Palladium-catalyzed intramolecular rearrangement of vinylidenecyclopropanes through C–C bond activation

Abstract

Vinylidenecyclopropanes bearing sulfonamide can undergo a novel intramolecular rearrangement to give the corresponding functionalized dimethylenecyclopropanes in moderate to good yields in the presence of Pd(OAc)₂ in toluene upon heating through C–C bond activation based on weak coordination of the sulfonamide directing group. The reaction pathway can be changed for phenyl substituted vinylidenecyclopropane, giving another type of dimethylenecyclopropane in methanol in the presence of K₂CO₃ under reflux.

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The use of coordinating moieties as directing groups for the C–H bond activation has become a powerful established method to enhance reactivity and regioselectivity.¹ In this very active research arena, weak coordination as a powerful means for developing broadly useful C–H functionalization reactions has attracted much attention.² For example, the group of Yu as well as other research groups have utilized carboxylic acids,³ alcohols,⁴ amides,⁵ sulfonamides,⁶N-methoxy amides,⁷etc. as weakly coordinating functional groups⁸ for a series of efficient metal-catalyzed C–H functionalizations (Scheme 1). Beside C–H bond activations, several examples of C–C bond activation with the coordinating moieties as directing groups have also been reported recently.⁹ However, to the best of our knowledge, the C–C bond activation through a weak-coordination approach has been seldom reported so far. Methylenecyclopropanes (MCPs) and vinylidenecyclopropanes (VDCPs) are both highly strained but readily accessible and adequately reactive molecules which can serve as useful building blocks in organic synthesis.¹⁰ They can undergo a variety of ring-opening reactions because the release of cyclopropyl ring strain can provide a thermodynamic driving force for reactions and the π-character of the bonds within the cyclopropane can afford the kinetic opportunity to initiate the unleashing of the strain.¹¹ During our ongoing investigation on the ring-opening reactions of the MCPs and VDCPs in the presence of metal catalysts, we found a new C–C bond activation mode of VDCPs bearing a weakly coordinating group in the presence of Pd(OAc)₂ under mild conditions (Scheme 1). Herein, we wish to report the details.

Scheme 1 C–H and C–C bond cleavages through weak coordination.

The starting materials sulfonamide-tethered vinylidene-cyclopropanes (VDCPs) 1 were prepared according to the previously reported procedure¹² and these functionalized VDCPs were utilized as substrates for further transformation in the presence of Pd catalysts.

The initial examination on the intramolecular rearrangement of VDCPs 1 was carried out upon heating 1a in toluene at 60 °C in the presence of Pd(OAc)₂ (10 mol%) and PPh₃ (20 mol%) as the ligand under an argon atmosphere. However, complex product mixtures were obtained after 10 h (Table 1, entry 1). In the absence of the PPh₃ ligand, the rearranged product 2a was formed in 76% isolated yield (91% NMR yield) (Table 1, entry 2). Its structure was determined by X-ray diffraction and its ORTEP drawing is shown in Fig. 1.¹³

Fig. 1 X-ray crystal structure of 2a.

Table 1 Optimization of the reaction conditions for the rearrangement of vinylidenecyclopropane 1a

Entry^a	Catalyst	Additive	Solvent	t (h)	T (°C)	Yield^b (%)
a The reaction conditions: catalyst (10 mol%), 0.1 M in solvent unless otherwise specified. b The yield was determined by H NMR spectroscopic data using 1,3,5-trimethoxybenzene as an internal standard. c The ligand pph3 (20 mol%) was added. d Isolated yields. e The quaternary ammonium salts were added with 20 mol%. f With catalyst (5 mol%). g With H2O (50 mol%). h Stoichiometric amount of the catalyst was used. i The reactions gave complex product mixtures.
1	Pd(OAc)2/PPh3 ^c	—	Toluene	5	60	—^i
2	Pd(OAc)2	—	Toluene	8	60	91 (76)^d
3	Pd/C	—	Toluene	5	60	N. R.
4	[Pd(η^3-C3H5)Cl]2	—	Toluene	5	60	—^i
5	Pd(OAc)2(Py)2	—	Toluene	5	60	—^i
6	Pd(PhCN)2Cl2	—	Toluene	5	60	—^i
7	PdCl2(PPh3)2	—	Toluene	5	60	—^i
8	Pd(dppf)(OTf)2	—	Toluene	5	60	—^i
9	Pd(dppf)Cl2	—	Toluene	5	60	—^i
10	PdCl2	—	Toluene	5	60	—^i
11	(2,2′bipy)Pd(OAc)2	—	Toluene	5	60	—^i
12	Pd(OAc)2 ^e	Bu4NCl	Toluene	10	60	N. R.
13	Pd(OAc)2 ^e	PhEt3NCl	Toluene	10	60	N. R.
14	Pd(TFA)2	—	Toluene	10	80	30
15	AuCl3	—	Toluene	10	80	—^i
16	Rh2(OAc)2	—	Toluene	10	80	—^i
17	PtCl2	—	Toluene	10	80	—^i
18	Cu(OAc)2	—	Toluene	10	80	N. R.
19	Pd(OAc)2	—	THF	24	rt	70
20	Pd(OAc)2	—	Et2O	24	rt	83
21	Pd(OAc)2	—	CH2Cl2	24	rt	85
22	Pd(OAc)2	—	DCE	10	60	73
23	Pd(OAc)2	—	MeCN	10	60	62
24	Pd(OAc)2	—	Toluene	24	rt	85
25	Pd(OAc)2	—	Toluene	8	80	91 (76)^d
26^f	Pd(OAc)2	—	Toluene	8	80	83
27^f	Pd(OAc)2	—	Toluene	8	100	57
28	Pd(OAc)2	O2	Toluene	8	60	45
29^g	Pd(OAc)2	H2O	Toluene	8	80	72
30^h	Pd(OAc)2	—	Toluene	8	60	—^i

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Then we studied other Pd catalysts such as Pd/C, Pd(η³-C₃H₅)Cl, Pd(OAc)₂(Py)₂, Pd(PhCN)₂Cl₂, PdCl₂(PPh₃)₂, Pd(dppf)(OTf)₂, Pd(dppf)Cl₂, PdCl₂ and (2,2′-biPy)Pd(OAc)₂ and the results are summarized in Table 1. We found that the reaction almost did not give the desired product cleanly using these Pd catalysts in toluene, suggesting that Pd(OAc)₂ is the best Pd catalyst for this reaction (Table 1, entries 3–11). Using Pd(OAc)₂ as the catalyst, the addition of Bu₄NCl or PhEt₃NCl completely stopped the reaction (Table 1, entries 12 and 13). The use of Pd(TFA)₂ as the catalyst gave 2a in 30% yield in toluene at 80 °C under otherwise identical conditions (Table 1, entry 14). Other transition metal catalysts such as AuCl₃, Rh₂(OAc)₂ and PtCl₂ produced complex product mixtures (Table 1, entries 15–17). No reaction occurred using Cu(OAc)₂ (10 mol%) as the catalyst (Table 1, entry 18). The examination of solvent effects revealed that toluene, CH₂Cl₂ and Et₂O were better than THF, DCE (1,2-dichloroethane) and MeCN (Table 1, entries 19–23) since upon heating in DCE (1,2-dichloroethane) or MeCN at 60 °C afforded 2a in 73% or 62% NMR yield, respectively (Table 1, entries 22 and 23). All these results indicated that toluene is best suited to this reaction. The effect of temperature has been also examined in toluene. Upon heating at 80 °C 2a in 91% NMR yield (76% isolated yield) was obtained, which is exactly the same as that at 60 °C (Table 1, entries 2 and 25). Reducing the employed amount of Pd(OAc)₂ to 5 mol% produced 2a in 83% yield under otherwise identical conditions (Table 2, entry 26) and increasing the reaction temperature up to 100 °C reduced the yield of 2a to 57% yield in the presence of 5 mol% Pd(OAc)₂ (Table 1, entry 27). Furthermore, this reaction should be carried out under an argon atmosphere and anhydrous conditions since under an oxygen atmosphere or in the presence of water also reduced the yield of 2a (Table 1, entries 28 and 29). The use of stoichiometric amount of Pd(OAc)₂ gave a complex product mixture (Table 1, entry 30). All these examinations revealed that this reaction should be carried out at 80 °C in toluene in the presence of 10 mol% Pd(OAc)₂.

Table 2 Substrate scope^a

a Reaction conditions: VDCP 1 (0.2 mmol), Pd(OAc)₂ (0.02 mmol), toluene (2 mL). Isolated yields.

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With the identification of the best reaction conditions, we next turned our efforts to investigate the scope and limitations of these intramolecular rearrangement and the results are summarized in Table 2. A variety of VDCPs 1 bearing different sulfonamide substituents have been tested and the corresponding products 2b–2g were obtained in moderate to good yields without the observation of significant electronic effects (Table 2). Substrate 2g having strongly electron-withdrawing trifluoromethylsulfonamide (R³ = triflamide) was also tolerated, affording the corresponding product 2g in 80% yield. A range of different substituents at the cyclopropane or allene moiety of 1 have also been tested, giving the desired products 2h–2m in 10–86% yields. As for substrate 1l having a cycloheptyl substituent (R¹ and R¹) and a triflamide functional group, the corresponding product 2l was obtained in 10% yield presumably due to the instability of this product at 80 °C.

The control experiment shown in Scheme 2 indicated that when the substituent R³ was a fully substituted sulfonamide group, carbonamides or a free hydroxyl group, none of the desired products could be formed, suggesting that the sulfonamide group (R³) is essential for this reaction.

Scheme 2 The control experiments.

A plausible reaction mechanism is depicted as below using 1a as a substrate model on the basis of the previous literature and the control experiments (Scheme 3). Since R³ should be a sulfonamide group with a N–H moiety, it may work as a weak-coordinating group for Pd(II) to give intermediate I,^5,6 which subsequently undergoes ring-opening upon intramolecular attacking of the NTs moiety to afford the corresponding allylic Pd intermediate II along with the formation of an aziridine. Then, the central carbon of the previous allene moiety attacks the aziridine to afford intermediate III. The protonation of III produces the thermodynamically stable product 2a. The N–H group in sulfonamide is important in proton exchange with Pd(OAc)₂ to incorporate the Pd(II) species into the directing group as shown in Scheme 3. The use of the Pd(0) catalyst such as Pd₂dba₃ and Pd(PPh₃)₄ as catalysts gave complex product mixtures, rendering that this is a Pd(II) catalyzed process.

Scheme 3 A plausible mechanism for the formation of 2a.

Interestingly, substrate 1q, bearing two phenyl groups at cyclopropane (R² = phenyl group), produced a complex mixture under the standard conditions. However, upon heating 1q in methanol in the presence of K₂CO₃ (2 equiv.) afforded another rearranged product 3q in 80% as the E-configuration (Scheme 4). Its structure was determined by X-ray diffraction and its ORTEP drawing is shown in Fig. 2.¹⁴ As a comparison, compound 1a was also subjected to the basic conditions, but none of the similar products were formed.

Scheme 4 The rearrangement of 1q under basic conditions.

Fig. 2 X-ray crystal structure of 3q.

A mechanistic explanation for the intramolecular rearrangement of 1q in the presence of K₂CO₃ has been proposed in Scheme 5. Firstly, deprotonation of 1q by K₂CO₃ gives anionic intermediate A, which undergoes intramolecular nucleophilic attack onto the cyclopropane affords anionic aziridine intermediate B accompanied by a ring-opening process. Then, a nucleophilic attack onto the central carbon of allene takes place along with the migration of a double bond, leading to the aziridine ring-opening intermediate C. Protonation of intermediate C gives the corresponding product 3q. The different reaction outcome on phenyl substituted substrate 1q may be due to the stabilization of the anionic intermediate by the phenyl group.

Scheme 5 A plausible mechanism for the formation of 3q.

In summary, we have developed a novel C–C bond activation mode of functionalized vinylidenecyclopropanes using a simple and weakly coordinating sulfonamide directing group. Different reaction pathways have been observed when R² was a phenyl group. The reaction mechanism has also been discussed on the basis of the control experiment and previous results. Further work is underway to elucidate further mechanistic details of these reactions and to understand their scope and limitations in our laboratory.

We are grateful for the financial support from the National Basic Research Program of China (973)-2015CB856603, and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203 and 20732008).

Notes and references

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13. The CIF data of 2a have been deposited in CCDC 958985 (see ESI†).
14. The CIF data of 3q have been deposited in CCDC 1031145 (see ESI†).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data of new compounds. CCDC 958985 and 1031145. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00127g

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