Remarkably Mild and Efficient Intramolecular Friedel-Crafts Cyclization Catalyzed by In(III)

Abstract

Indium(III) salts were found to be highly effective catalysts for the intramolecular Friedel-Crafts reaction of simple allylic bromides and arenes. In(III) salts appear to be the most general and possess unique halophilic properties as a Lewis acid for this reaction among the catalysts evaluated to date. Deactivated arenes possessing chloride, bromide, and fluoride underwent smooth reaction when activated by InCl₃.

More than 125 years after its inception, electrophilic aromatic substitution (the Friedel-Crafts (FC) reaction)¹ still remains an important method for C-C bond formation and is the subject of continued investigation today. FC reactions traditionally require a stoichiometric amount of strong Lewis acid and severe conditions.² Original conditions have been replaced by milder and more environmentally friendly procedures. While great strides have been made in catalytic FC reactions, there remain several challenges. Particularly reactions with electron deficient arenes are a continued problem with very few solutions. Therefore, new efficient, mild, and catalytic methods to activate electrophiles for Friedel-Crafts reactions are highly significant.

Lately the utility of indium(III) Lewis acids in organic synthesis has received a great deal of interest due to their relatively low toxicity, stability in air and water, and recyclability.³ There are a number of examples of catalytic indium(III) salts utilized in Friedel-Crafts reactions including electrophilic aromatic substitution with carbonyl compounds,⁴ sulfuryl chloride,⁵ electron deficient alkene,⁶ alkyne,⁷ aziridine⁸ and epoxide.⁹ These examples are all activated by Lewis acid coordination to strong Lewis basic functionality such as oxygen and nitrogen. Arene additions to allylic halides catalyzed by Lewis acids and indium metal have been shown,¹⁰ however, these reactions require an excess amount of arene to obtain useful yields. Examples of direct halide activation by catalytic Lewis acid are rare; however, as in Friedel and Crafts’ original reports, stoichiometric variants have been reported. Alkylation of aromatics with exo-2-chloro and 7-chloronorbornane with stoichiometric amount of Lewis acids (SnCl₄, AlCl₃, BF₃, and SbF₅) has been demonstrated.¹¹ And zinc(II) salts have been reported to activate allyl chlorides for cycloaddition onto alkynes.¹² Because of the difficulty in achieving catalytic activation of halides, their use in FC reactions has been limited.

We have recently demonstrated a mild and efficient atom transfer cyclization catalyzed by In(III) salts.¹³ Importantly, we found that the reaction was driven by cationic activation of allyl bromide by a catalytic amount of InCl₃. As shown in Scheme 1, treatment of 1 with catalytic indium chloride in dichloromethane at room temperature resulted in the efficient formation of the atom transfer cyclization product 2. This product arose via electrophilic allylation of the alkyne via the polarized species A or the cationic species B. Reasoning that this allylic activation would be amenable to FC reactions, we undertook a study to ascertain the effectiveness of In(III) Lewis acids on this reaction. Herein, we disclose a remarkably mild and efficient intramolecular FC cyclization of allylic halide onto a variety of arenes, both electron rich and electron poor, catalyzed by In(III) salts.

Scheme 1.

We have discovered that 10 mol % of InCl₃ in dichloromethane (0.05M) at room temperature in the presence of molecular sieves efficiently catalyzed the FC cyclization of allylic bromide onto electron rich arene with excellent yield (Table 1, entries 1–6). In the absence of molecular sieves the substrate decomposed. The sieves are thought to be performing the role of a neutral acid scavenger.¹⁴ Optimal efficiency was observed with 10 mol % catalyst loading although 5 mol % performed with only slightly diminished yield. The reaction proceeded well in non-coordinating solvents such as dichloromethane, dibromomethane, or toluene, but failed in other common solvents (CHCl₃, THF, MeCN, MeNO₂, EtOH, MeOH, acetone, H₂O). Application of In(I) salts, InF₃ and In(OAc)₃ in the reaction resulted in the formation of only a trace of product with recovery of unreacted starting material (entries 10–12).

Table 1.

Lewis Acid Catalyzed Friedel-Crafts Cyclization^a

entry	LA (mol %)	solvent	yieldb
1	InCl3(5)	CH2Cl2	79%
2	InCl3(5)	Toluene	81%
3	InCl3(10)	CH2Cl2	88%
4	InCl3(10)	Toluene	87%
5	InCl3(10)	CH2Br2	91%
6	InCl3(10)	ClCH2CH2Cl	76%
7	InBr3(10)	CH2Cl2	84%
8	In(OTf)3(10)	CH2Cl2	82%
9	In(NO3)3(10)	CH2Cl2	77%
10	Inl(10)	CH2Cl2	tracec
11	InF3(10)	CH2Cl2	tracec
12	In(OAc)3(10)	CH2Cl2	tracec
13	AlCl3(20)	CH2Cl2	0%c
14	Sc(OTf)3 (20)	CH2Cl2	0%c
15	Cu(OTf)2 (20)	CH2Cl2	0%c
16	Mg(OTf)2 (20)	CH2Cl2	0%c
17	ZrCl4 (20)	CH2Cl2	0%c
18	Y(OTf)3 (20)	CH2Cl2	0%c
19	AgOTf (20)	CH2Cl2	0%c
20	La(OTf)3 (20)	CH2Cl2	0%c
21	Sm(OTf)3 (20)	CH2Cl2	0%c
22	SnCl4 (20)	CH2Cl2	80%
23	Fe(ClO4)3 (20)	CH2Cl2	75%
24	Zn(OTf)2 (20)	CH2Cl2	95%

^aSubstrate, solvent, 4 Å MS, and catalyst were stirred together at rt in a screwcap scintillation vial for 16 h.

^bYield of isolated product.

^cStarting material was recovered intact.

We next screened a variety of common Lewis acids. Most completely failed to promote the cyclization (Table 1, entries 13–21). However, SnCl₄, Fe(ClO₄)₃, and Zn(OTf)₂ showed success in the catalytic activation of 3a (entries 22–24). It is important to note that only indium (III) Lewis acids catalyzed the reaction of arenes that were less electron rich than 3a. Zn(II), Fe(III) or Sn(IV) Lewis acids were ineffective at promoting the cyclization of the activated monomethoxyarene 3b. Thus, of the Lewis acids examined, In(III) salts were unique in their mildness and activity for this FC reaction.

The substrate scope of the reaction under the optimized conditions was investigated and the results are summarized in Table 2. The reaction was amenable to a wide variety of aromatic rings for the synthesis of benzocarbocycles.¹⁵ When meta-substituted arenes were employed, regioisomeric products resulted from both para- and ortho-attack of the electrophile. Remarkably to our great satisfaction, under In(III) catalysis, even electron deactivated arenes possessing a chlorine, fluorine or bromine substituent cyclized smoothly and cleanly in high yield (entries 7–12). However, electron withdrawing groups as strong as CF₃ were ineffective in this Friedel-Crafts cyclization. Nitrogen linkers in the tether were agreeable to the FC cyclization as well. Thus, isoquinolone derivatives¹⁶ were formed in quantitative yields. These reactions performed equally well when other In(III) salts were employed including InBr₃, In(OTf)₃ and In(NO₃)₃. Although slightly higher catalyst loads (25 mol %) and longer reaction times were required, incredibly even allyl chlorides could be activated by InCl₃. This was exemplified by the smooth cyclization of substrate 3q in 95% isolated yield (entry 18).

Table 2.

Substrate Scope in the Lewis Acid Catalyzed Friedel-Crafts Cyclization^a

entry	substrate	yieldb	product
1		88%
2		93%
3		87%
4		98%
5		97%
6		96%c
7		93%d
8		98%
9		80%e
10		92%
11		89%d
12		97%
13		97%
14		98%
15		100%
16		87%f
17		95%e

^aInCl₃ (10 mol %), 4 Å MS, CH₂Cl₂ (0.05 M) 16 h, rt.

^bYield of isolated product.

^c30 mol % catalyst, 16 h.

^d20 mol % catalyst, 48 h.

^e20 mol % catalyst, 72 h.

^f20 mol % catalyst, 16 h.

In conclusion, we have demonstrated a remarkably mild and efficient Friedel-Crafts cyclization catalyzed by In(III) salts. The reaction was driven by cationic activation of allylic bromide by substoichiometric amount of Lewis acid. In(III) salts appear to be the most general and possess unique halophilic properties as a Lewis acid for this reaction among the catalysts evaluated to date. We are currently examining the scope and limitation of this catalytic activation of halides by indium(III) salts and other metals in order to gain further insight into this distinctive reactivity.

Supplementary Material

si20070129_104. Supporting Information Available.

Cyclization experimental procedures, characterization data and NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.