Cu-catalyzed Recycling of Halogen Activating Groups via 1,3-Halogen Migration

Abstract

A Cu(I)-catalyzed 1,3-halogen migration reaction effectively recycles an activating group by transferring bromine or iodine from a sp² to a benzylic carbon with concomitant borylation of the Ar-X bond. The resulting benzyl halide can be reacted in the same vessel under a variety of conditions to form an additional carbon-heteroatom bond. Cross-over experiments using an isotopically enriched bromide source support intramolecular transfer of Br. The reaction is postulated to proceed via a Markovnikov hydrocupration of the o-halostyrene, oxidative addition of the resulting Cu(I) complex into the Ar-X bond, reductive elimination of the new sp³ C-X bond, and final borylation of an Ar-Cu(I) species to turn over the catalytic cycle.

The ability to functionalize aromatic rings is an important tool in the synthetic chemist's repertoire.¹ Typically, aryl halides or pseudohalides are employed to provide reliable regioselectivity (Scheme 1, top). However, use of an activating group imbues these transformations with less-than-ideal atom economy, as only one new bond is formed at the expense of the waste product. Direct C-H functionalization eliminates the need for pre-activation, yet the additives necessary for many of these reactions means it is not a foregone conclusion that this approach is less wasteful.² Important advances have recently been made towards more practical and general directing groups for C-H functionalization,³ but the use of halide or pseudohalide activating groups remains the most convenient and commonly employed route to aryl functionalization. We felt that the use of activating groups might be more attractive if a way to “recycle” the halide could be developed.⁴ In this communication, we report a Cu-catalyzed 1,3-halogen migration/borylation reaction that permits a halogen activating group to be used for the sequential formation of two new carbon-heteroatom bonds.

Scheme 1.

Traditional cross-coupling approach vs. a new mode of arene functionalization.

Conventional arene functionalization utilizes a range of transition metal catalysts and coupling partners to transform aryl-X bonds into new carbon-carbon or carbon-heteroatom bonds, as represented by C-Y in Scheme 1. Conceptually, our approach differs in that the catalyst does not interact with the C-X bond directly, but rather with a functional group, such as an olefin. Activation of the C-X bond then occurs with subsequent transfer of X to a new carbon in the molecule, followed by the formation of C-Y. The activating group X is recycled by the construction of a final C-Z bond.

The work described herein arose from our attempts to prepare 3 from 1 using a reported CuCl/dppbz catalyst (Table 1, entry 1).⁵ While none of the desired hydroboration was noted, due mainly to polymerization of the styrene, we observed small amounts of an unexpected by-product 2. Curious as to whether 2 might be obtained exclusively, we undertook an investigation of several mono- and bidentate ligands for CuCl (Table 1).

Table 1.

Initial ligand screen.

entrya	ligand	1	: 2 :	3	entry	ligand	1	: 2 :	3
1	dppbz	<10%	<10%	0%	7	dppb	68%	0%	0%
2	PPh3	50%	0%	0%	8	dppf	0%	0%	0%
3	PCy3	60%	0%	29%	9	phen	94%	0%	0%
4	dppm	51%	0%	41%	10	Xantphos	1%	0%	72%
5	dppe	30%	0%	0%	11	DPEphos	42%	0%	0%
6	dppp	19%	0%	0%	12	dCype	0%	70%	0%

^aNMR yields using 1,1,1,2-tetrachloroethane as internal standard.

These preliminary studies revealed that neither monodentate phosphine ligands (entries 2, 3) or electron-poor bidentate ligands (entries 4-8) were capable of promoting the desired reaction. Phenanthroline (entry 9) gave only recovered starting material. Interestingly, the trans-spanning Xantphos ligand (entry 10) gave exclusively the hydroboration product 3 in 72% yield, while a similar DPEphos ligand (entry 11) gave no 2 or 3. Finally, we found that the electron-rich and bulky bidentate phosphine ligand, bis(dicyclohexylphosphino)-ethane (dCype, entry 12), exclusively promoted the desired 1,3-halogen migration.⁶

Further reaction optimization was undertaken using the dCype ligand (Table 2). THF (entry 1) proved superior to toluene, CH₂Cl₂, Et₂O, CH₃CN and CHCl₃ (entries 3-7), although dioxane (entry 2) gave similar results. Lowering the temperature to 40 °C (entry 8) did not increase the yield compared to entry 1, but improved the mass balance. Finally, scaling the reaction to 5 mmol (entry 9) reproducibly increased the yield to 94% of 2.

Table 2.

Reaction optimization.

entry	solvent	temp (°C)	2 : 1
1a	THF	70	73% : 2%
2	dioxane	70	68% : 0%
3	toluene	70	41% : 0%
4	CH2Cl2	70	54% : 6%
5	Et2O	70	40% : 3%
6	CH3CN	70	0% : 2%
7	CHCl3	70	0% : 12%
8	THF	40	60% :27%
9b	THF	40	94% : 0%

^aNMR yields using 1,1,1,2-tetrachloroethane as the internal standard.

^bIsolated yield from the reaction on a 5 mmol scale.

With optimized conditions in hand, the scope of the reaction was explored (Table 3). In general, 1,3-bromine migration was favored with a variety of substrates. However, placing electron-withdrawing halogen groups meta to the olefin (entries 2 and 3) diminished the 1,3-halogen migration and resulted in significant hydroboration. Other groups at this position favored transposition. Curiously, if a bromide group (entry 8) was placed para to the olefin, the hydrocupration did not occur at all. Neutral and electron-donating substituents F, Ph, ^tBu and OMe (entries 9-12) para to the alkene yielded predominantly the 1,3-halogen migration products. For some of these cases, the benzyl bromide products were sensitive to elimination and were trapped with propargyl alcohol prior to isolation, illustrating the potential of this chemistry in cascade reactions to construct more complex compounds. Consistent with prior observations^5a, the 4-methoxy substrate (entry 12) reacted slowly. Finally, substitution on the β carbon of the styrene (entry 13) was tolerated in the 1,3-halogen migration, as trans-β-methylstyrene 4l gave 5l in 75% yield. Although 2-chlorostyrenes underwent halogen transposition with poor conversions, it was found that 2-iodostyrene 4m did produce the transposed product (entry 14), although only partial conversion was observed. The sensitive benzyl iodide had to be trapped with propargyl alcohol to give 5m in moderate yield. The reactivity of 2-bromo-3-methylstyrene and 2-bromo-6-methylstyrene was also examined. While the 1,3-halogen migration was observed, the conversion was low. Less bulky catalysts are being developed for sterically encumbered substrates.

Table 3.

Substituent effects on 1,3-halogen migration.

entrya		Rm	Rp	% yield
1	1	H	H	94%	2	0%	3
2	4a	Br	H	57%	5a	31%	6a
3	4b	F	H	49%	5b	28%	6b
4	4c	Ph	H	73%	5c	0%	6c
5	4d	1-Napth	H	69%	5db	0%	6d
6	4e	4-MeOC6H4	H	67%	5e	0%	6e
7	4f	OMe	H	87%	5f	0%	6f
8	4g	H	Br	0%	5g	0%	6g
9	4h	H	F	89%	5h	0%	6h
10	4i	H	Ph	66%	5ib	12%	6i
11	4j	H	tBu	65%	5jb	0%	6j
12	4k	H	OMe	36%	5kb,c	0%	6k
13	4ld	H	H	75%	5l	0%	6l
14	4m	H	H	59%	5mb,e	0%	6m

^aX=Br except for entry 14, where X=l.

^bProduct was trapped with propargyl alcohol prior to isolation.

^c79% conversion.

^dSubstrate was 1-bromo-2-((1E)-prop-1-en-1-yl)benzene.

^e87% conversion.

The benzyl boronic esters that result from the typical hydroboration of styrenes are often utilized as synthons for benzylic carbanions.⁷ In contrast, the 1,3-halogen migration observed in our chemistry allows access to intermediates which are electrophilic at the benzylic carbon. Facile recycling of the activating group was demonstrated by transforming 1 into a variety of benzyl-substituted boronic esters (Scheme 2). For example, propargyl and p-methoxybenzyl alcohols, aniline and sodium azide were all suitable nucleophiles for reacting with the benzyl bromide to yield 7-9. These reactions represent formal Cu-catalyzed hydroalkoxylation and hydroaminations that are typically accomplished using more expensive precious metal catalysts including Pd, Rh, or Au.^8,9

Scheme 2.

Recycling of the activating group.

In addition to functionalization at the benzylic carbon, the boronic ester could also be transformed into either a carbon-heteroatom or carbon-carbon bond. For example, treatment of 1 under Cu catalysis, followed by reaction with 3-phenyl-propan-1-ol and an oxidative work-up using H₂O₂ yielded the phenol 10.¹⁰ ecycling the bromine activating group also provided a flexible platform for convergent syntheses of heterocycles. Tandem 1,3-halogen migration/functionalization/Suzuki couplings of 1 were accomplished using (Z)-3-iodopent-2-en-1-ol and 2-iodobenzyl alcohol to yield the heterocyclic dihydroxepins 11 and 12.¹¹ Finally, halogen migration followed by reaction with 2-iodoaniline and subsequent Pd-catalyzed coupling/oxidation gave the biologically active phenanthridine core of 13.¹²

We wanted to ensure that we were not observing direct borylation of the Ar-Br bond, followed by an unexpected bromination of the alkene. Examples of aryl bromides that undergo Cu-catalyzed borylation in the absence of a directing group have been reported, but these reactions are rare.¹³ In our case, when both 1,4-dibromobenzene and 14 were subjected to the reaction conditions (eq 1 and 2), no borylation of either C-Br bond was observed. Subjecting the typical hydroboration product 3 to the reaction conditions also did not lead to 2, indicating direct borylation of 1 is not a likely reaction pathway.

(1)

(2)

We also demonstrated that the 1,3-halogen migration is likely an intramolecular process by performing a crossover experiment using isotopically enriched ⁷⁹Br. The enriched aryl bromide 4f (Scheme 3) was prepared by reacting the tributylaryl tin 16 with ca. 85% isotopically enriched NH₄⁷⁹Br (see the Supporting Information for further details).¹⁴ After ensuring that the unlabeled styrenes 1 and 4f reacted at comparable rates, reaction of 4f in the presence of non-isotopically enriched 1 showed no additional incorporation of ⁷⁹Br into 2 or degradation of the ^79/81Br ratio in the conversion of 4f to 5f within statistical error.

Scheme 3.

Cross-over experiment using isotopically enriched ⁷⁹Br.

One proposed mechanism for the 1,3-halogen migration is illustrated in Scheme 4. Reaction of the pre-catalyst 17 with HBpin generates the active, phosphinesupported Cu-H species 18.¹⁵ In the absence of an ortho C-Br bond, reversible Markovnikov hydrocupration of the styrenic double bond of 1 to 18 would be followed by reaction with HBpin to give the typical hydroboration product 3.^16,17 However, the presence of an ortho C-Br bond in 19 may promote a subsequent oxidative addition to yield a formal Cu(III) species 20.^18,19 Reductive elimination of 19 to 20 could then be followed by a o′-bond metathesis with HBpin to yield 2 and regenerate the active Cu-H catalyst 18.²⁰ Other possibilities for the mechanism of the 1,3-migration could involve intermediate π-allyl Cu species, single-electron transfer processes, halogen atom transfer or π complexation to the halide.²¹ Computational and further experimental studies are in progress to shed more light on whether a Cu(I)/Cu(III) or a Cu(I)/Cu(II) cycle is more likely and will used to guide our further exploration of this 1,3-halogen migration reaction.

Scheme 4.

A potential mechanism for the Cu-catalyzed 1,3-halogen migration.

In conclusion, Cu(I) promotes a cascade 1,3-halogen migration/borylation/functionalization that proceeds under mild conditions to recycle the bromine activating group. Future studies will focus on expanding the reaction scope to include other functional groups capable of directing the Cu catalysis and other activating groups that can be transferred. Initial promising results in enantioselective migration are being optimized. The development of other efficient cascade reactions and computational studies to better understand the mechanism of this unusual transformation are underway.