Rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles

Abstract

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.

Graphical abstract

1. Introduction

The [5,6]-bicyclic nitrogen heterocycle class is exemplified by the purine motif and is heavily represented in U.S. FDA approved drugs.¹ In recent years the sub-class of [5,6]-bicyclic heterocycles with a ring junction nitrogen have increasingly been investigated and have resulted in a number of approved drugs² as well as candidates in clinical trials.³ Transition-metal-catalyzed C–H functionalization can provide an efficient approach for the convergent synthesis of nitrogen heterocycles from readily available starting materials.⁴ Nevertheless, only a few approaches have been reported for the preparation of fused bicyclic heterocycles with ring-junction nitrogens. The most extensive related research has focused on C–H functionalization of C-aryl azoles for the synthesis of tricyclic and higher order aza-fused heterocycles.^5–13 Dong and co-workers reported the first examples of C–H functionalization for the preparation of ring-junction nitrogen [5,6]-bicyclic heterocycles by annulation of N-alkenyl imidazoles with internal alkynes.¹⁴ More recently, we reported the C–H functionalization of C-alkenyl azoles with various electrophiles, including internal alkynes and diazoketones, for the synthesis of bridgehead N-fused bicyclic heterocycles (Scheme 1A).¹⁵ While a variety of diferrent products were obtained with high regioselectivity, in all cases, the methods required placement of carbon substituents at both the R³ and R⁴ positions.

Scheme 1.

Rh(III)-catalyzed synthesis of fused [5,6]-bicyclic heterocycles from C-alkenyl azoles

Sulfoxonium ylides have been introduced as convenient carbene precursors¹⁶ that are a safer alternative to analogous diazo compounds.¹⁷ Recently these reagents have been shown to be particularly effective for the Rh(III)-catalyzed acylmethylation of arenes with the carbonyl functionality in the product available for further elaboration.^18,19 Herein, we report Rh(III)-catalyzed coupling of C-alkenyl azoles with sulfoxonium ylides with in situ cyclodehydration to give differently substituted bridgehead N-fused [5,6]-bicyclic heterocycles with complete regioselectivity (Scheme 1B).

2. Results and discussion

Preformed catalyst [Cp*Rh(MeCN)₃](SbF₆)₂ in toluene at 120 °C provided effective conditions for annulation of C-alkenyl imidazole 1a with sulfoxonium ylide 2a (entry 1, Table 1). Lowering the temperature to 100 °C resulted in a slightly lower yield (entry 2). The optimal conditions were similarly effective for the electron rich sulfoxonium ylide 2b (entry 3). When the stoichiometry of sulfoxonium ylide 2b was reduced from 2.0 to 1.5 equiv, only a slight reduction in yield was observed (entry 4). The importance of both PivOH and NaOAc were documented by the lower yields that were obtained in the absence of these additives (entries 5 and 6, respectively). As expected, the Rh(III) catalyst was essential to the reaction (entry 7). While the cationic Rh(III) catalyst could be prepared in situ without any effect on the reaction yield (entry 8), when the chlorides were not abstracted from [Cp*RhCl₂]₂, a lower yield was observed (entry 9). Doubling the concentration also resulted in a lower yield (entry 10). The reaction was dependent on solvent with dioxane, DCE and acetonitrile all resulting in lower yields (entries 11–13). The optimal reaction temperature of 120 °C required that a pressurized reaction vessel be used when toluene was used as the reaction solvent. Therefore, xylenes, with a boiling point higher than 120 °C was evaluated, with bench-top set up, and provided a comparable reaction yield (entry 14).

Table 1.

C–H functionalization of 1a and 2^a

entry	ylide	solvent	temp (°C)	variation	Yield %b
1	2a	toluene	120	none	73 (71)c
2	2a	toluene	100	none	61
3	2b	toluene	120	none	68 (69)c
4	2b	toluene	120	2 (1.5 equiv)	67
5	2b	toluene	120	no NaOAc	29
6	2b	toluene	120	no PivOH	33
7	2b	toluene	120	No Rh	0
8	2b	toluene	120	[Cp*RhCl2]2d	65
9	2b	toluene	120	[Cp*RhCl2]2e	45
10	2b	toluene	120	0.2 M	45
11	2b	dioxane	120	none	45
12	2b	DCE	120	none	53
13	2b	MeCN	120	none	50
14	2b	xylenes	120	bench-top	65

^aConditions: 1a (0.10 mmol), 2 (0.20 mmol), 0.1 M, 16 h.

^bYield determined by ¹H-NMR relative to 1,3,5-trimethoxybenzene as external standard.

^cIsolated yield of a 0.30 mmol scale (see Figure 1).

^d[Cp*RhCl₂]₂ (5 mol %) and AgSbF₆ (20 mol %).

^e[Cp*RhCl₂]₂ (5 mol %) only.

With optimized reaction conditions in hand, the scope for the sulfoxonium ylide input was next explored. A variety of aryl ylides with different electronic properties coupled equally well under the standard conditions to afford products 3aa–ad in good yields (63–72%). Both electron rich and deficient heteroaryl ylides were also effective coupling partners as exemplified for products 3ae–ag. A number of alkyl ylides, including methyl (2h), β-branched (2i), and α-branched (2j–l) were also effective inputs and provided good to excellent yields of the products 3ah–al. Under the reaction conditions, chiral product 3al is obtained in reasonable yield though with significant epimerization (3:1 er).²¹ Notably, the tertiary N-Boc piperidine- and secondary N-Cbz-containing adducts, 3ak and 3al, respectively, establish that N-protected amine functionality can readily be introduced to provide versatile handles for further elaboration.

We next turned our attention to different C-alkenyl azoles (Figure 2). Imidazoles 1b–e bearing a range of substituents at different sites on the alkene and/or imidazole ring all effectively coupled with both aryl and alkyl ylides (3ba–ek). Only the unsubstituted C-vinyl imidazole 1f was found to be ineffective (3fk). The C-alkenyl triazole 1g coupled with alkyl ylide 2k to provide 3gk in good yield. However, when the reaction was performed with aromatic ylide 2b, only trace amounts of 3gb was obtained and with no remaining triazole 1g. The electron deficient aromatic ylide 2a (R³ = 4-CF₃Ph) did provide product 3ga, albeit in only modest yield.²⁰ In addition, pyrazole 1h was not an effective coupling partner. Only trace amounts of remaining 1h and product 3hk were observed under standard conditions with ylide 2k.

Figure 2.

C-alkenyl azole scope in Rh(III)-catalyzed C–H functionalization with sulfoxonium ylides

A mechanism that is consistent with both our previously proposed C-H functionalization of C-alkenyl azoles¹⁵ and the previously proposed C–H functionalization of sulfoxonium ylides^18,19 is depicted in Figure 3. Concerted metalation-deprotonation provides the five-membered metallocycle A. Reaction with sulfoxonium ylide 2 then provides the six-membered metallocycle B. Proto-demetalation regenerates the Rh(III) catalyst and ketone C, which undergoes cyclodehydration to give heteroaromatic, N-fused bicyclic product 3.

Figure 3.

Proposed catalytic cycle

Lastly, the reaction was optimized to enhance its practicality for straightforward bench-top set up as demonstrated at a larger 2 mmol scale for aryl sulfoxonium ylide 2b and alkyl sulfoxonium ylide 2k (Scheme 2). Notably, xylene, which boils above the reaction temperature of 120 °C, was used without drying or purification. Moreover, the catalyst loading was lowered to 5 mol % without any reduction reaction yields.

Scheme 2.

Bench-top reaction set up on 2 mmol scale.

3. Conclusions

In summary, we have developed a method for the synthesis of ring-junction nitrogen fused bicyclic heterocycles by Rh(III)-catalyzed annulation of C-alkenyl azoles with sulfoxonium ylides. The reaction proceeds in good to high yields and with complete regioselectivity for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. Moreover, the reaction is applicable to straightforward bench-top set up with xylenes as solvent without drying or purification.

4. Experimental section

4.1. General

Unless otherwise noted, all commercially available reagents were purchased and used as received. Solvents including toluene, 1,4-dioxane, 1,2-dichloroethane (DCE), and acetonitrile (MeCN) were deoxygenated by sparging with argon and stored over activated 3Å molecular sieves in a nitrogen filled glove box. Xylenes (mixtures of isomers, not anhydrous) was purchased and used as received. Commercial AgSbF₆ was stored in a nitrogen filled glove box. ¹H-, ¹³C-, and ¹⁹F-NMR spectra were recorded on 400 MHz, 500 MHz or 600 MHz spectrometers. The chemical shift [δ (ppm)], coupling constants [J (Hz)], multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, m = multiplet, br = broad), and integration are reported. Chemical shifts for ¹H and ¹³C NMR are reported relative to residual undeuterated solvent in CDCl3 (7.26 ppm for 1H-NMR and 77.16 ppm for 13C-NMR) and (CD3)2CO (2.05 ppm for 1H-NMR and 29.84 ppm for 13C-NMR). Flash chromatography was carried out with SiliaFlash® P60 (particle size 40–63 µm, 230–400 mesh). Partial data are provided for IR spectra. Melting points are reported uncorrected. High-resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI) on a time of flight (TOF) mass spectrometer. Enantiomeric ratios were determined using an Agilent 1100 series HPLC equipped with Chiralpak-IB or Chiralcel-OD-H columns and a multiwavelength detector.

4.2. Preparation of catalysts and reactants

[Cp*Rh(MeCN)₃(SbF₆)₂] was synthesized according to literature procedures.^18b All C-alkenyl substrates were synthesized according to literature procedures.¹⁵ Sulfoxonium ylides 2a–f, 2h, 2i, and 2k were synthesized according to literature procedures.^18,22 Ylides 2g and 2i were prepared from the corresponding acid chlorides via literature procedures^18b with slight modification. Ylide 2l was prepared according to a literature procedure for a related compound.²³

4.2.1. 2-(Dimethyl(oxo)-λ⁶-sulfaneylidene)-1-(pyridin-3-yl)ethan-1-one (2g)

Ylide 2g from the corresponding acid chlorides via literature procedures^18b with slight modification. The mixture of trimethylsulfoxonium iodide (5.94 g, 27.0 mmol, 3 equiv) and potassium tert-butoxide (3.03 g, 27.0 mmol, 3 equiv) in THF (55 mL) was refluxed (67 °C) for 2 hours under nitrogen. After cooling to room temp then 0 °C, to the above mixture was added a solution of nicotinoyl chloride (prepared in situ by stirring a mixture of nicotinoyl chloride hydrochloride (1.60 g, 9.00 mmol, 1 equiv) and triethylamine (1.26 mL, 9.00 mmol, 1 equiv) in THF (10 mL) for 1 hour at room temp). The resulting mixture was slowly warmed to room temp and stirred overnight, filtered through a plug of celite, and concentrated under reduced pressure. Purification by silica gel column chromatography (10–50% MeOH/DCM) afforded 2g (851 mg, 48%) as a white solid. mp 120–122 °C. FTIR (neat): 3093, 2989, 1581, 1534, 1390, 1169, 1089, 1024, 991, 949, 897, 839, 727, 511 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ 8.92 (dd, J = 2.2, 0.9 Hz, 1H), 8.58 (dd, J = 4.8, 1.7 Hz, 1H), 8.02 (dt, J = 7.9, 2.0 Hz, 1H), 7.27 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 4.98 (s, 1H), 3.48 (s, 6H). ¹³C-NMR (100 MHz, CDCl₃) δ 179.9, 151.3, 148.2, 134.2, 134.0, 123.2, 69.5, 42.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₂NO₂S⁺, 198.0583; found 198.0578.

4.2.2. 1-(Dimethyl(oxo)-λ⁶-sulfaneylidene)-4-methylpentan-2-one (2i)

Ylide 2i was prepared following the procedures for the preparation of sulfoxonium ylide 2g but with isovaleraldehyde (0.970 mL, 9.00 mmol, 1 equiv). After purification by silica gel column chromatography (0–10% MeOH/DCM), 2i (1.11 g, 70%) was obtained as a white solid. mp 108.5–110 °C. FTIR (neat): 3014, 2954, 2924, 2868, 1548, 1388, 1326, 1165, 1032, 998, 853, 760, 542, 448 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ 4.30 (s, 1H), 3.34 (s, 6H), 2.05–1.95 (m, 3H), 0.88 (d, J = 6.3 Hz, 6H). ¹³C-NMR (100 MHz, CDCl₃) δ 190.6, 69.5, 50.2, 42.2, 26.2, 22.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₇O₂S⁺, 177.0944; found 177.0945.

4.2.3. Benzyl (S)-(4-(dimethyl(oxo)-λ⁶-sulfaneylidene)-3-oxobutan-2-yl)carbamate (2l)

Ylide 2l was prepared according to a literature procedure for a related compound.²³ To a flame-dried 100-mL 3-necked round bottom flask was added trimethylsulfoxonium iodide (3.52 g, 3.20 equiv, 15.0 mmol). The flask was connected to a flame-dried refluxed condenser, degassed, and filled with nitrogen. To the flask were added THF (15 mL) and potassium tert-butoxide (15.0 mL, 15.0 mmol, 1.00 M in THF, 3.00 equiv) sequentially. The reaction mixture was refluxed at 68 °C for 2 hours then slowly cooled to 0 °C. To the resulting mixture was added a solution of (4-nitrophenyl) (2S)-2-(benzyloxycarbonylamino)propanoate in THF (10 mL) dropwise over 15 min. After a stirring for one hour at 0 °C, the reaction was quenched by slow addition of water (5 mL), and the resulting mixture was stirred for another 15 min at 0 °C. The reaction mixture was slowly warmed to room temp and filtered through a pad of celite and washed with diethyl ether (10 mL). The filtrate was rinsed to a separatory funnel with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were sequentially washed with water (10 mL), brine (2 × 10 mL), dried (anhyd. Na₂SO₄), and concentrated under reduced pressure to afford the crude 2l as a light yellow solid (1.02 g). The crude 2l was then recrystallized with EtOAc:hexanes (1:10, ca. 55 mL; note: do not use heat to dissolve the crude in EtOAc) in a freezer for 2 hours and filtered to afford the title compound 2l as a light yellow solid (673 mg, 45% yield). ¹H and ¹³C NMR spectra matched with reported literature.²² Sulfoxonium ylide 2l was converted to the corresponding α-chloroketone by a literature procedure, LiCl and methansulfonic acid,²⁴ to confirm the enantiomeric purity; chiral HPLC analysis (Chiralpak-IB, 90:10 hexanes:isopropanol, flow rate = 1.0 mL/min) showed peaks at 15.7 min (2.0% (R)) and 17.9 min (98.0% (S)).

4.3. General Procedures for C–H Functionalization of C-Alkenyl Azoles with Sulfoxonium Ylides (0.3 mmol scale)

To a flame-dried 2–5 mL Biotage microwave reaction vial in a glove box was added alkenyl azole (0.3 mmol, 1 equiv), sulfoxonium ylide (0.600 mmol, 2 equiv), [Cp*Rh(MeCN)₃](SbF₆)₂ (10 mol %, 0.030 mmol, 25.0 mg), PivOH (0.600 mmol, 2 equiv, 61.2 mg), NaOAc (0.300 mmol, 1 equiv, 24.6 mg), and toluene (0.1 M, 3.0 mL). The vial was capped with a Teflon-lined cap, removed from the glove box, and the mixture was stirred at 120 °C for 16 h. The resultant mixture was then cooled to room temp, filtered through a pad of celite, washed thoroughly with acetone, and concentrated under reduced pressure. The product was purified by silica gel column chromatography.

4.3.1. 8-Methyl-5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3aa)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 159 mg of sulfoxonium ylide 2a. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3aa (59 mg, 71%) as a tan solid. mp 92.5–94.0 °C. FTIR (neat) 2920, 1323, 1173, 1101, 1060, 1015, 830, 704 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 7.92 (apparent s, 4H), 7.76 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.13 (dd, J = 7.0, 1.1 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 2.57 (s, 3H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 146.1, 138.6, 134.7, 133.0, 130.6 (q, J = 32.4 Hz), 129.1, 127.0, 126.1 (q, J = 3.8 Hz), 125.5, 123.0, 113.1, 111.1, 16.2. ¹⁹F-NMR (376 MHz, (CD₃)₂CO) δ –62.3. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₅H₁₂F₃N₂⁺, 277.0947; found 277.0944.

4.3.2. 8-Methyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3ab)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 126 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3ab (46 mg, 69%) as a yellow oil. FTIR (neat) 2920, 1511, 1483, 1330, 1302, 1273, 1247, 1146, 1097, 818, 787, 726, 699 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.62 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 1.3 Hz, 1H), 7.40–7.35 (m, 3H), 7.30–7.25 (m, 1H), 7.01 (dd, J = 7.0, 1.2 Hz, 1H), 6.62 (d, J = 6.9 Hz, 1H), 2.63 (s, 3H), 2.40 (s, 3H). ¹³C-NMR (151 MHz, CDCl₃) δ 146.3, 138.9, 136.4, 134.6, 132.4, 130.1, 128.9, 128.9, 126.0, 125.3, 123.6, 112.5, 111.4, 21.4, 17.1. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₅H₁₅N₂⁺, 223.1230; found 223.1232.

4.3.3. 5-(4-Methoxyphenyl)-8-methylimidazo[1,2-a]pyridine (3ac)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 136 mg of sulfoxonium ylide 2c. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3ac (45 mg, 63%) as a yellow oil. FTIR (neat) 1606, 1495, 1247, 1175, 1146, 1027, 813, 701, 596, 554, 506 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ 7.59 (dd, J = 14.7, 1.4 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.06– 6.96 (m, 3H), 6.59 (d, J = 7.0 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ 160.3, 146.5, 136.1, 132.6, 129.6, 127.1, 125.8, 123.5, 114.4, 112.3, 111.2, 55.4, 17.0. HRMS (ESI): m/z (M + H)⁺; calcd for C₁₅H₁₅N₂O⁺, 239.1179; found 239.1196.

4.3.4. 5-(4-Bromophenyl)-8-methylimidazo[1,2-a]pyridine (3ad)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 165 mg of sulfoxonium ylide 2d. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3ad (62 mg, 72%) as a white solid. mp 135–137 °C. FTIR (neat) 2918, 1484, 1196, 1146, 1100, 1074, 1010, 816, 704 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 8.4 Hz, 2H), 7.61–7.56 (m, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 6.9 Hz, 1H), 6.62 (d, J = 6.9 Hz, 1H), 2.63 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 146.4, 135.0, 133.6, 133.0, 132.4, 129.8, 126.8, 123.6, 123.4, 112.8, 111.1, 17.1. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₄H₁₂BrN₂⁺, 287.0178; found 287.0166.

4.3.5. 5-(Furan-2-yl)-8-methylimidazo[1,2-a]pyridine (3ae)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 112 mg of sulfoxonium ylide 2e. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3ae (35 mg, 59%) as a yellow solid. mp 63–65 °C. FTIR (neat) 3099, 1506, 1329, 1203, 1152, 754, 729, 590, 527 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 8.11 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.59 (dd, J = 1.8, 0.7 Hz, 1H), 7.10–7.00 (m, 2H), 6.85 (dd, J = 3.4, 0.7 Hz, 1H), 6.57 (dd, J = 3.5, 1.8 Hz, 1H), 2.63 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 147.6, 145.4, 143.1, 133.1, 126.8, 126.7, 123.1, 122.3, 111.8, 111.2, 109.6, 17.2. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₂H₁₁N₂O⁺, 199.0866; found 199.0869.

4.3.6. 8-Methyl-5-(thiophen-2-yl)imidazo[1,2-a]pyridine (3af)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 121 mg of sulfoxonium ylide 2f. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3af (44 mg, 68%) as a tan solid. mp 68–70 °C. FTIR (neat) 3103, 2918, 1656, 1494, 1412, 1328, 1274, 1147, 1100, 844, 812, 696, 525, 475 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 1.4 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.46–7.42 (m, 2H), 7.19–7.13 (m, 1H), 6.99 (dd, J = 7.1, 1.2 Hz, 1H), 6.80 (d, J = 7.1 Hz, 1H), 2.62 (s, 3H). ¹³C-NMR (101 MHz, CDCl₃) δ 146.4, 135.6, 132.9, 129.6, 127.7, 127.3, 127.0, 126.8, 123.2, 113.7, 111.7, 17.1. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₂H₁₁N₂S⁺, 215.0637; found 215.0642.

4.3.7. 8-Methyl-5-(pyridin-3-yl)imidazo[1,2-a]pyridine (3ag)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 118 mg of sulfoxonium ylide 2g. Purification by silica gel column chromatography (10–70% acetone/hexanes) afforded 3ag (40 mg, 64%) as a light yellow solid. mp 166–167.5 °C. FTIR (neat) 3034, 1511, 1480, 1420, 1304, 1271, 1147, 830, 800, 762, 709, 624, 530 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 8.81 (d, J = 2.4 Hz, 1H), 8.70 (d, J = 4.2 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.43 (dd, J = 7.8, 4.9 Hz, 1H), 7.04 (d, J = 6.9 Hz, 1H), 6.66 (d, J = 6.9 Hz, 1H), 2.62 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 150.5, 149.2, 146.4, 135.5, 133.2, 132.7, 130.7, 127.4, 123.7, 123.3, 113.5, 110.8, 17.1. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₃H₁₂N₃⁺, 210.1026; found 210.1029.

4.3.8. 5,8-Dimethylimidazo[1,2-a]pyridine (3ah)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 80.5 mg of sulfoxonium ylide 2h. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ah (40 mg, 91%) as a yellow oil. FTIR (neat) 3385, 2921, 1635, 1511, 1327, 1281, 1155, 1144, 1101, 809, 695, 524 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.65 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 1.2 Hz, 1H), 6.90 (dd, J = 6.9, 1.2 Hz, 1H), 6.49 (dd, J = 6.8, 1.1 Hz, 1H), 2.57 (s, 3H), 2.50 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 146.1, 132.8, 132.0, 124.6, 123.4, 111.3, 109.8, 18.5, 16.9. HRMS (ESI): m/z (M + H)⁺ calcd for C₉H₁₁N₂⁺, 147.0917; found 147.0916.

4.3.9. 5-Isobutyl-8-methylimidazo[1,2-a]pyridine (3ai)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 106 mg of sulfoxonium ylide 2i. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ai (41 mg, 73%) as a yellow oil. FTIR (neat) 2956, 1509, 1465, 1328, 1277, 1259, 1153, 832, 803, 695, 523 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.62 (s, 1H), 7.47 (s, 1H), 6.90 (dd, J = 6.9, 1.2 Hz, 1H), 6.45 (d, J = 6.9 Hz, 1H), 2.68 (d, J = 7.2 Hz, 2H), 2.55 (s, 3H), 2.15–2.05 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H). ¹³C-NMR (151 MHz, CDCl₃) δ 146.3, 135.2, 132.5, 124.6, 123.4, 111.6, 110.0, 41.6, 25.1, 22.6, 16.9. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₂H₁₇N₂⁺, 189.1386; found 189.1389.

4.3.10. 5-Isopropyl-8-methylimidazo[1,2-a]pyridine (3aj)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 97.3 mg of sulfoxonium ylide 2j. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3aj (38 mg, 73%) as a yellow solid. mp 71–73 °C. FTIR (neat) 3092, 2967, 1710, 1631, 1509, 1328, 1274, 1247, 1147, 822, 814, 746, 532 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.65 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 1.4 Hz, 1H), 6.95 (dd, J = 7.0, 1.3 Hz, 1H), 6.53 (d, J = 7.1 Hz, 1H), 3.16 (heptet, J = 6.8 Hz, 1H), 2.57 (s, 3H), 1.35 (d, J = 6.9 Hz, 6H). ¹³C-NMR (150 MHz, CDCl₃) δ 146.2, 141.9, 132.6, 124.6, 123.5, 109.8, 107.2, 29.9, 20.2, 16.9. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₁H₁₅N₂⁺, 175.1230; found 175.1233.

4.3.11. tert-Butyl 4-(8-methylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3ak)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ak (66 mg, 70%) as a yellow foamy solid. mp 48–50 °C (after trituration with pentane). FTIR (neat) 2924, 1684, 1421, 1364, 1275, 1231, 1158, 1125, 1030, 979, 870, 817, 695, 531 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 7.92 (d, J = 1.3 Hz, 1H), 7.59 (s, 1H), 7.00 (dd, J = 7.1, 1.3 Hz, 1H), 6.60 (d, J = 7.1 Hz, 1H), 4.35–4.15 (m, 2H), 3.20 (tt, J = 11.9, 3.3 Hz, 1H), 3.10–2.85 (m, 2H), 2.50 (s, 3H), 2.10–2.00 (m, 2H), 1.57 (qd, J = 12.5, 4.2 Hz, 2H), 1.45 (s, 9H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 154.1, 146.0, 139.8, 132.7, 124.7, 123.0, 110.1, 107.6, 78.6, 43.6, 37.9, 29.7, 27.7, 16.0. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₈H₂₆N₃O₂⁺, 316.2020; found 316.2022.

4.3.12. Benzyl (S)-(1-(8-methylimidazo[1,2-a]pyridin-5-yl)ethyl)carbamate (3al)

The reaction was performed according to the general procedure employing 32.5 mg of alkenyl azole 1a and 178 mg of sulfoxonium ylide 2l. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3al (54 mg, 58%) as a tan solid. mp 141–143 °C. Chiral HPLC analysis (Chiralcel-OD-H, 90:10 hexanes:isopropanol, flow rate = 1.0 mL/min) showed peaks at 38.0 min (23.3% (R)) and 45.5 min (76.6% (S)). FTIR (neat) 1698, 1553, 1247, 1050, 822, 739, 699 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.65 (s, 1H), 7.58 (s, 1H), 7.32–7.23 (m, 5H), 6.89 (dd, J = 7.0, 1.3 Hz, 1H), 6.64 (d, J = 7.0 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.18 (p, J = 7.2 Hz, 1H), 5.10 (s, 2H), 2.53 (s, 3H), 1.60 (d, J = 6.9 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 155.9, 146.1, 136.1, 135.9, 133.1, 128.5, 128.2, 128.0, 126.7, 122.6, 110.9, 108.7, 67.1, 46.7, 18.9, 16.9. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₈H₂₀N₃O₂⁺, 310.1550; found 310.1551.

4.3.13. 7,8-Dimethyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3bb)

The reaction was performed according to the general procedure employing 36.7 mg of alkenyl azole 1b and 126 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3bb (68 mg, 96%) as a yellow oil. FTIR (neat) 2920, 1507, 1483, 1298, 1153, 1091, 856, 788, 728, 698 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.56 (d, J = 1.3 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.40–7.35 (m, 3H), 7.30–7.25 (m, 1H), 6.55 (s, 1H), 2.57 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 147.0, 138.8, 135.1, 134.6, 132.5, 131.6, 130.0, 128.9, 128.9, 125.3, 122.7, 116.2, 110.8, 21.4, 18.6, 13.2. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₆H₁₇N₂⁺, 237.1386; found 237.1385.

4.3.14. 8-Methyl-7-phenyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3cb)

The reaction was performed according to the general procedure employing 55.3 mg of alkenyl azole 1c and 126 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3cb (79 mg, 88%) as a yellow oil. FTIR (neat) 2922, 1506, 1481, 1300, 1141, 771, 728, 699, 522 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.68 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.45–7.35 (m, 8H), 7.31–7.27 (m, 1H), 6.75 (s, 1H), 2.63 (s, 3H), 2.42 (s, 3H). ¹³C-NMR (151 MHz, CDCl₃) δ 146.8, 139.7, 138.9, 136.5, 135.5, 134.4, 133.2, 130.2, 129.3, 128.9, 128.3, 127.4, 125.3, 122.6, 115.4, 111.2, 21.5, 14.6. HRMS (ESI): m/z (M + H)⁺ calcd for C₂₁H₁₉N₂⁺, 299.1543; found 299.1541.

4.3.15. 2,8-Dimethyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3db)

The reaction was performed according to the general procedure employing 36.7 mg of alkenyl azole 1d and 126 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3db (43 mg, 61%) as a yellow oil. FTIR (neat) 2922, 1545, 1510, 1482, 1445, 1324, 1246, 1146, 838, 787, 741, 700 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.40–7.35 (m, 4H), 7.30–7.25 (m, 1H), 6.98 (dd, J = 7.0, 1.1 Hz, 1H), 6.57 (d, J = 7.0 Hz, 1H), 2.62 (s, 3H), 2.43 (s, 3H). 2.42 (s, 3H). ¹³C-NMR (151 MHz, CDCl₃) δ 146.0, 142.2, 138.8, 135.8, 134.8, 130.0, 128.9, 128.8, 125.3, 125.0, 123.5, 112.0, 108.5, 21.4, 17.2, 14.4. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₆H₁₇N₂⁺, 237.1386; found 237.1389.

4.3.16. 2,3,8-Trimethyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3eb)

The reaction was performed according to the general procedure employing 40.9 mg of alkenyl azole 1e and 126 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3eb (42 mg, 56%) as a yellow oil. FTIR (neat) 2922, 1506, 1482, 1438, 1358, 1249, 1157, 838, 787, 753, 707 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 7.31–7.24 (m, 2H), 7.18–7.14 (m, 2H), 6.89 (d, J = 6.9 Hz, 1H), 6.46 (d, J = 6.9 Hz, 1H), 2.61 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H), 1.74 (s, 3H). ¹³C-NMR (151 MHz, CDCl₃) δ 145.3, 139.8, 137.3, 136.3, 135.3, 130.5, 129.4, 127.5, 127.0, 125.2, 121.8, 117.9, 113.9, 21.4, 17.2, 13.4, 12.4. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₇H₁₉N₂⁺, 251.1543; found 251.1541.

4.3.17. tert-Butyl 4-(7,8-dimethylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3bk)

The reaction was performed according to the general procedure employing 36.7 mg of alkenyl azole 1b and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3bk (78 mg, 79%) as a tan foamy solid. mp 125–127 °C (after trituration with pentane). FTIR (neat) 2923, 1690, 1424, 1364, 1280, 1231, 1160, 1119, 978, 865, 766, 656, 542 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 7.82 (d, J = 1.3 Hz, 1H), 7.52 (d, J = 1.3 Hz, 1H), 6.54 (s, 1H), 4.36–4.14 (m, 2H), 3.15 (tt, J = 11.9, 3.2 Hz, 1H), 3.10–2.78 (m, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 2.10–2.00 (m, 2H), 1.58 (qd, J = 12.5, 4.2 Hz, 2H), 1.45 (s, 9H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 154.1, 146.6, 138.4, 132.6, 130.9, 121.3, 111.1, 109.5, 78.6, 43.6, 37.8, 29.8, 27.7, 17.7, 12.2. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₉H₂₈N₃O₂⁺, 330.2176; found 330.2179.

4.3.18. tert-Butyl 4-(8-methyl-7-phenylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3ck)

The reaction was performed according to the general procedure employing 55.3 mg of alkenyl azole 1c and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ck (104.5 mg, 89%) as a tan foamy solid. mp 136–138 °C (after trituration with pentane). FTIR (neat) 2926, 1689, 1423, 1365, 1231, 1163, 872, 772, 703, 542 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 7.96 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 1.3 Hz, 1H), 7.47–7.35 (m, 5H), 6.65 (s, 1H), 4.34–4.15 (m, 2H), 3.26 (tt, J = 11.9, 3.3 Hz, 1H), 3.10–2.80 (m, 2H), 2.49 (s, 3H), 2.15–2.07 (m, 2H), 1.65 (qd, J = 12.2, 3.9 Hz, 2H), 1.43 (s, 9H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 154.1, 146.3, 140.0, 139.0, 135.7, 133.2, 129.3, 128.3, 127.3, 121.1, 110.4, 110.1, 78.6, 43.6, 38.0, 29.7, 27.7, 13.8. HRMS (ESI): m/z (M + H)⁺ calcd for C₂₄H₃₀N₃O₂⁺, 392.2333; found 392.2336.

4.3.19. tert-Butyl 4-(2,8-dimethylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3dk)

The reaction was performed according to the general procedure employing 36.7 mg of alkenyl azole 1d and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3dk (74 mg, 75%) as a yellow oil. FTIR (neat) 2924, 1685, 1420, 1365, 1230, 1161, 1122, 980, 871, 817, 541 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 7.67 (s, 1H), 6.95 (dd, J = 7.3, 1.3 Hz, 1H), 6.54 (d, J = 7.1 Hz, 1H), 4.33–4.10 (m, 2H), 3.12 (tt, J = 12.0, 3.3 Hz, 1H), 3.07–2.85 (m, 2H), 2.46 (s, 3H), 2.38 (s, 3H), 2.10–2.01 (m, 2H), 1.55 (qd, J = 12.1, 3.9 Hz, 2H), 1.45 (s, 9H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 154.1, 145.5, 142.3, 139.2, 123.7, 122.8, 107.2, 107.1, 78.6, 43.8, 38.0, 29.6, 27.7, 16.0, 13.7. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₉H₂₈N₃O₂⁺, 330.2176; found 330.2178.

4.3.20. tert-Butyl 4-(2,3,8-trimethylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3ek)

The reaction was performed according to the general procedure employing 40.9 mg of alkenyl azole 1e and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ek (72 mg, 70%) as a yellow foamy solid. mp 60–62 °C (after trituration with pentane). FTIR (neat) 2927, 1687, 1421, 1364, 1230, 1160, 1125, 1014, 978, 871, 818, 769, 541 cm⁻¹. ¹H-NMR (400 MHz, (CD₃)₂CO) δ 6.84 (dd, J = 7.2, 1.3 Hz, 1H), 6.53 (d, J = 7.1 Hz, 1H), 4.30–4.10 (m, 2H), 3.71 (tt, J = 11.3, 2.9 Hz, 1H), 3.05–2.80 (m, 2H), 2.69 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H), 2.02–1.95 (m, 2H), 1.55 (qd, J = 12.6, 4.2 Hz, 2H), 1.45 (s, 9H). ¹³C-NMR (100 MHz, (CD₃)₂CO) δ 154.2, 145.5, 141.8, 140.0, 124.1, 121.8, 116.7, 108.2, 78.6, 43.5, 36.3, 32.5, 27.7, 16.2, 12.8, 12.2. HRMS (ESI): m/z (M + H)⁺ calcd for C₂₀H₃₀N₃O₂⁺, 344.2333; found 344.2340.

4.3.21. 2,8-Dimethyl-5-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (3ga)

The reaction was performed according to the general procedure employing 36.9 mg of alkenyl azole 1g and 159 mg of sulfoxonium ylide 2a. Purification by silica gel column chromatography (5–20% acetone/hexanes) afforded 3ga (23 mg, 26%) as a yellow oil. FTIR (neat) 1619, 1533, 1506, 1478, 1320, 1165, 1112, 1064, 1016, 848, 816 cm⁻¹. ¹H-NMR (600 MHz, CDCl₃) δ 8.03 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.33 (dd, J = 7.3, 1.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 2.65 (s, 3H), 2.61 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ 163.0, 152.2, 136.6, 136.0, 131.4 (q, J = 32.8 Hz), 129.3, 128.2, 125.8, 125.5 (q, J = 3.9 Hz), 123.8 (q, J = 272.3 Hz), 113.7, 17.0, 14.6. ¹⁹F-NMR (470 MHz, CDCl₃) δ –62.9. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₅H₁₃F₃N₃⁺, 292.1056; found 292.1054.

4.3.22. tert-Butyl 4-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperidine-1-carboxylate (3gk)

The reaction was performed according to the general procedure employing 36.9 mg of alkenyl azole 1g and 182 mg of sulfoxonium ylide 2k. Purification by silica gel column chromatography (5–20% acetone/hexanes) afforded 3gk (74 mg, 75%) as a yellow oil. FTIR (neat) 2974, 2927, 1687, 1418, 1365, 1234, 1161, 1124, 873, 730, 546 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ 7.17 (dd, J = 7.3, 1.3 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 4.40–4.10 (m, 2H), 3.54 (tt, J = 12.1, 3.4 Hz, 1H), 2.92 (t, J = 12.3 Hz, 2H), 2.59 (s, 3H), 2.54 (s, 3H), 2.15–2.03 (m, 2H), 1.68–1.02 (m, 2H), 1.45 (s, 9H). ¹³C-NMR (100 MHz, CDCl₃) δ 162.5, 154.7, 151.7, 142.4, 128.1, 123.4, 108.8, 79.6, 43.9, 36.9, 29.8, 28.4, 16.7, 14.6. HRMS (ESI): m/z (M + H)⁺ calcd for C₁₈H₂₇N₄O₂⁺, 331.2129; found 331.2126.

4.4. General Procedures for C–H Functionalization of C-Alkenyl Azoles with Sulfoxonium Ylides (2.0 mmol scale)

On the bench-top, to a flame-dried 50 mL RBF was added alkenyl azole (2.00 mmol, 1 equiv), sulfoxonium ylide (4.00 mmol, 2 equiv), [Cp*Rh(MeCN)₃](SbF₆)₂ (5 mol %, 0.10 mmol, 83 mg), PivOH (4.00 mmol, 2 equiv, 408 mg), and NaOAc (2.00 mmol, 1 equiv, 164 mg). The flask was connected to a reflux condenser, degassed three times, followed by the addition of xylenes (0.1 M, 20 mL). The resulting mixture was stirred at 120 °C for 16 h. The mixture was then cooled to room temp, filtered through a pad of celite, washed thoroughly with acetone, and concentrated under reduced pressure. The product was purified by silica gel column chromatography.

4.4.1. 8-Methyl-5-(m-tolyl)imidazo[1,2-a]pyridine (3ab)

The reaction was performed according to the general procedure employing 216 mg of alkenyl azole 1a and 841 mg of sulfoxonium ylide 2b. Purification by silica gel column chromatography (10–30% acetone/hexanes) afforded 3ab (280 mg, 63%) as a yellow oil. ¹H and ¹³C NMR spectra matched with 3ab obtained from smaller scale (0.3 mmol).

4.4.2. tert-Butyl 4-(8-methylimidazo[1,2-a]pyridin-5-yl)piperidine-1-carboxylate (3ak)

The reaction was performed according to the general procedure employing 216 mg of alkenyl azole 1a and 1.21 g of sulfoxonium ylide 2k. Purification by silica gel column chromatography (10–50% acetone/hexanes) afforded 3ak (448 mg, 71%) as a yellow foamy solid. ¹H and ¹³C NMR spectra matched with 3ak obtained from smaller scale (0.3 mmol).

Figure 1.

Sulfoxonium ylide scope in Rh(III)-catalyzed C–H functionalization of C-alkenyl imidazole