Sc(OTf)3-Mediated [4 + 2] Annulations of N-Carbonyl Aryldiazenes with Cyclopentadiene to Construct Cinnoline Derivatives: Azo-Povarov Reaction.

We disclose the first accomplishment of the azo-Povarov reaction involving Sc(OTf)3-catalyzed [4 + 2] annulations of N-carbonyl aryldiazenes with cyclopentadiene in chloroform, in which N-carbonyl aryldiazenes act as 4π-electron donors. Hence, this protocol offers a rapid access to an array of cinnoline derivatives in moderate to good yields for substrates over a wide scope. The synthetic potential of the protocol was achieved by the gram-scale reaction and further derivatization of the obtained polycyclic product.

Introduction

The cinnoline ring is an important structural subunit found in a wide range of compounds of significant pharmacological and chemical importance.[1] Cinnoline derivatives display a broad spectrum of pharmacological activities, such as anticancer, antibacterial, antimicrobial, antifungal, anti-inflammatory, antimalarial, antiparasitic, and analgesic activity (Figure ). For instance, Cinoxacin[2] is a synthetic antibiotic from the quinolone group used to treat urinary tract infections. On the other hand, some compounds with a cinnoline structure are found in preclinical tests, such as compound AZD7325,[3] a modulator of GABAA receptors that exhibits a powerful anxiolytic effect (Figure ). In particular, benzo[c]cinnolines are considered as important structures in medical chemistry due to the promising anticancer activities they possess. Several cinnoline derivatives such as dibenzo[c,h]cinnolines[4] or indolo[3,2-c]cinnolines[5] have been identified as potent anticancer agents and kinase inhibitors (Figure ). In fact, the dibenzo[c,h]cinnolines are also topoisomerase I inhibitors and possess significant cytotoxic activity.[4] The fact that none of these benzo[c]cinnolines is found in nature makes these skeletons highly interesting in organic synthesis.

Figure 1

Selected pharmaceutically and bioactive cinnoline derivatives.

However, traditional cinnoline access strategies such as intermolecular cycloaddition involving prefunctionalization of nitriles,[6] aryl hydrazines,[7] and aryl hydrazones,[8] or cyclization of phenyldiazonium ions with highly active triazenes ortho to a terminal phenylacetylene,[9] often involve a very limited synthetic scope and multi-stage reaction sequences and cannot represent a general synthetic method. The activation of the C–H bond catalyzed by transition metals is not only an important strategy in the synthesis and modification of heterocyclic systems,[10] but also one of the most valuable methods for the preparation of the cinnoline backbone[11] due to the high degree of regioselectivity, atom economy, and reaction stages. For instance, in 2012, Ge et al.[12] developed a copper-promoted intramolecular dehydrogenative cyclization of N-methyl-N-phenylhydrazones to afford cinnolines through C(sp3)H-oxidation, cyclization, and aromatization sequence (Scheme , eq 1). In 2016, Yao and Lin’s group[13] reported a rhodium-catalyzed redox-neutral annulation reaction between diazo and azo compounds for the preparation of cinnolines under mild conditions (Scheme , eq 2). Cinnolines have also been synthesized by Rh(III)-catalyzed C–H bond activation and cyclization of N-tert-butyl-aryldiazenes with alkynes (Scheme , eq 3).[14]

Scheme 1

Transition Metal-Catalyzed Synthesis of Cinnolines

Furthermore, azo compounds, valuable synthetic building blocks, have been widely used in cycloaddition reactions with a variety of partners for the preparation of many nitrogen-containing heterocyclic compounds. For example, they have been widely used not only as dienophiles in azo hetero-Diels–Alder reactions[15,16] [Scheme , eq 1)] but also as dienes in [4 + 2] cycloaddition reactions [Scheme , eq 2].[17] Conjugated azoalkenes have proven to be valuable starting materials for the synthesis of a plethora of multi-nitrogen-containing heterocycles and in target-oriented synthesis of naturally occurring and biologically active compounds.[18] We have reported the usefulness of phosphorous-substituted azoalkenes for the preparation of α-amino phosphonates,[19] functionalized mercapto diketones,[20] and heterocyclic compounds.[21,22]

Scheme 2

Annulations of Imines, Nitrosoarenes, and N-Carbonyl Aryldiazenes with Dienes

The classical Povarov reaction[23] between an aldimine, generated by the condensation of an aromatic amine and an aldehyde, and the olefinic or acetylenic component entails a useful tool for the construction of carbon–carbon and carbon-heteroatom bonds and the generation of six-membered rings with high molecular complexity. In this way, the Povarov reaction between imines and dienes is well known [Scheme , eq 3].[24] Our group has established the necessary methodology for the preparation and development of various TopI inhibitors with application as antiproliferative compounds using the Povarov reaction.[25] Very recently, an enantioselective gold-catalyzed [4 + 2]-annulation of nitrosoarenes and cyclopentadiene derivatives (nitroso-Povarov reaction) has been reported [Scheme , eq 4].[26]

To continue our interest in new azoalkene reactions, as depicted in [Scheme , eq 5], herein, we report the first [4 + 2] annulation reaction (azo-Povarov reaction) between N-carbonyl aryldiazenes and cyclopentadiene, in which the N-carbonyl aryldiazene acts as the 4π-electron (diene) system like N-arylimines in Povarov reactions.

Results and Discussion

As outlined in Table , we started our investigation with the optimization of the reaction conditions with aryldiazene carboxylate 2a as the model substrate and cyclopentadiene. Aryldiazene carboxylates are prepared by oxidation of aromatic hydrazine derivatives 1 using N-bromosuccinimide (NBS)/Py.[27] The effect of the catalyst on the azo-Povarov reaction was first evaluated with chloroform as the solvent. With ZnCl2 as the catalyst, the reaction proceeded smoothly at room temperature to give the product 3a in a 49% yield (entry 1). However, only a 9% yield of 3a could be achieved when Ag(OTf) was used as the catalyst in this process (entry 2). Magnesium catalysts, such as MgBr2·Et2O and Mg(ClO4)2, are not suitable for the current reaction since cinnoline 3a could not be detected, and only the starting aryldiazene carboxylate 2a was recovered instead (entries 3 and 4). A higher reaction temperature (55 °C) or longer reaction time (48 h) did not improve these results (entries 5 and 6). The use of RuCl3 as the catalyst gave similar results (entry 7). To our surprise, since MgBr2 afforded cinnoline 3a in 71% yield, BF3·Et2O, recently used by our group as the catalyst in the classical Povarov reaction,[25] only gave a 39% yield of 3a (entries 8 and 9). The use of Yb(OTf)3 (entry 10) was also unsuitable for this transformation. After a series of optimization experiments, we identified Sc(OTf)3 as the optimal catalyst. On performing the reaction at room temperature, product 3a was isolated in 91% yield after 1 h reaction time (entry 11). None of the other catalyst candidates that we explored (Cu(OTf)2 or InCl3) performed any better (entries 12 and 13). When examining the catalyst loading, the use of 1.5 equiv of catalyst seems necessary in the current reaction since we observed no reaction when different equivalents between 0.2 and 1.0 of Cu(OTf)2, InCl3, ZnCl2, or Sc(OTf)3 as Lewis acids were used.

Table 1

Reaction Condition Optimization

entrya	catalyst	time (h)	T (° C)	solvent	yield (%)b
1	ZnCl2	5	rt	CHCl3	49
2	Ag(OTf)	4	rt	CHCl3	9
3	MgBr2·Et2O	19	rt	CHCl3	0
4	Mg(ClO4)2	19	rt	CHCl3	0
5	MgBr2·Et2O	48	55	CHCl3	0
6	Mg(ClO4)2	48	55	CHCl3	0
7	RuCl3	24	rt	CHCl3	0
8	MgBr2	24	rt	CHCl3	71
9	BF3·Et2O	1	rt	CHCl3	39
10	Yb(OTf)3	6	rt	CHCl3	0
11	Sc(OTf)3	1	rt	CHCl3	91
12	Cu(OTf)2	3	rt	CHCl3	21
13	InCl3	2	rt	CHCl3	55
14	Sc(OTf)3	17	rt	THF	6
15	Sc(OTf)3	0.5	rt	DCM	87
16	Sc(OTf)3	1	rt	MeCN	57
17	Sc(OTf)3	0.5	rt	MeOH	0
18	Sc(OTf)3	24	rt	H2O	0
19	Sc(OTf)3	15	50	H2O	0
20	Sc(OTf)3	c	rt	CHCl3	60

Unless otherwise noted, reactions were conducted on a 0.5 mmol scale, catalyst (1.5 equiv), and solvent (3 mL).

Isolated yields.

The reaction was performed using 2a (0.5 mmol), catalyst (1.5 equiv), and solvent (1 mL) for 15 min.

The effect of the solvent on the azo-Povarov reaction was also studied. When performed with THF as the solvent, the reaction afforded traces of 3a (entry 14). In addition, using dichloromethane (DCM) as the solvent and lowering the reaction time to 0.5 h, led to similar results as before (compare entries 11 and 15). Starting aryldiazene carboxylate 2a was not fully consumed with MeCN (entry 16), whereas polar solvents such as MeOH (entry 17) and H2O (entries 18 and 19) do not work in the azo-Povarov reaction. Finally, lowering the reaction time to 15 min using chloroform as the solvent gave 3a with a moderate yield of 60% (entry 20).

With the optimal reaction conditions in hand, next we explored the substrate scope of the aromatic ring of aryldiazenes in the azo-Povarov reaction, and the results are summarized in Scheme . A large selection of functional groups at the aromatic ring in aryldiazene carboxylates 2 was well-tolerated. Both electron-donating (Me) and electron-withdrawing groups (Br, F, OCF3, and CF3) at the para-phenyl position afford desired products 3c, 3b, 3d, 3e, and 3g in 24–77% yields. Among them, 4-bromo derivative 3b and 4-methyl derivative 3c were achieved with the best yields (77% and 65%, respectively). Nevertheless, meta-phenyl diazene 2f (R1 = F, R2 = H) afforded a 64:36 mixture of azo-Povarov adducts 3f and 3f′ in 54% yield. The structure of 3a has been unambiguously determined by X-ray diffraction. The CIF data are presented in the Supporting Information, and the ORTEP drawing of 3a is shown in Scheme .

Scheme 3

Substrate Scope of the Aromatic Ring in Aryldiazene Carboxylates in the Azo-Povarov Reaction with Cyclopentadiene

See the Supporting Information for experimental details.

Stimulated by the above obtained results on the azo-Povarov reaction between aryldiazene carboxylates 2 and cyclopentadiene, we further investigated the substrate scope varying the functional group (R3) at the nitrogen atom of the aryldiazenes 2 (Scheme ). To our delight, it was found that the reaction proceeded smoothly using the same reaction conditions, and starting aryl 2i or alkyl aryldiazene carboxylates 2h and 2j–2l afforded cinnoline derivatives 3i or 3h and 3j–3l, respectively. For instance, the Sc(OTf)3-catalyzed [4 + 2] annulation reaction of phenyl aryldiazene carboxylate 2i (R3 = OPh) with cyclopentadiene afforded adduct 3i in 73% yield. N-Boc aryldiazene 2h (R3 = OBu) did not perform well since only 16% of cinnoline 3h was obtained. Nevertheless, annulations of other alkyl aryldiazene carboxylates (2j–2l) bearing R3 = OBn (N-Cbz), Oallyl (N-Alloc), and 2,2,2-trichloroethoxy (N-Troc) moieties delivered cinnoline derivatives 3j–2l in 66–78% yields. Conversely, when N-acetyl aryldiazene 2m (R3 = Me) derived from N′-phenylacetohydrazide was used in the azo-Povarov reaction, a 59:41 mixture of regioisomers 3m and 3m′ was observed in 92% yield. Similar results were attained with p-CF3 phenyl diazene 2n, and the corresponding adduct was obtained as a 74:26 regioisomeric mixture in 63% yield. Interestingly, only one regioisomer 3o in almost quantitative yield has been observed when N-benzoyl aryldiazene 2o (R3 = Ph) derived from N′-phenylbenzohydrazide was used in the current reaction. On comparing aryl and alkyl aryldiazene carboxylates 2h–l with N-acyl or N-benzoyl aryldiazenes 2m–o, better chemical yields were obtained for cinnolines derived from the latter (Scheme ).

Scheme 4

Substrate Scope Varying Functional Group R3 at the Nitrogen Atom of N-Carbonyl Aryldiazenes

See the Supporting Information for experimental details.

The gram-scale synthesis and further derivatization of 3a have been accomplished, as shown in Scheme . The use of 3.0 mmol of aryldiazene carboxylate 2a could give cinnoline derivative 3a in 71% yield (0.523 g) under the standard conditions. In addition, transesterification of 3a produced desired cinnoline 3p in 73% yield in the presence of MeOH, and the reduction of the carbon–carbon double bond in 3a was affected with hydrogenolysis using Ni/Raney as the catalyst affording product 4 in 97% yield.

Scheme 5

Gram-Scale Synthesis and the Further Transformation of 3a

A plausible mechanism for this Sc-catalyzed azo-Povarov reaction has been outlined in Scheme . Controversy exists about the mechanism of the Povarov reaction, suggesting a concerted mechanism[28] as well as evidences for a stepwise mechanism[29] have also arisen. Based on the stereochemistry of isolated compounds 3, a mechanism with both endo- or exo-π-facial approach would explain the formation of these cinnolines 3. Thus, the endo-facial approach of cyclopentadiene to 1 could lead to the [4 + 2] intermediate 6 and then the corresponding cycloadduct 3 (Scheme , approach from 5, pathway i). However, the exo-facial approach of cyclopentadiene to 1 (Scheme , approach from 7, pathway ii) would afford the same cinnoline 3 through intermediate cycloadduct 8. Conversely, as observed previously for the Povarov reaction between aryl imines and 1,3-dienes,[29] a stepwise reaction mechanism through ionic intermediate 9 (Scheme , pathway iii) cannot be discarded.

Scheme 6

Proposed Mechanism Pathways for the Azo-Povarov Reaction

Conclusions

In summary, we have developed a novel strategy to efficiently access the cinnoline scaffold from the [4 + 2] annulation reaction of N-carbonyl aryldiazenes and cyclopentadiene catalyzed by scandium triflate [Sc(OTf)3]. This success represents the first example of the azo-Povarov reaction. Most of these [4 + 2]-annulations proceeded smoothly in chloroform for 1 h, giving exclusive regioselectivity and satisfactory yields. This protocol was applicable to a wide range of substrates, including various aryldiazenes with electron-donating (Me) and electron-withdrawing groups (Br, F, OCF3, and CF3) at the para-phenyl position and different aryldiazenes with reactive functional groups at the nitrogen atom. The synthetic potential of this azo-Povarov protocol was demonstrated with the preparative–scale reaction and versatile synthetic transformations of the product. This strategy for the preparation of the cinnoline backbone entails a valued method due to the atom economy, reaction stages, and high degree of regioselectivity. Further synthetic applications of this methodology are underway in our group and will be reported in due course.

Experimental Section

General Experimental Information

Solvents for extraction and chromatography were of technical grade. All solvents used in reactions were freshly distilled and dried over molecular sieves of 3 Å before use. All other solvents and reagents were obtained from commercial sources and recrystallized or distilled as necessary or used without further purification. All reactions were performed under an atmosphere of dry nitrogen. Melting points are uncorrected. IR spectra were measured on the Nicolet iS10 Thermo Fisher Scientific spectrometer as neat solids. Absorbance frequencies are given at the maximum intensity in cm–1. High-resolution mass spectra (HRMS) were obtained by the positive-ion electrospray ionization (ESI) method with a time-of-flight Q-TOF system. Data are reported in the form of m/z (intensity relative to base = 100). 1H (300, 400 MHz), 13C (75, 100 MHz), and 19F (282, 376 MHz) spectra were recorded on Varian Unity Plus (300 MHz) or Bruker Avance 400 (400 MHz) spectrometers, respectively, in CDCl3, as specified below. Chemical shifts (δH) are reported in parts per million (ppm) with the internal chloroform signal at 7.24 ppm as the standard for 1H NMR. Chemical shifts (δC and δF) are reported in parts per million (ppm) with the internal chloroform signal at 77.0 ppm for 13C NMR and the external trichlorofluoromethane (Cl3CF) signal at 0.0 ppm as the standard for 19F NMR. All coupling constant (J) values are given in Hz. 19F and 13C NMR spectra were recorded in a broad band decoupling mode from hydrogen nuclei. Distortionless enhanced polarization transfer supported peak assignments for 13C NMR. The data is being reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, bs = broad singlet). Chromatographic purification was performed as flash chromatography using commercial grades of silica gel finer than 230 mesh with pressure or neutral aluminum oxide. Analytical thin layer chromatography (TLC) was performed on precoated Merck silica gel 60 F254 TLC aluminum plates, and spot visualized with UV light or permanganate stain. Functionalized hydrazines 1h and 1m are commercially available. However, functionalized hydrazines 1a,[30]1b,[30,31]1c,[30]1d,[30]1f,[30,31]1g,[30]1i,[30,32]1j,[30,31]1k,[30,33]1l,[30,31]1n,[34,35] and 1o(34) and N-carbonyl aryldizenes 2a,[30]2b,[30,31]2c,[30]2d,[30]2f,[30,31]2g,[30]2h,[30,31]2i,[30,32]2j,[30,31]2k,[30,33]2l,[30,31]2m,[30,36] and 2o(30,31) were prepared according to literature procedures.

Experimental Procedure and Characterization Data for Compounds 1–2

General Procedure and Spectral Data for Functionalized Hydrazines 1

To a 0 °C stirred solution of the corresponding hydrazine hydrochloride (15 mmol) in CH3CN (30 mL) and pyridine (2.5 mL, 31.5 mmol), ethyl chloroformate (1.6 mL, 16.5 mmol) was added dropwise. The reaction mixture was stirred for 15 min at 0 °C and then for 3 h at room temperature. Water (30 mL) was added and the resulting mixture was acidified with HCl (6 M) to pH 4–6. The crude product was extracted with CH2Cl2 (5 × 15 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness in a vacuum. The crude product was purified by recrystallization from an appropriate solvent, as indicated in the literature procedure,[30] to afford functionalized hydrazines 1.

Ethyl 2-(4-(trifluoromethoxy)phenyl)hydrazine-1-carboxylate (1e)

Following the literature procedure,[30]1e was obtained as a brown solid (80% yield). mp: 89–91 °C; IR (neat) vmax 3102, 3048, 2991, 1712, 1682 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.04 (d, J = 8.8 Hz, 2H), 6.78 (bs, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.07 (bs, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.29–1.19 (m, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 157.3, 146.7, 142.9 (q, 3JCF = 1.7 Hz), 122.2, 120.5 (q, 1JCF = 254.3 Hz), 113.5, 62.1, 14.4; 19F NMR (282 MHz, CDCl3) δ (ppm): −58.8. ESI-HRMS (CI) m/z: calcd for C10H12F3N2O3 ([M + H]+•), 265.0800; found, 265.0804.

General Procedure and Spectral Data for N-Carbonyl Aryldiazenes 2

To a stirred solution of the corresponding functionalized hydrazines 1 (3 mmol) in CH2Cl2 (21 mL), pyridine (0.68 mL, 8.4 mmol) was added. Then, NBS (599 mg, 3.30 mmol) was added portionwise. The reaction mixture was stirred for 30 min and then washed with aqueous HCl (5%, 30 mL), aqueous sodium thiosulfate (1.5%, 15 mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to dryness in a vacuum to give pure aryl and alkyldiazene carboxylates 2, as indicated in the literature procedure.[30]

Ethyl 2-(4-(trifluoromethoxy)phenyl)diazene-1-carboxylate (2e)

Following the literature procedure,[30]2e was obtained as a red oil (95% yield) and was used immediately without purification in the next reaction step. IR (neat) vmax 3081, 2987, 2940, 1761 cm–1; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.94 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.9 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 161.8, 152.9 (q, 3JCF = 1.7 Hz), 149.4, 125.4, 121.0 (q, 4JCF = 0.8 Hz), 120.2 (q, 1JCF = 257.7 Hz), 64.5, 14.0; 19F NMR (282 MHz, CDCl3) δ(ppm): −58.2.

1-((4-(Trifluoromethyl)phenyl)diazenyl)ethan-1-one (2n)

Following the literature procedure,[30]2n was obtained as a red oil (<99%) and was used immediately without purification in the next reaction step. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 2.42 (s, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 188.1, 153.0, 134.4 (q, 2JCF = 32.8 Hz), 126.6 (q, 3JCF = 3.7 Hz), 123.6, 123.4 (q, 1JCF = 273.7 Hz), 21.2; 19F NMR (376 MHz, CDCl3) δ (ppm): −62.9.

Experimental Procedure and Characterization Data for Functionalized Cinnolines 3

To a stirred solution of the corresponding N-carbonyl aryldiazene 2 (0.5 mmol, 1 equiv) in CHCl3 (3 mL), was added cyclopentadiene (63 μL, 0.75 mmol, 1.5 equiv) and Sc(OTf)3 (373 mg, 0.75 mmol, 1.5 equiv) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1–6 h, and then, it was diluted with CH2Cl2 (40 mL) and washed with NaOH (2 M, 50 mL) and water (2 × 50 mL). The organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness in a vacuum. The crude product was purified by recrystallization in hexane at −24 °C or by column chromatography to afford the corresponding cinnoline derivatives 3.

Ethyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3a)

(111 mg, 91%) as a black solid from aryldiazene carboxylate 2a (99 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3a. mp: 97–99 °C; IR (neat) vmax 3058, 2982, 2930, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.07 (dq, J = 7.6, 0.6 Hz, 1H), 7.03 (tdd, J = 7.6, 1.5, 0.6 Hz, 1H), 6.88 (td, J = 7.6, 1.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.33 (bs, 1H), 5.75 (dq, J = 6.0, 2.2 Hz, 1H), 5.63 (dq, J = 6.0, 2.2 Hz, 1H), 5.35 (q, J = 8.7 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.02 (dq, J = 8.7, 2.2 Hz, 1H), 2.83–2.68 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 155.3, 144.7, 132.5, 129.8, 128.7, 126.6, 126.2, 122.0, 115.2, 62.2, 55.8, 44.7, 36.1, 14.5; ESI-HRMS (CI) m/z: calcd for C14H17N2O2 ([M + H]+•), 245.1290; found, 245.1285.

Ethyl (3aR*,9bR*)-8-bromo-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3b)

(125 mg, 77%) as a black solid from aryldiazene carboxylate 2b (161 mg, 0.5 mmol) was obtained after 1.5 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3b. mp: 114–116 °C; IR (neat) vmax 3062, 2964, 2927, 1644 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.20 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.4, 2.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.23 (bs, 1H), 5.76 (dq, J = 6.1, 2.4 Hz, 1H), 5.60 (dq, J = 6.1, 2.3 Hz, 1H), 5.32 (q, J = 6.6 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H, OCH2), 3.96 (d, J = 8.9 Hz, 1H) 2.76–2.71 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 155.4, 143.8, 131.8, 131.3, 130.3, 129.0, 128.8, 116.8, 114.0, 62.3, 55.6, 44.5, 35.9, 14.4; ESI-HRMS (CI) m/z: calcd for C14H16BrN2O2 ([M + H]+•), 323.0395; found, 323.0399.

Ethyl (3aR*,9bR*)-8-methyl-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3c)

(84 mg, 65%) as a brown solid from aryldiazene carboxylate 2c (101 mg, 0.5 mmol) was obtained after 1.5 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3c. mp: 60–62 °C; IR (neat) vmax 3331, 3054, 2924, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 6.90 (t, J = 1.6 Hz, 1H), 6.84 (dd, J = 8.0, 1.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.21 (bs, 1H), 5.74 (dq, J = 6.0, 2.3 Hz, 1H), 5.63 (dq, J = 6.0, 2.4 Hz, 1H), 5.33 (q, J = 5.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.97 (dd, J = 9.3, 2.4 Hz, 1H), 2.82–2.64 (m, 2H), 2.24 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 155.4, 142.2, 132.6, 131.5, 129.7, 129.4, 129.2, 126.8, 115.3, 62.2, 55.7, 44.8, 36.1, 20.7, 14.5; ESI-HRMS (CI) m/z: calcd for C15H19N2O2 ([M + H]+•), 259.1447; found, 259.1451.

Ethyl (3aR*,9bR*)-8-fluoro-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3d)

(54 mg, 41%) as a black solid from aryldiazene carboxylate 2d (109 mg, 0.5 mmol) was obtained after 3 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3d. mp: 91–94 °C; IR (neat) vmax 3061, 2925, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 6.81–6.78 (m, 1H), 6.75–6.72 (m, 2H), 6.15 (bs, 1H), 5.77 (dq, J = 6.1, 2.3 Hz, 1H), 5.59 (dq, J = 6.1, 2.3 Hz, 1H), 5.31 (q, J = 7.2 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.97 (dt, J = 9.2, 2.3 Hz, 1H), 2.76–2.72 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 158.2 (d, 1JCF = 240.2 Hz), 156.6, 140.9 (d, 4JCF = 2.5 Hz), 131.8, 130.4, 128.7, 116.6 (d, 3JCF = 8.0 Hz), 115.2 (d, 2JCF = 22.4 Hz), 112.9 (d, 2JCF = 22.8 Hz), 62.4, 55.4, 45.1, 36.2, 14.5; 19F NMR (282 MHz, CDCl3) δ (ppm): −121.7. ESI-HRMS (CI) m/z: calcd for C14H16FN2O2 ([M + H]+•), 263.1196; found, 263.1198.

Ethyl (3aR*,9bR*)-8-(trifluoromethoxy)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3e)

(83 mg, 51%) as a black solid from aryldiazene carboxylate 2e (131 mg, 0.5 mmol) was obtained after 6 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3e. mp: 69–71 °C; IR (neat) vmax 3324, 3088, 2985, 2933, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 6.94 (d, J = 2.3 Hz, 1H), 6.91–6.87 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.30 (bs, 1H), 5.77 (dq, J = 6.1, 2.3 Hz, 1H), 5.60 (dq, J = 6.1, 2.3 Hz, 1H), 5.33 (q, J = 7.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 9.1 Hz, 1H), 2.81–2.68 (m, 2H), 1.24 (t, J = 7.1 Hz); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 155.4, 143.7 (q, 3JCF = 2.1 Hz), 143.5, 131.8, 130.5, 128.2, 121.7, 120.5 (q, 1JCF = 256.1 Hz, CF3), 119.3 (C2), 116.1, 62.5, 55.5, 44.8, 36.1, 14.5; 19F NMR (282 MHz, CDCl3) δ (ppm): −58.6. ESI-HRMS (CI) m/z: calcd for C15H16F3N2O3 ([M + H]+•), 329.1113; found, 329.1123.

Ethyl (3aR*,9bR*)-7-fluoro-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3f) and Ethyl (3aR*,9bR*)-9-fluoro-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3f′)

(71 mg, 54%) as a brown solid from aryldiazene carboxylate 2f (117 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 98:2) to afford the title compound 3f/3f′ as a mixture in a ratio of 64:36. mp: 86–88 °C; IR (neat) vmax 3067, 2982, 2930, 1682, 1620 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.01–6.95 (m, 2H, H9major, H7minor), 6.61–6.55 (m, 3H, H6major, H6minor, H8minor), 6.51 (d, J = 9.5 Hz, 1H, H8major), 6.31(bs, 2H, H5major, H5minor), 5.79–5.74 (m, 2H, H2major, H2minor), 5.73–5.72 (m, 1H, H1minor), 5.61–5.58 (m, 1H, H1major), 5.40–5.30 (m, 2H, H3amajor, H3aminor), 4.19–4.13 (m, 4H, OCH2major, OCH2minor), 4.11 (bs, 1H, H9b)minor, 3.97 (d, J = 9.5 Hz, 1H, H9bmajor), 2.85–2.79 (m, 2H, H3minor), 2.79–2.65 (m, 2H, H3major), 1.27–1.23 (m, 6H, CH3major, CH3minor); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 161.1 (d, 1JCF = 245.43 Hz, C9minor), 161.0 (d, 1JCF = 244.9 Hz, C7major), 155.4 (C=O)minor, 155.4 (C=O)major, 146.1 (d, 3JCF = 8.2 Hz, C5aminor), 146.0 (d, 3JCF = 9.1 Hz, C5amajor), 132.4 (C1major), 131.0 (d, 4JCF = 1.9 Hz, C1minor), 130.1 (C2minor), 130.0 (d, 3JCF = 9.1 Hz, C9major), 129.9 (C2major), 127.1 (d, 3JCF = 9.8 Hz, C7minor), 122.3 (C9amajor), 114.3 (d, 2JCF = 20.2 Hz, C9aminor), 110.6 (d, 4JCF = 3.0 Hz, C6minor), 108.8 (d, 2JCF = 21.6 Hz, C8major), 108.2 (d, 2JCF = 21.8 Hz, C8minor), 102.4 (d, 2JCF = 24.6 Hz, C6major), 62.4 (OCH2major+minor), 55.8 (C3amajor), 55.5 (C3aminor), 44.2 (C9bmajor), 39.3 (C9bminor), 36.0 (CH2major), 35.3 (CH2minor), 14.5 (CH3major+minor); 19F NMR (376 MHz, CDCl3) δ (ppm): −115.7major, −117.9minor; ESI-HRMS (CI) m/z: calcd for C14H16FN2O2 ([M + H]+•), 263.1196; found, 263.1171.

Ethyl (3aR*,9bR*)-8-(trifluoromethyl)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3g)

(38 mg, 24%) as a brown solid from aryldiazene carboxylate 2g (123 mg, 0.5 mmol) was obtained after 2.5 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (Al2O3, hexanes/AcOEt 95:5) to afford the title compound 3g. mp: 61–63 °C; IR (neat) vmax 3064, 2987, 2931, 1682, 1619 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.31–7.30 (m, 1H), 7.29–7.26 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.45 (bs, 1H), 5.77 (dq, J = 6.0, 1.9 Hz, 1H), 5.63 (dq, J = 6.0, 1.9 Hz, 1H), 5.37 (q, J = 6.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.03 (dd, J = 9.2, 1.9 Hz, 1H), 2.82–2.68 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 155.3, 147.7, 131.9, 130.5, 126.7, 126.0 (q, 3JCF = 3.5 Hz), 124.3 (q, 1JCF = 272.7 Hz), 123.8 (q, 2JCF = 33.3 Hz), 123.6 (q, 3JCF = 3.8 Hz), 114.9, 62.6, 55.9, 44.5, 35.9, 14.6; 19F NMR (376 MHz, CDCl3) δ (ppm): −61.7. ESI-HRMS (CI) m/z: calcd for C15H16F3N2O2 ([M + H]+•), 313.1164; found, 313.1171.

tert-Butyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3h)

(30 mg, 16%) as a brown oil from aryldiazene carboxylate 2h (103 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (Al2O3, hexanes/AcOEt 97:3) to afford the title compound 3h. IR (neat) vmax 3056, 2998, 2925, 2866, 1964 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.07 (d, J = 7.5 Hz, 1H), 7.04–7.00 (m, 1H), 6.86 (td, J = 7.5, 1.2 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.27 (bs, 1H), 5.74 (dq, J = 6.0, 2.2 Hz, 1H), 5.63–5.60 (m, 1H), 5.28 (q, J = 5.8 Hz, 1H), 4.00 (dd, J = 9.2, 1.8 Hz, 1H), 2.81–2.67 (m, 2H), 1.41 (s, 9H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 154.9, 145.1, 132.6, 129.9, 128.8, 126.8, 126.2, 121.9, 115.1, 81.3, 55.9, 44.8, 36.3, 28.3; ESI-HRMS (CI) m/z: calcd for C12H13N2O2 ([M – Bu + 2H]+•), 217.0977; found, 217.0970.

Phenyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3i)

(106 mg, 73%) as a white powder from aryldiazene carboxylate 2i (119 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3i. mp: 113–116 °C; IR (neat) vmax 3327, 3061, 2936, 1690 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.33 (t, J = 7.6 Hz, 2H), 7.19 (tt, J = 7.6, 1.1 Hz 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.12 (dt, J = 7.6, 1.1 Hz, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.7, 1.0 Hz, 1H), 6.48 (bs, 1H), 5.80 (dq, J = 6.0, 2.2 Hz, 1H), 5.68 (dq, J = 6.0, 2.3 Hz, 1H), 5.50 (qd, J = 9.3 Hz, 1.4 Hz, 1H), 4.14 (d, J = 9.3 Hz, 1H), 2.93–2.79 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 153.0, 151.0, 144.4, 132.5, 129.8, 129.3, 128.8, 126.5, 126.3, 125.6, 122.5, 121.5, 115.5, 56.4, 45.2, 36.5 (CH2); ESI-HRMS (CI) m/z: calcd for C18H17N2O2 ([M + H]+•), 293.1290; found, 293.1282.

Benzyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3j)

(120 mg, 78%) as a white powder from aryldiazene carboxylate 2j (133 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3j. mp: 108–110 °C; IR (neat) vmax 3296, 3059, 2944, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.36–7.28 (m, 5H), 7.08 (d, J = 7.5 Hz, 1H), 7.04 (td, J = 7.5, 1.4 Hz, 1H), 6.89 (td, J = 7.5, 1.2 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.35 (bs, 1H), 5.74 (dq, J = 6.1, 2.3 Hz, 1H), 5.62 (dq, J = 6.1, 2.3 Hz, 1H), 5.37 (bs, 1H), 5.13 (s, 2H), 4.02 (d, J = 9.3 Hz, 1H), 2.80 (ddq, J = 17.0, 6.4, 2.3 Hz, 1H), 2.75–2.68 (m, 1H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 155.2, 144.7, 136.0, 132.5, 129.7, 128.7, 128.5, 128.1, 127.9, 126.6, 126.3, 122.2, 115.3, 67.9, 56.0, 44.9, 36.2; ESI-HRMS (CI) m/z: calcd for C19H19N2O2 ([M + H]+•), 307.1447; found, 307.1439.

Allyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3k)

(84 mg, 66%) as a brown oil from aryldiazene carboxylate 2k (102 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by flash-column chromatography (Al2O3, hexanes/AcOEt 95:5) to afford the title compound 3k. IR (neat) vmax 3059, 3018, 2988, 1964 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.08 (d, J = 7.5 Hz, 1H), 7.06–7.02 (m, 1H), 6.89 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.34 (bs, 1H), 5.90 (ddt, J = 16.8, 10.6, 5.5 Hz, 1H), 5.75 (dq, J = 6.0, 2.1 Hz, 1H), 5.64 (dq, J = 6.0, 2.1 Hz, 1H), 5.38 (q, J = 9.1 Hz, 1H), 5.26 (d, J = 16.8 Hz, 1H), 5.24 (d, J = 10.6 Hz, 1H), 4.61 (dt, J = 5.5, 1.4 Hz, 2H), 4.04 (dd, J = 9.1, 2.1 Hz, 1H), 2.81 (ddq, J = 17.2, 6.8, 2.3 Hz, 1H), 2.75–2.69 (m, 1H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 154.9, 144.6, 132.5, 132.3, 129.7, 128.7, 126.6, 126.3, 122.1, 117.8, 115.3, 66.7, 55.9, 44.8, 36.1; ESI-HRMS (CI) m/z: calcd for C15H17N2O2 ([M + H]+•), 257.1290; found, 257.1264.

2,2,2-Trichloroethyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3l)

(115 mg, 66%) as a white powder from aryldiazene carboxylate 2l (141 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3l. mp: 91–93 °C; IR (neat) vmax 3315, 3063, 3004, 2956, 2916, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.09 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.91 (td, J = 7.6, 1.0 Hz, 1H), 6.84–6.80 (m, 1H), 6.39 (bs, 1H) 5.77 (dq, J = 5.9, 2.2 Hz, 1H), 5.64–5.62 (m, 1H), 5.41 (q, J = 8.6 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H), 4.72 (d, J = 10.8 Hz, 1H), 4.08 (d, J = 8.6 Hz, 1H), 2.88–2.75 (m, 2H, CH2); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 153.1, 144.3, 132.4, 129.7, 129.0, 128.7, 126.5, 122.5, 115.5, 95.2, 75.4, 56.5, 45.2, 36.4; ESI-HRMS (CI) m/z: calcd for C14H14Cl3N2O2 ([M + H]+•), 347.0121; found, 347.0111.

(3aR*,9bR*)-1-(3,3a,5,9b-Tetrahydro-4H-cyclopenta[c]cinnolin-4-yl)ethan-1-one (3m) and (3aR*,9bR*)-1-(1,3a,5,9b-Tetrahydro-4H-cyclopenta[c]cinnolin-4-yl)ethan-1-one (3m′)

(99 mg, 92%) as a brown solid from N-acetyl aryldiazene 2m (74 mg, 0.5 mmol) was obtained after 1.5 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3m/3m′ as a mixture of regioisomers in a ratio of 59:41. mp: 57–60 °C; IR (neat) vmax 3067, 2923, 2850, 1634 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.70 (bs, 1H, H5major), 7.12–7.10 (m, 2H, H7minor, H9minor), 7.08–7.01 (m, 3H, H7major, H9major, H8minor), 6.95 (d, J = 7.9 Hz, 1H, H6minor), 6.86 (td, J = 7.5, 1.2 Hz, 1H, H8major), 6.80 (dd, J = 7.9, 1.2 Hz, 1H, H6major), 5.77–5.71 (m, 4H, H2major, H2minor, H3minor, H3aminor), 5.68 (dq, J = 6.0, 2.4 Hz, 1H, H1major), 5.51 (bs, 1H, H5minor), 5.04 (qd, J = 9.2, 1.4 Hz, 1H, H3amajor), 4.09 (dd, J = 9.2, 2.1 Hz, 1H, H9bmajor), 4.00 (d, J = 9.2 Hz, 1H, H9bminor), 2.84 (ddq, J = 16.8, 6.5, 2.4 Hz, 1H, H3major), 2.75–2.65 (m, 2H, H3major, H1minor), 2.46–2.39 (m, 1H, H1minor), 2.20 (s, 3H, CH3minor), 2.17 (s, 3H, CH3major); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 172.9 (C=O)minor, 163.4 (C=O)major, 143.8 (C5amajor), 141.6 (C5aminor), 133.1 (C3)minor, 132.5 (C1major), 130.4 (C9aminor), 129.8 (C2minor), 129.3 (C2major), 128.8 (C9minor), 128.4 (C7major), 126.7 (C9major), 126.6 (C7minor), 125.4 (C9amajor), 124.9 (C8minor), 121.9 (C8major), 121.1 (C6minor), 115.1 (C6major), 57.3 (C3amajor), 52.2 (C3aminor), 45.4 (C9bmajor), 44.2 (C9bminor), 36.5 (C3major), 34.7 (C1minor), 21.5 (CH3minor), 20.2 (CH3major); ESI-HRMS (CI) m/z: calcd for C13H15N2O ([M + H]+•), 215.1184; found, 215.1184.

(3aR*,9bR*)-1-(8-(Trifluoromethyl)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnolin-4-yl)ethan-1-one (3n) and (3aR*,9bR*)-1-(8-(Ttrifluoromethyl)-1,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnolin-4-yl)ethan-1-one (3n′)

(125 mg, 63%) as a white powder from N-acetyl aryldiazene 2n (152 mg, 0.7 mmol), cyclopentadiene (73 μL, 0.87 mmol), and Sc(OTf)3 (378 mg, 0.77 mmol) was obtained after 1.5 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3n/3n′ as a mixture of regioisomers in a ratio of 74:26. mp: 128–134 °C; IR (neat) vmax 3060, 3058, 2920, 2850, 1634 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (bs, 1H, H5major), 7.36–7.34 (m, 2H, H7minor, H9minor), 7.31–7.28 (m, 2H, H7major, H9major), 7.01 (d, J = 8.6 Hz, 1H, H6minor), 6.86 (d, J = 8.1 Hz, 1H, H6major), 5.82–5.75 (m, 3H, H2major, H2minor, H3minor), 5.71 (dq, d, J = 6.0, 2.3 Hz 1H, H1major), 5.65 (bs, 2H, H3aminor, H5minor), 5.09 (tdd, J = 8.9, 6.8, 1.7 Hz, 1H, H3amajor), 4.11 (dd, J = 8.9, 2.3 Hz, 1H, H9bmajor), 4.02 (d, J = 8.9 Hz, 1H, H9bminor), 2.83 (ddq, J = 16.9, 6.8, 2.3 Hz, 1H, C3major), 2.72 (ddt, J = 16.9, 8.9, 2.3 Hz, 1H, C3)major, 2.44 (dd, J = 7.8, 2.1 Hz, 1H, C1mino)r, 2.40 (dd, J = 7.8, 1.8 Hz, 1H C1minor), 2.20 (s, 6H, CH3major, CH3minor); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 172.8 (C=O)minor, 163.6 (C=O)major, 146.4 (q, 5JCF = 1.1 Hz, C5amajor), 144.4 (C5aminor), 132.4 (C3minor), 131.8 (C1major), 130.3 (C2minor), 130.0 (C2major), 129.7 (C9aminor), 126.2 (q, 3JCF = 3.9 Hz, C9minor), 126.2 (q, 2JCF = 32.3 Hz, C8minor), 125.6 (q, 3JCF = 3.8 Hz, C9major), 125.3 (C9amajor), 124.3 (q, 1JCF = 271.7 Hz, CF3major), 124.1 (q, 1JCF = 272.7 Hz, CF3minor), 123.8 (q, 3JCF = 3.8 Hz, C7major), 123.6 (q, 3JCF = 3.7 Hz, C7minor), 123.6 (q, 2JCF = 32.3 Hz, C8major), 120.0 (C6minor), 114.8 (C6major), 57.2 (C3amajor), 52.0 (C3aminor), 45.0 (C9bmajor), 43.7 (C9bminor), 36.1 (C3major), 33.7 (C1minor), 21.5 (CH3minor), 20.0 (CH3major); 19F NMR (376 MHz, CDCl3) δ (ppm): −61.7major, −62.0minor; ESI-HRMS (CI) m/z: calcd for C14H14F3N2O ([M + H]+•), 283.1058; found, 283.1033.

Phenyl((3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnolin-4-yl)methanone (3o)

(138 mg, >99%) as a brown solid from N-benzoyl aryldiazene 2o (108 mg, 0.5 mmol) was obtained after 1 h reaction, as described in the general procedure. The crude product was purified by recrystallization in hexane at −24 °C to afford the title compound 3o. mp: 53–56 °C; IR (neat) vmax 3286, 3057, 2922, 1628 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.71 (bs, 1H), 7.48–7.41 (m, 5H), 7.11–7.06 (m, 2H), 6.92–6.89 (m, 2H), 5.72–5.66 (m, 2H), 5.05–4.99 (m, 1H), 3.97 (d, J = 8.3 Hz, 1H), 3.02 (d, J = 11.9 Hz, 1H), 2.67–2.61 (m, 1H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 165.2, 143.8, 134.4, 132.5, 130.2, 129.3, 128.6, 128.5, 127.1, 126.7, 125.6, 122.0, 115.3, 58.3, 45.1, 36.6; ESI-HRMS (CI) m/z: calcd for C18H17N2O ([M + H]+•), 277.1341; found, 277.1336.

Gram Scale Procedure of Cinnoline 3a

To a stirred solution of aryldiazene carboxylate 2a (535 mg, 3 mmol) in CHCl3 (9 mL), was added cyclopentadiene (0.38 mL, 4.5 mmol, 1.5 equiv) and Sc(OTf)3 (2.237 g, 4.5 mmol, 1.5 equiv) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1–6 h, and then, it was diluted with CH2Cl2 (40 mL) and washed with NaOH (2 M, 50 mL) and water (2 × 50 mL). The organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness in vacuum. The crude product was purified by column chromatography to afford the desired cinnoline 3a (523 mg, 71% yield).

Synthetic Transformations

Synthesis of Compound 3p

A stirred solution of 3a (0.2 mmol, 49 mg) in MeOH (3 mL) was refluxed using a heating mantle for 48 h under a nitrogen atmosphere. Then, the crude reaction was diluted with H2O (25 mL), and the product was extracted with CH2Cl2 (2 × 25 mL). The organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness in a vacuum. The crude product was purified by flash-column chromatography (SiO2, hexanes/AcOEt 97:3) to afford the title compound 3p.

Methyl (3aR*,9bR*)-3,3a,5,9b-tetrahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (3p)

Brown solid, 34 mg, 73%; mp: 86–89 °C; IR (neat) vmax 3058, 2956, 2924, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.07 (dt, J = 7.5, 0.7 Hz, 1H), 7.06–7.01 (m, 1H), 6.89 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.16 (bs, 1H), 5.74 (dq, J = 6.0, 2.3 Hz, 1H), 5.62 (dq, J = 6.0, 2.3 Hz, 1H), 5.33 (s, 1H), 4.01 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 2.82–2.67 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm): 155.7, 144.6, 132.5, 129.8, 128.8, 126.7, 126.4, 122.3, 115.4, 55.9, 53.3, 44.8, 36.2; ESI-HRMS (CI) m/z: calcd for C13H15N2O2 ([M + H]+•), 231.1134; found, 231.1126.

Synthesis of Compound 4

To a stirred solution of 3a (0.2 mmol, 49 mg) in MeOH (10 mL), Ni-Raney (∼50 mg, washed with MeOH) was added, and the reaction mixture was stirred under a hydrogen atmosphere (2 bar) for 22 h. Then, the crude product was filtered through a pad of Celite to obtain the pure title compound 4.

Ethyl (3aR*,9bR*)-1,2,3,3a,5,9b-hexahydro-4H-cyclopenta[c]cinnoline-4-carboxylate (4)

Brown oil, 48 mg, 97%; IR (neat) vmax 3327, 3061, 2956, 2867, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.08 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.88 (t, J = 7.4, Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.27 (bs, 1H), 4.87 (q, J = 8.1 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.26 (q, J = 8.1 Hz, 1H), 2.10–1.97 (m, 2H), 1.95–1.88 (m, 1H), 1.74–1.65 (m, 1H), 1.64–1.57 (m, 1H), 1.53–1.44 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3) δ (ppm): 155.0, 144.5, 128.9, 128.7, 125.9, 121.8, 114.7, 62.0, 57.1, 38.2, 34.8, 29.2, 23.7, 14.5; ESI-HRMS (CI) m/z: calcd for C14H19N2O2 ([M + H]+•), 247.1447; found, 247.1437.