Combining Pd(π-allyl)Cp and PPh₃ as a unique catalyst for efficient synthesis of alkyliodo indoles via C(sp³)–I reductive elimination

Abstract

The combination of Pd(π-allyl)Cp and PPh₃ was found to generate an efficient catalyst for the formation of indole-containing alkyl iodides from ortho-amino iodobenzenes and both aromatic and aliphatic alkynes. A unique feature of this reaction is a palladium-promoted C(sp³)–I bond formation via reductive elimination. This catalytic process was found to be very sensitive to the size and equivalents of phosphine ligands and the nature of the base.

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Introduction

Alkyl iodides are important reagents in synthetic organic chemistry and their synthesis has attracted much attention. Traditionally, they are prepared by the reaction of alcohols with I₂/PPh₃ or by conversion of alcohols to sulfonates followed by treatment with NaI.¹ Despite the widespread use of such reactions, new methods to prepare these classic electrophiles with increasing degrees of functionality remain in demand.

Recently it has been shown that alkyl iodides can be prepared using transition metal catalysts via an unusual reductive elimination pathway.^2–5 The C–I bond-forming reductive elimination step takes place from an intermediate L_nM(alkyl)(I) that can also undergo facial β-hydride elimination,⁶ limiting the synthetic utility of this approach. As a consequence, the alkyl groups of [L_nM(alkyl)(I)] intermediates usually do not contain syn-β-hydrogen atoms to circumvent generation of alkene byproducts.

We recently reported a unique Pd-catalyzed tandem reaction between alkynes and ortho-NR₂ iodobenzene derivatives such as 1a to afford indole-containing alkyl iodides (Scheme 1).² The proposed mechanism (Scheme 2) involves initial oxidative addition of the aryl iodide, alkyne insertion, and a C–N bond cleavage/formation sequence to give intermediate III. The alkyliodide product 2 is formed via a rare reductive elimination of the alkylpalladium iodide intermediate III. This chemistry is particularly noteworthy because it represents the first example of reductive elimination of alkylpalladium halide complexes possessing syn-β-hydrogens.^3–10 A drawback of our initial approach is that different catalysts were required for different alkyne substrates. For aliphatic alkynes such as 3-hexyne, reaction conditions A, employing Pd(PPh₃)₄ as the palladium source, were found to be effective to generate the alkyl iodide 2a (85% yield). The yield of product 2a was significantly lower (65%) when Pd(OAc)₂ and PPh₃ were employed (conditions B). On the contrary, for aromatic alkynes such as diphenylacetylene, reaction conditions B were found to afford product 2b in good yield (67%) but reaction conditions A generated only traces of 2b with most of 1a unreacted.

Scheme 1 Catalytic formation of alkyliodo indoles from 1a and alkynes.

Scheme 2 Catalytic cycle for the formation of alkyliodo indoles from 1a and alkynes.

Results and discussion

Based on these results, we set out to find an improved reaction system for this catalytic process that would be effective for both aliphatic and aromatic alkynes. In our preliminary study,² we realized that the ratio of Pd : PPh₃ was important in optimizing reactivity. Previous theoretical studies also highlight the importance of this ratio in palladium-catalyzed reactions.¹¹ Therefore, we now focus on the use of a precatalyst that will enable better control of this crucial variable.

In contrast to other palladium precatalysts,¹² a unique feature of the Pd(π-allyl)Cp precatalyst is that it has been recently reported to generate PdL₂ reactive species in the presence of 2 equivalents of phosphine (L = phosphine ligand, NHC, etc.) without the assistance of base.¹³ We anticipated that this property of Pd(π-allyl)Cp, along with the ability to accurately control the Pd : ligand stoichiometry, would be useful for us to investigate the effects of ligands and bases for the above-mentioned Pd-catalyzed alkyl iodide formation. Herein we report that the combination of Pd(π-allyl)Cp and PPh₃ (1 : 2 ratio) is found to lead to an efficient catalyst for the formation of alkyliodides 2 from ortho-NR₂ iodobenzene derivatives 1 with both aromatic and aliphatic alkynes.

We initially screened various mono- and bidentate phosphine ligands in the reaction of 3-hexyne with orthoamino iodobenzene 1a to give iodo indole 2a (Table 1). When Pd(π-allyl)Cp was substituted for Pd(PPh₃)₄ (conditions A, but with no added phosphine, Table 1), no reaction took place (entry 1). However, when Pd(π-allyl)Cp (5 mol %) was employed with 10 mol % PPh₃, the alkyliodide product 2a was obtained in 92% GC yield (entry 2). Notably, with additional equivalents of PPh₃, the yield of 2a decreased dramatically (entries 3, 4). Use of tri(2-fural) phosphine (TFP) in place of triphenyl phosphine resulted in a drop in yield to 78% (entry 5). The yield of 2a was found to be highly dependent on the cone angle of phosphine ligands used. Thus, with increasing size of the ligands (TFP, L1, L2, L3), the yield of 2a went from moderate to traces (entries 5–8), with most of the starting material 1a found unreacted. Q-phos¹⁴ has been successfully applied by Lautens's group in palladium-catalyzed generation of alkyl iodides that do not possess accessible β-hydrogens.^4a,d–h However, in the present system we observed a maximum of 32% yield of 2a with this ligand (entries 9–10). The cyclopentadiene-phosphine ligand L4, which exhibited high efficiency in our Pd-catalyzed C–N bond cleavage reaction,¹⁵ was not effective in the present case, resulting in only 8% yield of 2a (entry 11). Other bulkyl monophosphines and bidentate phosphine ligands such as PCy₃, PtBu₂Me, PtBu₃, DPPF, DPPE and DPPP were also tested. Yields with these ligands ranged from 33% down to trace product (entries 12–17).

Table 1 Ligand effects^a

Entry	Ligand	Yield of 2a^b (%)	Entry	Ligand	Yield of 2a^b (%)
a Reaction conditions: 1a (0.3 mmol), 3-hexyne (0.36 mmol), Pd(π-allyl)Cp (5 mol %, 0.015 mmol), ligand (10 mol %, 0.03 mmol), LiOtBu (1.2 equiv., 0.36 mmol), 2 mL cyclohexane, 12 h. b Yields were determined by GC analysis of the crude reaction mixture using dodecane as an internal standard. c PPh3 (30 mol %, 0.09 mmol) was added. d PPh3 (50 mol %, 0.15 mmol) was added. e LiOtBu was not added.
1	—	0	10^e	Q-Phos	<5
2	PPh3	92	11	L4	8
3^c	PPh3	65	12	PCy3	33
4^d	PPh3	15	13	P^tBu2Me	32
5	TFP	78	14	P^tBu3	28
6	L1	9	15	DPPF	<5
7	L2	<5	16	DPPE	<5
8	L3	<5	17	DPPP	<5
9	Q-Phos	32

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The effect of bases was next investigated (Table 2).¹⁶ Our previous work² and Lautens's^4e–g publications showed that base was necessary to promote the reaction, although the exact role of the base remains elusive. We reported that LiOtBu could promote this reaction efficiently and in its absence, no product was observed (Table 2, entries 1 and 2). Furthermore, we demonstrated that the alkyliodide products were stable to both E2 elimination and S_N2 with –OtBu in cyclohexane at 130 °C.² According to the literature,¹³ Pd(π-allyl)Cp reacts with 2 equiv. PPh₃ to form Pd(PPh₃)₂ along with the allyl/Cp coupling product C₈H₁₀ without base assistance. With the precatalyst Pd(π-allyl)Cp, LiOtBu was found to be the most effective with other bases, including NaOtBu and KOtBu, giving much lower yields of product 2a. The amount of LiOtBu also had a significant influence on the yield of 2a, with 1.2 equiv. giving better yield (92%, entry 2) compared to 0.5 equiv. (65%, entry 5) or 2.0 equiv. (80%, entry 6). We previously demonstrated that crown ethers can be beneficial additives in palladium-catalyzed reactions with strong bases.¹⁷ When 12-crown-4 was added to the reaction mixture, however, the yield of 2a decreased to 36% (entry 7). As shown in Table 2, entries 8–17, weaker bases, including both anionic and neutral organic bases, were less effective than LiOtBu.

Table 2 Base effects^a

Entry	Base	Yield of 2a^b (%)	Entry	Base	Yield of 2a^b (%)
a Reaction conditions: 1a (0.3 mmol), 3-hexyne (0.36 mmol), [Pd] (5 mol %, 0.015 mmol), PPh3 (10 mol %, 0.03 mmol), base (1.2 equiv., 0.36 mmol), 2 mL cyclohexane, 12 h. b Yields were determined by GC analysis of the crude reaction mixture using dodecane as an internal standard. c LiOtBu (50 mol %, 0.15 mmol) was added. d LiOtBu (200 mol %, 0.6 mmol) was added. e 2.4 equiv. of 12-crown-4 was added.
1	—	0	10	Li2CO3	0
2	LiO^tBu	92	11	LiOEt	54
3	NaO^tBu	52	12	K2CO3	54
4	KO^tBu	0	13	K3PO4	68
5^c	LiO^tBu	65	14	KF	0
6^d	LiO^tBu	80	15	CsF	30
7^e	LiO^tBu	36	16	DBU	<5
8	LiOAc	0	17	Et3N	25
9	LiOH	28

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With the results of ligand and base screening in hand, the optimized reaction conditions are 1a (0.3 mmol), alkyne (0.36 mmol), Pd(π-allyl)Cp (5 mol %, 0.015 mmol), PPh₃ (10 mol %, 0.03 mmol), LiOtBu (1.2 equiv., 0.36 mmol) in 2 mL of cyclohexane at 130 °C as a homogeneous reaction solution. Fortunately, these conditions were suitable for both aliphatic alkynes and aromatic alkynes, enabling the synthesis of a variety of iodoindoles in 62–90% yields (Scheme 3). For the substrate 1-(2-iodophenyl)piperidine (1a), the yields of corresponding products using Pd(π-allyl)Cp are higher than with our previous conditions. The aryl iodide with a five-membered azacycle could be also used, thereby affording the alkyliodide products with shorter linkers. For aromatic alkynes, the reaction times are longer than those with aliphatic alkynes. This may be a result of their lower reactivity due to conjugation. The yields with aromatic alkynes are 62–75%.

Scheme 3 Substrate scope of alkynes and orthoamino iodobenzenes 1 in the synthesis of iodoindoles 2. ^a 12 h reaction time. ^b 48 h reaction time.

The results in Scheme 3 led us to reflect on the possibility of reductive elimination to form other C(sp³)–X bonds.⁹ Previous theoretical and experimental results suggest that reductive elimination of alkyl bromides is more difficult than reductive elimination of alkyl iodides.^2,8 These observations are consistent with a recent study by Tong's group on reductive elimination of C–X bonds (X = I, Br, Cl),⁴ⁱ which was published during the preparation of this manuscript. Like previous works, Tong's substrates were limited to those lacking of β-hydrogens to circumvent the β-hydride elimination pathway.

We were encouraged by the high yields in the formation of alkyl iodides described in Scheme 3, so we explored the possibility of reductive elimination of alkyl bromides from our palladium catalyst. As demonstrated in Scheme 4, when the orthoamino bromobenzene 3 was used, the expected reductive elimination product 4 was obtained in 32% isolated yield, with most 3 remaining unreacted. Although the yield is moderate, this result indicates such a reaction is indeed possible and an interesting topic of future study.

Scheme 4 Pd-catalyzed reaction of 1-(2-bromophenyl)piperidine with 3-hexyne.

Conclusions

In summary, we have developed a general catalyst for tandem carboiodination process leading to iodo alkyl indoles. Indoles are among the most important heterocycles in medicinal chemistry and the iodoindoles prepared herein could be used in the synthesis of novel indole-based structures. The synthesis was facilitated by the use of the Pd(π-allyl)Cp precatalyst in combination with PPh₃ and LiOtBu as the base. Future work will include the elucidation on the role of base and study of the reaction mechanism to understand the factors that enable these unique C(sp³)–I and C(sp³)–Br reductive elimination processes in the presence of accessible β-hydrogen atoms.

Acknowledgements

This work was supported by the 973 Program (2012CB821600) and the National Natural Science Foundation of China (NSFC).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00197h

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