% yield. This result suggests that mono-selective iodination of α-substituted phenylacetic amides is possible.

Table 2. Ortho-Iodination of Phenylacetic Amides^{a ,b, c, d, e}.

^aAr = (4-CF₃)C₆F₄.

^bReaction conditions for mono-iodination: 0.30 mmol of phenylacetic amide, 2 mol % Pd(OAc)₂, 0.75 mmol I₂, 0.36 mmol CsOAc, 0.30 mmol NaHCO₃, 150 mg 4 Å molecular sieves and 5.0 mL of t-AmylOH/DMF (1:1) in a sealed tube, 65 °C, 20 h.

^cFor products 2g, 2h and 2r, 5 mol % Pd(OAc)₂ was used.

^dReaction conditions for di-iodination: 0.10 mmol of phenylacetic amide, 5 mol % Pd(OAc)₂, 0.50 mmol I₂, 0.24 mmol CsOAc, 0.20 mmol NaHCO3, 50 mg 4 ° molecular sieves and 2.0 mL of t-AmylOH/DMF (1:1) in a sealed tube, 65 °C, 20 h.

^eYields of the isolated product.

^fRatio was determined by the ¹H NMR spectroscopy.

To further demonstrate the advantage of this method, we carried out gram-scale reactions using o-MeO, CH₃ and CF₃-substituted phenylacetic amide substrates in the presence of only 0.5 mol% of Pd(OAc)₂ (Scheme 2). The o-Me-substituted amide was iodinated to give the desired product in 75% yield (150 turnovers) while the iodination of o-CF₃-substituted substrate afforded a lower yield.

Scheme 2.

Gram-Scale Iodination with 0.5 mol % Pd(OAc)₂

Next, we subjected benzamide 3a to the optimized iodination conditions. Unfortunately, severe decomposition occurred to give an unidentified mixture. In the absence of NaHCO₃, reaction proceeded to give small amount of the iodination product 4a (15%) and the dimer 4a’ as the main product (58%). The dimer is likely formed via the C–H arylation of the mono-iodinated product with 4a which could be catalyzed by the traces of Pd(0) species present in the reaction. Switching the solvent to DMSO and use of K₂S₂O₈ (0.2 eq) as an additive to remove Pd(0) from the system increased the yield of 4a (41%), with only a slight decrease of the formation of 4a’ (48% yield). Nonetheless, mono-iodination of ortho-substituted benzamide substrates under these conditions proceeded to give the desired products in excellent yields without forming the dimers (4b-e). To probe the potential of developing a late-stage iodination method we subjected the complex drug candidate 3f¹⁶ to our iodination procedure and obtained the desired iodinated product 4f in 75% yield. Aryl iodide 4f can potentially react with a wide range of coupling partners using metal catalysts to provide a series of analogs for drug discovery. In particular, iodoarenes are superior substrates over bromo or chloro analogs for the preparation of tritium labeled compounds in high yield and radiospecific activity which are of great importance to late-stage tritio-dehalogenation of drug molecules to facilitate in vivo study of metabolic processes.¹⁷

Considering the lack of success of directed C–H activation reactions of heterocycles^18,19 and the prevalence of heteroarenes in drug molecules,²⁰ we were eager to test whether this iodination protocol is compatible with heterocyclic substrates. Remarkably, directed ortho-iodination readily occurred with a wide range of heterocycles under the standard conditions (Table 4). Minor adjustment of the reaction solvent and the temperature were needed for obtaining the optimum yields with each substrate. In general, either N-methylformamide (NMF) or DMSO is the most effective solvent. Unlike the iodination of benzamides (Table 3), dimerization did not occur with most of the heterocyclic substrates. However, additive K₂S₂O₈ (0.2 eq) was needed to minimize dimerization with pyrazole 5e and pyridines 5k and 5l.

Table 4. Ortho-Iodination of Heterocyclic Compounds^{a, b,c}.

^aAr = (4-CF₃)C₆F₄.

^bReaction conditions: 0.10 mmol substrate, 10 mol % Pd(OAc)₂, 0.40 mmol I₂, 0.24 mmol CsOAc, 0.10 mmol NaHCO₃, 50 mg 4 Å molecular sieves and 2.0 mL of solvent in a sealed tube, 16-48 h.

^cYields of the isolated product.

^d0.2 eq K₂S₂O₈ was used in place of NaHCO₃.

Table 3. Ortho-Iodination of Benzamides^{a, b, c, d, e}.

^aReaction conditions: 0.30 mmol of benzamide, 2 mol % Pd(OAc)₂, 0.75 mmol I₂, 0.36 mmol CsOAc, 0.06 mmol K2S2O8, 150 mg 4 Å molecular sieves and 4.0 mL DMSO in a sealed tube, 65 °C, 16 h.

^bFor 4a, 5 mol % Pd(OAc)₂ was used, the loadings of I₂ and CsOAc were doubled, and the reaction time was shortened to 5 h.

^cFor 4e, 5 mol % Pd(OAc)₂ was used.

^dFor 4f, 10 mol % Pd(OAc)₂ was used and the reaction solvent was changed to DMF.

^eYields of the isolated product.

^fTrace dimer was formed.

Notably, various regioisomers of iodinated pyrazoles (5b-e), oxazoles (5g, 5h) and thiazoles (5i, 5j) can be prepared using these heterocycles containing the amide directing group at different positions. Although electrophilic iodination of electron-rich pyrazoles can occur at C-4 positions,²¹ the presence of other electron-rich arenes within a complex molecule could scramble the site selectivity under such conditions. We were pleased to find that pyridine-containing isonicotinic amide and methylnicotinic amide were also suitable substrates for this iodination reaction (5k, 5l). Although a single example of Pd(0)/PR₃-catalyzed arylation of these pyridine substrates has been reported,^19a this iodination represents the first example of Pd(II)-catalyzed C–H activation reactions for a broad range of heterocycles using a directing group. The observed reactivity of these strongly coordinative heterocycles, especially the thiazole and pyridine substrates, can be attributed to the following two factors. First, a strong trans-effect and sterics between the pyridyl groups in complex I (Scheme 3) can promote formation of a small amount complex II,²² in which the moderately coordinating amide is bound to the Pd center. Second, this amide directing group is highly effective in promoting C–H activation: the coordinated amide contains a strongly electron-withdrawing aryl group [Ar = (4-CF₃)C₆F₄], rendering the Pd(II) center sufficiently electrophilic for C–H bond cleavage and the imidate structure enables the assembly of an approximately co-planar pre-transition state with minimum entropic cost.

Scheme 3.

Assembly of the Reactive Precursor

In summary, we have developed the first Pd-catalyzed C–H iodination reaction using molecular iodine as the sole oxidant. The Pd catalyst loading can be reduced to 0.5 mol% in gram scale reaction. This reaction also demonstrates broad substrate scope with respect to a wide range of heterocycles that were previously incompatible with directed C–H activation. Our collaborators in Bristol-Myers Squibb Co. are currently applying this reaction for late-stage tritio-deiodination of drug molecules to facilitate in vivo study of metabolic processes.