Hydrogen-Bonding-Assisted Brønsted Acid and Gold Catalysis: Access to Both (E)- and (Z)-1,2-Haloalkenes via Hydrochlorination of Haloalkynes.

We have developed an efficient synthesis of both (Z)- and (E)-chlorohaloalkenes via hydrochlorination of haloalkynes, based on two distinct hydrogen-bond-network-assisted catalytic systems: Brønsted acid catalysis and gold catalysis. Both systems offer high stereoselectivity, good chemical yields, and diverse functional group tolerance.

Alkenyl chlorides are important synthetic building blocks that have been used extensively in cross-coupling reactions[1] such as Stille couplings,[2] Suzuki couplings,[3] Sonogashira couplings,[4] and Buchwald–Hartwig aminations.[5] In addition, alkenyl chlorides are commonly found in biologically active natural products.[6,7] More specifically, 1,2-chlorohaloalkenes are especially important synthons due to presence of two synthetic handles.[8] The possibility of consecutive transition-metal-catalyzed cross-coupling reactions permits stereocontrolled synthesis of highly substituted alkenes.[8] For example, 1,2-chlorohaloalkenes have been exploited as key building blocks en route to natural products Pan-Bcl-2-Inhibitor[9] and chartellines[10] (Figure ).

Figure 1

Alkenyl chloride-containing natural products that can be prepared from 1,2-chlorohaloalkenes.

1,2-Chlorohaloalkenes can be prepared via directly halogenation of alkynes (Scheme a).[11] These reactions usually give anti addition products via a halonium intermediate, but poor regio- and stereoselectivies restrict their usefulness.[11] Given that the hydrochlorination of alkynes is a well-established method to prepare chloroalkenes,[12] the hydrochlorination of haloalkynes should be a straightforward method to prepare 1,2-chlorohaloalkenes.[13] Indeed, Zhu and co-workers[14] described a clever route to (Z)-1,2-chlorohaloalkenes via Pd catalyzed anti-hydrochlorination of haloalkynes (Scheme b). Ochiai and co-workers reported a metal-free Michael type addition of halides to alkynyl(phenyl)iodonium tetrafluoroborates (Scheme c).[11b] However, these methods suffer from moderate chemical yields, and only provide access to anti-addition products. Herein we present two distinct hydrogen bond network assisted catalytic systems that offer selective access to both (E)- and (Z)-chlorohaloalkenes, based on Brønsted acid and gold catalysis[15] (Scheme d).

Scheme 1

Existing Methods for the Synthesis of 1,2-Chlorohaloalkenes

We first tested our newly developed hydrochlorination reagent DMPU/HCl on model substrate bromoalkyne 1a (Table ).[16] Although HCl is a strong acid, almost no reaction took place when 1a was treated with DMPU/HCl alone (Table , entries 1–3). Strong hydrogen-bond-donating solvents such as HFIP (hexafluoro-2-propanol) can form hydrogen bond networks or clusters,[17] which have been shown to provide significant increases in the rate of many reactions.[18] To our delight, by using a two-component solvent mixture of DCM/HFIP, an excellent yield of syn-addition product 2a was obtained (Table , entry 4). Notably, lower reactivity and stereoselectivity were observed when commercial solutions of HCl were used (Table , entries 5–7).

Table 1

Optimization of the Hydrochlorination of Bromoalkyne 1aa

no.	solvent	catalyst	HCl source	temp (°C)	yield % (2a:3a)
1	DCM	-	HCl/DMPU	50	trace
2	DCE	-	HCl/DMPU	70	trace
3	PhCH3	-	HCl/DMPU	80	trace
4	DCM/HFIP (3/1)	-	HCl/DMPU	50	98 (20:1)
5	DCM/HFIP (3/1)	-	HCl/Et2O	50	35 (4:1)
6	DCM/HFIP (3/1)	-	HCl/i-PrOH	50	98 (8:1)
7	DCM/HFIP (3/1)	-	HCl/dioxane	50	97 (11:1)
8	dioxane	TiO2/Au, 3A MS	HCl/dioxane	90	0
9	DCM	CpRuCl(cod)/PPh3	HCl/DMPU	50	46 (1:0.6)
10	DCM	JohnPhosAuCl	HCl/DMPU	50	10
11	DCE	JohnPhosAuCl	HCl/DMPU	80	37 (1:17)
12	DCM/HFIP (3/1)	JohnPhosAuCl	HCl/DMPU	50	98 (1:0.5)
13	HOAc	JohnPhosAuCl	LiClb	80	97 (<1/99)
14	DCE	JohnPhosAuCl	TMSClb/H2O	80	50 (1/49)
15	DCE	JohnPhosAuCl	AcClb/H2O	80	71 (1/8)

Conditions: 1a (0.2 mmol), HCl source (0.4 mmol), DCM/HFIP (3:1, 0.4 mL), 8 h.

5 equiv.

We then focused our attention on obtaining the anti-addition isomer using transition-metal catalysis. First, we evaluated several literature-known alkyne hydrochlorination catalytic systems, and we found that neither TiO2/Au[12e] nor CpRuCl(cod)/PPh3[12d] gave good yields and stereoselectivity (Table , entries 8–9). Recently, we reported an efficient homogeneous gold-catalyzed hydrochlorination procedure,[19] but when the same conditions were used in this case, 3a was obtained in low yields, although good stereoselectivity was observed (Table , entries 10–11). We reasoned that we could enhance the reactivity by adding hydrogen bond donor HFIP as a part of the solvent mixture, but this resulted in an E/Z mixture (Table , entry 12), possibly due to competition of the Brønsted-acid-catalyzed process (see Table , entry 4). This prompted us to turn to alternative chloride sources. To our satisfaction, a combination of LiCl/AcOH with JohnPhosAuCl dramatically increased both chemical yield and anti-selectivity (Table , entry 13). We also investigated chlorination systems using in situ generated HCl, but they were less effective (Table , entries 14–15).

With the optimized conditions in hand, we first evaluated the hydrogen-bonding-assisted syn-hydrochlorinations (Table ). We found that iodo-, bromo-, and chloroalkynes were all suitable substrates (Table , 2a–c).[20] Our conditions exhibited high compatibility with halogens (F, Cl, or Br) (Table , 2d–f) and the acid-sensitive acetyl group (Table , 2g). Electron-withdrawing groups such as esters or ketones reduced the reactivity, and a higher temperature (70 °C) was needed (Table , 2i,j). Furthermore, the trifluoromethoxy group and the tert-butyl group were also well-tolerated, achieving yields of 80% and 75%, respectively (Table , 2k,l). However, aliphatic haloalkynes showed no reactivity under the same conditions.

Table 2

Substrate Scope of (E)-2-Halo-1-chloroalkenes

Condition: haloalkyne 1 (0.2 mmol), DMPU/HCI (0.4 mmol), DCM/HFIP (3:1, 0.4 mL), 50 °C for 8 h.

Reaction carried out at 70 °C.

We next investigated the scope of the gold-catalyzed anti-hydrochlorination of bromoalkynes (Table , entries 3a–3w). Because of higher reactivity and milder conditions, this system offers outstanding functional group tolerance and excellent chemical yields aromatic alkynes substituted with halogens in both the ortho and para positions (Table , 3b–e); acid-sensitive groups such as esters (3f, 3j), nitriles (3h), and sulfonates (3k); ketones (3g), nitro groups (3i), and ethers (3m) all worked very well. The aromatic diyne 3l was also shown to be a suitable substrate. In general, substrates with electron-withdrawing groups on the phenyl ring gave higher yields (3f–i) than those with electron-donating groups such as 3m. Substrates containing heteroaromatics such as thiophene (3n) and pyridine (3o) also reacted efficiently, albeit with lower stereoselectivity. Contrary to the Brønsted acid-catalyzed process, we also found aliphatic haloalkynes to be suitable substrates with good to excellent yields (3p–w) in the gold-catalyzed process. A variety of functional groups, including benzyl groups (3p), phthalimides (3q), alkenes (3t), alcohols (3u), and carboxylic acids (3v) were all well-tolerated. Even the cholesterol-tethered substrate 3w gave a high yield and selectivity. We also explored the substrate scope of chloroalkynes (3x–3ab). It should be noted that some functional groups such as −OTs and −OH were chlorinated or esterified (3s, 3u) under the reaction condition. While chloroalkynes are less reactive, thus requiring high temperatures (100 °C), the excellent yields and exclusive anti-selectivity were maintained. Various functional groups such as tert-butyl (3y), trifluoromethoxyl (3z), and chloroalkyl (3ab) were well-tolerated. We also tested reactions of iodoalkynes, but they did not give clean transformations.

Table 3

Scope of Gold-Catalyzed Hydrochlorination of Haloalkynes

Reaction conditions: haloalkynes 1 (0.2 mmol), LiCl (1.0 mmol), JohnPhosAuCl (5 mol %), and HOAc (0.5 mL), 80 °C (for bromoalkynes) or 100 °C (for chloroalkynes).

Start from 1s (R = −OTs).

Start from 1u (R = −OH).

The proposed mechanism is shown in Scheme .[21] The hydrogen-bonding cluster generated from HFIP forms a hydrogen-bonding complex with HCl (A) and grants the HCl increased acidity, facilitating the rate-determining proton-transfer step (Scheme a). This gives rise to intermediate vinyl cation B,[22] which should have a linear geometry,[23] which we confirmed with DFT calculations (Scheme a). Orbitals from the bromine atom participate in stabilizing the LUMO of B. Attack at the upper face is hindered by the bulky bromine atom, thus favoring chloride attack syn to the H atom[24]

Scheme 2

Proposed Mechanism

LUMO of vinyl cation was calculated at B3LYP/6-311+G(2df,2p) level of theory.

On the other hand, the gold-catalyzed process gave the expected anti-selectivity, consistent with typical homogeneous gold catalysis (Scheme b).[25] Contrary to traditional silver-based cationic gold catalysis, we used hydrogen bonding network to activate cationic gold catalyst precursor (L–Au–Cl).[26] We proposed that the H-bond network generated from acetic acid might weaken the Au–Cl bond, thereby generating a gold species [Au] with a partial positive charge that coordinated to the haloalkyne (Scheme b). The chloride nucleophile would then attack the gold-activated haloalkyne to generate a vinyl–gold intermediate C in an anti-manner. Subsequent protodeauration of C by (AcOH) would therefore afford the anti-product.[27] This is consistent with our deuterium-labeling experiment: using d4-AcOH as the solvent, the deuterated product was obtained in 92% yield (eq ). This result indicates that AcOH is the proton source; hence, this method could be used to synthesize other deuterium labeled haloalkenes.

Our protocol is scalable: similarly good yields were obtained at a larger scale (Scheme a). Alkenyl chlorides have become increasingly suitable substrates in cross-coupling reactions due to the advances in catalyst design.[28] Taking advantage of the difference in reactivity between chloro-and bromo/chloro-alkenes, we were able to conduct sequential cross-coupling reactions to synthesize both E- and Z-trisubstituted alkenes: Sonogashira[4b] and Suzuki–Miyaura[29] coupling reactions provided an efficient and selective way to make both (Z)- and (E)-enynes (Scheme b,c).[14] What’s more, our method represents a simple way of accessing chlorinated 1,3-dienes such as 3t (Table ), which can be further transformed into multifunctional aromatics in good yields via tandem Diels–Alder-aromatization.[14]

Scheme 3

Larger-Scale Reactions and Further Transformations of (Z)- and (E)-1,2-Haloalkenes

Phenylacetylene (1.5 equiv), Pd(PPh3)2Cl2 (5 mol %), Cul (15%), Et3N (3.0 equiv), toluene, 80 °C.

Pd(OAc)2 (5 mol %), PPh3 (10%), p-CH3–C6H4B(OH)2 (1.5 equiv), Cs2CO3 (2.0 equiv), dioxane, 90 °C.

In summary, we have developed a widely applicable, highly efficient synthesis of both (Z)- and (E)-1,2-haloalkenes via hydrochlorination of haloalkynes. Other applications of hydrogen bonding network-assisted Brønsted acid and gold catalytic systems are currently being investigated in our laboratories.