The Concept of Sequential Multicomponent Reactions: A Short Synthesis of Thiazolo- and Oxazolo[1,4]benzodiazepine-2,5-diones

Abstract

A new synthetic sequence including two sequential multicomponent reactions leading to a wide range of thiazolo- and oxazolo-annulated benzodiazepinediones is described. This strategy features simple one-pot operations under mild conditions in combination with a high degree of diversity, and can be realized based on commercially available or easily accessible starting materials.

The benzodiazepinedione core is present in many natural products and is a prominent structure in numerous pharmaceutically important compounds.[1] Successful examples of the synthesis of benzodiazepinediones have been described to date. Specifically, the contribution of Lu et al. showed that 1,4-benzodiazepine-2,5-diones could be constructed through high-performance processes utilizing the Ugi four-component condensation reaction.[2] In addition, Hiller et al. reported a two-step synthesis of annulated 1,4-benzodiazepine-2,5-diones starting from the Ugi four-component reaction and a subsequent palladium-catalyzed ring-closure.[3] Recently, Zemribo and Smits presented a one-step synthesis from anthranilic acids and proline esters.[4] Most approaches to these and related benzo-fused heterocycles typically involve the elegant application of multicomponent reactions, such as the Ugi reaction, and a subsequent post-modification that requires precursors with appropriately positioned activating groups.[5]

Multicomponent reactions (MCRs) are convergent reactions in which at least three starting materials are transformed into a new product by simultaneous formation of at least two bonds with high atom economy in one-pot procedures.[6] MCRs benefit not only from commercially available and low-priced substrates, but also from the exclusive possibility to enable the direct preparation of densely substituted molecules containing various structural features for elaboration of substance libraries. In recent years, multicomponent reactions have become a powerful tool in many aspects of medicinal and organic chemistry, highlighted by their unique performance to create molecular complexity in single-step operations.[7] Beside these privileges, MCRs stand out due to the rapid construction of (hetero-)cyclic frameworks and the straightforward opportunity of classical post-modification by the employment of prefunctionalized substrates.[8]

Two well-established examples of MCRs are represented by the Asinger and the Ugi reactions. Studies by Friedrich Asinger revealed that the solvent-free interaction of ketones or aldehydes with ammonia and sulfur resulted in the synthesis of iminic 2,5-dihydro-1,3-thiazoles (3-thiazolines).[9] Later on, driven by the continuous importance of 3-thiazolines as key intermediates in the pharmaceutical chemistry sector,[10] the procedure was simplified by the use of α-chloro aldehydes, aqueous ammonia and sodium hydrosulfide.[11] Furthermore, this modified protocol was extended to oxygen-containing 2,5-dihydro-1,3-oxazoles (3-oxazolines) by means of sodium hydroxide, giving an example of an environmentally friendly reaction (only water and sodium chloride are lost).[12] In contrast to the rarely described Asinger 4CR,[13] the Ugi 3CR has a prestigious history in the field of synthetic chemistry.[6] Ivar Ugi discovered a three-component reaction that included an imine, an isocyanide and a carboxylic acid as substrates, and that resulted in the design of a peptoid structure.[14] In the recent past, we evaluated the Ugi 3CR in connection with the products of the Asinger 4CR as suitable imine components to assemble richly functionalized heterocyclic systems and were amazed at the high functional group tolerance of this reaction.[15]

Considering the great biological significance and application of benzodiazepinediones, and inspired by the efficiency of multicomponent reactions, we became interested in the development of a linear sequence of multicomponent reactions leading to a broad variety of annulated benzodiazepinedione derivatives under mild and operationally simple conditions (Scheme [1]). The first part of the intended sequence is the Asinger 4CR (A-4CR) that provides thiazolines 1 (X = S) and oxazolines 1 (X = O) as the desired key precursors. The high performance of the Ugi 3CR (U-3CR) associated with the good potential for post-modifications is the reason we chose this multicomponent reaction for the conversion of the imines 1 in combination with isocyanides and carboxylic acids as further substrates. This transformation results in highly substituted bisamides 2, whereby the incorporation of a secondary amido group in particular serves as a perfect starting point for a final single-step cyclization via an S_NAr process in the absence of high-priced reagents. Very recently, our group described classical nu­cleo­philic substitutions at electron-deficient aromatic compounds with high efficiency.[16] [17] The processes proceeded quickly at room temperature and avoided harsh conditions and cost-intensive reagents, while the waste materials were non-toxic ammonium salts. Our findings that displacement of the fluorine in 2-fluoro-5-nitro-substituted aromatic compounds can be quite facile suggests that such structural properties offer a benign strategy for the synthesis of thiazolo- and oxazolo-fused benzodiazepinediones 3. In addition, the sequential combination of both multicomponent reactions seems to be ideally suited to open access to target molecules with high levels of structural diversification. Furthermore, this attractive concept is part of an increasing pool of applications for diversity-oriented synthesis.[18]

According to our proposed synthetic route (Scheme [1]), we devoted our initial efforts into the Asinger 4CR, expecting that the reaction of a ketone, an α-chloro aldehyde, ammonia and sodium hydrogen sulfide or sodium hydroxide would result in a rapid synthesis of known heterocyclic imines 1.[17] Indeed, the reproduction of this known multicomponent reaction proceeded effectively, independently of the structural nature of the carbonyl compounds, and we obtained smoothly various types of thiazolines and oxazolines 1 in one-pot procedures; the substitution patterns are depicted in Table [1]. One advantage of this transformation is the direct generation of the reactive iminic bond, which enables a straightforward conversion of the precursors 1 in the intended sequence of multicomponent reactions. Hence, we turned our attention to the Ugi 3CR as a second multicomponent reaction and forceful one-pot method for the preparation of bisamides 2. We started our investigations with tetramethyl thiazoline 1a, 2-fluoro-5-nitrobenzoic acid and allyl isocyanide in methanol, and isolated the desired bisamide 2a in almost quantitative yield (Table [1], entry 1). Since the final cyclization of bisamides 2 is the key step for the formation of the benzodiazepinedione substructure, we considered a small selection of appropriate bases to increase the nucleophilicity of the secondary amido group for the nucleophilic aromatic substitution (Scheme [2]). It turned out that the combination of lithium diisopropylamide (LDA) in refluxing THF was well-suited to generate the desired benzodiazepinedione 3a in good yield (64%).

Next, we focused on the scope of the substrates and were able to telescope this two-step sequence leading to various benzodiazepinediones 3b –j in good isolated yields, which are summarized in Table [1] (entries 2–10). Besides a representative range of substitution patterns on the iminic heterocycle 1 (i.e., sulfur-containing thiazolines and oxygen-containing oxazolines), we expanded our concept to different classes of isocyanides. It was found that allyl, alkyl, aryl and benzyl isocyanides could be successfully applied generating bisamides 2b–j in good to very good yields while using 2-fluoro-5-nitrobenzoic acid derivatives as the third component in the Ugi reaction.

Table 1 Preparation of Precursors 2 and Products 3 ^a

Entry	Imineb	Bisamide	Yield (%)c	Benzodiazepinedione	Yield (%)c
1			98		64
2			25		89
3			79		trace
4			61		40
5			35		45
6			58		67
7			96		71
8			98		36
9			47		32
10			80		42

^a See experimental section for details.

^b The synthesis of imines 1 is well-established. For details, see our recent report.[17]

^c Yields of isolated products.

Apart from sterically hindered secondary amido groups (i.e., bisamide 2c), all the prepared bisamides 2 underwent efficient cyclization under the optimized reaction conditions. Allyl-, alkyl-, benzyl- and even aryl-bearing amido groups were well-tolerated in our single-step transformation providing the corresponding benzodiazepinediones 3b and 3d–j in moderate to good yields (Table [1], entries 2 and 4–10). A profound effect on the cyclization rate based on the electronic nature of the substrate was not observed. Furthermore, we found that naphthalene derivative 2g underwent clean cyclization leading to benzodiazepinedione 3g in a good isolated yield of 71% (Table [1], entry 7). Finally, we explored a carboxylic acid that contains a highly derivatizable bromo substituent on the aryl ring as a representative example for a broad range of potential molecular scaffolds (Table [1], entries 8–10). This substrate underwent the Ugi reaction and the subsequent cyclization in good yields affording benzodiazepinediones 3h–j as the final products.

Bearing various functional groups, the new thiazolo- and oxazolo-annulated benzodiazepinediones 3 offer a convenient platform for selective derivatizations to construct heterocyclic structures by classical operations. Specifically, the utility of the nitro group as a starting point for the elaboration of a diverse-orientated substance library has recently been shown by us.[16]

In conclusion, we have developed a new and efficient synthetic route toward thiazolo- and oxazolo-annulated benzodiazepinediones by employing two sequential multicomponent reactions (i.e., A-4CR and U-3CR). With a synthetically simple cyclization as the final step, this strategy enables a rapid approach to multifunctionalized heterocyclic frameworks from a wide range of commercially available or easily accessible starting materials. Furthermore, the sequence was performed in one-pot procedures under mild conditions and opens new possibilities for the preparation of biologically important benzodiazepinedione motifs.

Synthetic procedures, conducted under argon atmosphere, were performed on a vacuum line using standard Schlenk techniques. Preparative column chromatography was carried out using Grace SiO₂ (0.035–0.070 mm, type KG 60) and CH₂Cl₂, EtOAc, n-hexane and methyl tert-butyl ether were used as eluents. EtOAc and n-hexane were distilled prior to use. CH₂Cl₂ was dried and distilled from CaH₂. TLC was performed with Machery-Nagel SiO₂ F254 plates on aluminum sheets. Melting points were obtained using a melting point apparatus (Laboratory Devices) and are uncorrected. IR spectra were recorded with a Bruker Tensor 27 spectrometer fitted with a “Golden Gate” diamond-ATR (attenuated total reflection) unit. ¹H and ¹³C NMR spectra were recorded with a Bruker AMX R 500 (measuring frequency: ¹H NMR = 500.1 MHz, ¹³C NMR = 125.8 MHz) or a Bruker Avance III 500 (measuring frequency: ¹H NMR = 499.9 MHz, ¹³C NMR = 125.7 MHz) spectrometer in CDCl₃ or DMSO-d ₆ solution. Chemical shifts are referenced to the residual peaks of the solvent [CDCl₃: 7.26 ppm (¹H NMR), 77.16 ppm (¹³C NMR); DMSO-d ₆: 2.50 ppm (¹H NMR), 39.52 ppm (¹³C NMR)].[19] Signal assignments were supported by measurements applying DEPT and COSY techniques. Mass spectra were obtained with Finnigan-MAT 95 (CI, EI) and Waters Q-TOF Premier (ESI) spectrometers. The syntheses of 2,2,5,5-tetramethyl-1,3-thiazoline (1a), 2,2,5,5-tetramethyl-1,3-oxazoline (1b), 2,2-dimethyl-1-thia-4-azaspiro[4,5]dec-3-ene (1c), 2,2-dimethyl-1-oxa-4-azaspiro[4.5]dec-3-ene (1d) and 7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadec-14-ene (1e) were recently reported by us.[17] Allyl isocyanide,[20] 4-methoxybenzyl isocyanide[21] and 3-bromo-2-fluoro-5-nitrobenzoic acid[17] were prepared according to published procedures.

Ugi 3CR; General Procedure A (GPA)

A solution of the respective carboxylic acid (1 equiv) in anhydrous MeOH (1.0 mL per mmol of imine) was added dropwise to a solution of the respective imine 1 (1 equiv) in anhydrous MeOH (2.0 mL per mmol of imine) at 0 °C. After stirring for 30 min at r.t., the respective isocyanide (1 equiv) was added dropwise, and the solution was stirred for 2 d at r.t. The solvent was removed (rotary evaporator). The crude mixture was purified by recrystallization or by column chromatography on silica gel.

(RS)-4-N-Allylcarbamoyl-3-(2-fluoro-5-nitrobenzoyl)-2,2,5,5-tetramethyl-1,3-thiazolidine (2a)

Following GPA, 2,2,5,5-tetramethyl-1,3-thiazoline (1a) (430 mg, 3.00 mmol), 2-fluoro-5-nitrobenzoic acid (555 mg, 3.00 mmol) and allyl isocyanide (201 mg, 3.00 mmol) were used. Purification was not necessary. Product 2a was obtained as a colorless solid (1.160 g, 98%).

Mp 153–156 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3309, 3070, 2984, 1689, 1624, 1533, 1481, 1427, 1391, 1309, 1254, 766, 748 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.30–8.26 (m, 1 H, p-CH_ArCO), 8.13–8.11 (m, 1 H, o-CH_ArCO), 7.29–7.25 (m, 1 H, m-CH_ArCO), 6.33–6.09 (m, 1 H, NH), 5.85–5.77 (m, 1 H, CH=CH₂), 5.25–5.21, 5.20–5.18 (2 m, 2 H, CH=CH ₂), 4.09 (s, 1 H, NCH), 3.83–3.81 (m, 2 H, NCH₂), 2.14, 2.10, 1.73, 1.31 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 168.6 (CONH), 162.7 (CON), 160.7 (d, ¹ J _C–F = 258.4 Hz, C_ArF), 144.4 (C_ArNO₂), 133.2 (CH=CH₂), 127.3 (d, ² J _C–F = 21.6 Hz, C _ArCO), 127.0 (d, ³ J _C–F = 10.0 Hz, p-CH_ArCO), 124.6 (o-CH_ArCO), 117.8 (CH=CH₂), 117.5 (d, ² J _C–F = 25.2 Hz, m-CH_ArCO), 79.4 (NCH), 74.1 [C(CH₃)₂N], 50.4 [C(CH₃)₂CH], 42.2 (NHCH₂), 33.5, 31.4, 29.9, 24.9 (4 × CH₃).

MS (CI, isobutane): m/z (%) = 396.3 (100) [M + H]⁺.

HRMS (CI, isobutane): m/z [M + H]⁺ calcd for C₁₈H₂₃FN₃O₄S: 396.1393; found: 396.1403.

(RS)-4-N-Ethylcarbamoyl-3-(2-fluoro-5-nitrobenzoyl)-2,2,5,5-tetramethyl-1,3-oxazolidine (2b)

Following GPA, 2,2,5,5-tetramethyl-1,3-oxazoline (1b) (254 mg, 2.00 mmol), 2-fluoro-5-nitrobenzoic acid (370 mg, 2.00 mmol) and ethyl isocyanide (110 mg, 2.00 mmol) were used. Column chromatography on silica gel (n-hexane/EtOH, 7:3; R_f = 0.58) provided 2b as a colorless solid (184 mg, 25%).

Mp 132–134 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3328, 3083, 2982, 2940, 1685, 1630, 1534, 1439, 1349, 1255, 1236, 1198, 1157, 1075, 1014, 922, 851, 747 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.28–8.25 (m, 1 H, p-CH_ArCO), 8.19–8.17 (m, 1 H, o-CH_ArCO), 7.28–7.24 (m, 1 H, m-CH_ArCO), 5.64–5.61 (m, 1 H, NH), 3.88 (s, 1 H, NCH), 3.13–3.07 (m, 2 H, CH₂), 1.88, 1.82, 1.50, 1.27 [4 s, 12 H, 2 × C(CH₃)₂], 0.97–0.94 (m, 3 H, CH₂CH ₃).

¹³C NMR (125.7 MHz, CDCl₃): δ = 168.1 (CONH), 161.7 (CON), 161.1 (d, ¹ J _C–F = 258.0 Hz, C_ArF), 144.4 (C_ArNO₂), 127.0 (d, ³ J _C–F = 10.0 Hz, p-CH_ArCO), 126.7 (d, ² J _C–F = 21.1 Hz, C _ArCO), 125.1 (d, ³ J _C–F = 5.2 Hz, o-CH_ArCO), 117.4 (d, ² J _C–F = 24.1 Hz, m-CH_ArCO), 97.3 [C(CH₃)₂N], 81.4 [C(CH₃)₂CH], 71.5 (NCH), 34.7 (CH₂), 30.7, 27.6, 25.3 [C(CH₃)₂], 14.7 (CH₂ CH₃).

MS (ESI, TOF): m/z (%) = 390.1 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₁₇H₂₂FN₃NaO₅: 390.1441; found: 390.1436.

(RS)-4-N-Cyclohexylcarbamoyl-3-(2-fluoro-5-nitrobenzoyl)-2,2,5,5-tetramethyl-1,3-oxazolidine (2c)

Following GPA, 2,2,5,5-tetramethyl-1,3-oxazoline (1b) (382 mg, 3.00 mmol), 2-fluoro-5-nitrobenzoic acid (555 mg, 3.00 mmol) and cyclohexyl isocyanide (328 mg, 3.00 mmol) were used. Recrystallization from CH₂Cl₂/n-hexane provided 2c as a pale yellow solid (997 mg, 79%).

Mp 195–197 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3317, 3063, 2932, 2857, 1680, 1631, 1536, 1447, 1350, 1256, 1199, 1082, 917, 884, 750 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.30–8.26 (m, 1 H, p-CH_ArCO), 8.21–8.19 (m, 1 H, o-CH_ArCO), 7.28–7.24 (m, 1 H, m-CH_ArCO), 5.35 (d, ³ J = 7.8 Hz, 1 H, NH), 3.86 (s, 1 H, NCH), 3.61–3.55 (m, 1 H, CH_Cy), 1.89, 1.84, 1.52, 1.28 (4 s, 12 H, 4 × CH₃), 1.69–1.57, 1.47–1.33, 1.15–1.06, 0.94–0.87 (4 m, 10 H, 5 × CH_2,Cy).

¹³C NMR (125.8 MHz, CDCl₃): δ = 167.2 (CONH), 161.8 (CON), 161.0 (d, ¹ J _C–F = 257.7 Hz, C_ArF), 144.5 (C_ArNO₂), 127.1 (d, ³ J _C–F = 10.4 Hz, p-CH_ArCO), 126.6 (d, ² J _C–F = 21.5 Hz, C _ArCO), 125.3 (d, ³ J _C–F = 6.1 Hz, o-CH_ArCO), 117.4 (d, ² J _C–F = 24.0 Hz, m-CH_ArCO), 97.2 [C(CH₃)₂N], 81.5 [C(CH₃)₂CH], 71.5 (NCH), 48.7 (CH_Cy), 33.1, 33.0, 25.4, 24.8, 24.7 (5 × CH_2,Cy), 30.8, 27.8, 27.6, 25.3 (4 × CH₃).

MS (CI, isobutane): m/z (%) = 422.6 (100) [M + H]⁺.

HRMS (CI, isobutane): m/z [M + H]⁺ calcd for C₂₁H₂₉FN₃O₅: 422.2086; found: 422.2085.

(RS)-3-N-(4-Chlorophenyl)carbamoyl-4-(2-fluoro-5-nitrobenzoyl)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane (2d)

Following GPA, 2,2-dimethyl-1-thia-4-azaspiro[4,5]dec-3-ene (1c) (367 mg, 2.00 mmol), 2-fluoro-5-nitrobenzoic acid (370 mg, 2.00 mmol) and 4-chlorophenyl isocyanide (274 mg, 2.00 mmol) were used. Recrystallization from CH₂Cl₂ provided 2d as a yellow solid (610 mg, 61%).

Mp 259–261 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3248, 3069, 2933, 2850, 1695, 1618, 1537, 1492, 1428, 1387, 1346, 1232, 1123, 1095, 834, 783 cm^–1.

¹H NMR (500.1 MHz, DMSO-d ₆): δ = 9.70–9.66 (m, 1 H, NH), 8.33–8.27 (m, 1 H, p-CH_ArCO), 7.75–7.69 (m, 1 H, o-CH_ArCO), 7.29–7.26 (m, 5 H, 2 × m-CHArCl, 2 × o-CHArCl, m-CHArCO), 4.31 (s, 1 H, NCH), 3.11–3.06, 2.86–2.84, 2.69–2.66, 1.91–1.80, 1.66–1.57, 1.24–1.16 (6 m, 10 H, 5 × CH_2,Cy), 1.63, 1.24 (2 s, 6 H, 2 × CH₃).

¹³C NMR (125.8 MHz, DMSO-d ₆): δ = 167.3 (CONH), 161.8 (d, ³ J _C–F = 4.0 Hz, CON), 159.8 (d, ¹ J _C–F = 254.3 Hz, C_ArF), 143.6 (C_ArNO₂), 136.5 (C_ArCl), 128.7 (2 × o-CH_ArCl), 127.5 (C_ArNH), 127.2 (d, ² J _C–F = 24.4 Hz, C _ArCO), 126.8 (d, ³ J _C–F = 9.3 Hz, p-CH_ArCO), 122.9 (o-CH_ArCO), 120.7 (2 × m-CH_ArCl), 118.5 (d, ² J _C–F = 25.7 Hz, m-CH_ArCO), 81.0 [C(CH_2,Cy)₅], 77.3 (NCH), 49.5 [C(CH₃)₂], 37.0, 34.8, 25.4, 25.0, 24.2 (5 × CH_2,Cy), 33.2, 24.8 (2 × CH₃).

MS (ESI, TOF): m/z (%) = 528.1 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₄H₂₅ClFN₃NaO₄S: 528.1136; found: 528.1127.

(RS)-4-(2-Fluoro-5-nitrobenzoyl)-3-N-(4-methoxybenzyl)carbamoyl-2,2-dimethyl-1-oxa-4-azaspiro[4.5]decane (2e)

Following GPA, 2,2-dimethyl-1-oxa-4-azaspiro[4.5]dec-3-ene (1d) (334 mg, 2.00 mmol), 2-fluoro-5-nitrobenzoic acid (370 mg, 2.00 mmol) and 4-methoxybenzyl isocyanide (294 mg, 2.00 mmol) were used. Column chromatography on silica gel (n-hexane/EtOAc, 3:1; R_f = 0.15) provided 2e as a colorless solid (350 mg, 35%).

Mp 180–182 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3076, 2987, 2936, 1693, 1616, 1537, 1515, 1444, 1348, 1243, 1141, 1075, 1034, 1012, 915, 817, 743 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.22–8.19 (m, 1 H, p-CH_ArCO), 8.14–8.12 (m, 1 H, o-CH_ArCO), 7.20–7.16 (m, 1 H, m-CH_ArCO), 7.04–7.02 (m, 2 H, 2 × m-CH _ArOCH₃), 6.83–6.81 (m, 2 H, 2 × o-CH _ArOCH₃), 5.79–5.74 (m, 1 H, NH), 4.23 (dd, ² J = 14.3 Hz, ³ J = 5.9 Hz, 1 H, CH₂N), 4.12 (dd, ² J = 14.1 Hz, ³ J = 4.5 Hz, 1 H, CH₂N), 3.94 (s, 1 H, NCH), 3.81 (s, 3 H, OCH₃), 2.71–2.63, 1.85–1.60, 1.38–1.24 (3 m, 10 H, 5 × CH_2,Cy), 1.51, 1.28 [2 s, 6 H, C(CH₃)₂].

¹³C NMR (125.7 MHz, CDCl₃): δ = 168.1 (CONH), 162.0 (CON), 160.9 (d, ¹ J _C–F = 257.8 Hz, C_ArF), 159.5 (C _ArOCH₃), 144.5 (C_ArNO₂), 129.4 (2 × m-CH_ArOCH₃), 129.1 (C _ArCH₂), 127.0 (d, ³ J _C–F = 9.6 Hz, p-CH_ArCO), 126.9 (d, ² J _C–F = 22.6 Hz, C _ArCO), 125.2 (d, ³ J _C–F = 4.3 Hz, o-CH_ArCO), 117.4 (d, ² J _C–F = 24.4 Hz, m-CH_ArCO), 114.4 (2 × o-CH_ArOCH₃), 99.4 [C(CH_2,Cy)₅], 81.3 [C(CH₃)₂], 71.5 (NCH), 55.4 (OCH₃), 43.5 (CH₂N), 36.0, 34.5, 24.7, 23.5, 23.4 (5 × CH_2,Cy), 31.0, 25.7 [C(CH₃)₂].

MS (ESI, TOF): m/z (%) = 522.2 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₆H₃₀FN₃NaO₆: 522.2016; found: 522.2003.

(RS)-4-(2-Fluoro-5-nitrobenzoyl)-3-N-phenethylcarbamoyl-2,2-dimethyl-1-oxa-4-azaspiro[4.5]decane (2f)

Following GPA, 2,2-dimethyl-1-oxa-4-azaspiro[4.5]dec-3-ene (1d) (334 mg, 2.00 mmol), 2-fluoro-5-nitrobenzoic acid (370 mg, 2.00 mmol) and phenethyl isocyanide (262 mg, 2.00 mmol) were used. Recrystallization from CH₂Cl₂ provided 2f as a colorless solid (560 mg, 58%).

Mp 204–206 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3085, 2929, 2859, 1683, 1627, 1553, 1537, 1448, 1347, 1255, 1235, 1182, 1136, 1038, 1009, 915, 850, 748 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.26–8.22 (m, 1 H, p-CH_ArCO), 8.07–8.05 (m, 1 H, o-CH_ArCO), 7.34–7.31 (m, 2 H, 2 × o-CH_ArCH₂), 7.25–7.21 (m, 2 H, p-CH_ArCH₂, m-CH_ArCO), 7.18–7.16 (m, 2 H, 2 × m-CH_ArCH₂), 5.68–5.66 (m, 1 H, NH), 3.85 (s, 1 H, NCH), 3.53–3.46, 3.41–3.34 (2 m, 2 H, CH₂NH), 2.82–2.76, 2.75–2.69 (2 m, 2 H, CH₂C_Ar), 2.65–2.59, 2.54–2.47, 1.78–1.54, 1.38–1.26 (4 m, 10 H, 5 × CH_2,Cy), 1.46, 1.21 (2 s, 6 H, 2 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 168.4 (CONH), 161.9 (CON), 160.9 (d, ¹ J _C–F = 254.0 Hz, C_ArF), 144.4 (C_ArNO₂), 137.9 (C _ArCH₂), 129.1 (2 × m-CH_ArCH₂), 128.7 (2 × o-CH_ArCH₂), 127.1 (p-CH_ArCH₂), 127.1 (d, ³ J _C–F = 9.6 Hz, p-CH_ArCO), 126.8 (d, ² J _C–F = 21.3 Hz, C _ArCO), 124.7 (d, ³ J _C–F = 5.0 Hz, o-CH_ArCO), 117.5 (d, ² J _C–F = 24.0 Hz, m-CH_ArCO), 99.0 [C(CH_2,Cy)₅], 81.1 [C(CH₃)₂], 71.7 (NCH), 40.4 (CH₂NH), 36.2, 34.2, 24.6, 23.4, 23.4 (5 × CH_2,Cy), 35.2 (CH₂C_Ar), 30.9, 25.6 (2 × CH₃).

MS (ESI, TOF): m/z (%) = 506.2 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₆H₃₀FN₃NaO₅: 506.2067; found: 506.2056.

(RS)-14-(2-Fluoro-5-nitrobenzoyl)-15-N-(naphthalene-2-ylmethyl)carbamoyl-7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadecane (2g)

Following GPA, 7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadec-14-ene (1e) (670 mg, 3.00 mmol), 2-fluoro-5-nitrobenzoic acid (555 mg, 3.00 mmol) and 2-(isocyanomethyl)naphthalene (502 mg, 3.00 mmol) were used. Recrystallization from CH₂Cl₂/n-hexane provided 2g as a pale yellow solid (1.660 g, 96%).

Mp 169–172 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3319, 3061, 2936, 2855, 1651, 1626, 1531, 1424, 1374, 1345, 1252, 1128, 741, 714 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.17–8.14 (m, 1 H, p-CH_ArCO), 8.13–8.09 (m, 1 H, CH_Ar), 7.82–7.79 (m, 3 H, 3 × CH_Ar), 7.71–7.68 (m, 1 H, o-CH_ArCO), 7.50–7.46 (m, 2 H, 2 × CH_Ar), 7.32–7.31 (m, 1 H, CH_Ar), 7.19–7.13 (m, 1 H, m-CH_ArCO), 6.70–6.50 (m, 1 H, NH), 4.56–4.49 (m, 2 H, CH₂NH), 4.18 (s, 1 H, NCH), 3.17–3.07, 2.15–2.06, 1.86–1.61, 1.37–1.17 (5 m, 20 H, CH_2,Cy).

¹³C NMR (125.8 MHz, CDCl₃): δ = 168.4 (CONH), 163.9 (d, ¹ J _C–F = 261.8 Hz, C_ArF), 162.8 (CON), 144.2 (C_ArNO₂), 134.6, 133.3, 132.8 (3 × C_Ar), 128.8, 127.8, 126.7, 126.7, 126.5, 126.2, 125.7 (o-CH_ArCO, p-CH_ArCO, 7 × CH_Ar), 127.8 (d, ² J _C–F = 21.6 Hz, C _ArCO), 117.4 (d, ² J _C–F = 26.4 Hz, m-CH_ArCO), 81.0 [C(CH_2,Cy)₅N], 79.0 (NCH), 56.0 [C(CH_2,Cy)₅CH], 44.0 (CH₂NH), 39.9, 37.5, 36.9, 34.6, 25.6, 25.6, 25.2, 24.4, 24.3, 22.6 (10 × CH_2,Cy).

MS (CI, isobutane): m/z (%) = 576.5 (100) [M + H]⁺.

HRMS (CI, isobutane): m/z [M + H]⁺ calcd for C₃₂H₃₅FN₃O₄S: 576.2327; found: 576.2324.

(RS)-4-N-Allylcarbamoyl-3-(3-bromo-2-fluoro-5-nitrobenzoyl)-2,2,5,5-tetramethyl-1,3-thiazolidine (2h)

Following GPA, 2,2,5,5-tetramethyl-1,3-thiazoline (1a) (286 mg, 2.00 mmol), 3-bromo-2-fluoro-5-nitrobenzoic acid (528 mg, 2.00 mmol) and allyl isocyanide (134 mg, 2.00 mmol) were used. Column chromatography on silica gel (CH₂Cl₂; R_f = 0.23) provided 2h as a yellow solid (930 mg, 98%).

Mp 154–156 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3318, 3087, 2987, 2936, 1682, 1626, 1537, 1430, 1392, 1346, 1231, 1166, 1129, 1080, 919, 739 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.43–8.41 (m, 1 H, p-CH_ArCO), 8.01–7.99 (m, 1 H, o-CH_ArCO), 6.28–6.20 (m, 1 H, NH), 5.75–5.66 (m, 1 H, CH=CH₂), 5.14–5.11 (m, 2 H, CH=CH ₂), 3.97 (s, 1 H, NCH), 3.77–3.71 (m, 2 H, CH ₂NH), 2.07, 2.05, 1.67, 1.27 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 168.3 (CONH), 161.4 (CON), 157.4 (d, ¹ J _C–F = 254.6 Hz, C_ArF), 144.2 (C_ArNO₂), 133.1 (CH=CH₂), 129.9 (p-CH_ArCO), 127.7 (d, ² J _C–F = 23.0 Hz, C _ArCO), 123.3 (o-CH_ArCO), 117.6 (CH=CH₂), 110.8 (C_ArBr), 79.0 (NCH), 74.2 [C(CH₃)₂N], 50.3 [C(CH₃)₂CH], 42.1 (CH₂NH), 33.3, 31.2, 29.3, 24.8 (4 × CH₃).

MS (ESI, TOF): m/z (%) = 496.0 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₁₈H₂₁BrFN₃NaO₄S: 496.0318; found: 496.0319.

(RS)-4-N-Allylcarbamoyl-3-(3-bromo-2-fluoro-5-nitrobenzoyl)-2,2,5,5-tetramethyl-1,3-oxazolidine (2i)

Following GPA, 2,2,5,5-tetramethyl-1,3-oxazoline (1b) (254 mg, 2.00 mmol), 3-bromo-2-fluoro-5-nitrobenzoic acid (528 mg, 2.00 mmol) and allyl isocyanide (134 mg, 2.00 mmol) were used. Column chromatography on silica gel (n-hexane/MTBE, 3:2; R_f = 0.13) provided 2i as a yellow oil (431 mg, 47%).

IR (ATR): 3309, 3086, 2987, 2941, 1633, 1536, 1435, 1374, 1346, 1256, 1196, 1157, 1136, 1014, 919, 739 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.47–8.46 (m, 1 H, p-CH_ArCO), 8.13–8.10 (m, 1 H, o-CH_ArCO), 5.67–5.59 (m, 1 H, CH=CH₂), 5.58–5.54 (m, 1 H, NH), 5.11–5.09, 5.08–5.05 (2 m, 2 H, CH=CH ₂), 3.85 (s, 1 H, NCH), 3.79–3.73, 3.69–3.64 (m, 2 H, CH ₂NH), 1.88, 1.83, 1.53, 1.29 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.7 MHz, CDCl₃): δ = 167.9 (CONH), 160.7 (CON), 158.0 (d, ¹ J _C–F = 257.3 Hz, C_ArF), 144.5 (C_ArNO₂), 133.0 (CH=CH₂), 130.1 (p-CH_ArCO), 127.2 (d, ² J _C–F = 22.4 Hz, C _ArCO), 123.7 (o-CH_ArCO), 118.0 (CH=CH₂), 110.9 (d, ² J _C–F = 24.0 Hz, C_ArBr), 97.6 [C(CH₃)₂N], 81.5 [C(CH₃)₂CH], 71.5 (NCH), 42.3 (CH₂NH), 30.7, 27.6, 27.6, 25.4 (4 × CH₃).

MS (ESI, TOF): m/z (%) = 458.1 (100) [M + H]⁺.

HRMS (ESI, TOF): m/z [M + H]⁺ calcd for C₁₈H₂₂BrFN₃O₅: 458.0727; found: 458.0713.

(RS)-3-(3-Bromo-2-fluoro-5-nitrobenzoyl)-4-N-(4-methoxybenzyl)carbamoyl-2,2,5,5-tetramethyl-1,3-thiazolidine (2j)

Following GPA, 2,2,5,5-tetramethyl-1,3-thiazoline (1a) (286 mg, 2.00 mmol), 3-bromo-2-fluoro-5-nitrobenzoic acid (528 mg, 2.00 mmol) and 4-methoxybenzyl isocyanide (294 mg, 2.00 mmol) were used. Column chromatography on silica gel (n-hexane/EtOAc, 7:3; R_f = 0.35) provided 2j as a yellow solid (880 mg, 80%).

Mp 65–70 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3315, 3068, 2935, 1659, 1633, 1537, 1513, 1448, 1427, 1345, 1248, 1166, 1032, 820, 742 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.48–8.47 (m, 1 H, p-CH_ArCO), 8.04–8.00 (m, 1 H, o-CH_ArCO), 7.19–7.17 (m, 2 H, 2 × m-CH _ArOCH₃), 6.89–6.88 (m, 2 H, 2 × o-CH _ArOCH₃), 6.43–6.30 (m, 1 H, NH), 4.30 (d, ³ J = 4.7 Hz, 2 H, CH₂), 4.03 (s, 1 H, NCH), 3.82 (s, 3 H, OCH₃), 2.11, 1.99, 1.72, 1.31 [4 s, 12 H, 2 × C(CH₃)₂].

¹³C NMR (125.7 MHz, CDCl₃): δ = 168.3 (CONH), 161.6 (CON), 159.7 (d, ¹ J _C–F = 258.5 Hz, C_ArF), 159.4 (C _ArOCH₃), 144.4 (C_ArNO₂), 130.1 (p-CH_ArCO), 129.4 (2 × m-CH_ArOCH₃), 129.2 (C _ArCH₂), 127.8 (d, ² J _C–F = 22.8 Hz, C _ArCO), 123.5 (o-CH_ArCO), 114.5 (2 × o-CH_ArOCH₃), 110.9 (d, ² J _C–F = 29.4 Hz, C_ArBr), 79.3 (NCH), 74.3 [C(CH₃)₂N], 55.4 (OCH₃), 50.5 [C(CH₃)₂CH], 43.6 (CH₂), 33.4, 31.3, 29.6, 24.7 [2 × C(CH₃)₂].

MS (ESI, TOF): m/z (%) = 576.1 (96) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₅BrFN₃NaO₅S: 576.0580; found: 576.0577.

Intramolecular Cyclization; General Procedure B (GPB)

Under an argon atm, n-BuLi (1.6 M in hexane, 1.2 equiv) was added to a solution of diisopropylamine (1.3 equiv) in anhydrous THF (5 mL per mmol of bisamide) at –65 °C. After stirring for 1 h at –30 °C, a solution of the respective bisamide 2 (1 equiv) in anhydrous THF (5 mL per mmol of bisamide) was added dropwise. The solution was stirred for 3 d under reflux. The mixture was quenched with a sat. aq solution of NH₄Cl (10 mL per mmol of bisamide), and the aq layer was extracted with CH₂Cl₂ (3 × 10 mL per mmol of bisamide). The combined organic layers were dried (MgSO₄), and the solvent was removed (rotary evaporator). The crude mixture was purified by column chromatography on silica gel.

(RS)-10-Allyl-1,1,3,3-tetramethyl-7-nitro-1,11a-dihydro-3H,5H-benzothiazolo[3,4-a][1,4]diazepine-5,11-dione (3a)

Following GPB, (RS)-bisamide 2a (395 mg, 1.00 mmol), diisopropylamine (132 mg, 1.30 mmol) and n-BuLi (1.6 M in hexane, 77 mg, 1.20 mmol) were used. Column chromatography on silica gel (MTBE; R_f = 0.76) provided 3a as a pale yellow solid (240 mg, 64%).

Mp 85–87 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3086, 2966, 2931, 2866, 1698, 1649, 1524, 1436, 1340, 1208, 1163, 1126, 1083, 914, 730 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.72 (d, ⁴ J = 2.7 Hz, 1 H, o-CH_ArCO), 8.31 (dd, ³ J = 9.0 Hz, ⁴ J = 2.7 Hz, 1 H, p-CH_ArCO), 7.45 (d, ³ J = 9.0 Hz, 1 H, m-CH_ArCO), 5.89–5.82 (m, 1 H, CH=CH₂), 5.25–5.22, 5.20–5.16 (2 m, 2 H, CH=CH ₂), 4.62–4.57, 4.53–4.48 (2 m, 2 H, CH₂NH), 4.09 (s, 1 H, NCH), 2.14, 1.82, 1.68, 1.63 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.7 MHz, CDCl₃): δ = 165.5 (CONCH), 162.9 (COC_Ar), 144.8 (C_ArNO₂), 144.6 (C_ArN), 133.2 (COC _Ar), 132.2 (CH=CH₂), 126.7 (p-CH_ArCO), 126.1 (o-CH_ArCO), 122.6 (m-CH_ArCO), 118.4 (CH=CH₂), 74.7 [C(CH₃)₂N], 70.2 (NCH), 50.9 (CH₂NH), 49.3 [C(CH₃)₂CH], 34.7, 32.3, 28.9, 22.9 (4 × CH₃).

MS (CI, isobutane): m/z (%) = 376.2 (22) [M + H]⁺.

HRMS (CI, isobutane): m/z [M + H]⁺ calcd for C₁₈H₂₂N₃O₄S: 376.1326; found: 376.1320.

(RS)-10-Ethyl-1,1,3,3-tetramethyl-7-nitro-1,11a-dihydro-3H,5H-benzooxazolo[3,4-a][1,4]diazepine-5,11-dione (3b)

Following GPB, (RS)-bisamide 2b (100 mg, 0.27 mmol), diisopropylamine (35 mg, 0.35 mmol) and n-BuLi (1.6 M in hexane, 20 mg, 0.32 mmol) were used. Column chromatography on silica gel (n-hexane/MTBE, 7:3; R_f = 0.40) provided 3b as a yellow solid (83 mg, 89%).

Mp 197–199 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3114, 2987, 2942, 1694, 1643, 1612, 1528, 1444, 1342, 1257, 1189, 1124, 1091, 1003, 905, 845, 809, 708 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.72 (d, ⁴ J = 2.7 Hz, 1 H, o-CH_ArCO), 8.33 (dd, ³ J = 9.0 Hz, ⁴ J = 2.7 Hz, 1 H, p-CH_ArCO), 7.44 (d, ³ J = 9.0 Hz, 1 H, m-CH_ArCO), 4.18, 3.79 (2 dq, ² J = 14.3 Hz, ³ J = 7.0 Hz, 2 H, CH₂), 3.77 (s, 1 H, NCH), 1.84, 1.77, 1.59, 1.37 [4 s, 12 H, 2 × C(CH₃)₂], 1.19–1.16 (m, 3 H, CH₂CH ₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 165.7 (CONCH), 161.6 (COC_Ar), 144.8 (C_ArNO₂), 144.7 (C_ArN), 133.0 (COC _Ar), 126.8 (p-CH_ArCO), 126.0 (o-CH_ArCO), 123.5 (m-CH_ArCO), 96.8 [C(CH₃)₂N], 80.5 [C(CH₃)₂CH], 63.0 (NCH), 44.4 (CH₂), 30.9, 27.6, 26.3, 23.2 [2 × C(CH₃)₂], 13.5 (CH₂ CH₃).

MS (CI, isobutane): m/z (%) = 348.4 (100) [M + H]⁺.

HRMS (CI, isobutane): m/z [M + H]⁺ calcd for C₁₇H₂₂N₃O₅: 348.1559; found: 348.1562.

(RS)-10-(4-Chlorophenyl)-1,1-dimethyl-7-nitro-1,11a-dihydro-5H-spiro(benzothiazolo[3,4-a][1,4]diazepine-3,1′-cyclohexane)-5,11-dione (3d)

Following GPB, (RS)-bisamide 2c (200 mg, 0.40 mmol), diisopropylamine (53 mg, 0.52 mmol) and n-BuLi (1.6 M in hexane, 31 mg, 0.48 mmol) were used. Column chromatography on silica gel (n-hexane/EtOAc, 4:1; R_f = 0.46) provided 3c as a yellow solid (80 mg, 40%).

Mp 280–282 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3084, 2928, 2851, 1708, 1650, 1522, 1491, 1341, 1260, 1222, 1122, 1091, 825, 801, 727 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.75 (d, ⁴ J = 2.7 Hz, 1 H, o-CH_ArCO), 8.16 (dd, ³ J = 9.0 Hz, ⁴ J = 2.7 Hz, 1 H, p-CH_ArCO), 7.44–7.42 (m, 2 H, 2 × m-CH_ArCl), 7.14–7.12 (m, 2 H, 2 × o-CH_ArCl), 6.95 (d, ³ J = 9.0 Hz, 1 H, m-CH_ArCO), 4.27 (s, 1 H, NCH), 3.30–3.24, 2.82–2.76, 2.02–2.00, 1.89–1.86, 1.77–1.73, 1.66–1.58, 1.34–1.21 (7 m, 10 H, 5 × CH_2,Cy), 1.72, 1.63 (2 s, 6 H, 2 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 165.6 (CONCH), 163.0 (COC_Ar), 144.8 (C_ArNO₂), 144.3 (p-C_ArNO₂), 138.4 (p-C_ArCl), 134.6 (C_ArCl), 133.5 (COC _Ar), 130.2 (2 × m-CH_ArCl), 129.8 (2 × o-CH_ArCl), 126.4 (p-CH_ArCO), 126.2 (o-CH_ArCO), 125.3 (m-CH_ArCO), 82.4 [C(CH_2,Cy)₅], 70.2 (NCH), 48.5 [C(CH₃)₂], 38.1, 36.5, 25.7, 25.1, 24.4 (5 × CH_2,Cy), 34.7, 23.1 (2 × CH₃).

MS (EI, 70 eV): m/z (%) = 485.2 (100) [M]⁺.

HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₄H₂₄ClN₃O₄S: 485.1171; found: 485.1173.

(RS)-10-(4-Methoxybenzyl)-1,1-dimethyl-7-nitro-1,11a-dihydro-5H-spiro(benzooxazolo[3,4-a][1,4]diazepine-3,1′-cyclohexane)-5,11-dione (3e)

Following GPB, (RS)-bisamide 2e (200 mg, 0.40 mmol), diisopropylamine (53 mg, 0.52 mmol) and n-BuLi (1.6 M in hexane, 31 mg, 0.48 mmol) were used. Column chromatography on silica gel (CH₂Cl₂; R_f = 0.33) provided 3e as a yellow solid (88 mg, 45%).

Mp 78–80 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3089, 2935, 2862, 1696, 1649, 1611, 1513, 1442, 1341, 1246, 1183, 1142, 1090, 1034, 910, 802, 729 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.65 (d, ⁴ J = 2.8 Hz, 1 H, o-CH_ArCO), 8.24 (dd, ³ J = 9.0 Hz, ⁴ J = 2.8 Hz, 1 H, p-CH_ArCO), 7.42 (d, ³ J = 9.0 Hz, 1 H, m-CH_ArCO), 7.01–6.99 (m, 2 H, 2 × m-CH _ArOCH₃), 6.78–6.75 (m, 2 H, 2 × o-CH _ArOCH₃), 5.31, 4.85 (2 d, ² J = 15.3 Hz, 2 H, CH₂N), 3.84 (s, 1 H, NCH), 3.73 (s, 3 H, OCH₃), 2.79–2.73, 2.24–2.16, 1.78–1.62, 1.53–1.51, 1.33–1.24 (5 m, 10 H, 5 × CH_2,Cy), 1.80, 1.37 [2 s, 6 H, C(CH₃)₂].

¹³C NMR (125.8 MHz, CDCl₃): δ = 166.5 (CONCH), 161.6 (COC_Ar), 159.3 (C _ArOCH₃), 144.8 (C_ArNO₂), 144.4 (p-C_ArNO₂), 133.5 (COC _Ar), 128.7 (2 × m-CH_ArOCH₃), 127.9 (C _ArCH₂), 126.5 (p-CH_ArCO), 126.0 (o-CH_ArCO), 123.6 (m-CH_ArCO), 114.4 (2 × o-CH_ArOCH₃), 98.8 [C(CH_2,Cy)₅], 80.2 [C(CH₃)₂], 63.0 (NCH), 55.3 (OCH₃), 50.9 (CH₂N), 34.9, 34.3, 24.6, 23.5, 23.0 (5 × CH_2,Cy), 31.1, 23.6 [2 × C(CH₃)₂].

MS (ESI, TOF): m/z (%) = 502.2 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₆H₂₉N₃NaO₆: 502.1954; found: 502.1953.

(RS)-1,1-Dimethyl-7-nitro-10-phenethyl-1,11a-dihydro-5H-spiro(benzooxazolo[3,4-a][1,4]diazepine-3,1′-cyclohexane)-5,11-dione (3f)

Following GPB, (RS)-bisamide 2f (100 mg, 0.21 mmol), diisopropylamine (27 mg, 0.27 mmol) and n-BuLi (1.6 M in hexane, 16 mg, 0.25 mmol) were used. Column chromatography on silica gel (CH₂Cl₂; R_f = 0.29) provided 3f as a yellow solid (65 mg, 67%).

Mp 153–155 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3086, 3029, 2933, 2860, 1696, 1651, 1524, 1440, 1342, 1142, 1091, 1036, 997, 911, 735, 700 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.69 (d, ⁴ J = 2.7 Hz, 1 H, o-CH_ArCO), 8.30 (dd, ³ J = 9.0 Hz, ⁴ J = 2.8 Hz, 1 H, p-CH_ArCO), 7.33 (d, ³ J = 9.0 Hz, 1 H, m-CH_ArCO), 7.24–7.21 (m, 2 H, 2 × o-CH _ArCH₂), 7.18–7.15 (m, 1 H, p-CH _ArCH₂), 7.05–7.04 (m, 2 H, 2 × m-CH _ArCH₂), 4.60 (dt, ² J = 14.1 Hz, ³ J = 7.8 Hz, 1 H, CH₂N), 3.88 (dt, ² J = 14.1 Hz, ³ J = 7.0 Hz, 1 H, CH₂N), 3.72 (s, 1 H, NCH), 2.84–2.81 (m, 2 H, CH₂C_Ar), 2.76–2.70, 2.13–2.07, 1.75–1.60, 1.36–1.35, 1.29–1.25 (5 m, 10 H, 5 × CH_2,Cy), 1.77, 1.34 (2 s, 6 H, 2 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 166.4 (CONCH), 161.4 (COC_Ar), 144.7 (C_ArNO₂), 144.2 (p-C_ArNO₂), 137.3 (C _ArCH₂), 133.5 (COC _Ar), 128.9 (2 × m-CH_ArCH₂), 128.8 (2 × o-CH_ArCH₂), 126.9 (p-CH_ArCH₂), 126.6 (p-CH_ArCO), 126.2 (o-CH_ArCO), 123.3 (m-CH_ArCO), 98.8 [C(CH_2,Cy)₅], 80.1 [C(CH₃)₂], 63.0 (NCH), 49.4 (CH₂N), 34.8, 34.5, 24.6, 23.5, 22.9 (5 × CH_2,Cy), 34.1 (CH₂C_Ar), 31.1, 23.6 [2 × C(CH₃)₂].

MS (ESI, TOF): m/z (%) = 486.2 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₆H₂₉N₃NaO₅: 486.2005; found: 486.1994.

(RS)-10′-(Naphthalen-2-ylmethyl)-7′-nitrodispiro(cyclohexane-1,1′-benzothiazolo[3,4-a][1,4]diazepine-3′,1′′-cyclohexane)-5′,11′-dione (3g)

Following GPB, (RS)-bisamide 2g (576 mg, 1.00 mmol), diisopropylamine (132 mg, 1.30 mmol) and n-BuLi (1.6 M in hexane, 77 mg, 1.20 mmol) were used. Column chromatography on silica gel (n-hexane/MTBE, 1:1; R_f = 0.37) provided 3g as a colorless solid (395 mg, 71%).

Mp 168–170 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3059, 2931, 2856, 1649, 1629, 1519, 1427, 1339, 1271, 1130, 1083, 1020, 817, 735 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.64 (d, ⁴ J = 2.7 Hz, 1 H, o-CH_ArCO), 8.23 (dd, ³ J = 9.0 Hz, ⁴ J = 2.8 Hz, 1 H, p-CH_ArCO), 7.78–7.71 (m, 3 H, 3 × CH_Ar), 7.59–7.57 (m, 1 H, CH_Ar), 7.47–7.42 (m, 3 H, 3 × CH_Ar), 7.19–7.17 (m, 1 H, CH_Ar), 5.48, 5.17 (2 d, ² J = 15.5 Hz, 2 H, CH₂N), 4.30 (s, 1 H, NCH), 3.21–3.15, 2.70–2.67, 2.64–2.59, 2.01–1.99, 1.90–1.78, 1.66–1.44, 1.36–1.19 (7 m, 20 H, 10 × CH_2,Cy).

¹³C NMR (125.8 MHz, CDCl₃): δ = 165.9 (CONCH), 163.0 (COC_Ar), 144.7 (C_ArNO₂), 144.2 (p-C_ArNO₂), 134.1 (COC _Ar), 133.2, 133.2, 132.9 (3 × C_Ar), 129.0, 127.8, 126.6, 126.5, 126.3, 126.0, 124.8, 122.9 (10 × CH_Ar), 80.9 [C(CH_2,Cy)₅N], 68.8 (NCH), 54.6 [C(CH₃)₂CH], 51.4 (CH₂N), 40.4, 38.2, 36.1, 34.7, 27.0, 25.5, 25.3, 24.6, 24.3, 22.5 (10 × CH_2,Cy).

MS (EI, 70 eV): m/z (%) = 552.2 (100) [M]⁺.

HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₃₂H₃₃N₃O₄S: 555.2192; found: 555.2184.

(RS)-10-Allyl-9-bromo-1,1,3,3-tetramethyl-7-nitro-1,11a-dihydro-3H,5H-benzothiazolo[3,4-a][1,4]diazepine-5,11-dione (3h)

Following GPB, (RS)-bisamide 2h (200 mg, 0.42 mmol), diisopropylamine (56 mg, 0.55 mmol) and n-BuLi (1.6 M in hexane, 32 mg, 0.50 mmol) were used. Column chromatography on silica gel (CH₂Cl₂/EtOAc, 9:1; R_f = 0.70) provided 3h as a pale yellow solid (68 mg, 36%).

Mp 204–206 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3098, 3063, 2980, 2932, 1697, 1654, 1525, 1338, 1213, 1122, 1084, 918, 742, 720 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.65–8.61 (m, 2 H, o-CH_ArCO, p-CH_ArCO), 5.59–5.51 (m, 1 H, CH=CH₂), 5.17–5.14, 5.12–5.10 (2 m, 2 H, CH=CH ₂), 5.06–5.02, 4.07–4.02 (2 m, 2 H, CH₂N), 3.96 (s, 1 H, NCH), 2.09, 1.83, 1.67, 1.58 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 165.9 (CONCH), 162.0 (COC_Ar), 146.1 (C_ArNO₂), 143.0 (p-C_ArNO₂), 137.8 (COC _Ar), 131.5 (CH_Ar), 130.3 (CH=CH₂), 124.1 (CH_Ar), 121.3 (CH=CH₂), 120.6 (C_ArBr), 74.8 [C(CH₃)₂N], 70.6 (NCH), 50.8 (CH₂N), 48.9 [C(CH₃)₂CH], 34.7, 32.2, 28.5, 22.7 (4 × CH₃).

MS (ESI, TOF): m/z (%) = 476.0 (97) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₁₈H₂₀BrN₃NaO₄S: 476.0256; found: 476.0249.

(RS)-10-Allyl-9-bromo-1,1,3,3-tetramethyl-7-nitro-1,11a-dihydro-3H,5H-benzooxazolo[3,4-a][1,4]diazepine-5,11-dione (3i)

Following GPB, (RS)-bisamide 2i (200 mg, 0.44 mmol), diisopropylamine (58 mg, 0.57 mmol) and n-BuLi (1.6 M in hexane, 34 mg, 0.53 mmol) were used. Column chromatography on silica gel (CH₂Cl₂/EtOAc, 9:1; R_f = 0.63) provided 3i as a yellow solid (61 mg, 32%).

Mp 168–170 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3077, 2968, 2933, 1697, 1658, 1525, 1438, 1371, 1341, 1189, 1081, 915, 809, 742, 707 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 8.68–8.63 (m, 2 H, o-CH_ArCO, p-CH_ArCO), 5.58–5.50 (m, 1 H, CH=CH₂), 5.12–5.11, 5.10–5.09 (2 m, 2 H, CH=CH ₂), 5.04–5.00, 4.00–3.96 (m, 2 H, CH₂N), 3.71 (s, 1 H, NCH), 1.82, 1.78, 1.61, 1.36 (4 s, 12 H, 4 × CH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 166.2 (CONCH), 160.9 (COC_Ar), 146.2 (C_ArNO₂), 143.2 (p-C_ArNO₂), 137.2 (COC _Ar), 131.5 (CH_Ar), 130.3 (CH=CH₂), 124.1 (CH_Ar), 121.0 (CH=CH₂), 121.0 (C_ArBr), 97.1 [C(CH₃)₂N], 80.3 [C(CH₃)₂CH], 63.4 (NCH), 50.9 (CH₂N), 30.9, 27.6, 26.0, 23.0 (4 × CH₃).

MS (ESI, TOF): m/z (%) = 460.0 (100) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₁₈H₂₀BrN₃NaO₅: 460.0484; found: 460.0478.

(RS)-9-Bromo-10-(4-methoxybenzyl)-1,1,3,3-tetramethyl-7-nitro-1,11a-dihydro-3H,5H-benzothiazolo[3,4-a][1,4]diazepine-5,11-dione (3j)

Following GPB, (RS)-bisamide 2j (200 mg, 0.36 mmol), diisopropylamine (48 mg, 0.47 mmol) and n-BuLi (1.6 M in hexane, 28 mg, 0.43 mmol) were used. Column chromatography on silica gel (CH₂Cl₂; R_f = 0.13) provided 3j as a yellow solid (80 mg, 42%).

Mp 189–190 °C (CH₂Cl₂/n-hexane).

IR (ATR): 3083, 2963, 2934, 1703, 1654, 1512, 1438, 1342, 1247, 1088, 1031, 808, 741, 723 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 8.65–8.61 (m, 2 H, o-CH_ArCO, p-CH_ArCO), 6.97–6.95 (m, 2 H, 2 × m-CH _ArOCH₃), 6.72–6.70 (m, 2 H, 2 × o-CH _ArOCH₃), 5.44, 4.52 (2 d, ² J = 14.5 Hz, 2 H, CH₂), 3.92 (s, 1 H, NCH), 3.71 (s, 3 H, OCH₃), 1.97, 1.66, 1.53, 1.20 [4 s, 12 H, 2 × C(CH₃)₂].

¹³C NMR (125.7 MHz, CDCl₃): δ = 165.5 (CONCH), 161.6 (COC_Ar), 159.8 (C _ArOCH₃), 146.0 (C_ArNO₂), 143.6 (p-C_ArNO₂), 137.8 (COC _Ar), 131.5 (CH_Ar), 130.7 (2 × m-CH_ArOCH₃), 126.9 (C _ArCH₂), 124.1 (CH_Ar), 120.6 (C_ArBr), 114.2 (2 × o-CH_ArOCH₃), 74.8 [C(CH₃)₂N], 70.5 (NCH), 55.4 (OCH₃), 52.1 (CH₂), 48.8 [C(CH₃)₂CH], 34.7, 32.1, 27.6, 22.6 [2 × C(CH₃)₂].

MS (ESI, TOF): m/z (%) = 556.1 (95) [M + Na]⁺.

HRMS (ESI, TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₄BrN₃NaO₅S: 556.0518; found: 556.0516.

Acknowledgment

We are thankful to the Central analytic section of the University of Oldenburg for retrieving NMR and MS data.

• References

• 1a Koblish HK, Zhao S. Mol. Cancer Ther. 2006; 5: 160
  CrossrefSearch in Google Scholar
• 1b Kuno F, Otoguro K, Shiomi K, Iwai Y, Omura S. J. Antibiot. 1996; 49: 742
  CrossrefSearch in Google Scholar
• 1c Mohamed LW, El-Yamany MF. Arch. Pharm. Res. 2012; 35: 1369
  CrossrefSearch in Google Scholar
• 2 Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. Bioorg. Med. Chem. Lett. 2005; 15: 765
  CrossrefSearch in Google Scholar
• 3 Kalinski C, Umkehrer M, Ross G, Kolb J, Burdack C, Hiller W. Tetrahedron Lett. 2006; 47: 3423
  CrossrefSearch in Google Scholar
• 4 Smits G, Zemribo R. Synlett 2015; 26: 2272
  Thieme ConnectSearch in Google Scholar
• 5a Tempest P, Ma V, Thomas S, Hua Z, Kelly MG, Hulme C. Tetrahedron Lett. 2001; 42: 4959
  CrossrefSearch in Google Scholar
• 5b Tempest P, Ma V, Kelly MG, Jones W, Hulme C. Tetrahedron Lett. 2001; 42: 4963
  CrossrefSearch in Google Scholar
• 5c Kalinski C, Umkehrer M, Gonnard S, Jäger N, Ross G, Hiller W. Tetrahedron Lett. 2006; 47: 2041
  CrossrefSearch in Google Scholar
• 5d Xu Z, De Moliner F, Cappelli AP, Hulme C. Org. Lett. 2013; 15: 2738
  CrossrefSearch in Google Scholar
• 6a Ugi I. J. Prakt. Chem. 1997; 339: 499
  CrossrefSearch in Google Scholar
• 6b Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
  CrossrefPubMedSearch in Google Scholar
• 7a Colombo M, Peretto I. Drug Discovery Today 2008; 13: 677
  CrossrefSearch in Google Scholar
• 7b Slobbe P, Ruijter E, Orru RV. A. Med. Chem. Commun. 2012; 3: 1189
  CrossrefSearch in Google Scholar
• 7c Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  CrossrefPubMedSearch in Google Scholar
• 7d van der Heijden G, Ruijter E, Orru RV. A. Synlett 2013; 24: 666
  Thieme ConnectSearch in Google Scholar
• 7e Dömling A, Zarganes-Tzitzikas T. Org. Chem. Front. 2014; 1: 834
  CrossrefSearch in Google Scholar
• 7f Hulme C, Ayaz M, Martinez-Ariza G, Medda F, Shaw A In Small Molecule Medicinal Chemistry: Strategies and Technologies . Czechtizky W, Hamley P. Wiley; Weinheim: 2015. Chap. 6
  Search in Google Scholar
• 7g Gollner A. Synlett 2015; 26: 426
  Thieme ConnectSearch in Google Scholar
• 8a Dömling A. Chem. Rev. 2006; 106: 17
  CrossrefPubMedSearch in Google Scholar
• 8b Huang Y, Dömling A In Isocyanide Chemistry: Applications in Synthesis and Material Science . Nenajdenko VG. Wiley-VCH; Weinheim: 2012. Chap. 12
  Search in Google Scholar
• 9 Asinger F. Angew. Chem. 1956; 68: 376
  CrossrefSearch in Google Scholar
• 10 Weigert WM, Offermanns H, Degussa PS. Angew. Chem., Int. Ed. Engl. 1975; 14: 330
  CrossrefSearch in Google Scholar
• 11 Martens J, Offermanns H, Scherberich P. Angew. Chem., Int. Ed. Engl. 1981; 20: 668
  Search in Google Scholar
• 12 Weber M, Jakob J, Martens J. Liebigs Ann. Chem. 1992; 1
• 13 Liu Z.-Q. Curr. Org. Synth. 2015; 12: 20
  CrossrefSearch in Google Scholar
• 14a Ugi I, Meyer R, Fetzer U, Steinbrückner C. Angew. Chem. 1959; 71: 386
  Search in Google Scholar
• 14b Ugi I. Angew. Chem., Int. Ed. Engl. 1962; 1: 8
  CrossrefSearch in Google Scholar
• 14c Ugi I, Wischhöfer E. Chem. Ber. 1962; 95: 136
  CrossrefSearch in Google Scholar

For selected examples, see:
• 15a Kintscher J, Martens J. Synthesis 1992; 837
  Thieme Connect
• 15b Hatam M, Tehranfar D, Martens J. Synth. Commun. 1995; 25: 1677
  CrossrefSearch in Google Scholar
• 15c Brockmeyer F, Kröger D, Stalling T, Schwäblein A, Martens J. Helv. Chim. Acta 2012; 95: 1857
  CrossrefSearch in Google Scholar
• 16 Stalling T, Pauly J, Kröger D, Martens J. Tetrahedron 2015; 71: 8290
  CrossrefSearch in Google Scholar
• 17 Kröger D, Schlüter T, Fischer M, Geibel I, Martens J. ACS Comb. Sci. 2015; 17: 202
  CrossrefSearch in Google Scholar
• 18a Van Berkel SS, Bögels BG. M, Wijdeven MA, Westermann B, Rutjes FP. J. T. Eur. J. Org. Chem. 2012; 3543
• 18b Banfi L, Riva R, Basso A. Synlett 2010; 23
  Thieme Connect
• 18c Brockmeyer F, van Gerven D, Saak W, Martens J. Synthesis 2014; 46: 1603
  Thieme ConnectSearch in Google Scholar
• 19 Fulmer GR, Miller AJ. M, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, Bercaw JE, Goldberg KI. Organometallics 2010; 29: 2176
  CrossrefSearch in Google Scholar
• 20 Guirado A, Zapata A, Gómez JL, Trabalón L, Gálvez J. Tetrahedron 1999; 55: 9631
  CrossrefSearch in Google Scholar
• 21 Herman LW, Sharma W, Kronauge JF, Barbarics E, Herman LA, Piwnica-Worms D. J. Med. Chem. 1995; 38: 2955
  CrossrefSearch in Google Scholar

• References

• 1a Koblish HK, Zhao S. Mol. Cancer Ther. 2006; 5: 160
  CrossrefSearch in Google Scholar
• 1b Kuno F, Otoguro K, Shiomi K, Iwai Y, Omura S. J. Antibiot. 1996; 49: 742
  CrossrefSearch in Google Scholar
• 1c Mohamed LW, El-Yamany MF. Arch. Pharm. Res. 2012; 35: 1369
  CrossrefSearch in Google Scholar
• 2 Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. Bioorg. Med. Chem. Lett. 2005; 15: 765
  CrossrefSearch in Google Scholar
• 3 Kalinski C, Umkehrer M, Ross G, Kolb J, Burdack C, Hiller W. Tetrahedron Lett. 2006; 47: 3423
  CrossrefSearch in Google Scholar
• 4 Smits G, Zemribo R. Synlett 2015; 26: 2272
  Thieme ConnectSearch in Google Scholar
• 5a Tempest P, Ma V, Thomas S, Hua Z, Kelly MG, Hulme C. Tetrahedron Lett. 2001; 42: 4959
  CrossrefSearch in Google Scholar
• 5b Tempest P, Ma V, Kelly MG, Jones W, Hulme C. Tetrahedron Lett. 2001; 42: 4963
  CrossrefSearch in Google Scholar
• 5c Kalinski C, Umkehrer M, Gonnard S, Jäger N, Ross G, Hiller W. Tetrahedron Lett. 2006; 47: 2041
  CrossrefSearch in Google Scholar
• 5d Xu Z, De Moliner F, Cappelli AP, Hulme C. Org. Lett. 2013; 15: 2738
  CrossrefSearch in Google Scholar
• 6a Ugi I. J. Prakt. Chem. 1997; 339: 499
  CrossrefSearch in Google Scholar
• 6b Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
  CrossrefPubMedSearch in Google Scholar
• 7a Colombo M, Peretto I. Drug Discovery Today 2008; 13: 677
  CrossrefSearch in Google Scholar
• 7b Slobbe P, Ruijter E, Orru RV. A. Med. Chem. Commun. 2012; 3: 1189
  CrossrefSearch in Google Scholar
• 7c Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  CrossrefPubMedSearch in Google Scholar
• 7d van der Heijden G, Ruijter E, Orru RV. A. Synlett 2013; 24: 666
  Thieme ConnectSearch in Google Scholar
• 7e Dömling A, Zarganes-Tzitzikas T. Org. Chem. Front. 2014; 1: 834
  CrossrefSearch in Google Scholar
• 7f Hulme C, Ayaz M, Martinez-Ariza G, Medda F, Shaw A In Small Molecule Medicinal Chemistry: Strategies and Technologies . Czechtizky W, Hamley P. Wiley; Weinheim: 2015. Chap. 6
  Search in Google Scholar
• 7g Gollner A. Synlett 2015; 26: 426
  Thieme ConnectSearch in Google Scholar
• 8a Dömling A. Chem. Rev. 2006; 106: 17
  CrossrefPubMedSearch in Google Scholar
• 8b Huang Y, Dömling A In Isocyanide Chemistry: Applications in Synthesis and Material Science . Nenajdenko VG. Wiley-VCH; Weinheim: 2012. Chap. 12
  Search in Google Scholar
• 9 Asinger F. Angew. Chem. 1956; 68: 376
  CrossrefSearch in Google Scholar
• 10 Weigert WM, Offermanns H, Degussa PS. Angew. Chem., Int. Ed. Engl. 1975; 14: 330
  CrossrefSearch in Google Scholar
• 11 Martens J, Offermanns H, Scherberich P. Angew. Chem., Int. Ed. Engl. 1981; 20: 668
  Search in Google Scholar
• 12 Weber M, Jakob J, Martens J. Liebigs Ann. Chem. 1992; 1
• 13 Liu Z.-Q. Curr. Org. Synth. 2015; 12: 20
  CrossrefSearch in Google Scholar
• 14a Ugi I, Meyer R, Fetzer U, Steinbrückner C. Angew. Chem. 1959; 71: 386
  Search in Google Scholar
• 14b Ugi I. Angew. Chem., Int. Ed. Engl. 1962; 1: 8
  CrossrefSearch in Google Scholar
• 14c Ugi I, Wischhöfer E. Chem. Ber. 1962; 95: 136
  CrossrefSearch in Google Scholar

For selected examples, see:
• 15a Kintscher J, Martens J. Synthesis 1992; 837
  Thieme Connect
• 15b Hatam M, Tehranfar D, Martens J. Synth. Commun. 1995; 25: 1677
  CrossrefSearch in Google Scholar
• 15c Brockmeyer F, Kröger D, Stalling T, Schwäblein A, Martens J. Helv. Chim. Acta 2012; 95: 1857
  CrossrefSearch in Google Scholar
• 16 Stalling T, Pauly J, Kröger D, Martens J. Tetrahedron 2015; 71: 8290
  CrossrefSearch in Google Scholar
• 17 Kröger D, Schlüter T, Fischer M, Geibel I, Martens J. ACS Comb. Sci. 2015; 17: 202
  CrossrefSearch in Google Scholar
• 18a Van Berkel SS, Bögels BG. M, Wijdeven MA, Westermann B, Rutjes FP. J. T. Eur. J. Org. Chem. 2012; 3543
• 18b Banfi L, Riva R, Basso A. Synlett 2010; 23
  Thieme Connect
• 18c Brockmeyer F, van Gerven D, Saak W, Martens J. Synthesis 2014; 46: 1603
  Thieme ConnectSearch in Google Scholar
• 19 Fulmer GR, Miller AJ. M, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, Bercaw JE, Goldberg KI. Organometallics 2010; 29: 2176
  CrossrefSearch in Google Scholar
• 20 Guirado A, Zapata A, Gómez JL, Trabalón L, Gálvez J. Tetrahedron 1999; 55: 9631
  CrossrefSearch in Google Scholar
• 21 Herman LW, Sharma W, Kronauge JF, Barbarics E, Herman LA, Piwnica-Worms D. J. Med. Chem. 1995; 38: 2955
  CrossrefSearch in Google Scholar

• Supplementary Material