Intramolecular Cyclization of Alkynylheteroaromatic Substrates Bearing a Tethered Cyano Group: A Strategy for Accessing Fused Pyridoheterocycles

Abstract

Heterocyclic substrates containing a conjugated alkyne and a pendant nitrile were shown to cyclize in an overall tetradehydro-Diels–Alder reaction to give products in which the initial heterocycle bears a newly fused pyridine ring. Base-promoted tautomerization of the alkyne to its isomeric allene allows this process to occur at ambient temperature. DFT studies support many of the mechanistic interpretations of the overall results.

Graphical Abstract

INTRODUCTION

Heteroaromatic moieties are valuable building blocks in the pharmaceutical industry. When incorporated into ligands, they reduce conformational freedom and provide anchor points for binding to biomacromolecules. Representative drug candidates or approved pharmaceuticals that contain a fused pyridoheterocyclic substructure are shown in Figure 1a. The immunomodulatory agent sotirimod (1)¹ contains a 1,5-napthyridine (pyridopyridine) heteroaromatic core. Anagliptin (2, Suiny^®),² a DPP-4 inhibitor approved in Japan to treat type 2 diabetes, features a pyridopyrazole moiety. The pyridoimidazole derivative sulmazole (3, Vardax^®)³ exhibits favorable vasodilator effects. Sitravatinib (4),⁴ a receptor tyrosine kinase inhibitor currently undergoing late stage clinical trials, contains a central pyridothiophene core. New methods for constructing compounds with pyridine rings fused to another heterocycle are of interest.

Figure 1.

(a) Biologically significant compounds containing pyrido-fused heteroaromatics. (b) Current work examining the cyclization of allenyl heteroaromatics with pendant nitriles.

Previously we have reported the net-[4 + 2]-cycloaddition of an in situ-generated allenyl arene with a pendant alkyne or nitrile, which generates a naphthalene or quinoline derivative.⁵ We wanted to expand the types of substrates amenable for this cyclization reaction with the goal of producing useful classes of heterocyclic compounds by a novel and complementary method. More specifically, if the C_sp2=C_sp2 bond endocyclic to the aromatic ring bearing the alkyne in a substrate is within a heteroaromatic ring (HAR), such as the 2-pyridine 5a, a wider variety of heterocyclic products can be envisioned. We anticipate that, as with the previous study, we would be able to isomerize the alkyne in substrates such as 5a to their tautomeric allenes (cf. 6a) upon treatment with base (Figure 1b). These allenyl HARs, in turn, should undergo the net-[4 + 2]-cycloaddition to engage the pendant nitrile and produce pyridine derivatives that have incorporated the HAR (cf. 7a), now fused to the newly created pyridine ring.

RESULTS AND DISCUSSION

The alkynyl HAR substrates 5 feature a common three-atom linker with a central methanesulfonamide and gem-dimethyl moiety adjacent to the pendant nitrile. This design leverages the Thorpe–Ingold (or gem-disubstituent) effect, likely increasing the rate of cyclization. ⁶ The various HAR substrates were synthesized from the common alkyne precursor 8 by a Sonogashira reaction with a variety of iodo- or bromo-HARs 9a-j (Figure 2a).⁷ The alkynes 5a-j are thermally stable at, and well past, room temperature. For example, when 5f was heated even to ca. 250 °C overnight in the absence of added base, no thermal tetradehydro-Diels–Alder reaction was observed (and a substantial amount of 5f was recovered).⁸ When these alkynyl-HARs were exposed to the non-nucleophilic base 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) at ambient temperature, products 7a-j were formed in very good to excellent yields (Figure 2b). This suggested that intermediate allenes 6a-j were being generated, thereby enabling engagement with the pendant nitrile and cycloisomerization to the dearomatized species 10a-j. Final tautomerization would then lead to 7a-j.

Figure 2.

(a) Synthesis and cyclization of alkynyl heteroaromatic substrates 5a-j to produce pyrido-fused heterocycles 7a-j. [5a-j: a, 2-pyridinyl; b, 3-pyridinyl; c, 2-fluoro-4-pyridinyl; d, 4-methoxy-2-pyridinyl; e, 2-pyrazinyl; f, 2-thiophenyl; g, 1-methyl-2-imidazolyl; h, 6-pyrazolo[1,5-a]pyrimidinyl; i, 5-isoquinolinyl; j, N-Boc-5-indolyl] (b) Structure and isolated yield of 7a-j. ^a24 h. ^b2.5 h. ^c2 h. ^d2.5 h. ^e1 h; 75% on a 1 mmol scale, 12 min. ^f1 h. ^g22 d. ^h24 h. ⁱ12 h. ^j24 h. (c) Deuterium incorporation observed in the cyclization of 5f. (d) Additional HAR compounds reported in ref. 5.

Substrates 5a-d all contain a terminal pyridine ring. Cyclizations of 5a and 5d to give the pyridopyridines 7a and 7d proceeded very efficiently (85% and 88% yield, respectively). The 3-alkynylpyridine substrate 5b contains two different aromatic carbon atoms, C2 and C4 in the 3-pyridinyl moiety, that could participate in the cyclization. Both possible regioisomers, the 1,6-naphthyridine 7b-maj and the 1,8-naphthyridine 7b-min were formed (ca. 7:3 ratio) in a combined near-quantitative yield. We also observed a small preference in the cyclization of the 2-fluoro-4-pyridinyl substrate 5c. Isomer 7c-maj, which arises from cyclization upon C3 ortho to F, was slightly favored (ca. 7:4 ratio) over cyclization to C5 leading to 7c-min.

Additional HAR moieties were examined to demonstrate some of the generality of this approach for synthesizing interesting heterocyclic skeletons. For example, treatment of the 2-alkynylpyrazine 5e with TBD resulted in the formation of the pyrido[2,3-b]pyrazine derivative 7e in 75% yield within an hour at room temperature (75% on a 1 mmol scale). The 2-alkynylthiophene precursor 5f likewise cyclized rapidly to give the pyridothiophene 7f in excellent yield. An analogous cyclization of this substrate was performed in deuterated chloroform, resulting in the partial deuteration of 7f shown in Figure 2c. A control experiment in which all-protio 7f was incubated in CDCl₃ containing TBD showed no proton/deuterium exchange of the cyclized product after 24 h. The presence of deuterium at C8 in 7f results from the initial base-mediated tautomerization of the alkyne to the allene via the ion pair 5f⁻•TBD⁺. During the rearomatization process of the intermediate 10f the methylene carbon is reestablished whereby either a protium or deuterium is incorporated from another molecule of TBDH/D⁺. The imidazole derivative 5g, was the slowest substrate to react, furnishing the pyridoimidazole product 7g over the course of three weeks at room temperature. Presumably the electron-rich imidazolyl group slows the rate of the initial deprotonation by TBD (cf. 5f to 5f⁻).

Several substrates containing terminal bicyclic HARs were also studied. The pyrazolo[1,5-a]pyrimidine 5h cyclized to give a single regioisomer 7h in excellent yield. DP4⁺, a probability analysis that compares calculated NMR chemical shifts of all possible isomers with the experimentally obtained ¹H and ¹³C shifts, was performed to assign its structure as the indicated angular cyclization regioisomer over the alternative linear product [see Supporting Information (SI) for details].⁹ The 5-alkynylisoquinoline substrate 5i underwent the net-[4 + 2]-cycloaddition to give 7i in 72% yield. A second possible regioisomer made by cyclization onto the ring fusion carbon adjacent to the alkyne was not observed; this would have led to a dearomatized product. Finally, the indole derivative 5j cyclized to give two regioisomers, 7j-maj and 7j-min, in near-quantitative yield in an ca. 10:1 ratio. The regioselectivity observed in this case presumably reflects a higher degree of aromaticity within the pyrrole substructure that can be maintained in the rate-limiting step for formation of 7j-maj.

We looked at several substrates that were blocked from undergoing the final rearomatization process because of the absence of the sp³CH proton in 10 (Figure 2a). Might these give rise to products similar to 10, thereby reflecting mechanistic overlap with the initial stages of the reaction manifold? The alkynyl HARs examined, 5n–5p, are shown in Figure 3. To generate an intermediate analogous to 10 would require the nitrogen atom of the cyano group to engage either a methylated carbon atom (cf. C3 in 5n) or a heteroatom. Upon treatment with base, each of these compounds were consumed over time but none gave rise to tractable product mixtures (see SI). The reluctance to form a N─N bond is consistent with the absence of such products in the reactions leading to 7a,d,e (Figure 2b).

Figure 3.

Substrates that failed to cyclize.

For several of the substrates (5a-j), we attempted to detect an intermediate allene by in situ NMR monitoring but were never successful. We had also examined 11a in our earlier study, but the intermediate allene was not observed in that instance as well.⁵ These results implied that the rate-limiting step for these reactions is generation of the allenes and not the subsequent, more rapid cyclization events.

We now report that the p-cyanophenyl terminated analog 11b, lacking the gem-dimethyl groups present in 11a, has allowed us for the first time to detect the intermediate allene species. The reaction of the benzonitrile derivative 11b, when treated with ca. 0.5 equiv of TBD in benzene-d₆, was monitored by ¹H NMR spectroscopy (Figure 4). Interpretation of a similar experiment in CDCl3 was complicated by concomitant deuterium incorporation, a complication that was avoided using benzene-d₆ as the solvent. Minutes after adding TBD a new set of resonances had begun to emerge. Key to assigning the structure to this intermediate as the allene 12b were the diastereotopic methylene protons (H_a and H_b) alpha to the pendant nitrile group. These showed a geminal coupling constant of J = 18.1 Hz. Additionally, the resonance for one allene proton (H_d) was clearly visible at 6.26 ppm (J = 6.0 Hz). The second allene proton (H_c) could be discerned at 6.74 ppm, overlapping with a new (non-first order) doublet of the 1,4-disubstituted benzonitrile moiety in the allene. Observation of 12b marked the first time we could detect the transient allene intermediate prior to its cyclization. The half-life for the base-mediated alkyne to allene tautomerization was seen to be ca. 20 min under these reaction conditions. Gradually the cyclization of the allene 12b to the quinoline derivative 13b interceded. For example, even at just 10 minutes after adding base to the reaction mixture, resonances corresponding to the product 13b (<1%) were first detected. A meaningful half-life for the cyclization of 12b to 13b could not be judged, because the product 13b crystalized from solution as the reaction progressed, complicating the analysis.

Figure 4.

Cyclization of 11b at ambient temperature via the observable allene 12b to give the quinoline 13b as monitored by ¹H NMR spectroscopy. The vertical scales of each different vertical panel has been adjusted to more easily identify the onset of appearance of resonances for 12b and 13b.

The ability to observe the allene intermediate using 11b and not 11a presumably reflects the slower rate of the cycloisomerization of the former because of i) the absence of the gem-dimethyl (Thorpe–Ingold) effect operative in the reaction of 11a and ii) the need to overcome greater resonance energy present in the arene moiety compared to that in the heterocyclic analogs where, again, we were unable to detect the allene.¹⁰

In addition to the benzonitrile 11b, we synthesized two other substrates lacking the geminal dimethyl groups in the linker and examined their cyclization (Figure 5). Upon treatment with base, we observed a significant decrease in reactivity at room temperature for both the phenyl analog 11c and the electron rich aniline compound 11d compared to the electron withdrawing benzonitrile substrate 11b. These observations were consistent with the reactivity we previously reported for the gem-dimethylated analogs of 11b-11d and are reflective of a slower tautomerization to the requisite allene intermediates 12.⁵

Figure 5.

Cyclization of substrates lacking a gem-dimethyl moiety.

To better understand the energetic differences required to achieve cyclization of 11a vs 11b, we undertook density functional theory (DFT) calculations. We were unable to find a concerted transition state structure (TSS) connecting either of the allenes 12 with its corresponding dearomatized intermediate 15.¹¹ Stepwise, diradical cyclizations are shown in Figure 6a [energies in kcal mol⁻¹ of 11a (R = Me) on top, in red, and 11b (R = H) on the bottom, in blue]. We found that each of the reactive allene conformers 12a or 12b was slightly lower in energy than its precursor alkyne 11a or 11b (−0.7 or −2.3 kcal mol⁻¹, respectively). Given our inability to observe 12a, we can surmise that the base-mediated alkyne to allene isomerization is the rate-determining step for substrates containing the gem-dimethyl linker.¹² The first bond formation step proceeds with a 20.5 vs 27.1 kcal mol⁻¹ barrier to give 14a or 14b, respectively. Both of the TSSs TS1 exhibit expectation values of the total spin(⟨S²⟩) of zero, i.e., containing no diradical character. This observation is indicative of a post-transition state conical intersection, where, in this case, the energy along a zwitterionic pathway is lower in energy than the diradical pathway up to and past the TSS, yet a crossover occurs after the TSS along the reaction coordinate, with the diradical product being lower in energy than the analogous zwitterion.¹³ Examining the intrinsic reaction coordinate (IRC) shows a crossover of the zwitterionic to a diradical species after the TSSs (see SI for additional details). A second, exergonic bond forming step follows with a 5.3 kcal mol⁻¹ barrier for the gem-dimethyl containing diradical 14a to give the dearomatized intermediate 15a. In contrast, the non-methylated diradical 14b, is seen to be formed from the allene 12b in a pre-equilibrium event; C─N bond formation is the rate-determining step leading to 15b. The significantly higher overall barrier for 12b to cyclize to 15b is consistent with the observation of allene 12b seen in Figure 4.

Figure 6.

DFT calculations done at the [SMD(chloroform)/(U)MN15/6-311+G(d,p)//(U)MN15/6-31G(d)] level of theory. (a) Comparison of the stepwise, diradical cyclization of 11a vs 11b. (b) Examining the origin of regioselectivity in the cycloisomerization of the 3-alkynylpyridine 5b, the tautomer of allenes 6b, to give 7b-min and 7b-maj.

We also performed DFT calculations to investigate the subtle regioselectivity in the cyclization of the 3-alkynylpyridine substrate 5b (Figure 6b).¹⁴ The ΔΔG^‡ between the rate-limiting, initial bond closure via TS3-min and TS3-maj leading to the diradical 16-min or 16-maj, was calculated to be a mere 0.5 kcal mol⁻¹, aligning well with the experimentally observed ca. 7:3 distribution of products. The C─C bond rotation interconverting the diradical conformers 16-maj and 16-min was found to have a slightly higher barrier (17.4 kcal mol⁻¹) compared to either of the second bond forming TSSs (TS4-maj or -min). An analogous study of the cyclization of the 2-alkynylpyridine derivative 5a, which experimentally showed exclusive cyclization onto C3 rather than N1 of the pyridine ring, could also be recapitulated by DFT (ΔΔG^‡ 2.2 kcal mol⁻¹, see Figures S10 and S11, SI).

CONCLUSION

In conclusion, we have synthesized a variety of interesting pyrido-fused HAR derivatives under ambient, basic conditions. Key to this transformation is the TBD-catalyzed tautomerization of the alkynyl-HAR substrates to give an allene intermediate, which readily undergoes a net-[4 + 2]-cycloaddition with the pendant nitrile. By removing the gem-dimethyl moiety in the methanesulfonamide linker, we were able to slow the cyclization reaction to allow for the direct observation of a steady-state level of the key allene intermediate by ¹H NMR analysis. DFT computational studies supported many of these mechanistic aspects.

EXPERIMENTAL SECTION

General experimental protocols.

“¹H NMR and ¹³C spectra were obtained on a Bruker Avance III HD 400, a Bruker Avance III HD 500, or a Bruker Avance III 500 spectrometer. Chemical shifts are referenced to TMS at δ 0.00 ppm for spectra in CDCl₃ solution. A non-first order multiplet (nfom), a non-first order doublet (nfod), or a non-first order triplet (nfot) in a ¹H NMR spectrum is specifically denoted as such. Apparent (i.e., not the actual) coupling constant for non-first order coupling is signified by J_app. Multiplets are listed as: chemical shift (ppm) [multiplicity, coupling constant(s) in Hz, integral value (to the nearest integer), and assignment of the substructural environment either by indicating neighboring atoms or by using the numbering of the carbon atom to which the proton is attached]. Coupling constant analysis of first-order multiplets was done using previously published methods.¹⁵” ^{16 1}H NMR spectra recorded in benzene-d₆ were referenced to the shift of C₆HD₅ (d = 7.16 ppm). ¹⁹F NMR spectra were referenced to an internal standard of hexafluorobenzene (d = −164.9 ppm). “¹³C NMR chemical shifts are taken from the 1D spectrum and referenced to δ 77.16 ppm for spectra in CDCl₃ solution.”¹⁶ Structural assignments for 7j-maj, 7j-min, 13b, and 13d were made with the aid of additional information from HSQC and HMBC experiments.

“Infrared (IR) spectra were taken in the attenuated total reflectance (ATR) mode on a Bruker Alpha II Spectrometer. Absorption maxima are given in cm^-1. The samples were prepared as thin films from neat material or by evaporation of a DCM solution on the diamond window.

High-resolution mass spectrometry (HRMS) was performed on a Thermo Orbitrap Velos instrument in ESI-TOF mode having a mass accuracy of ≤3 ppm. The samples were injected directly into the ion source. Pierce^™ LTQ was used as an external calibrant.”¹⁶ Additional HRMS data were obtained on an Agilent 7200 GC/QTOF-MS on a J&W Scientific 60 m DB-5 capillary column with a mass accuracy of ≤5 ppm.

“Thin layer chromatography (TLC) was carried out using silica-gel coated, plastic or aluminum plates that were visualized by UV, or when necessary, by staining with a KMnO₄ solution and heating.

Melting points were measured using a Köfler hot-stage and are uncorrected. The crystalline nature or solids was judged by the refraction of light (aka, twinkling) observed with a polarizing microscope.

Medium pressure liquid chromatography (MPLC) was used to purify most new compounds. The apparatus was constructed with a HPLC pump (Waters model 510), differential refractive index detector (Waters R403), and UV detector (Gilson 112 UV). Hand-packed silica gel columns (Teledyne RediSep Rf Gold^®; normal-phase, 20-40 μm, 60 Å pore size) were used. Preparative flash chromatography was done on Agela silica gel (230-400 mesh).

Reaction temperatures refer to the temperatures of an external heating oil bath. Reactions conducted at temperatures higher than that of the boiling point of the solvent, were done in a screw-top culture tube that was sealed with an inert Teflon^®-lined cap.”¹⁶

Chloroform was used as the solvent for many of the cycloisomerization reactions. A small portion (e.g. 50 mL) was passed through a column of flash chromatography silica gel (ca. 20 mL) immediately before use to remove ethanol stabilizer.

Unless otherwise indicated all compounds were obtained commercially and used directly as received.

General Procedure A: Sonogashira Coupling Reaction.

To an appropriately sized culture tube was added a terminal alkyne, aryl iodide or bromide, base, and solvent (amounts specified in each procedure). The headspace of the reaction vessel was flushed with N₂. A Pd catalyst and CuI were added, the culture tube was sealed with a Teflon^®-lined cap, and the reaction mixture was stirred at room temperature or reflux. Upon consumption of the starting materials (GC monitoring), the reaction was quenched by the addition of sat. aq. NH₄Cl. The layers were separated and the aqueous portion was extracted using dichloromethane (3x). The combined organic layers were dried using sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography or MPLC using an appropriate elution solvent.

N-(2-Cyanopropan-2-yl)-N-(3-(pyridin-2-yl)prop-2-yn-1-yl)methanesulfonamide (5a).

Following general procedure A, the alkynylnitrile 8¹⁷ (40 mg, 0.2 mmol), 2-bromopyridine (9a, 95 mL, 0.24 mmol), triethylamine (140 mL, 1.0 mmol), toluene (2 mL, 0.12 M), Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), and CuI (4 mg, 0.02 mmol) were used to prepare the pyridine derivative 5a. The reaction mixture was stirred at 95 °C for 4 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:1) to give brown rod-like crystals (27 mg, 50% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.59 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, H6), 7.68 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H, H4), 7.47 (ddd, J = 7.8, 1.1, 1.1 Hz, 1H, H3), 7.28 (ddd, J = 7.7, 4.9, 1.3 Hz, 1H, H5), 4.50 (s, 2H, CH₂), 3.27 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 150.4, 142.2, 136.5, 127.4, 123.7, 120.7, 85.8, 83.3, 53.9, 41.7, 36.5, and 29.3. IR (neat): 2994 (C_sp3–H), 2916 (C_sp3–H), 1328 (SO₂NR₂), and 1145 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₆N₃O₂S⁺ 278.0958; Found 278.0955. TLC: R_f 0.37 (hexanes:EtOAc, 1:1). mp: 48–51 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(pyridin-3-yl)prop-2-yn-1-yl)methanesulfonamide (5b).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), 3-bromopyridine (9b, 48 mL, 0.5 mmol), triethylamine (0.349 mL, 2.5 mmol), THF (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the pyridine derivative 5b. The reaction mixture was stirred at 80 °C for 28 h, and the organic residue was purified by MPLC (hexanes:EtOAc 1:3) to give yellow cubic crystals (34 mg, 24% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.68 (dd, J = 2.2, 1.0 Hz, 1H, H2), 8.58 (dd, J = 4.9, 1.7 Hz, 1H, H6), 7.76 (dt, J = 7.9, 1.7 Hz, 1H, H4), 7.28 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H, H5), 4.50 (s, 2H, CH₂), 3.24 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 152.4, 149.6, 138.8, 123.3, 120.7, 119.0, 86.8, 83.4, 53.8, 41.6, 36.9, and 29.3. IR (neat): 3033 (C_sp2–H), 2989 (C_sp3–H), 2933 (C_sp3–H), 2232 (C≡ N), 1328 (SO₂NR₂), and 1143 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] C₁₃H₁₆N₃O₂S⁺ 278.0958; Found 278.0953. TLC: R_f 0.28 (hexanes:EtOAc, 1:4). mp: 65–67 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(2-fluoropyridin-4-yl)prop-2-yn-1-yl)methanesulfonamide (5c).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), the bromopyridine 9c (88 mg, 0.5 mmol), diisopropylethylamine (0.261 mL, 1.5 mmol), dimethylformamide (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the pyridine derivative 5c. The reaction mixture was stirred at 23 °C for 24 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give yellow cubic crystals (63.2 mg, 43% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.21 (ddd, J = 5.2, 0.8, 0.8 Hz, 1H, H6), 7.22 (ddd, J = 5.1, 1.9, 1.2 Hz, 1H, H5), 6.98 (ddd, J = 2.1, 1.2, 0.8 Hz, 1H, H3), 4.51 (s, 2H, CH₂), 3.22 (s, 3H, MsCH₃), and 1.98 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 163.8 (d, ¹J_CF = 239.4 Hz, C2), 148.2 (d, ³J_CF = 15.7 Hz, C6), 134.8 (d, ³J_CF = 9.4 Hz, C4), 123.5 (d, ⁴J_CF = 4.5 Hz, C5), 120.6 (C≡ N), 111.8 (d, ²J_CF = 39.4 Hz, C3), 89.4 (C≡ CAr), 82.8 (d, ⁴J_CF = 5.0 Hz, C≡ CAr), 53.8 (C(CH₃)₂), 41.7 (MsCH₃), 36.8 (CH₂), and 29.2 [C(CH₃)₂]. ¹⁹F NMR (471 MHz, CDCl₃): δ −69.9 (s, 1F, F2). IR (neat): 3072 (C_sp2–H), 3002 (C_sp2–H), 2927 (C_sp3–H), 2235 (C≡ N), 1325 (SO₂NR₂), and 1143 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₅FN₃O₂S⁺ 296.0864; Found 296.0856. TLC: R_f 0.30 (hexanes:EtOAc, 1:1). mp: 104–106 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(4-methoxypyridin-2-yl)prop-2-yn-1-yl)methanesulfonamide (5d).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), the bromopyridine 9d (94 mg, 0.5 mmol), triethylamine (0.349 mL, 2.5 mmol), THF (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the pyridine derivative 5d. The reaction mixture was stirred at 90 °C for 17 h, and the organic residue was purified by MPLC (hexanes:EtOAc 1:2) to give pale yellow rod-like crystals (56 mg, 37% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.38 (dd, J = 5.8, 0.6 Hz, 1H, H6), 7.02 (dd, J = 2.6, 0.6 Hz, 1H, H3), 6.80 (dd, J = 5.8, 2.6 Hz, 1H, H5), 4.48 (s, 2H, CH₂), 3.85 (s, 3H, OCH₃), 3.26 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 165.9, 151.5, 143.3, 120.8, 113.5, 110.3, 85.9, 82.8, 55.5, 53.9, 41.7, 36.5, and 29.3. IR (neat): 2941 (C_sp3–H), 2865 (C_sp3–H), 2240 (C≡ N), 1332 (SO₂NR₂), and 1147 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₄H₁₈N₃O₃S⁺ 308.1063; Found 308.1059. TLC: R_f 0.24 (EtOAc). mp: 70–73 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(pyrazin-2-yl)prop-2-yn-1-yl)methanesulfonamide (5e).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), 2-bromopyrazine (9e, 45.2 mL, 0.5 mmol), diisopropylethylamine (0.261 mL, 1.5 mmol), DMF (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the pyrazine derivative 5e. The reaction mixture was stirred at 23 °C for 3 d, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:1) to give orange cubic crystals (0.1016 g, 73% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.71 (d, J = 1.6 Hz, 1H, H3), 8.57 (dd, J = 2.6, 1.6 Hz, 1H, H5), 8.55 (d, J = 2.6 Hz, 1H, H6), 4.54 (s, 2H, CH₂), 3.27 (s, 3H, MsCH₃), and 2.00 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 147.6, 144.6, 143.8, 138.9, 120.5, 87.5, 82.6, 53.9, 41.8, 36.2, and 28.9. IR (neat): 3066 (C_sp2–H), 2996 (C_sp3–H), 2935 (C_sp3–H), 2231 (C≡ N), 1333 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₅N₄O₂S⁺ 279.0910; Found 279.0902. TLC: R_f 0.16 (hexanes:EtOAc, 1:1). mp: 76–79 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)methanesulfonamide (5f).

Following general procedure A, the alkynylnitrile 8¹⁷ (60 mg, 0.30 mmol), 2-bromothiophene (9f, 41 mL, 0.43 mmol), triethylamine (2.0 mL, 1.5 mmol), tetrahydrofuran (4 mL, 0.075 M), Pd(PPh₃)₂Cl₂ (11 mg, 0.015 mmol), and CuI (3 mg, 0.015 mmol) were used to prepare the thiophene derivative 5f. The reaction mixture was stirred at room temperature for 21 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 5f as cream-colored rod-like crystals (42 mg, 50% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.30 (dd, J = 5.1, 1.2 Hz, 1H, H5 or H3), 7.25 (dd, J = 3.7, 1.3 Hz, 1H, H3 or H5), 6.99 (dd, J = 5.2, 3.8 Hz, 1H, H4), 4.48 (s, 2H, CH₂), 3.23 (s, 3H, MsCH₃), and 1.97 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 133.0, 128.1, 127.3, 121.5, 120.6, 87.3, 80.2, 53.9, 41.6, 36.9, 29.8, and 29.2. IR (neat): 2957 (Csp3–H), 2921 (Csp3–H), 2851 (Csp3–H), 1325 (SO₂NR₂), and 1144 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₅N₂O₂S₂⁺ 283.0569; Found 283.0563. TLC: R_f 0.24 (hexanes:EtOAc, 3:1). mp: 37–39 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl)methanesulfonamide (5g).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), the bromoimidazole 9g (81 mg, 0.5 mmol), triethylamine (0.349 mL, 2.5 mmol), DMF (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the imidazole derivative 5g. The reaction mixture was stirred at 80 °C for 22 h, and the organic residue was purified by MPLC (5% MeOH in DCM) to give orange cubic crystals (27.4 mg, 20% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.46 (br s, 1H, H2), 7.29 (br s, 1H, H4), 4.52 (s, 2H, CH₂), 3.69 (s, 3H, NCH₃), 3.20 (s, 3H, MsCH₃), and 1.97 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 138.9, 135.6, 120.6, 114.9, 91.1, 74.9, 54.0, 41.9, 37.1, 32.3, and 29.1. IR (neat): 3019 (C_sp2–H), 2971 (C_sp3–H), 2918 (C_sp3–H), 2239 (C≡ N),1323 (SO₂NR₂), and 1137 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₇N₄O₂S⁺ 281.1067; Found 281.1055. TLC: R_f 0.17 (5% MeOH in DCM). mp: 106–109 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(pyrazolo[1,5-a]pyrimidin-6-yl)prop-2-yn-1-yl)methanesulfonamide (5h).

Following general procedure A, the alkynylnitrile 8¹⁷ (40 mg, 0.2 mmol), the aryl bromide 9h (48 mg, 0.24 mmol), triethylamine (140 mL, 1.0 mmol), toluene (2 mL, 0.12 M), Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), and CuI (4 mg, 0.02 mmol) were used to prepare the nitrile 5h. The reaction mixture was stirred and heated at 95 °C for 4 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:1) to give 5h as a cream-colored flaky powder (34 mg, 54% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.81 (dd, J = 2.1, 0.9 Hz, 1H, H7), 8.47 (d, J = 2.2 Hz, 1H, H5), 8.18 (d, J = 2.4 Hz, 1H, H2), 6.74 (dd, J = 2.3, 1.0 Hz, 1H, H3), 4.53 (s, 2H, CH₂), 3.24 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 150.6, 147.4, 146.7, 137.8, 120.7, 104.4, 98.3, 87.7, 79.9, 53.9, 41.8, 37.0, and 29.3. IR (neat): 3074 (C_sp2–H), 2987 (C_sp3–H), 2923 (C_sp3–H), 2240 (C≡ N), 1331 (SO₂NR₂), and 1143 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₄H₁₆N₅O₂S⁺ 318.1019; Found 318.1017. TLC: R_f 0.38 (hexanes:EtOAc, 1:1). mp: 127–129 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(isoquinolin-5-yl)prop-2-yn-1-yl)methanesulfonamide (5i).

Following general procedure A, the alkynylnitrile 8¹⁷ (40 mg, 0.2 mmol), 5-iodoisoquinoline (9i, 61mg, 0.24 mmol), triethylamine (140 mL, 1.0 mmol), acetonitrile (2 mL, 0.12 M), Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), and CuI (4 mg, 0.02 mmol) were used to prepare the quinoline derivative 5i. The reaction mixture was stirred at room temperature for 4 h, and the organic residue was purified by MPLC (hexanes:EtOAc 1:3) to give 5i as cream-colored flaky crystals (37 mg, 56% yield). ¹H NMR (500 MHz, CDCl₃): δ 9.28 (d, J = 1.1 Hz, 1H, H1), 8.64 (d, J = 5.9 Hz, 1H, H3), 8.03 (ddd, J = 5.9, 1.0, 1.0 Hz, 1H, H4), 8.00 (ddd, J = 8.3, 1.1, 1.1 Hz, 1H, H8), 7.90 (dd, J = 7.2, 1.2 Hz, 1H, H6), 7.58 (dd, J = 8.3, 7.2 Hz, 1H, H7), 4.64 (s, 2H, CH₂C≡ C), 3.27 (s, 3H, MsCH₃), and 2.04 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 153.0, 144.5, 136.2, 135.0, 129.0, 128.4, 126.9, 120.7, 118.9, 118.5, 89.4, 83.3, 54.1, 41.8, 37.1, and 29.3. IR (neat): 2937 (C_sp3–H), 1337 (SO₂NR₂), and 1147 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₇H₁₈N₃O₂S⁺ 328.1114; Found 328.1109. TLC: R_f 0.4 (hexanes:EtOAc, 1:3). mp: 131–135 °C.

tert-Butyl 5-(3-(N-(2-cyanopropan-2-yl)methylsulfonamido)prop-1-yn-1-yl)-1H-indole-1-carboxylate (5j).

Following general procedure A, the alkynylnitrile 8¹⁷ (40 mg, 0.2 mmol), iodoindole 9j (82 mg, 0.24 mmol), triethylamine (140 mL, 1.0 mmol), dichloromethane (2 mL, 0.12 M), Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), and CuI (4 mg, 0.02 mmol) were used to prepare the indole derivative 5j. The reaction mixture was stirred at room temperature for 24 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 3:1) to give a brown viscous oil (25 mg, 30% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.10 (br d, J = 8.6 Hz, 1H, H7), 7.67 (dd, J = 1.7, 0.7 Hz, 1H, H4), 7.62 (dd, J = 3.8, 0.5 Hz, 1H, H2), 7.37 (dd, J = 8.6, 1.7 Hz, 1H, H6), 6.54 (d, J = 3.8, 0.8 Hz, 1H, H3), 4.49 (s, 2H, CH₂), 3.28 (s, 3H, MsCH₃), 2.00 [s, 6H, MsNC(CH₃)₂], and 1.67 [s, 9H, C(CH₃)₃]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 149.5, 135.3, 130.7, 127.6, 127.2, 124.7, 120.8, 115.8, 115.5, 107.1, 87.5, 84.4, 81.9, 53.7, 41.3, 36.9, 29.4, and 28.3. IR (neat): 2980 (C_sp3–H), 2231 (C≡ N), 1732 (C=O), 1338 (SO₂NR₂), and 1149 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₂₁H₂₆N₃O₄S⁺ 416.1639; Found 416.1637. TLC: R_f 0.34 (hexanes:EtOAc, 3:1).

N-(2-Cyanopropan-2-yl)-N-(3-(3-methylpyridin-2-yl)prop-2-yn-1-yl)methanesulfonamide (5n).

Following general procedure A, the alkynylnitrile 8¹⁷ (0.11 g, 0.55 mmol), the bromopyridine 9n (56 mg, 0.5 mmol), triethylamine (0.349 mL, 2.5 mmol), THF (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the pyridine derivative 5n. The reaction mixture was stirred at 80 °C for 28 h, and the organic residue was purified by MPLC (hexanes:EtOAc 1:3) to give red cubic crystals (60 mg, 41% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.42 (ddq, J = 4.8, 1.7, 0.6 Hz, 1H, H6), 7.53 (ddq, J = 7.8, 1.7, 0.8 Hz, 1H, H4), 7.19 (ddq, J = 7.8, 4.8, 0.5 Hz, 1H, H5), 4.54 (s, 2H, CH₂), 3.26 (s, 3H, MsCH₃), 2.46 (ddd, J = 0.7, 0.5, 0.5 Hz, 3H, ArCH₃), and 2.00 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 147.7, 141.9, 137.4, 136.4, 123.6, 120.6, 87.0, 84.6, 54.1, 41.9, 36.5, 29.2, and 19.6. IR (neat): 2999 (C_sp3–H), 2924 (C_sp3–H), 2866 (C_sp3–H), 1332 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₄H₁₈N₃O₂S⁺ 292.1114; Found 292.1110. TLC: R_f 0.40 (EtOAc). mp: 74–77 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(pyrimidin-2-yl)prop-2-yn-1-yl)methanesulfonamide (5o)

Following general procedure A, the alkynylnitrile 8¹⁷ (100 mg, 0.5 mmol), the aryl bromide 9o (159 mg, 1.0 mmol), triethylamine (349 mL, 2.5 mmol), dimethylformamide (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the nitrile 5o. The reaction mixture was stirred at 100 °C for 3 d, and the organic residue was purified by MPLC (hexanes:EtOAc 2:9) to give cream-colored cubic crystals (18.1 mg, 13% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.73 (d, J = 4.9 Hz, 2H, H4+6), 7.29 (t, J = 4.9 Hz, 1H, H5), 4.51 (s, 2H, CH₂), 3.30 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 157.5, 152.2, 120.7, 120.5, 84.8, 82.2, 54.2, 42.1, 36.0, and 29.0. IR (neat): 3021 (C_sp2–H), 2975 (C_sp3–H), 2238 (C≡ N), 1330 (SO₂NR₂), and 1145 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₅N₄O₂S⁺ 279.0910; Found 279.0904. TLC: R_f 0.12 (hexanes:EtOAc, 1:1). mp: 170–172 °C.

N-(2-Cyanopropan-2-yl)-N-(3-(6-methoxybenzo[d]thiazol-2-yl)prop-2-yn-1-yl)methanesulfonamide (5p).

Following general procedure A, the alkynylnitrile 8¹⁷ (150 mg, 0.75 mmol), the aryl iodide 9p¹⁸ (146 mg, 0.5 mmol), triethylamine (349 mL, 2.5 mmol), dimethylformamide (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare the nitrile 5p. The reaction mixture was stirred at 100 °C for 19 h, and the organic residue was purified by MPLC (hexanes:EtOAc 1:1) to give 5p as cream-colored cubic crystals (66.7 mg, 37% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.93 (dd, J = 9.1, 0.5 Hz, 1H, H4), 7.28 (dd, J = 2.6, 0.5 Hz, 1H, H7), 7.13 (dd, J = 9.0, 2.6 Hz, 1H, H5), 4.55 (s, 2H, CH₂), 3.88 (s, 3H, OCH₃), 3.26 (s, 3H, MsCH₃), and 1.99 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 159.1, 147.3, 144.2, 137.0, 124.5, 120.4, 117.0, 103.4, 89.7, 79.7, 55.9, 54.2, 42.1, 36.4, and 29.0. IR (neat): 3016 (C_sp2–H), 2989 (C_sp3–H), 2936 (C_sp3–H), 1325 (SO₂NR₂), and 1141 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₆H₁₈N₃O₃S₂⁺ 364.0784; Found 364.0778. TLC: R_f 0.53 (hexanes:EtOAc, 1:1). mp: 155–160 °C.

6,6-Dimethyl-7-(methylsulfonyl)-7,8-dihydro-6H-pyrrolo[3,4-b][1,5]naphthyridine (7a).

A solution of nitrile 5a (14 mg, 0.05 mmol) and TBD (3 mg, 0.025 mmol) in CHCl₃ (0.5 mL, 0.1 M) was allowed to stir at 23 °C. After 24 h the solution was concentrated and the organic residue was purified by flash column chromatography in (hexanes:EtOAc 1:6) to give 7a as cream-colored rod-like crystals (12 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.97 (dd, J = 4.1, 1.6 Hz, 1H, H2), 8.40 (ddd, J = 8.6, 1.7, 0.8 Hz, 1H, H4), 8.26 (td, J = 1.5, 0.9 Hz, 1H, H9), 7.65 (dd, J = 8.6, 4.2 Hz, 1H, H3), 4.87 (d, J = 1.5, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.88 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.8, 151.2, 144.2, 143.6, 137.3, 131.5, 129.7, 124.4, 68.8, 50.2, 40.3, and 27.7. IR (neat): 2992 (C_sp3–H), 2956 (C_sp3–H), 2922 (C_sp3–H), 2852 (C_sp3–H), 1324 (SO₂NR₂), and 1162 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₆N₃O₂S⁺ 278.0958; Found 278.0956. TLC: R_f 0.25 (hexanes:EtOAc, 1:6). mp: 161–164 °C.

3,3-Dimethyl-2-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b][1,6]naphthyridine (7b-maj).

A solution of nitrile 5b (16.3 mg, 0.06 mmol) and TBD (4 mg, 0.03 mmol) in CHCl₃ (1.18 mL, 0.05 M) was allowed to stir at 23 °C. After 2.5 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 1:4) to give, in order of elution, 7b-min as cream rod-like crystals (5.5 mg, 34% yield) and 7b-maj as cream cubic crystals (12.5 mg, 77% yield). ¹H NMR (500 MHz, CDCl₃): δ 9.28 (d, J = 1.0 Hz, 1H, H8), 8.76 (d, J = 6.0 Hz, 1H, H6), 8.17 (td, J = 1.5, 0.9 Hz, 1H, H9), 7.93 (ddd, J = 6.0, 0.9, 0.9 Hz, 1H, H5), 4.85 (d, J = 1.5, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.88 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 170.7, 152.8, 151.1, 147.1, 129.9, 127.7, 123.2, 122.2, 69.0, 50.2, 40.4, and 27.6. IR (neat): 3045 (C_sp2–H), 2999 (C_sp3–H), 2919 (C_sp3–H), 2863 (C_sp3–H), 1323 (SO₂NR₂), 1138 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₆N₃O₂S⁺ 278.0958; Found 278.0954. TLC: R_f 0.09 (EtOAc). mp: 231–235 °C.

8,8-Dimethyl-7-(methylsulfonyl)-7,8-dihydro-6H-pyrrolo[3,4-b][1,8]naphthyridine (7b-min).

¹H NMR (500 MHz, CDCl₃): δ 9.12 (dd, J = 4.3, 2.0 Hz, 1H, H2), 8.23 (dd, J = 8.1, 2.0 Hz, 1H, H4), 8.09 (t, J = 1.4 Hz, 1H, H5), 7.53 (dd, J = 8.1, 4.3 Hz, 1H, H3), 4.86 (d, J = 1.4, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.92 [s, 6H, C(CH₃)₂]. ¹³C NMR (126 MHz, CDCl₃): δ 169.7, 156.6, 153.7, 137.3, 131.2, 127.3, 122.4, 122.2, 69.2, 50.2, 40.3, and 27.6. IR (neat): 3029 (C_sp2–H), 2994 (C_sp3–H), 2929 (C_sp3–H), 2859 (C_sp3–H), 1325 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₆N₃O₂S⁺ 278.0958; Found 278.0954. TLC: R_f 0.16 (EtOAc). mp: 131–135 °C.

5-Fluoro-3,3-dimethyl-2-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b][1,7]naphthyridine (7c-maj).

A solution of nitrile 5c (39.6 mg, 0.13 mmol) and TBD (9.3 mg, 0.07 mmol) in CHCl₃ (2.6 mL, 0.05 M) was allowed to stir at 23 °C. After 2 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 1:1) to give, in order of elution, 7c-min as yellow cubic crystals (11.3 mg, 29% yield) and 7c-maj as yellow cubic crystals (20.2 mg, 51% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.15 (dd, J = 5.7, 1.4 Hz, 1H, H7), 8.07 (td, J = 1.5, 1.1 Hz, 1H, H9), 7.56 (dd, J = 5.7, 1.1 Hz, 1H, H8), 4.86 (d, J = 1.5 Hz, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.89 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 168.3 (C3a), 159.6 (d, ¹J_CF = 252.2 Hz, C5), 140.3 (d, ³J_CF = 15.3 Hz, C7), 134.6 (d, J_CF = 4.4 Hz, C8a), 133.4 (d, ²J_CF = 28.5 Hz, C4a), 131.8 (C9a), 128.7 (d, J_CF = 3.6 Hz, C8 or C9), 119.1 (d, J_CF = 5.5 Hz, C8 or C9), 69.0 (C(CH₃)₂), 50.3 (CH₂), 40.5 (MsCH₃), and 27.7 (C(CH₃)₂). ¹⁹F NMR (471 MHz, CDCl₃): δ −75.7 (s, 1F, F5). IR (neat): 3009 (C_sp2–H), 2978 (C_sp3–H), 2941 (C_sp3–H), 1327 (SO₂NR₂), and 1140 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₅FN₃O₂S⁺ 296.0864; Found 296.0857. TLC: R_f 0.10 (hexanes:EtOAc, 1:1). mp: 181–185 °C.

7-Fluoro-3,3-dimethyl-2-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b][1,7]naphthyridine (7c-min).

¹H NMR (500 MHz, CDCl₃): δ 9.20 (dd, J = 1.5, 0.8 Hz, 1H, H5), 8.01 (td, J = 1.5, 0.9 Hz, 1H, H9), 7.26 (d, J = 0.8 Hz, 1H, H8), 4.84 (d, J = 1.6 Hz, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.87 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 167.6 (C3a), 161.1 (d, ¹J_CF = 236.8 Hz, C7), 152.6 (d, ³J_CF = 16.0 Hz, C5), 142.2 (d, ⁴J_CF = 3.2 Hz, C4a), 134.4 (d, ³J_CF = 9.5 Hz, C8a), 131.4 (C9a), 128.2 (d, ⁴J_CF = 6.5 Hz, C9), 102.6 (d, ²J_CF = 38.1 Hz, C8), 68.7 (C(CH₃)₂), 50.1 (CH₂), 40.5 (MsCH₃), and 27.6 (C(CH₃)₂). ¹⁹F NMR (471 MHz, CDCl₃): δ −79.1 (s, 1F, F7). IR (neat): 3008 (C_sp2–H), 2982 (C_sp3–H), 2934 (C_sp3–H), 1335 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₅FN₃O₂S⁺ 296.0864; Found 296.0858. TLC: R_f 0.20 (hexanes:EtOAc, 1:1). mp: 177–182 °C.

4-Methoxy-6,6-dimethyl-7-(methylsulfonyl)-7,8-dihydro-6H-pyrrolo[3,4-b][1,5]naphthyridine (7d).

A solution of nitrile 5d (25.9 mg, 0.08 mmol) and TBD (6 mg, 0.04 mmol) in CHCl₃ (1.69 mL, 0.05 M) was allowed to stir at 23 °C. After 2.5 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 1:4) to give 7d as yellow cubic crystals (22.9 mg, 88% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.80 (d, J = 5.2 Hz, 1H, H2), 8.21 (t, J = 1.5 Hz, 1H, H9), 6.99 (d, J = 5.3 Hz, 1H, H3), 4.85 (d, J = 1.5, 2H, CH₂), 4.14 (s, 3H, OCH₃), 3.04 (s, 3H, MsCH₃), and 1.90 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 165.3, 162.1, 152.1, 144.3, 137.3, 131.4, 130.0, 103.9, 69.0, 56.6, 50.1, 40.3, and 27.8. IR (neat): 2982 (C_sp3–H), 2932 (C_sp3–H), 2850 (C_sp3–H), 1321 (SO₂NR₂), and 1140 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₄H₁₈N₃O₃S⁺ 308.1063; Found 308.1058. TLC: R_f 0.09 (EtOAc). mp: 240–245 °C.

6,6-Dimethyl-7-(methylsulfonyl)-7,8-dihydro-6H-pyrrolo[3',4':5,6]pyrido[2,3-b]pyrazine (7e).

A solution of nitrile 5e (17.5 mg, 0.06 mmol) and TBD (4.4 mg, 0.03 mmol) in CHCl₃ (1.2 mL, 0.05 M) was allowed to stir at 23 °C. After 1 h the solution was concentrated and the organic residue was purified by flash column chromatography (EtOAc) to give 7e as yellow cubic crystals (13.1 mg, 75% yield). In a larger scale experiment, the nitrile 5e (0.264 g, 0.95 mmol) was dissolved in CHCl₃ (19.0 mL, 0.05 M). TBD (66.0 mg, 0.47 mmol) was added to the stirring solution at 23 °C. Within seconds the solution turned dark green and after 12 min the solution was concentrated and the organic residue was purified by flash column chromatography (EtOAc) to give 7e as yellow cubic crystals (0.197 g, 75% yield). ¹H NMR (500 MHz, CDCl₃): δ 9.06 (d, J = 1.8 Hz, 1H, H2 or H3), 8.96 (d, J = 1.8 Hz, 1H, H2 or H3), 8.35 (t, J = 1.5 Hz, 1H, H9), 4.92 (d, J = 1.5 Hz, 2H, CH₂), 3.06 (s, 3H, MsCH₃), and 1.93 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 170.6, 151.7, 147.6, 146.1, 138.1, 132.7, 131.2, 69.0, 50.1, 40.5, and 27.6. IR (neat): 3007 (Csp2–H), 2938 (Csp3–H), 1315 (SO₂NR₂), and 1140 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₅N₄O₂S⁺ 279.0910; Found 279.0905. TLC: R_f 0.21 (EtOAc). mp: blackening onset at 212 °C.

5,5-Dimethyl-6-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]thieno[2,3-e]pyridine (7f).

A solution of nitrile 5f (5.0 mg, 0.02 mmol) and TBD (3.0 mg, 0.02 mmol) in CDCl₃ (0.55 mL, 0.04 M) was allowed to stand at room temperature. After 1 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 3:1) to give 7f as cream-colored, rod-like crystals (4.4 mg, 89% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 0.3H, H8), 7.78 (d, J = 5.6 Hz, 1H, H2), 7.56 (d, J = 5.6 Hz, 1H, H3), 4.77 (s, 1H, C7H₂), 4.76 (br s, 0.5H, C7HD), 3.02 (s, 1.8H, MsCH₃), 3.01 (t, J_HD = 2.0 Hz, 0.8H, MsCH₂D), 2.99 (br m, 0.2H, MsCHD₂), and 1.84 [s, 6H, C(CH₃)₂]. IR (neat): 3075 (C_sp2–H), 3021 (C_sp2–H), 2923 (C_sp3–H), 2853 (C_sp3–H), 1318 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (EI-TOF) m/z: [M⁺ - CH₃^•] Calcd for C₁₁H₁₀DN₂O₂S₂^•+ 268.0319; Found 268.0318 (mono-deuterated product). TLC: R_f 0.21 (hexanes:EtOAc, 1:1). mp: 170–172 °C.

An analogous experiment performed in CHCl₃ gave a sample of all-protio 7f from which the following NMR data were obtained. ¹H NMR (500 MHz, CDCl₃): δ 8.06 (td, J = 1.2, 0.9 Hz, 1H, H8), 7.77 (d, J = 5.6 Hz, 1H, H2), 7.56 (dd, J = 5.6, 0.9 Hz, 1H, H3), 4.77 (d, J = 1.3 Hz, 2H, CH₂), 3.02 (s, 2H, MsCH₃), and 1.84 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 163.0, 156.5, 132.7, 131.2, 125.0, 124.8, 123.3, 68.8, 50.5, 40.1, and 27.8. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₅N₂O₂S₂⁺ 283.0569; Found 283.0563 (all protio product).

1,5,5-Trimethyl-6-(methylsulfonyl)-1,5,6,7-tetrahydroimidazo[4,5-b]pyrrolo[3,4-e]pyridine (7g).

A solution of nitrile 5g (10.0 mg, 0.036 mmol) and TBD (2.5 mg, 0.018 mmol) in CHCl₃ (0.72 mL, 0.05 M) was allowed to stir at 23 °C. After 22 d the solution was concentrated and the organic residue was purified by MPLC (5% MeOH in DCM) to give 7g as white cubic crystals (6.9 mg, 69% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.10 (s, 1H, H2), 7.61 (t, J = 1.2 Hz, 1H, H8), 4.79 (d, J = 1.1 Hz, 2H, CH₂), 3.89 (s, 3H, NCH₃), 3.01 (s, 3H, MsCH₃), and 1.84 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 160.1, 157.1, 146.3, 126.7, 122.2, 112.4, 68.9, 50.8, 40.0, 31.8, and 28.0. IR (neat): 3099 (Csp2–H), 2927 (Csp3–H), 1321 (SO₂NR₂), and 1144 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₇N₄O₂S⁺ 281.1067; Found 281.1056. TLC: R_f 0.14 (5% MeOH in DCM). mp: 240–244 °C.

9,9-Dimethyl-8-(methylsulfonyl)-8,9-dihydro-7H-pyrazolo[1,5-a]pyrrolo[3',4':5,6]pyrido[3,2-e]pyrimidine (7h).

A solution of nitrile 5h (16 mg, 0.05 mmol) and TBD (3 mg, 0.025 mmol) in CHCl₃ (0.5 mL, 0.1 M) was allowed to stir at 23 °C. After 24 h the solution was concentrated and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:5) to give 7h as a cream-colored, thread-like powder (15 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.87 (s, 1H, H5), 8.26 (d, J = 2.2 Hz, 1H, H2), 8.19 (t, J = 1.2 Hz, 1H, H6), 6.93 (d, J = 2.1 Hz, 1H, H3), 4.86 (d, J = 1.2 Hz, 2H, CH₂), 3.05 (s, 3H, MsCH₃), and 1.95 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 170.7, 150.8, 148.3, 147.0, 144.8, 132.0, 126.0, 113.2, 101.5, 69.8, 50.3, 40.4, and 27.7. IR (neat): 3123 (C_sp2–H), 2957 (C_sp3–H), 2925 (C_sp3–H), 2853 (C_sp3–H), 1320 (SO₂NR₂), and 1142 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₄H₁₆N₅O₂S⁺ 318.1019; Found 318.1016. TLC: R_f 0.21 (hexanes:EtOAc, 1:5). mp: 204–210 °C.

8,8-Dimethyl-9-(methylsulfonyl)-9,10-dihydro-8H-pyrrolo[3,4-b][4,7]phenanthroline (7i).

A solution of nitrile 5i (25 mg, 0.075 mmol) and TBD (5 mg, 0.0375 mmol) in CHCl₃ (0.8 mL, 0.09 M) was allowed to stir at 23 °C. After 12 h the solution was concentrated and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:3) to give 7i as a cream-colored flaky powder (18 mg, 72% yield). ¹H NMR (500 MHz, CDCl₃): δ 9.34 (d, J = 1.0 Hz, 1H, H4), 8.84 (td, J = 1.3, 0.6 Hz, 1H, H11), 8.83 (d, J = 5.7 Hz, 1H, H2), 8.37 (d, J = 5.8 Hz, 1H, H1), 8.12 (dd, J = 9.1, 0.6 Hz, 1H, H6), 8.09 (d, J = 9.1 Hz, 1H, H5), 4.93 (d, J = 1.3 Hz, 2H, CH₂), 3.06 (s, 3H, MsCH₃), and 1.91 [s, 6H, C(CH₃)₂]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 167.3, 152.1, 150.1, 145.8, 134.4, 129.9, 129.0, 126.7, 126.6, 125.7, 123.3, 116.0, 69.2, 50.7, 40.3, and 27.7. IR (neat): 2983 (C_sp3–H), 2923 (C_sp3–H), 2852 (C_sp3–H), 1314 (SO₂NR₂), and 1139 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₇H₁₈N₃O₂S⁺ 328.1114; Found 328.1111. TLC: R_f 0.25 (hexanes:EtOAc, 1:3). mp: 185–190 °C.

tert-Butyl 9,9-dimethyl-8-(methylsulfonyl)-8,9-dihydrodipyrrolo[3,4-b:2',3'-h]quinoline-3(7H)-carboxylate (7j-maj).

A solution of the nitrile 5j (12 mg, 0.03 mmol) and TBD (2 mg, 0.015 mmol) in CHCl₃ (0.55 mL, 0.05 M) was allowed to stir at 23 °C. After 24 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 3:1) to give, in order of elution, 7j-maj as a cream-colored, powdery crystals (11 mg, 92% yield) and 7j-min as white rod-like crystals (1.1 mg, 9% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.40 (br d, J = 9.0 Hz, 1H, H4), 8.07 (t, J = 1.3 Hz, 1H, H6), 7.72 (d, J = 3.6 Hz, 1H, H2), 7.66 (d, J = 9.0 Hz, 1H, H5), 7.41 (dd, J = 3.6, 0.8 Hz, 1H, H1), 4.83 (d, J = 1.3 Hz, 2H, CH₂), 3.04 (s, 3H, MsCH₃), 1.90 [s, 6H, MsNC(CH₃)₂], and 1.72 [s, 9H, C(CH₃)₃]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 164.9 (C9a), 149.8 (C=O), 143.6 (C10a), 134.9 (C3a, v. weak in 1D spectrum but strong correlations in the HMBC), 130.1 (C6), 127.5 (C10b), 125.1 (C2), 124.3 (C5a or C6a), 124.1 (C5a or C6a), 123.9 (C5), 116.4 (C4), 106.6 (C1), 84.5 (Me₃CO), 69.1 (C9), 50.6 (C7), 40.1 (CH₃SO₂), 28.3 [C(CH₃)₃], and 27.9 [C9(CH₃)₂]. (Assignments based on interpretation of the HSQC and HMBC spectra) IR (neat): 3133 (C_sp2–H), 2923 (C_sp3–H), 2852 (C_sp3–H), 1724 (C=O), 1328 (SO₂NR₂), and 1126 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₂₁H₂₆N₃O₄S⁺ 416.1639; Found 416.1636. TLC: R_f 0.75 (hexanes:EtOAc, 1:1). mp: 162–165 °C.

tert-Butyl 8,8-dimethyl-7-(methylsulfonyl)-7,8-dihydrodipyrrolo[3,4-b:3',2'-g]quinoline-1(6H)-carboxylate (7j-min).

¹H NMR (500 MHz, CDCl₃): δ 8.87 (br s, 1H, H10), 8.08 (td, J = 1.3, 0.9 Hz, 1H, H5), 7.96 (d, J = 0.8 Hz, 1H, H4), 7.80 (br d, J = 3.9 Hz, 1H, H2), 6.71 (dd, J = 3.9, 0.9 Hz, 1H, H3), 4.82 (d, J = 1.4 Hz, 2H, CH₂), 3.04 (s, 3H, MsCH₃), 1.88 [s, 6H, C8(CH₃)₂], and 1.73 [s, 9H, C(CH₃)₃]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 164.9 (C8a), 146.4 (C9a), 137.0, 130.1, 129.7, 124.1 (C5a), 130.2 (C2), 129.8 (C5), 118.2 (C4), 113.9 (C10), 107.0 (C3), 84.2 (Me₃CO), 68.8 (C8), 50.4 (C6), 40.3 (CH₃SO₂), 28.5 [OC(CH₃)₃], and 27.7 [C8(CH₃)₂]. (From the HSQC spectrum. From the HMBC spectrum. Boc carbonyl not observable.) HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₂₁H₂₆N₃O₄S⁺ 416.1639; Found 416.1632. TLC: R_f 0.52 (hexanes:EtOAc, 1:1). mp: >240 °C.

N-(Cyanomethyl)-N-(3-(4-cyanophenyl)prop-2-yn-1-yl)methanesulfonamide (11b).

Following general procedure A, the alkynylnitrile S2 (see SI, 85 mg, 0.5 mmol), 4-iodobenzonitrile (120 mg, 0.6 mmol), triethylamine (350 mL, 2.5 mmol), acetonitrile (5 mL, 0.1 M), Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol), and CuI (10 mg, 0.05 mmol) were used to prepare the sulfonamide 11b. The reaction mixture was stirred at 23 °C for 60 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 1:1) to give cream-colored flakey crystals (95 mg, 70% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.64 (nfod, J_app = 8.4 Hz, 2H, o- or m-Ar C≡ C), 7.57 (nfod, J_app = 8.4 Hz, 2H, o- or m-Ar C≡ C), 4.47 (s, 2H, CH₂C≡ C), 4.37 (s, 2H, CH₂CN), and 3.13 (s, 3H, MsCH₃). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 132.4, 132.3, 126.3, 118.2, 114.5, 112.9, 86.1, 84.8, 39.4, 39.1, and 36.0. IR (neat): 3090 (C_sp2–H), 3000 (C_sp2–H), 2965 (C_sp3–H), 2226 (C≡ N), 1320 (SO₂NR₂), and 1156 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₂N₃O₂S⁺ 274.0645; Found 274.0644. TLC: R_f 0.52 (hexanes:EtOAc, 1:1). mp: 94–96 °C.

N-(Cyanomethyl)-N-(3-phenylprop-2-yn-1-yl)methanesulfonamide (11c).

Following general procedure A, the alkynylnitrile S2 (see SI, 85 mg, 0.50 mmol), iodobenzene (65 mL, 0.6 mmol), triethylamine (350 mL, 0.50 mmol), acetonitrile (5 mL, 0.10 M), Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol), and CuI (10 mg, 0.05 mmol) were used to prepare the sulfonamide 11c. The reaction mixture was stirred at room temperature for 60 h, and the organic residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give yellow flakey crystals (92 mg, 74% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.49–7.44 (nfom, 2H, o-Ar), 7.39–7.31 (m, 3H, m- and p-Ar), 4.44 (s, 2H, CH₂C≡ C), 4.37 (s, 2H, CH₂CN), and 3.12 (s, 3H, MsCH₃). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 131.9 (ArC_o), 129.4 (ArC_p), 128.7 (ArC_m), 121.5 (C_spC_Ar), 114.5 (CH₂CN), 88.0 (ArC_sp), 80.3 (ArCC_sp), 39.2 (CH₃S), 39.1 (CH₂C≡ C), and 35.8 (CH₂CN). IR (neat): 3015 (C_sp2–H), 2989 (C_sp3–H), 2951 (C_sp3–H), 2245 (C≡ N), 1323 (SO₂NR₂), and 1149 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₃N₂O₂S⁺ 249.0692; Found 249.0689; [M + Na⁺] Calcd for C₁₂H₁₂N₂NaO₂S⁺ 271.0512; Found 271.0510. TLC: R_f 0.32 (hexanes:EtOAc, 3:1). mp: 70–72 °C.

N-(3-(4-Aminophenyl)prop-2-yn-1-yl)-N-(cyanomethyl)methanesulfonamide (11d).

Following general procedure A, the alkynylnitrile S2 (see SI, 34 mg, 0.20 mmol), 4-iodoaniline (40 mg, 0.18 mmol), triethylamine (139 mL, 1.0 mmol), acetonitrile (1 mL, 0.2 M), Pd(PPh₃)₂Cl₂ (4.2 mg, 0.006 mmol), and CuI (2.3 mg, 0.012 mmol) were used to prepare the sulfonamide 11d. The reaction mixture was stirred at 90 °C for 5 h, and the organic residue was purified by flash column chromatography (1% MeOH in DCM) to give orange rod-like crystals (20 mg, 42% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.26 (nfod, J_app = 8.5 Hz, 2H, o-Ar), 6.60 (nfod, J_app = 8.6 Hz, 2H, m-Ar), 4.41 (s, 2H, CH₂C≡ C), 4.36 (s, 2H, CH₂CN), 3.86 (br s, 2H, NH₂), and 3.10 (s, 3H, MsCH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 147.6, 133.4, 114.8, 114.6, 110.6, 88.8, 78.0, 39.3, 39.0, and 35.7. IR (neat): 3474 (NH₂), 3382 (NH₂), 2925 (C_sp3–H), 2204 (C≡ N), 1311 (SO₂NR₂), and 1150 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₄N₃O₂S⁺ 264.0801; Found 264.0797. TLC: R_f 0.35 (1% MeOH in DCM). mp: 117–120 °C.

2-(Methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carbonitrile (13b).

A solution of methanesulfonamide 11b (10.6 mg, 0.04 mmol) and TBD (5.4 mg, 0.04 mmol) in CHCl₃ (0.78 mL, 0.05 M) was allowed to stir at 23 °C. After 24 h the solution was concentrated and the organic residue was purified by MPLC (5% MeOH in DCM) to give 13b as white cubic crystals (8.7 mg, 82% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.44 (dt, J = 1.6, 0.8 Hz, 1H, H5), 8.10 (nfom, 1H, H9), 7.93 (dd, J = 8.5, 0.7 Hz, 1H, H8), 7.73 (dd, J = 8.4, 1.6 Hz, 1H, H7), 4.93 (nfom, 2H, H1), 4.88 (nfom, 2H, H3), and 2.99 (s, 3H, MsCH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 161.0 (C3a), 147.3 (C4a), 135.2 (C5), 131.0 (C9a), 130.2 (C9), 129.5 (C8), 128.9 (C8a), 127.9 (C7), 118.1 (CN), 113.4 (C6), 53.5 (C3), 51.7 (C1), and 36.4 (MsCH₃). (From the HSQC spectrum. From the HMBC spectrum.) IR (neat): 3065 (C_sp2–H), 3019 (C_sp2–H), 2923 (C_sp3–H), 2227 (C≡ N), 1326 (SO₂NR₂), and 1141 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₃H₁₂N₃O₂S⁺ 274.0645; Found 274.0643. TLC: R_f 0.43 (5% MeOH in DCM). mp: blackening onset at 110 °C (fully charred by ~200 °C).

2-(Methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline (13c).

A solution of methanesulfonamide 11c (25 mg, 0.1 mmol) and TBD (14 mg, 0.1 mmol) in CHCl₃ (1 mL, 0.1 M) was allowed to stir at 50 °C. After 60 h the solution was concentrated and the organic residue was purified by MPLC (hexanes:EtOAc 3:1) to give 13c as cream-colored, rod-like crystals (13 mg, 52% yield) along with recovered starting material 11c (8 mg). ¹H NMR (500 MHz, CDCl₃): δ 8.07 (dddd, J = 8.5, 0.9, 0.9, 0.9 Hz, 1H, H5), 8.05 (td, J = 1.2, 1.2 Hz, 1H, H9), 7.84 (ddd, J = 8.2, 1.7, 0.6 Hz, 1H, H8), 7.74 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, H6), 7.57 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, H7), 4.90 (td, J = 1.2, 1.2 Hz, 2H, H1), 4.86 (nfom, 2H, H3), and 2.96 (s, 3H, MsCH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 158.7, 148.4, 130.3, 130.1, 129.1, 128.1, 128.0, 127.5, 127.0, 53.7, 51.8, and 35.7. IR (neat): 3054 (C_sp2–H), 3007 (C_sp2–H), 2960 (C_sp3–H), 1314 (SO₂NR₂), and 1146 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₃N₂O₂S⁺ 249.0692; Found 249.0688. TLC: R_f 0.18 (hexanes:EtOAc, 1:1). mp: 180–185 °C.

2-(Methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-6-amine (13d).

A solution of methanesulfonamide 11d (2.7 mg, 0.01 mmol) and TBD (1.4 mg, 0.01 mmol) in o-dichlorobenzene (1.0 mL, 0.01 M) was sealed in a screw-capped, Teflon-lined, threaded vial and allowed to stir at 150 °C. After 22 h the solution was concentrated and the organic residue was purified by flash column chromatography (EtOAc) to give 13d as a red amorphous solid (0.8 mg, 30% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.85 (td, J = 1.2, 1.0 Hz, 1H, H9), 7.61 (d, J = 8.7 Hz, 1H, H8), 7.15 (ddd, J = 2.4, 0.6, 0.6 Hz, 1H, H5), 6.99 (dd, J = 8.7, 2.4 Hz, 1H, H7), 4.82 (td, J = 1.3, 1.2 Hz, 2H, H1), 4.77 (t, J = 1.3 Hz, 2H, H3), 4.12 (br s, 2H, NH₂), and 2.93 (s, 3H, MsCH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 158.8, 150.4, 148.3, 130.1, 129.2, 124.3, 121.4, 118.9, 109.0, 53.9, 51.9, and 35.4. (From the HSQC spectrum. From the HMBC spectrum.) IR (neat): 3453 (NH₂), 3301 (NH₂), 2921 (C_sp3–H), 1323 (SO₂NR₂), and 1140 (SO₂NR₂) cm⁻¹. HRMS (ESI-TOF) m/z: [M + H⁺] Calcd for C₁₂H₁₄N₃O₂S⁺ 264.0801; Found 264.0790. TLC: R_f 0.19 (EtOAc). mp: turned black with decomposition at ~170 °C.

COMPUTATIONAL METHODS

A conformational search was conducted for all ground state structures using the Schrödinger software package.¹⁹ Specifically, candidate conformers were generated with MacroModel using the OPLS_2005 force field in Maestro (Maestro Version 12.9.137, MMshare Version 5.5.137, Release 2021-3, Platform Linux-x86_64). Gaussian 16²⁰ was used to conduct all DFT calculations. All conformers generated by the conformational search were subjected to a geometry optimization and frequency calculation (298 K) using the ultrafine integration grid at the (U)MN15²¹/6-31G(d) level of theory with SMD(chloroform) solvation.²² Transition state structures (TSSs) were found by first scanning the bond length of the respective bond(s) being formed or broken, followed by subjecting the geometry obtained from the highest energy step in the scan calculation to a TS calculation at the same level of theory as described above. The identity of all TSSs were confirmed to contain a single imaginary frequency. An intrinsic reaction coordinate (IRC)²³ calculation was also performed to ensure that the TSSs connected the corresponding reactant to the product. The reactive allene conformer was identified by performing a geometry optimization and frequency calculation for the allene obtained in the final step (of ten) of the IRC for the TSS for the first bond-formation leading to the diradical intermediate. Single point energy calculations were conducted for all reactive, intermediate conformers and TSSs at the (U)MN15²¹/6-311+G(d,p) level of theory using the ultrafine integration grid and SMD(chloroform) solvation.²² Full reaction coordinates that include all stationary structures are given in the SI for each system investigated, followed by the output from the IRC calculation for each TSS. Furthermore, for each calculated structure in the reaction coordinate, the following data are provided: (1) a CYLview20¹⁴-generated three-dimensional image of the optimized structure, (2) the thermal correction to "Gibbs Free Energy" obtained from the geometry optimization and frequency calculation, (3) the energy obtained from the single point energy calculation done using a larger basis set, (4) the spin expectation value ⟨S²⟩ for any structure containing radical character, (5) the imaginary frequency for each TSS, and (6) the Cartesian coordinates for each stationary point.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.