Palladium-Catalyzed Double C–H Functionalization of Arenes at the Positions ortho and meta to Their Directing Group: Concise Synthesis of Benzocyclobutenes

Abstract

The synthesis of benzocyclobutenes from simple arenes bearing a directing group was investigated via the palladium-catalyzed cyclization of norbornene derivatives. This approach allowed for the facile construction of benzocyclobutenes along with the double functionalization of the C–H bonds at the positions ortho and meta to the directing group. This result shows that the key palladacyclopentene intermediate in the Catellani reaction can be prepared by the directed double ortho C–H activation of the substrate. The results of this study also revealed that the combination of an N-protected amino acid with benzoquinone (BQ) was effective for this transformation.

The functionalization of aromatic rings has been widely investigated as a fundamental transformation for over a century. In particular, the simultaneous functionalization of two C–H bonds at adjacent positions on an aromatic ring is a direct and effective approach for the synthesis of multi-substituted arenes. Two major routes have been developed for the multiple functionalization of arenes in this way, including (i) the reaction of benzyne intermediates^1–4) and (ii) the norbornene-mediated ortho C–H functionalization of arenes.^5–7) Benzyne is a highly reactive species because of its strained structure, making it a useful intermediate for the transformation of aromatic rings through cycloaddition and multicomponent reactions.^1–4) Regarding the ortho C–H functionalization of arenes, various norbornene-mediated strategies have been developed for the ipso and ortho functionalization of aryl halides using palladium catalysts, including those reported by Catellani et al.,^8,9) Lautens and colleagues,^10–12) Malacria and colleagues,¹³⁾ Dong Z. and Dong G.,¹⁴⁾ Liang and colleagues,¹⁵⁾ Ritter and colleagues¹⁶⁾ and Zhou and colleagues.¹⁷⁾ Although these strategies can be applied to various transformations involving aromatic rings by simply changing the reagents, they need at least one reactive substituent such as a halogen at the appropriate position of the aromatic ring to achieve the desired transformation. The norbornene-mediated C–H functionalization of arenes has been extended to the direct functionalization of indoles^18,19) and the meta-selective C–H functionalization of arenes and heteroaerenes.^20–24) However, only one functional group can be introduced at the meta position using these reactions, thus the development of a more efficient approach is still highly desired.

The metal-catalyzed double C–H functionalization of arenes has recently attracted considerable interest from numerous researchers. For example, the research groups of Miura and colleagues and Jiao and colleagues reported the rhodium-catalyzed double C–H functionalization of arenes bearing a directing group at the positions ortho and meta to the directing group.^25–29) These methods can also be applied to the construction of benzene and indole rings fused to another arene ring system. Furthermore, Hiyama and colleagues developed a dehydrogenative carbon–carbon bond forming reaction involving ortho and meta C–H functionalization steps using an alkynyloxy moiety as a directing group. It is noteworthy that the alkynyloxy moiety works as a hydrogen acceptor in this case, thereby avoiding the need to add an oxidant and base to the reaction.³⁰⁾

During the course of our recent studies,³¹⁾ we became interested in the way in which norbornene facilitates the ortho functionalization of aryl halides (Chart 1). According to the mechanism reported by Catellani, this reaction proceeds by the oxidative addition of an aryl halide to palladium(0) (Pd(0)) to give an arylpalladium intermediate (Chart 1a). This intermediate would then react with norbornene to form a palladacycle intermediate via the activation of the ortho C–H bond. Given that the directed ortho C–H activation step in this mechanism occurs in the presence of a Pd(II) catalyst, we envisaged that the norbornene-mediated meta C–H activation of a benzene ring bearing a directing group would provide the same palladacycle (Chart 1b). Yu and colleagues recently reported the formation of benzocyclobutene during the course of their work towards the development of a new meta C–H functionalization strategy based on the ideas discussed above.^21,22) However, they only investigated this reaction using a specific substrate for their double functionalization, leaving the scope of this reaction unexplored. Herein, we report the palladium-catalyzed, norbornene-mediated double C–H functionalization of arenes bearing a directing group at the positions ortho and meta to the directing group. Notably, this strategy provides a direct and concise approach for a synthesis of benzocyclobutene,³²⁾ which is a useful intermediate for the preparation of complicated aromatic compounds. We have also investigated the scope and limitations of this reaction in detail.

Chart 1. (a) Catellani Reaction and (b) Our Strategy for the Double Functionalization of the ortho and meta C–H Bonds of a Benzene Ring Bearing a Directing Group

The initial reaction of the O-methyloxime of tetralone 1a³³⁾ with norbornene (2a) in the presence of Pd(OAc)₂ (10 mol%) in N,N-dimethylformamide (DMF) at 100°C gave a trace amount of the desired benzocyclobutene 3aa (Table 1, entry 1). We subsequently screened a variety of different oxidants against the reaction to affect the oxidation of the palladium catalyst. Although the addition of PhI(OAc)₂ or N-fluorobis(phenylsulfonyl)amine (NFSI) resulted in a complex mixture (Table 1, entries 2, 3), a combination of Cu(OAc)₂ and oxygen gave a small amount of the desired product 3aa (Table 1, entry 4). Interestingly, the use of K₂S₂O₈ as an oxidant resulted in the formation of compound 4 (Table 1, entry 5). Pleasingly, we found that the addition of a silver salt was effective for this conversion, with Ag₂CO₃ affording the best conversion of all of the silver salts tested in the current study (Table 1, entries 6–9). It is noteworthy that the addition of benzoquinone (BQ) led to an increase in the conversion of 1a, although the yield of 3aa was still low (3aa : 1a=10 : 90) (Table 1, entry 9).

Table 1. Screening of Various Oxidants

Entry	Oxidant (eq)	Conversion (3aa : 1a)a)
1	None	Trace
2	PhI(OAc)2 (2)	Complex mixtureb)
3	NFSI (2)	Complex mixture
4	Cu(OAc)2 (1), O2	5 : 95
5	K2S2O8 (2)	N.D.c)
6	AgOAc (8)	Trace
7	Ag2O (4)	Trace
8	Ag2CO3 (4)	7 : 93
9	Ag2CO3 (4), BQ (0.5)	10 : 90

a) The ratio was determined by ¹H-NMR analysis of the crude reaction mixture. b) The starting material was also recovered in approximately 70% yield. c) Compound 4 was obtained (4 : 1a=33 : 67). NFSI=N-fluorobis(phenylsulfonyl)amine, BQ=1,4-benzoquinone, N.D.=Not detected.

We subsequently investigated the addition of various acids to this reaction at 80°C to improve the yield of the desired product 3aa (Table 2). The addition of a carboxylic acid such as AcOH or trifluoroacetic acid (TFA) led to an increase in the production-ratio of 3aa, whereas the addition of pivalic acid had no discernible impact on the conversion (Table 2, entries 1–4). Further screening revealed that the addition of a catalytic amount of N-9-fluorenylmethoxycarbonyl (Fmoc)-protected amino acid (20 mol%) led to a dramatic increase in the conversion of 1a to the desired product 3aa. This result was consistent with the results reported by Yu for a related reaction,³⁴⁾ with valine providing the best result of all of the amino acids tested in the current study (Table 2, entries 5–9). The nature of the protecting group on the nitrogen atom of the amino acid was also found to be very important. Although the use of a formyl or acetyl (Ac) group did not lead to an improvement in the conversion of 1a (Table 2, entries 10, 11), the use of a carbamate protecting group such as a t-butyloxycarbonyl (Boc), methoxycarbonyl or (−)-menthyloxycarbonyl (Men) group led to an increase in the conversion (Table 2, entries 12–14). In contrast to previous reports from the literature,³⁴⁾ the use of a smaller charge of (−)-Men-Val-OH (5 mol%) led to an increase in the conversion of 1a (Table 2, entry 15). After fine tuning the conditions for this reaction, we established that the use of 2.0 eq of Ag₂CO₃ with 1.5 eq of BQ led to the complete conversion of 1a, with benzocyclobutene 3aa being isolated in 84% yield after silica gel column chromatography (Table 2, entry 16).

Table 2. Screening of Several Acid-Additives

Entry	Acid (mol%)	Conversion (3aa : 1a)a)
1	None	8 : 92
2	PivOH (100)	7 : 93
3	TFA (100)	11 : 89
4	AcOH (100)	16 : 84
5	Fmoc-Ile-OH (20)	49 : 51
6	Fmoc-Leu-OH (20)	42 : 58
7	Fmoc-Ala-OH (20)	34 : 66
8	Fmoc-Phe-OH (20)	42 : 58
9	Fmoc-Val-OH (20)	50 : 50
10	Formyl-Val-OH (20)	17 : 83
11	Ac-Val-OH (20)	6 : 94
12	Boc-Val-OH (20)	43 : 57
13	MeO2C-Val-OH (20)	51 : 49
14	(−)-Men-Val-OH (20)	58 : 42
15	(−)-Men-Val-OH (5)	75 : 25
16b)	(−)-Men-Val-OH (5)	>98 : 2 (84%)c)

a) The ratio was determined by ¹H-NMR analysis of the crude reaction mixture. b) 1.5 eq of BQ and 2 eq of Ag₂CO₃ were used in this reaction over a reaction time of 96 h. c) Isolated yield. (−)-Men-=(−)-menthyl-OC(O)-.

With the optimal conditions in hand, we screened several other directing groups against this transformation (Chart 2). The reaction of 2-(pyridylmethyl)toluene (1b)^35,36) under the optimal conditions gave benzocyclobutene 3ba in 81% yield. The 2-pyrimidylmethyl and pyridyl-2-oxy bearing substrates 1c and d also performed well in this transformation, affording the corresponding cyclobutene products 3ca and da in lower yields. In these reactions, the nitrogen atoms in the aromatic rings behaved as directing groups for the C–H activation. In contrast, the reaction of 2-(2-pyridyl)toluene (1e) did not afford any of the corresponding benzocyclobutene 3ea, with 1e being recovered unchanged. These results therefore indicate that the location of the directing groups is critical to the stability and reactivity of the palladium complex generated by the ortho C–H activation step. We also investigated the use of a carboxylic acid as a directing group. Notably, o-toluic acid (1f) and o-tolylacetic acid (1g) afforded the corresponding benzocyclobutenes 3fa and ga, respectively, albeit in very low yields with the starting materials being recovered largely unchanged. These results can be rationalized in terms of the differences in the coordinative affinities of the different directing groups to the palladium catalyst (i.e., oxime and pyridine vs. carboxylic acid).

Chart 2. Screening of Different Directing Groups

^a Isolated yield. ^b NMR yield. ^c The reaction was performed in the absence of (−)-Men-Val-OH and BQ. ^d Starting material 1e was recovered. N.D.=Not detected.

Having identified the most applicable directing groups for this reaction, we subsequently investigated the scope of the arene substrate under the optimal conditions (Table 3). The reactions of O-methyloximes 1h³³⁾ and i,³⁷⁾ which were derived from acetophenone and propiophenone, gave the desired products 3ha and ia in moderate yields, respectively (Table 3, entries 1, 2). These reactions also afforded the corresponding symmetrical products 4ha and ia, which were generated by the reactions of 3ha and ia. The yield of 3ja was low because of the unreactive nature of the (Z)-isomer of the oxime substrate 1j (ca. 50%), which did not isomerize under the reaction conditions to give the more reactive (E)-isomer (Table 3, entry 3). When O-benzyloxime was used instead of O-methyloxime, the desired product 3ka was obtained in 63% yield (Table 3, entry 4). The reaction of the 3-methylacetophenone oxime 1l gave the desired product 3la in 35% yield (Table 3, entry 5). We subsequently investigated the electronic effects of the arene substrate using various 2-substituted 1-(2-pyridylmethyl)benzenes (1m–p). The reaction of substrate 1m bearing a methoxy group on its benzene ring proceeded smoothly to give benzocyclobutene 3ma in 72% yield (Table 3, entry 6). Compared with 1b and m, the reactions of 1n and o bearing electron-withdrawing groups on their benzene ring resulted in relatively lower yields (Table 3, entries 7, 8). Notably, the reaction of the simple (2-pyridylmethyl)benzene substrate 1p gave a mixture of 3pa and 4pa in a combined yield of 68% (Table 3, entry 9). The reaction of substrate 1q bearing a methyl group at its 3-position under the optimized conditions led to a decrease in the yield to 49%, presumably because the product can react with norbornene (2a) (Table 3, entry 10). The introduction of a methyl group at the 4-position of the benzene ring of the substrate also had an adverse impact of the reaction, most likely because of steric hindrance in the key palladacycle (3ra) (Table 3, entry 11).

Table 3. Scope of Arenes

Entry	Arene		Total yield (%)a)	Ratio (3xa : 4xa)
1		1h (R1=Me)	38	20 : 18
2		1i (R1=Et)	39	22 : 17
3		1j (R1=iPr)	22	11 : 11
4		1k	63	NAb)
5		1l	35	NAb)
6		1m (R1=OMe, R2=R3=H)	72	NAb)
7		1n (R1=F, R2=R3=H)	62	NAb)
8		1o (R1=CO2Me, R2=R3=H)	43	NAb)
9		1p (R1=H, R2=R3=H)	68	13 : 55
10		1q (R1=H, R2=Me, R3=H)	49	NAb)
11		1r (R1=Me, R2=H, R3=Me)	15	NAb)

a) Isolated yield. b) Compound 3xa was only produced. NA=Not applicable.

We then proceeded to investigate the scope of the norbornene (Chart 3). Norbornenes 2b and c bearing a cyano and an acetal group gave the corresponding benzocyclobutenes 3ab and ac in 60 and 77% yields, respectively. Although the inclusion of a cyano group had no discernible impact on the yield of the product 3ab, the presence of an acetyl group accelerated the formation of palladium black, leading to a decrease in the yield of 3ad. The reaction of norbornene analogue 2e fused with a benzene ring provided benzocyclobutene 3ae in 62% yield. The use of bicyclo[2.2.2]octadiene 2f failed to afford any of the desired product 3af, indicating that the bicyclo[2.2.1]nonene skeleton would be essential for this transformation. Additionally, norbornadiene 2g did not afford benzocyclobutene 3ag, probably because of the inhibition of the catalytic cycle by the coordination to the palladium catalyst.

Chart 3. Scope of the Norbornene

^a Isolated yield. N.D.=Not detected.

To gain an insight into the mechanism of this reaction, we conducted two kinetic isotope effect (KIE) experiments (Chart 4). The reaction of the ortho-deuterated substrate 1e-d₃³⁸⁾ under the optimized conditions gave a KIE value 1.4, which was estimated from a ratio of the products (a). In contrast, the meta-deuterated substrate 1e-d₆ showed a KIE value of 2.3 (b). These results indicated that the cleavage of the C–H bond at the meta position required a larger activation energy rather than that of the ortho position.

Chart 4. KIE Study

Based on the results of the KIE experiments, we have proposed a plausible mechanism for this reaction, which is shown in Chart 5. The directing group of substrate 1 and (−)-Men-Val-OH would initially coordinate to the divalent Pd center, resulting in the cleavage of the ortho C–H bond along with the formation of a C–Pd bond. The results of our screening experiments showed that the protected amino acid ligand was essential for this step.³⁴⁾ The subsequent insertion of norbornene (2) into the resulting intermediate, followed by the meta C–H activation of the benzene ring would afford the key palladacycle from Catellani’s ortho C–H functionalization mechanism. Reductive elimination from the palladacycle, which is assumed to be a rate-determining step in this transformation, would give the desired benzocyclobutene product 3 along with a Pd(0) species, which would be re-oxidized to Pd(II) by the oxidant. BQ improved the yield of the product, but was not essential for the catalytic reaction.³⁹⁾ In contrast, the presence of Ag₂CO₃ was critical to the success of this reaction. Taken together, these results indicate that BQ simply enhanced the rate of the reductive elimination, with Ag₂CO₃ acting as an oxidant.

Chart 5. Plausible Mechanism

In summary, we have conducted an extensive investigation of the palladium-catalyzed double C–H functionalization of arenes bearing a directing group, with the functionalization taking place at the positions ortho and meta to the directing groups. Notably, this transformation allows for the facile construction of benzocyclobutenes from simple arenes. This reaction presumably proceeds via the key palladacycle intermediate formed in Catellani’s reaction, and we are currently investigating the development of this reaction as a general method for the double C–H functionalization of arenes.

Experimental

General Experimental Details

Unless otherwise noted, all the reagents were purchased from chemical companies and used without further purification. Analytical TLC was performed with Merck Silica gel 60. Silica gel column chromatography was performed with Kanto silica gel 60 (particle size, 63–210 µm) and Fuji silysia Chromatorex BW-300. All melting points (mp) were determined on YANAGIMOTO micro melting point apparatus. ¹H-NMR spectra were recorded on a JEOL JNM-LA 500 at 500 MHz. Chemical shifts are reported relative to Me₄Si (δ 0.00) in CDCl₃. Multiplicity is indicated by one or more of the following: s (singlet); d (doublet); t (triplet); q (quartet); sep (septet); m (multiplet); br (broad). ¹³C-NMR spectra were recorded on a JEOL JNM-LA 500 at 126 MHz. Chemical shifts are reported relative to CDCl₃ (δ 77.0). Infrared spectra were recorded on a FT/IR-4100 (JASCO). Low and high resolution mass spectra were recorded on JEOL MS700 mass spectrometer for FAB-MS, and Shimadzu LCMS-IT-TOF for ESI-MS.

Procedure for the Synthesis of Benzocyclobutenes

General Procedure

In a sealed tube, to a mixture of substrate (0.200 mmol, 1.0 equiv.), norbornene derivative (0.400 mmol, 2.0 eq) in DMF (2 mL) were added benzoquinone (32.4 mg, 0.300 mmol, 1.5 eq), Ag₂CO₃ (110 mg, 0.4 mmol, 2.0 eq), (−)-Men-Val-OH (3.0 mg, 0.0100 mmol, 0.05 eq) and Pd(OAc)₂ (4.5 mg, 0.0200 mmol, 0.1 eq). The tube was filled with argon and the mixture was heated to 80°C. After stirring for 48–96 h, the mixture was cooled to room temperature, diluted with EtOAc and filtrated. The solution was washed with water and brine, dried over Na₂SO_4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane–EtOAc or hexane–CH₂Cl₂) to give the corresponding benzocyclobutene.

3,4,6b,7,8,9,10,10a-Octahydro-7,10-methanobenzo[a]biphenylen-1(2H)-one O-Methyl Oxime (3aa)

According to the general procedure, the reaction gave the product in 84% yield as a white solid: mp 89.9–91.4°C; ¹H-NMR (500 MHz, CDCl₃) δ: 6.96 (d, 1H, J=7.5 Hz), 6.84 (d, 1H, J=7.5 Hz), 3.98 (s, 3H), 3.26 (d, 1H, J=3.0 Hz), 3.07 (d, 1H, J=3.0 Hz), 2.72–2.67 (m, 4H), 2.55 (s, 1H), 2.24 (s, 1H), 1.88–1.74 (m, 2H), 1.63–1.54 (m, 2H), 1.22–1.15 (m, 2H), 0.92 (d, 1H, J=10.0 Hz), 0.85 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.9, 144.5, 143.9, 138.1, 127.6, 125.6, 122.0, 62.0, 52.3, 49.8, 36.6, 35.1, 32.0, 30.3, 27.9, 27.8, 24.0, 21.8; IR (attenuated total reflectance (ATR)) 2937, 1617, 1417, 1050 cm⁻¹; high resolution (HR)-MS (FAB⁺) Calcd for C₁₈H₂₂NO: ([M+H]⁺) 268.1701: Found 268.1694.

2-((6-Methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3ba)

According to the general procedure, the reaction gave the product in 81% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.54 (d, 1H, J=4.9 Hz), 7.51 (ddd, 1H, J₁=J₂=7.8 Hz, J₃=1.7 Hz), 7.11 (dd, 1H, J₁=J₂=7.5 Hz), 7.03 (d, 1H, J=7.8 Hz), 6.88 (d, 1H, J=7.8 Hz), 6.81 (d, 1H, J=7.5 Hz), 4.11 (d, 1H, J=16.1 Hz), 4.07 (d, 1H, J=16.1 Hz), 3.07 (d, 1H, J=3.8 Hz), 3.00 (d, 1H, J=3.8 Hz), 2.23 (d, 1H, J=3.2 Hz), 2.19 (s, 3H), 1.95 (d, 1H, J=3.2 Hz), 1.58–1.46 (m, 2H), 1.16–1.04 (m, 2H), 0.90 (d, 1H, J=10.1 Hz), 0.88 (d, 1H, J=10.1 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.6, 149.1, 145.9, 143.7, 136.3, 135.4, 131.7, 129.5, 122.3, 121.0, 120.3, 49.4, 48.9, 37.6, 36.5, 36.1, 31.9, 27.8, 27.8, 19.8; IR (ATR) 2946, 1588, 1472, 1434 cm⁻¹; HR-MS (electrospray ionization (ESI)⁺) Calcd for C₂₀H₂₂N: ([M+H]⁺) 276.1752: Found 267.1754.

2-((6-Methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyrimidine (3ca)

According to the general procedure, the reaction gave the product in 69% yield as a colorless: ¹H-NMR (500 MHz, CDCl₃) δ: 8.65 (d, 2H, J=4.9 Hz), 7.09 (t, 1H, J=4.9 Hz), 7.03 (d, 1H, J=7.2 Hz), 6.79 (d, 1H, J=7.2 Hz), 4.24 (d, 1H, J=15.4 Hz), 4.20 (d, 1H, J=15.4 Hz), 3.04 (d, 1H, J=4.0 Hz), 2.95 (d, 1H, J=4.0 Hz), 2.31 (s, 3H), 2.20 (d, 1H, J=2.9 Hz), 2.00 (d, 1H, J=2.9 Hz), 1.56–1.45 (m, 2H), 1.14–1.03 (m, 2H), 0.88–0.84 (m, 2H); ¹³C-NMR (126 MHz, CDCl₃) δ: 170.0, 157.1, 145.7, 143.5, 135.2, 131.2, 129.3, 120.3, 118.4, 49.4, 48.9, 39.2, 36.4, 36.0, 31.9, 27.8, 27.7, 20.1; IR (ATR) 2946, 1559, 1417 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₉H₂₁N₂: ([M+H]⁺) 277.1705: Found 277.1700.

2-((6-Methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)oxy)pyridine (3da)

According to the general procedure, the reaction gave the product in 39% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.22–8.21 (m, 1H), 7.68–7.65 (m, 1H), 7.12 (d, 1H, J=7.5 Hz), 6.99–6.97 (m, 1H), 6.86–6.85 (m, 1H), 6.76 (d, 1H, J=7.5 Hz), 3.09 (d, 1H, J=3.8 Hz), 2.88 (d, 1H, J=3.8 Hz), 2.23–2.21 (m, 4H), 1.78–1.77 (m, 1H), 1.54–1.41 (m, 2H), 1.12–1.07 (m, 1H), 0.98–0.90 (m, 3H); ¹³C-NMR (126 MHz, CDCl₃) δ: 163.3, 147.9, 146.2, 145.6, 139.2, 135.6, 130.7, 128.3, 118.8, 118.2, 110.9, 49.8, 48.9, 36.4, 35.7, 32.0, 27.7, 27.5, 16.6; IR (ATR) 2948, 1586, 1464, 1426, 1243 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₉H₂₀NO: ([M+H]⁺) 278.1545: Found 278.1537.

1-(1,2,3,4,4a,8b-Hexahydro-1,4-methanobiphenylen-5-yl)ethan-1-one O-Methyl Oxime (3ha)

According to the general procedure, the reaction gave the product in 20% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.49 (d, 1H, J=8.0 Hz), 7.20 (dd, 1H, J₁=8.0 Hz, J₂=7.3 Hz), 6.96 (d, 1H, J=7.3 Hz), 3.99 (s, 3H), 3.31 (d, 1H, J=4.0 Hz), 3.16 (d, 1H, J=4.0 Hz), 2.41 (d, 1H, J=2.8 Hz), 2.28 (d, 1H, J=2.8 Hz), 2.20 (s, 3H), 1.64–1.56 (m, 2H), 1.25–1.18 (m, 2H), 0.96 (d, 1H, J=10.3 Hz), 0.88 (d, 1H, J=10.3 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.5, 146.9, 144.2, 130.8, 127.7, 124.1, 122.2, 61.9, 52.0, 50.1, 36.7, 36.4, 32.0, 27.84, 27.81, 12.7; IR (ATR) 2951, 1472, 1057 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₆H₂₀NO: ([M+H]⁺) 242.1545: Found 242.1544.

1,2,3,4,4a,5b,6,7,8,9,9a,10b-Dodecahydro-1,4:6,9-dimethanobenzo[3,4]cyclobuta[1,2-b]biphenylen-5-yl)ethan-1-one O-Methyl Oxime (4ha)

According to the general procedure, the reaction gave the mixture of the products in 18% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 6.62–6.60 (m, 1H), 3.99–3.98 (m, 3H), 3.24–3.19 (m, 2H), 3.05 (m, 2H), 2.41 (s, 0.8H), 2.35 (s, 1.2H), 2.23–2.19 (m, 5H), 1.59–1.56, (m, 4H), 1.19–1.14 (m, 4H), 0.94–0.85 (m, 2.8H), 0.81 (d, 1.2H, J=10.3 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.0, 152.9, 145.8, 142.4, 142.3, 125.7, 125.5, 116.2, 116.1, 61.9, 51.8, 51.6, 49.7, 49.5, 36.9, 36.8, 36.6, 36.3, 31.9, 27.9, 27.8, 12.9, 12.8 (some peaks were missing due to overlapping); IR (ATR) 2945, 1453, 1052 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₃H₂₈NO: ([M+H]⁺) 334.2171: Found 334.2166.

1-(1,2,3,4,4a,8b-Hexahydro-1,4-methanobiphenylen-5-yl)propan-1-one O-Methyl Oxime (3ia)

According to the general procedure, the reaction gave the product in 22% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.41 (d, 1H, J=8.0 Hz), 7.17 (dd, 1H, J₁=8.0 Hz, J₂=7.2 Hz), 6.93 (d, 1H, J=7.2 Hz), 3.94 (s, 3H), 3.25 (d, 1H, J=3.7 Hz), 3.11 (d, 1H, J=3.7 Hz), 2.74 (dq, 1H, J₁=12.9 Hz, J₂=7.8 Hz), 2.61 (dq, 1H, J₁=12.9 Hz, J₂=7.8 Hz), 2.37 (d, 1H, J=2.8 Hz), 2.24 (d, 1H, J=2.8 Hz), 1.59–1.53 (m, 2H), 1.18–1.14 (m, 2H), 1.08 (t, 3H, J=7.8 Hz), 0.93 (d, 1H, J=10.0 Hz), 0.85 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 158.8, 147.0, 144.3, 129.9, 127.7, 124.7, 122.1, 61.9, 51.9, 50.0, 36.7, 36.4, 32.0, 27.8, 19.9, 11.1 (one peak was missing due to overlapping.); IR (ATR) 2951, 1463, 1053 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₇H₂₂NO: ([M+H]⁺) 256.1701: Found 256.1699.

1,2,3,4,4a,5b,6,7,8,9,9a,10b-Dodecahydro-1,4:6,9-dimethanobenzo[3,4]cyclobuta[1,2-b]biphenylen-5-yl)propan-1-one O-Methyl Oxime (4ia)

According to the general procedure, the reaction gave the mixture of the products in 17% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 6.63–6.60 (m, 1H), 3.97–3.96 (m, 3H), 3.22–3.17 (m, 2H), 3.04 (m, 2H), 2.83–2.76 (m, 0.6H), 2.71–2.66 (m, 0.8H), 2.60–2.53 (m, 0.6H), 2.40 (s, 0.8H), 2.34 (s, 1.2H), 2.23–2.21 (m, 2H), 1.62–1.51 (m, 4H), 1.18–1.14 (m, 4H), 1.10 (t, 3H, J=7.6 Hz), 0.94–0.87 (m, 2.8H), 0.84 (d, 1.2H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 158.3, 158.1, 145.9, 145.8, 142.6, 142.5, 124.89, 124.85, 116.1, 116.0, 61.9, 51.6, 51.5, 49.6, 49.5, 36.84, 36.79, 36.7, 36.4, 31.9, 27.9, 20.2, 20.0, 11.21, 11.19 (some peaks were missing due to overlapping); IR (ATR) 2951, 1453, 1051 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₄H₃₀NO: ([M+H]⁺) 348.2327: Found 348.2321.

1-(1,2,3,4,4a,8b-Hexahydro-1,4-methanobiphenylen-5-yl)-2-methylpropan-1-one O-Methyl Oxime (3ja)

According to the general procedure, the reaction gave the product in 11% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.24 (d, 1H, J=7.8 Hz), 7.18 (dd, 1H, J₁=7.8 Hz, J₂=7.2 Hz), 6.96 (d, 1H, J=7.2 Hz), 3.93 (s, 3H), 3.38 (sep, 1H, J=7.2 Hz), 3.25 (d, 1H, J=3.8 Hz), 3.14 (d, 1H, J=3.8 Hz), 2.37 (s, 1H), 2.27 (s, 1H), 1.61–1.56 (m, 2H), 1.24 (d, 3H, J=7.2 Hz), 1.19 (d, 3H, J=7.2 Hz), 1.19–1.17 (m, 2H), 0.97 (d, 1H, J=10.3 Hz), 0.89 (d, 1H, J=10.3 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 162.4, 146.8, 144.7, 130.5, 127.3, 126.3, 121.9, 61.7, 51.3, 49.9, 36.6, 31.9, 28.9, 27.9, 27.8, 19.3, 19.2; IR (ATR) 2952, 1465, 1059 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₈H₂₄NO: ([M+H]⁺) 270.1858: Found 270.1859.

1,2,3,4,4a,5b,6,7,8,9,9a,10b-Dodecahydro-1,4:6,9-dimethanobenzo[3,4]cyclobuta[1,2-b]biphenylen-5-yl)-2-methylpropan-1-one O-Methyl Oxime (4ja_meso)

According to the general procedure, the reaction gave the product in 4% yield as a white solid: mp 136.5–138.0°C; ¹H-NMR (500 MHz, CDCl₃) δ: 6.62 (s, 1H), 3.93 (s, 3H), 3.23 (sep, 1H, 7.2 Hz), 3.13 (d, 2H, J=3.7 Hz), 3.02 (d, 2H, J=3.7 Hz), 2.37 (s, 2H), 2.22 (s, 2H), 1.58–1.57 (m, 4H), 1.25 (d, 6H, J=7.2 Hz), 1.16–1.15 (m, 4H), 0.94–0.89 (m, 4H); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.7, 145.6, 142.9, 126.0, 116.0, 61.8, 51.2, 49.3, 37.0, 36.7, 31.9, 30.0, 28.0, 27.9, 18.8; IR (ATR) 2947, 1454, 1326, 1043 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₅H₃₂NO: ([M+H]⁺) 362.2484: Found 362.2480.

1,2,3,4,4a,5b,6,7,8,9,9a,10b-Dodecahydro-1,4:6,9-dimethanobenzo[3,4]cyclobuta[1,2-b]biphenylen-5-yl)-2-methylpropan-1-one O-Methyl Oxime (4ja_racemic)

According to the general procedure, the reaction gave the product in 7% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 6.60 (s, 1H), 3.92 (s, 3H), 3.26 (sep, 1H, 7.3 Hz), 3.20 (d, 2H, J=3.8 Hz), 3.04 (d, 2H, J=3.8 Hz), 2.26 (s, 2H), 2.20 (s, 2H), 1.61–1.50 (m, 4H), 1.28 (d, 3H, J=7.3 Hz), 1.19 (d, 3H, J=7.3 Hz), 1.17–1.13 (m, 4H), 0.89 (d, 2H, J=10.0 Hz), 0.81 (d, 2H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 161.1, 145.7, 142.7, 125.6, 115.9, 61.8, 51.1, 49.4, 36.9, 36.4, 31.9, 29.7, 27.9, 19.0, 18.9; IR (ATR) 2948, 1454, 1327, 1040 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₅H₃₂NO: ([M+H]⁺) 362.2484: Found 362.2483.

3,4,6b,7,8,9,10,10a-Octahydro-7,10-methanobenzo[a]biphenylen-1(2H)-one O-Benzyl Oxime (3ka)

According to the general procedure, the reaction gave the product in 63% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃, 50°C) δ: 7.43 (d, 2H, J=8.0 Hz), 7.35 (dd, 2H, J₁=J₂=8.0 Hz), 7.29 (t, 1H, J=8.0 Hz), 6.95 (d, 1H, J=7.4 Hz), 6.83 (d, 1H, J=7.4 Hz), 5.20 (d, 1H, J=12.3 Hz), 5.16 (d, 1H, J=12.3 Hz), 3.16 (s, 1H), 3.05 (s, 1H), 2.74 (t, 2H, J=6.6 Hz), 2.69 (t, 2H, J=6.0 Hz), 2.32 (s, 1H), 2.22 (s, 1H), 1.87–1.74 (m, 2H), 1.56–1.54 (m, 2H), 1.17–1.13 (m, 2H), 0.87 (d, 1H, J=10.0 Hz), 0.79 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃, 50°C) δ: 154.3, 144.4, 143.9, 138.6, 138.1, 128.5, 128.2, 127.6, 127.5, 125.6, 122.0, 76.2, 52.2, 49.8, 36.6, 35.0, 32.0, 30.3, 27.9, 27.8, 24.3, 21.8; IR (ATR) 2946, 1455, 910 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₄H₂₆NO: ([M+H]⁺) 344.2014: Found 344.2009.

1-(7-Methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)ethan-1-one O-Methyl Oxime (3la)

According to the general procedure, the reaction gave the product in 35% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.33 (s, 1H), 6.80 (s, 1H), 3.99 (s, 3H), 3.25 (d, 1H, J=3.8 Hz), 3.12 (d, 1H, J=3.8 Hz), 2.36 (d, 1H, J=2.8 Hz), 2.33 (s, 3H), 2.25 (d, 1H, J=2.8 Hz), 2.19 (s, 3H), 1.61–1.56 (m, 2H), 1.20–1.16 (m, 2H), 0.94 (d, 1H, J=10.3 Hz), 0.88 (d, 1H, J=10.3 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.8, 146.9, 141.2, 137.4, 130.5, 124.6, 123.1, 61.9, 51.4, 49.8, 36.7, 36.5, 31.9, 27.83, 27.82, 22.0, 12.8; IR (ATR) 2869, 1602, 1053 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₇H₂₂NO: ([M+H]⁺) 256.1701: Found 256.1702.

2-((6-Methoxy-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3ma)

According to the general procedure, the reaction gave the product in 72% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.52 (d, 1H, J=4.9 Hz), 7.51 (dd, 1H, J₁=J₂=7.8 Hz), 7.08–7.06 (m, 1H), 7.02 (d, 1H, J=8.0 Hz), 6.84 (d, 1H, J=7.8 Hz), 6.74 (d, 1H, J=8.0 Hz), 4.09 (s, 2H), 3.75 (s, 3H), 3.02 (d, 1H, J=3.8 Hz), 2.92 (d, 1H, J=3.8 Hz), 2.19 (d, 1H, J=3.2 Hz), 1.90 (d, 1H, J=3.2 Hz), 1.55–1.43 (m, 2H), 1.13–1.01 (m, 2H), 0.86 (d, 1H, J=10.0 Hz), 0.82 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 161.0, 157.0, 148.9, 146.6, 138.3, 136.1, 122.6, 122.5, 120.9, 120.8, 110.3, 55.7, 49.0, 48.7, 36.7, 36.0, 34.7, 31.9, 27.73, 27.66; IR (ATR) 2948, 1590, 1542, 1473, 1250 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₀H₂₂NO: ([M+H]⁺) 292.1701: Found 292.1701.

2-((6-Fluoro-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3na)

According to the general procedure, the reaction gave the product in 62% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.54 (d, 1H, J=4.9 Hz), 7.56 (ddd, 1H, J₁=J₂=7.8 Hz, J₃=1.7 Hz), 7.12–7.08 (m, 2H), 6.90 (dd, 1H, J₁=12.1, J₂=8.1 Hz), 6.82 (dd, 1H, J₁=7.7 J₂=4.0 Hz), 4.10 (s, 2H), 3.02 (d, 1H, J=4.0 Hz), 2.92 (d, 1H, J=4.0 Hz), 2.20 (d, 1H, J=3.0 Hz), 2.00 (d, 1H, J=3.0 Hz), 1.56–1.44 (m, 2H), 1.13–1.02 (m, 2H), 0.87 (d, 1H, J=10.0 Hz), 0.77 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.6 (d, J=244.0 Hz), 159.8, 149.1, 146.7 (d, J=3.6 Hz), 141.4 (d, J=3.6 Hz), 136.4, 122.8, 121.7 (d, J=8.4 Hz), 121.4, 121.2, 114.7 (d, J=24.2 Hz), 48.9 (d, J=2.4 Hz), 48.8, 36.5, 36.0, 34.1 (d, J=2.4 Hz), 31.8, 27.62, 27.58; IR (ATR) 2949, 1590, 1471, 1434, 1231 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₉H₁₉FN: ([M+H]⁺) 280.1502: Found 280.1501.

Methyl 5-(Pyridin-2-ylmethyl)-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylene-6-carboxylate (3oa)

According to the general procedure, the reaction gave the product in 43% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.54–8.52 (m, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.50 (ddd, 1H, J₁=J₂=7.8 Hz, J₃=1.7 Hz), 7.09–7.06 (m, 1H), 6.97 (d, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.8 Hz), 4.47 (d, 1H, J=16.0 Hz), 4.44 (d, 1H, J=16.0 Hz), 3.75 (s, 3H), 3.11 (d, 1H, J=3.7 Hz), 3.02 (d, 1H, J=3.7 Hz), 2.27 (d, 1H, J=3.0 Hz), 1.97 (d, 1H, J=3.0 Hz), 1.58–1.47 (m, 2H), 1.17–1.05 (m, 2H), 0.90 (d, 1H, J=10.3 Hz), 0.80 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 168.4, 160.9, 151.1, 148.9, 147.3, 136.2, 134.5, 131.0, 128.6, 122.3, 120.8, 120.4, 51.7, 49.5, 49.2, 38.2, 36.3, 35.9, 31.9, 27.7, 27.6; IR (ATR) 2950, 1716, 1590, 1433, 1271 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₁H₂₂NO₂: ([M+H]⁺) 320.1651: Found 320.1649.

2-((1,2,3,4,4a,8b-Hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3pa)

According to the general procedure, the reaction gave the product in 13% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.55–8.54 (m, 1H), 7.56 (ddd, 1H, J₁=7.8 Hz, J₂=7.4 Hz, J₃=1.7 Hz), 7.16 (dd, 1H, J₁=J₂=7.5 Hz), 7.12–7.09 (m, 1H), 7.07–7.05 (m, 2H), 6.87 (d, 1H, J=7.2 Hz), 4.06 (s, 2H), 3.11 (d, 1H, J=3.8 Hz), 3.02 (d, 1H, J=3.8 Hz), 2.23 (d, 1H, J=2.8 Hz), 1.92 (d, 1H, J=2.8 Hz), 1.58–1.46 (m, 2H), 1.15–1.05 (m, 2H), 0.89 (d, 1H, J=10.0 Hz), 0.81 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.8, 149.1, 146.6, 145.2, 136.3, 133.6, 127.84, 127.83, 123.1, 121.1, 120.0, 49.9, 49.8, 40.7, 36.5, 35.9, 31.9, 27.8, 27.7; IR (ATR) 2949, 1590, 1472, 1434 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₉H₂₀N: ([M+H]⁺) 262.1596: Found 262.1589.

1,2,3,4,4a,5b,6,7,8,9,9a,10b-Dodecahydro-1,4 : 6,9-dimethanobenzo[3,4]cyclobuta[1,2-b]biphenylen-5-yl)methyl)pyridine (4pa)

According to the general procedure, the reaction gave the mixture of the product in 55% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.54 (d, 1H, J=4.3 Hz), 7.54 (ddd, 1H, J₁=J₂=8.0 Hz, J₃=1.5 Hz), 7.10 (dd, 1H, J₁=J₂=6.2 Hz), 7.00 (m, 1H), 6.55–6.54 (m, 1H), 3.98 (m, 2H), 3.03–3.01 (m, 2H), 2.96–2.94 (m, 2H), 2.20–2.17 (m, 2H), 1.91–1.89 (m, 2H), 1.56–1.43 (m, 4H), 1.13 (m, 4H), 0.88–0.76, (m, 4H); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.8, 148.9, 145.5, 145.4, 143.4, 143.4, 136.2, 128.1, 128.0, 123.0, 121.1, 121.0, 114.3, 114.2, 49.4, 49.3, 49.1, 36.84, 36.83, 36.6, 36.08, 36.05, 31.8, 27.8, 27.74, 27.73 (Some peaks were missing due to overlapping); IR (ATR) 2944, 1590, 1452, 1434, 1328 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₆H₂₈N: ([M+H]⁺) 354.2222: Found 354.2213.

2-((7-Methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3qa)

According to the general procedure, the reaction gave the product in 49% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.55–8.53 (m, 1H), 7.55 (ddd, 1H, J₁=J₂=7.6 Hz, J₃=1.7 Hz), 7.11–7.08 (m, 1H), 7.02 (d, 1H, J=7.8 Hz), 6.90 (s, 1H), 6.70 (s, 1H), 4.02 (s, 2H), 3.06 (d, 1H, J=3.8 Hz), 2.95 (d, 1H, J=3.8 Hz), 2.29 (s, 3H), 2.20 (d, 1H, J=3.0 Hz), 1.90 (d, 1H, J=3.0 Hz), 1.56–1.44 (m, 2H), 1.14–1.03 (m, 2H), 0.88–0.80 (m, 2H); ¹³C-NMR (126 MHz, CDCl₃) δ: 160.9, 149.1, 146.5, 141.9, 137.5, 136.3, 133.3, 128.6, 123.1, 121.1, 120.7, 49.6, 49.2, 40.7, 36.4, 35.9, 31.9, 27.8, 27.7, 22.0; IR (ATR) 2948, 1591, 1472, 1434 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₀H₂₂N: ([M+H]⁺) 276.1752: Found 276.1752.

2-((6,8-Dimethyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylen-5-yl)methyl)pyridine (3ra)

According to the general procedure, the reaction gave the product in 15% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 8.54–8.53 (m, 1H), 7.51 (ddd, 1H, J₁=J₂=7.5 Hz, J₃=1.7 Hz), 7.09 (dd, 1H, J₁=7.5 Hz, J₂=4.9 Hz), 6.89 (d, 1H, J₁=7.5 Hz), 6.84 (s, 1H), 4.07 (d, 1H, J=16.1 Hz), 4.03 (d, 1H, J=16.1 Hz), 3.04 (d, 1H, J=3.7 Hz), 2.96 (d, 1H, J=3.7 Hz), 2.26 (d, 1H, J=3.2 Hz), 2.16 (s, 3H), 2.14 (s, 3H), 1.94 (d, 1H, J=3.2 Hz), 1.60–1.44 (m, 2H), 1.22–1.04 (m, 2H), 0.92–0.87 (m, 2H); ¹³C-NMR (126 MHz, CDCl₃) δ: 161.0, 149.1, 145.4, 142.0, 136.3, 135.7, 130.4, 130.3, 128.9, 122.3, 120.9, 48.7, 48.0, 37.4, 35.9, 35.7, 32.0, 27.9, 27.8, 19.8, 16.3.; IR (ATR) 2946, 1589, 1472, 1434 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₁H₂₄N: ([M+H]⁺) 290.1909: Found 290.1906.

1-(Methoxyimino)-1,2,3,4,6b,7,8,9,10,10a-decahydro-7,10-methanobenzo[a]biphenylenecarbonitrile (3ab)

According to the general procedure, the reaction gave the mixture of the products in 60% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.02–7.00 (m, 1H), 6.89–6.85 (m, 1H), 4.00–3.97 (m, 3H), 3.89 (d, 0.15H, J=3.8 Hz), 3.71 (d, 0.4H, J=3.4 Hz), 3.43 (d, 0.4H, J=3.4 Hz), 3.30–3.29 (m, 0.6H), 3.12 (s, 0.45H), 2.95 (s, 0.15H), 2.90–2.89 (m, 0.15H), 2.84–2.80 (m, 0.6H), 2.73–2.65 (m, 5H), 2.58 (m, 0.45H), 2.43 (d, 0.15H, J=3.7 Hz), 2.40–2.34 (m, 0.6H), 2.13–2.10 (m, 0.45H), 1.96–1.94 (m, 0.45H), 1.87–1.67 (m, 2.5H), 1.53–1.45 (m, 0.45H), 1.37–1.34 (m, 0.45H), 1.08–1.07 (m, 1H), 1.02–1.00 (m, 0.6H); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.7, 153.7, 153.4, 143.3, 143.1, 142.7, 142.54, 142.51, 142.3, 142.0, 141.6, 138.9, 138.7, 138.6, 128.5, 128.3, 128.2, 126.0, 125.89, 125.86, 123.6, 123.5, 122.2, 122.14, 122.08, 122.05, 122.0, 62.15, 62.13, 62.0, 51.3, 51.0, 50.5, 49.0, 48.6, 48.1, 47.5, 45.1, 42.0, 40.6, 39.8, 38.5, 36.7, 36.4, 35.2, 34.9, 34.5, 34.4, 33.5, 32.53, 32.49, 31.0, 30.21, 30.16, 29.40, 29.37, 28.9, 28.8, 23.91, 23.89, 23.8, 21.68, 21.66, 21.6 (Some peaks were missing due to overlapping); IR (ATR) 2939, 2235, 1465, 1432, 1043 cm⁻¹; HR-MS (ESI⁺) Calcd for C₁₉H₂₁N₂O: ([M+H]⁺) 293.1654: Found 293.1659.

9,9-Dimethyl-3,4,6b,7,7a,10a,11,11a-octahydro-7,11-methanobenzo[5,6]biphenyleno[2,3-d][1,3]dioxol-1(2H)-one O-Methyl Oxime (3ac)

According to the general procedure, the reaction gave the product in 77% yield as a white solid: mp 117.6–119.8°C; ¹H-NMR (500 MHz, CDCl₃) δ: 7.00 (d, 1H, J=7.5 Hz), 6.88 (d, 1H, J=7.5 Hz), 4.11 (d, 1H, J=5.0 Hz), 4.06 (d, 1H, J=5.0 Hz), 3.96 (s, 3H), 3.18 (d, 1H, J=3.5 Hz), 3.00 (d, 1H, J=3.5 Hz), 2.73–2.66 (m, 5H), 2.36 (s, 1H), 1.90–1.73 (m, 2H), 1.51 (d, 1H, J=10.9 Hz), 1.47 (s, 3H), 1.34 (s, 3H), 0.76 (d, 1H, J=10.9 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.6, 142.2, 141.7, 138.6, 128.1, 126.0, 122.2, 109.3, 81.6, 81.4, 62.1, 46.7, 44.3, 41.0, 39.5, 30.2, 25.7, 25.5, 24.0, 23.9, 21.7; IR (ATR) 2934, 1618, 1205, 1045 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₁H₂₆NO₃: ([M+H]⁺) 340.1913: Found 340.1913.

1-(Methoxyimino)-1,2,3,4,6b,7,8,9,10,10a-decahydro-7,10-methanobenzo[a]biphenylenyl Acetate (3ad)

According to the general procedure, the reaction gave the mixture of the products in 13% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.00–6.98 (m, 1H), 6.90–6.83 (m, 1H), 4.00–3.97 (m, 3H), 3.39–3.35 (m, 1H), 3.19 (s, 1H), 2.85 (s, 0.4H), 2.73–2.67 (m, 4H), 2.61 (d, 0.6H, J=4.0 Hz), 2.51 (s, 0.4H), 2.48–2.43 (m, 1H), 2.32–2.31 (m, 0.6H), 2.23–2.22 (m, 3H), 2.11–2.00 (m, 1H), 1.89–1.75 (m, 2H), 1.39–1.34 (m, 0.4H), 1.29–1.24 (m, 0.6H), 1.01–0.95 (m, 1H), 0.81–0.75 (m, 1H); ¹³C-NMR (126 MHz, CDCl₃) δ: 209.8, 209.6, 153.9, 153.8, 144.0, 143.4, 143.0, 142.5, 138.5, 138.4, 128.0, 127.9, 125.8, 122.2, 122.14, 122.11, 62.04, 61.96, 53.6, 53.5, 52.2, 52.0, 49.75, 49.67, 40.2, 39.3, 36.6, 35.08, 35.05, 30.5, 30.3, 30.2, 29.8, 29.6, 29.4, 29.13, 29.05, 24.0, 23.9, 21.7 (some peaks were missing due to overlapping); IR (ATR) 2935, 1705, 1431, 1357, 1044 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₀H₂₄NO₂: ([M+H]⁺) 310.1807: Found 310.1797.

3,4,6b,7,12,12a-Hexahydro-7,12-methanodibenzo[a,h]biphenylen-1(2H)-one O-Methyl Oxime (3ae)

According to the general procedure, the reaction gave the product in 62% yield as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ: 7.29–7.25 (m, 2H), 7.11 (m, 2H), 7.03 (d, 1H, J=7.5 Hz), 6.97 (d, 1H, J=7.5 Hz), 4.09 (s, 3H), 3.58 (s, 1H), 3.39 (d, 1H, J=3.5 Hz), 3.29 (s, 1H), 3.21 (d, 1H, J=7.5 Hz), 2.75–2.73 (m, 4H), 1.91–1.79 (m, 2H), 1.66 (d, 1H, J=10.0 Hz), 1.29 (d, 1H, J=10.0 Hz); ¹³C-NMR (126 MHz, CDCl₃) δ: 153.8, 148.2, 147.9, 143.1, 142.7, 138.5, 128.0, 125.8, 125.6, 125.5, 122.1, 121.4, 121.3, 62.1, 51.1, 48.8, 43.7, 42.5, 42.4, 30.2, 24.0, 21.8; IR (ATR) 2938, 1463, 1430, 1458, 1052 cm⁻¹; HR-MS (ESI⁺) Calcd for C₂₂H₂₂NO: ([M+H]⁺) 316.1701: Found 316.1693.

KIE Studies

In a sealed tube, to a mixture of 1e (1.0 eq), 1e-d₃/1e-d₆ (1.0 eq), norbornene 2a (1.0 eq) in DMF were added benzoquinone (1.5 eq), Ag₂CO₃ (2.0 eq), (−)-Men-Val-OH (0.05 eq), and Pd(OAc)₂ (0.1 eq). The tube was filled with argon and the mixture was heated to 100°C. After stirring for 12 h, the mixture was cooled to room temperature, diluted with EtOAc and filtrated. The solution was washed with water and brine, dried over Na₂SO_4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane–EtOAc or hexane–CH₂Cl₂) to give the corresponding benzocyclobutene. The ratio of 3ea and 3ea-d₂/3ea-d₅ were estimated by ¹H-NMR spectra.

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research on Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Y.T.) and JSPS Research Fellowships for Young Scientists (T.N.).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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