Palladium-Catalyzed Reaction of Propargylic Carbonates with Benzyne

Abstract

Under the catalysis of palladium acetate, 1,2-allenyl­palladium formed from propargylic carbonates may react with two molecules of benzyne to afford phenanthrene derivatives by cyclization and β-H elimination.

Phenanthrene unit exists widely in natural products, pharmaceuticals, agrochemicals, dyes, organic materials, and many other important organic molecules.[1]Although there are a number of synthetic procedures that could be used for the preparation of phenanthrenes,[2] the development of new, selective, and efficient procedures is still highly desirable. In 1985, Tsuji’s group first reported the palladium-catalyzed transformations of propargylic carbonates.[3] From then on, it has become a powerful tool for constructing carbon–carbon and carbon–heteroatom bonds.[4] Recently, we have developed the palladium-catalyzed cyclization of allenes bearing a nucleophilic moiety in the presence of propargylic carbonates affording allenyl cyclic products, in which the CO₂ was eliminated and released.[5] Based on these previous reports, we envisioned that the intermolecular reaction between benzyne and ­allenylpalladium complexes may take place (Scheme [1]). In principle, propargylic palladium Int 1/allenylic palladium Int 2 would be formed from the oxidative addition of palladium(0) with 1a. Then benzyne inserts into Int 2 to form aryl palladium Int 3. Subsequent cyclic carbopalladation with one of the two C=C bonds would afford Int 4 or Int 5. The final product would be obtained by β-H elimination of Int 4 or β-H elimination/reductive elimination of Int 5. Here, we wish to report a palladium-catalyzed cyclization reaction of propargylic carbonates with benzyne.

Our initial work began with methyl (2-methyloct-3-yn-2-yl) carbonate (1a) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2) under the following reaction conditions: Pd(OAc)₂ (5 mol%), PCy₃ (5 mol%), and CsF (6.0 equiv) in MeCN at 60 °C. To our disappointment, only 51% of material 1a was recovered (Table [1], entry 1). When the ligand was changed to (4-MeOC₆H₄)₃P, no expected 3a′ or 3a′′ was formed. However, after careful analysis of all the data, we were happy to notice that 42% yield of 9-butyl-10-(prop-1-en-2-yl)phenanthrene (3a), which incorporates two molecules of benzyne, was formed as determined by ¹H NMR spectroscopy (Table [1], entry 2). The yield dropped to 12% when (2,4,6-MeOC₆H₂)₃P was used (Table [1], entry 3). Further screening led to the observation that TFP was the best ligand (Table [1], entry 4). Two and four equivalents of benzyne precursor 2 both afforded lower yield of the product 3a (Table [1], entries 5 and 6).

Increasing the loading of ligand TFP to 10 mol% had little effect to the reaction (Table [1], entry 7). Then different catalysts were screened: When Pd(O₂CCF₃)₂ was used, 16% of product 3a was observed (Table [1], entry 8); Pd(PPh₃)₄ failed to yield any product (Table [1], entry 9); PdI₂ and PdCl₂(MeCN)₂ were so inefficient that only 2% and 4% of product 3a were obtained (Table [1], entries 10 and 11).

Then the effects of solvent and temperature were explored. As can be seen from Table [2], other solvents except MeCN were ineffective with no corresponding products formed (Table [2], entries 1–5). When a mixed solvent of toluene and MeCN (1:1) was used, 37% of product 3a were obtained (Table [2], entry 6). When the reaction was conducted at 40 °C, the reaction became slow with 26% of product 3a formed and 21% of starting material 1a recovered (Table [2], entry 8). The reaction at 80 °C was over within 24 hours with 47% yield of product 3a (Table [2], entry 9).

With the optimized conditions in hand (Table [2], entry 7), the scope of the reaction was explored. When R² = Me and R³ = H and if R¹ = Me (Table [3], entry 2), 38% isolated yield of 3b was observed; if R¹ is a long-chain alkyl group, such as n-butyl (Table [3], entry 1), n-hexyl (Table [3], entry 3), or n-octyl (Table [3], entry 4), the products were obtained in >50% isolated yields. The yield of product 3e dropped to 49% when R¹ = All (Table [3], entry 5) and if R¹ = Ph, 41% NMR yield of product 3f (Table [3], entry 6) was formed. When R¹ = n-butyl, alkynylcyclopentanol carbonate 1g afforded product 3g in 45% yield (Table [3], entry 7). When cyclopentyl was replaced with cyclohexyl, 42% isolated yield of 3h was observed (Table [3], entry 8). However, it should be noted that the reaction with substituted benzyne precursors, such as 2-methyl-6-(trimethylsilyl)phenyltriflate, 3-methoxy-, or 4,5-dimethoxy-­2-(trimethylsilyl)phenyltriflate led to the recovery of the starting propargylic carbonate 1a.

Table 1 Optimization of Catalyst and Ligand of Palladium-Catalyzed Reaction of Propargylic Carbonates with Benzyne^a

Entry	Catalyst	Ligand	Yield of 3a (%)b	Recovery of 1a (%)b
1	Pd(OAc)2	PCy3	–	51
2	Pd(OAc)2	(4-MeOC6H4)3P	42	–
3	Pd(OAc)2	(2,4,6-MeOC6H2)3P	12	51
4	Pd(OAc)2	TFPc	52	–
5	Pd(OAc)2	TFPd	25	–
6	Pd(OAc)2	TFPe	50	–
7	Pd(OAc)2	TFPf	52	–
8	Pd(O2CCF3)2	TFP	16	–
9	Pd(PPh3)4	–	–	–
10	PdI2	TFP	2	63
11	PdCl2(MeCN)2	TFP	4	45

^a Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), catalyst (5 mol%), ligand (5 mol%), and CsF (6.0 equiv) in MeCN at 60 °C in a Schlenk tube.

^b The yield was determined by ¹H NMR spectroscopic analysis with MeNO₂ as the internal standard.

^c TFP = tri(2-furyl)phosphine.

^d Conditions: 2.0 equiv of 2 were used.

^e Conditions: 4.0 equiv of 2 were used.

^f Conditions: 10 mol% of TFP was used.

Table 2 Temperature and Solvent Effects of Palladium-Catalyzed Reaction of Propargylic Carbonates with Benzyne^a

Entry	Solvent	Temp (°C)	Time (h)	NMR yield of 3a (%)b	Recoveryb of 1a (%)
1	CH2Cl2	60	24	–	–
2	DCE	60	24	–	21
3	toluene	60	23	–	–
4	THF	60	23	–	67
5	dioxane	60	19	–	14
6	toluene–MeCN (1:1)	60	24	37	–
7	MeCN	60	24	52	–
8	MeCN	40	24	26	21
9	MeCN	80	24	47	–

^a Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Pd(OAc)₂ (5 mol%), TFP (5 mol%), and CsF (6.0 equiv) in a Schlenk tube.

^b The yield was determined by ¹H NMR spectroscopic analysis with MeNO₂ as the internal standard.

To test the practicability of the catalytic system, the reaction was carried out in gram scale (6.0 mmol) of 1a and 2 (18 mmol). The desired product 3a was obtained in 52% yield (Scheme [2]). The product 3f was further confirmed by its X-ray diffraction study (Figure [1]).[6]

Table 3 The Scope of Palladium-Catalyzed Reaction of Propargylic Carbonates with Benzynes^a

Entry	R1	R2	R3	Time (h)	Isolated yield of 3 (%)
1	1a n-Bu	Me	H	24	3a 53b
2	1b Me	Me	H	24	3b 38
3	1c n-C6H13	Me	H	24	3c 54b
4	1d n-C8H17	Me	H	24	3d 50b
5	1e All	Me	H	22	3e 49
6c	1f Ph	Me	H	24	3f 41d
7	1g n-Bu	–CH2CH2CH2–		35	3g 45
8	1h n-Bu	–CH2(CH2)2CH2–		22	3h 42

^a Reaction conditions: 1 (0.4 mmol), 2 (1.2 mmol), Pd(OAc)₂ (5 mol%), TFP (5 mol%), and CsF (6.0 equiv) in MeCN at 60 °C.

^b Purity of 3a, 3c, 3d is 95%, 94%, and 95% separately.

^c CsF was added at last.

^d The yield was determined by ¹H NMR spectroscopic analysis with MeNO₂ as the internal standard.

A plausible mechanism for this transformation is shown in Scheme [3]. Initially, propargylic palladium Int 1/allenylic palladium Int 2 would be formed from the oxidative addition of palladium(0) with 1a. Benzyne, which is in situ generated from the reaction of CsF and 2, would insert into Int 2 to afford the aryl palladium Int 3. Insertion of the second benzyne into Int 3 would produce Int 6. Subsequent carbopalladation of the intramolecular C=C bond substituted with two methyl groups would afford Int 7. β-H elimination of Int 7 gave 3a.

Representative Procedure for the Synthesis of 9-Butyl-10-isopropenyl Phenanthrene (3a)

To a flame-dried Schlenk tube were added CsF (364.9 mg, 2.4 mmol), Pd(OAc)₂ (4.5 mg, 0.02 mmol), TFP (4.6 mg, 0.02 mmol), propargylic carbonate 1a (80.0 mg, 0.4 mmol), and MeCN (2 mL). After the mixture was stirred at r.t. for 5 min, benzyne precursor 2 (357.3 mg, 1.2 mmol) and MeCN (2 mL) were added to the reaction mixture sequentially. The resulting mixture was stirred at 60 °C. After 24 h the reaction was over as monitored by TLC. The resulting mixture was then filtered through a short pad of silica gel (2 cm) to remove the inorganic salts (eluent: 70 mL of Et₂O) for easy NMR analysis of the crude product. After evaporation, the mixture was purified by column chromatography on silica gel (eluent: PE) to afford the desired product 3a (62.1 mg, 53%, purity 95% based on the ¹H NMR analysis with MeNO₂ as the internal standard; eluent: PE).

Analytical Data

Oil. ¹H NMR (300 MHz, CDCl₃): d = 8.76–8.64 (m, 2 H, ArH), 8.14–8.05 (m, 1 H, ArH), 8.03–7.94 (m, 1 H, ArH), 7.66–7.54 (m, 4 H, ArH), 5.54 (s, 1 H, one proton of CH₂=), 5.02 (s, 1 H, one proton of CH₂=), 3.23–3.09 (m, 1 H, CH₂), 3.04–2.90 (m, 1 H, CH₂), 2.15 (s, 3 H, CH₃), 1.82–1.48 (m, 4 H, 2 × CH₂), 1.00 (t, J = 6.9 Hz, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): d = 144.1, 138.0, 132.6, 131.1, 130.4, 130.1, 129.5, 126.54, 126.53, 126.5, 125.7, 125.6, 125.1, 123.0, 122.5, 116.6, 33.7, 30.2, 25.1, 23.5, 14.0. MS (EI): m/z = 275 (7.79) [M⁺ + 1], 274 (32.17) [M⁺], 217 (100). IR (neat): 3074, 2956, 2928, 2870, 1641, 1586, 1492, 1447, 1429, 1372, 1103, 1046 cm^–1. HRMS (EI): m/z calcd for C₂₁H₂₂ [M⁺]: 274.1722; found: 274.1718.

Acknowledgment

Financial support from the National Basic Research Program of China (2011CB808700) and National Natural Science Foundation of China (21232006) is greatly appreciated. We thank Xin Huang in our group for reproducing the results presented in Table [3], entries 2 and 5.

• References and Notes

• 1a Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M. Chem. Rev. 2002; 102: 1359
  CrossrefPubMedSearch in Google Scholar
• 1b Gellert E. J. Nat. Prod. 1982; 45: 50
  CrossrefSearch in Google Scholar
• 1c Li ZG, Jin Z, Huang RQ. Synthesis 2001; 2365
  Thieme Connect

For recent reports on synthesis of phenanthrene, see:
• 2a Matsumoto A, Ilies L, Nakamura E. J. Am. Chem. Soc. 2011; 133: 6557
  CrossrefSearch in Google Scholar
• 2b Wang C, Rakshit S, Glorius F. J. Am. Chem. Soc. 2010; 132: 14006
  CrossrefPubMedSearch in Google Scholar
• 2c Neo AG, López C, Romero V, Antelo B, Delamano J, Pérez A, Fernández D, Almeida JF, Castedo L, Tojo G. J. Org. Chem. 2010; 75: 6764
  CrossrefSearch in Google Scholar
• 2d Yoshikawa E, Yamamoto Y. Angew. Chem. Int. Ed. 2000; 39: 173
  CrossrefPubMedSearch in Google Scholar
• 2e Yoshikawa E, Radhakrishnan KV, Yamamoto Y. J. Am. Chem. Soc. 2000; 122: 7280
  CrossrefSearch in Google Scholar
• 2f Liu Z, Larock RC. Angew. Chem. Int. Ed. 2007; 46: 2535
  CrossrefPubMedSearch in Google Scholar
• 2g Peña D, Pérez D, Guitián E, Castedo L. J. Am. Chem. Soc. 1999; 121: 5827
  CrossrefSearch in Google Scholar
• 3 Tsuji J, Watanabe H, Minami I, Shimizu I. J. Am. Chem. Soc. 1985; 107: 2196
  CrossrefSearch in Google Scholar

For reviews on Pd-catalyzed transformations of propargylic carbonates, see
• 4a Tsuji J, Mandai T. Angew. Chem., Int. Ed. Engl. 1995; 34: 2589
  Search in Google Scholar
• 4b Guo L, Duan X, Liang Y. Acc. Chem. Res. 2011; 44: 111 ; and references cited therein
  CrossrefSearch in Google Scholar
• 5a Ma S, Gu Z, Deng Y. Chem. Commun. 2006; 94
• 5b Shu W, Jia G, Ma S. Org. Lett. 2009; 11: 117
  CrossrefSearch in Google Scholar
• 5c Shu W, Ma S. Tetrahedron 2010; 66: 2869
  CrossrefSearch in Google Scholar
• 5d Chen G, Zhang Y, Fu C, Ma S. Tetrahedron 2011; 67: 2332
  CrossrefSearch in Google Scholar
• 5e Ye J, Li S, Ma S. Org. Lett. 2012; 14: 2312
  CrossrefSearch in Google Scholar
• 6 Crystal Data for Compound 3f C₂₃H₁₈, MW = 294.14, monoclinic, space group P₂ (1), final R indices [I > 2σ(I)], R ₁ = 0.0472, wR ₂ = 0.1223, R indices (all data), R ₁ = 0.0593, wR ₂ = 0.1310, a = 6.2434(5) Å, b = 8.0127(7) Å, c = 21.1301(18) Å, α = 90^o, β = 90.262(2)^o, γ = 90^o, V = 1057.05(15) ų, T = 293 (2) K, Z = 2, reflections collected/unique: 6377/4106 [R(int) = 0.0195], number of observations [>2σ(I)] 3264; parameter: 256. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center (CCDC 941026).

• References and Notes

• 1a Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M. Chem. Rev. 2002; 102: 1359
  CrossrefPubMedSearch in Google Scholar
• 1b Gellert E. J. Nat. Prod. 1982; 45: 50
  CrossrefSearch in Google Scholar
• 1c Li ZG, Jin Z, Huang RQ. Synthesis 2001; 2365
  Thieme Connect

For recent reports on synthesis of phenanthrene, see:
• 2a Matsumoto A, Ilies L, Nakamura E. J. Am. Chem. Soc. 2011; 133: 6557
  CrossrefSearch in Google Scholar
• 2b Wang C, Rakshit S, Glorius F. J. Am. Chem. Soc. 2010; 132: 14006
  CrossrefPubMedSearch in Google Scholar
• 2c Neo AG, López C, Romero V, Antelo B, Delamano J, Pérez A, Fernández D, Almeida JF, Castedo L, Tojo G. J. Org. Chem. 2010; 75: 6764
  CrossrefSearch in Google Scholar
• 2d Yoshikawa E, Yamamoto Y. Angew. Chem. Int. Ed. 2000; 39: 173
  CrossrefPubMedSearch in Google Scholar
• 2e Yoshikawa E, Radhakrishnan KV, Yamamoto Y. J. Am. Chem. Soc. 2000; 122: 7280
  CrossrefSearch in Google Scholar
• 2f Liu Z, Larock RC. Angew. Chem. Int. Ed. 2007; 46: 2535
  CrossrefPubMedSearch in Google Scholar
• 2g Peña D, Pérez D, Guitián E, Castedo L. J. Am. Chem. Soc. 1999; 121: 5827
  CrossrefSearch in Google Scholar
• 3 Tsuji J, Watanabe H, Minami I, Shimizu I. J. Am. Chem. Soc. 1985; 107: 2196
  CrossrefSearch in Google Scholar

For reviews on Pd-catalyzed transformations of propargylic carbonates, see
• 4a Tsuji J, Mandai T. Angew. Chem., Int. Ed. Engl. 1995; 34: 2589
  Search in Google Scholar
• 4b Guo L, Duan X, Liang Y. Acc. Chem. Res. 2011; 44: 111 ; and references cited therein
  CrossrefSearch in Google Scholar
• 5a Ma S, Gu Z, Deng Y. Chem. Commun. 2006; 94
• 5b Shu W, Jia G, Ma S. Org. Lett. 2009; 11: 117
  CrossrefSearch in Google Scholar
• 5c Shu W, Ma S. Tetrahedron 2010; 66: 2869
  CrossrefSearch in Google Scholar
• 5d Chen G, Zhang Y, Fu C, Ma S. Tetrahedron 2011; 67: 2332
  CrossrefSearch in Google Scholar
• 5e Ye J, Li S, Ma S. Org. Lett. 2012; 14: 2312
  CrossrefSearch in Google Scholar
• 6 Crystal Data for Compound 3f C₂₃H₁₈, MW = 294.14, monoclinic, space group P₂ (1), final R indices [I > 2σ(I)], R ₁ = 0.0472, wR ₂ = 0.1223, R indices (all data), R ₁ = 0.0593, wR ₂ = 0.1310, a = 6.2434(5) Å, b = 8.0127(7) Å, c = 21.1301(18) Å, α = 90^o, β = 90.262(2)^o, γ = 90^o, V = 1057.05(15) ų, T = 293 (2) K, Z = 2, reflections collected/unique: 6377/4106 [R(int) = 0.0195], number of observations [>2σ(I)] 3264; parameter: 256. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center (CCDC 941026).

• Supplementary Material