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. Author manuscript; available in PMC: 2021 Jul 20.
Published in final edited form as: Synthesis (Stuttg). 2020;52(8):1247–1252. doi: 10.1055/s-0039-1690756

Rhodium(III)-Catalyzed Three-Component 1,2-Diamination of Unactivated Terminal Alkenes

Sumin Lee 1, Young Jin Jang 1, Erik J T Phipps 1, Honghui Lei 1, Tomislav Rovis 1
PMCID: PMC8290961  NIHMSID: NIHMS1609704  PMID: 34290458

Abstract

We report a three-component diamination of simple unactivated alkenes using an electrophilic nitrene source and amine nucleophiles. The reaction provides rapid access to 1,2-vicinal diamines from terminal alkenes through a one-pot protocol. The transformation proceeds smoothly with excellent tolerance for a broad array of primary and secondary amines, affording the desired product with good yield and regioselectivity. The mechanism is proposed to proceed through a Rh(III)-catalyzed aziridination of alkenes with subsequent ring opening by primary or secondary amines.

Keywords: alkene diamination, Rh(III)-catalysis, One-pot synthesis, nitrene

Graphical Abstract

graphic file with name nihms-1609704-f0001.jpg

The 1,2-vicinal diamine is a prevalent structural motif in natural products and pharmaceuticals. Moreover, they are commonly utilized as ligands on various metal complexes to catalyze essential organic transformations.1 Owing to the high demand, the development of efficient synthetic strategies for the synthesis of 1,2-diamines has been actively pursued. Several notable synthetic approaches exist including aza-Henry reaction,2 Mannich reaction between α-amino-compounds and imines,3 and the addition of nucleophile into α-amino imines.4 Among the potential synthetic precursors for the synthesis of vicinal amines, alkenes are ideal – they are ubiquitous feedstock materials, and unreactive functionality that is well tolerated in other transformations. Thus, the simultaneous addition of two nitrogen functionalities to the alkene double bond is a straightforward and useful way to access 1,2-vicinal diamines (Scheme 1). However, aside from some prominent successes,5,6 transition-metal-catalyzed 1,2-diamination of alkenes is significantly underdeveloped compared to the much better established dihydroxylation and aminohydroxylation of alkenes. Presumably, this is because 1,2-diamines are generally good ligands and can act as a chelating ligand for the metal complex.

Scheme 1.

Scheme 1

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Transition metal-catalyzed alkene diaminations

Alternatively, the nucleophilic ring opening of aziridines by amines is an efficient strategy to access diamines from readily available starting materials.7 Recently, we reported a Rh(III)-catalyzed formal [4+1] approach to pyrrolidines from simple unactivated terminal alkenes and nitrene sources.8 Mechanistic investigations led us to propose a Rh-catalyzed intermolecular aziridination with subsequent ring expansion by triflic acid for the synthesis of 5-membered saturated N-heterocycle.

Motivated by the fact that aziridine formation is highly efficient in this system, we envisioned that this intermediate can be utilized for the one-pot synthesis of vicinal diamines in the presence of exogenous nitrogen nucleophiles. In order to test this idea, we added morpholine (2a) as amine nucleophile after the initial aziridination of 1-hexene (1a) and 4-methyl-N-(pivaloyloxy)benzenesulfonamide (Ts-NH-OPiv) in the presence of a catalytic amount of Cs2CO3 (0.1 equiv.) and [Ind*RhCl2]2 catalyst (2.5 mol%) in HFIP.

Preliminary results showed that when 2 equiv. of morpholine was added and stirred at room temperature and 40 °C, desired diamination products were formed as a single regioisomer albeit low yield (entry 1, 2). Increasing reaction temperature to 80 °C further improved the reaction yield to 63% (entry 3). Since we observed unreacted aziridine on workup, longer reaction time and higher concentration were applied to complete the reaction, and the yield of 3aa improved to 87% when the reaction was conducted at 80 °C for 16 hours in 0.2 M of HFIP (entry 6). Lewis acid-promoted aziridine ring opening by amines is well-known;7 however, adding AgSbF6 together with morpholine after aziridination gives a lower yield of 3aa (entry 4). Finally, a quantitative yield of the desired product is observed at 0.2 M with 3 equiv. of morpholine (entry 7). Having optimized the reaction conditions, we next sought to explore the scope of this methodology. First, various commercially available primary and secondary amines were examined using 1-hexene as an alkene coupling partner (Scheme 2). Cyclic secondary amines such as pyrrolidine (2b) and piperidine (2c) provide diamination products with good yield (3ab, 3ac). Bicyclic 1,2,3,4-tetrahydroisoquinoline (2d) also works well as a nucleophile giving 65% of corresponding 1,2-diamine (3ad). The reaction with dibutyl amine also delivers 1,2-vicinal diamine product with good yield (3ae). The reaction also proceeds smoothly with primary amines, giving desired products (3af - 3ai) in good yield. When aniline (2h) and 4-methoxyaniline (2i) are used as a nucleophile, the minor regioisomer is also observed in small amounts. Hydrazine-type nucleophile (1-aminopyrrolidine) was also tested but only trace amount of desired product was observed.

Scheme 2.

Scheme 2

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Amine Nucleophile Substrate Scope a Determined by 1H NMR analysis of unpurified reaction mixture

Next, we tested the synthetic utility of this method with a variety of terminal unactivated alkene substrates (Scheme 3). Allyl cyclohexane and 2-allyladamantane are successfully converted to the corresponding diamination products in good yield (3ba, 3ca). A variety of functional groups such as phenyl (3da), tert-butyldiphenylsilyl protected alcohol (3ea), ethyl ester (3fa), and protected amine (3ga) are all well tolerated, giving the desired 1,2-diamination product in good yield.

Scheme 3.

Scheme 3

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Terminal Alkene Substrate Scope

Based on our previous work8 and aziridine ring opening precedent,7 we propose the following mechanism for the reaction. First, [Ind*RhCl2]2 catalyst metalates Ts-NH-OPiv to generate Rh complex II, which undergoes Rh-nitrene formation to yield intermediate III. Subsequent aziridination with an unactivated alkene coupling partner (1a) would give aziridine intermediate with the regeneration of active Rh(III) catalyst. Alternatively, the alkene coupling partner (1a) can coordinate with Rh complex II and undergoes alkene migratory insertion to form complex IV. Subsequent C-N bond formation and N-O bond cleavage would generate aziridine intermediate. Nucleophilic attack of primary and/or secondary amines to sterically less hindered terminal carbon of aziridine produces diamination products at elevated temperature.

In summary, we demonstrate the one-pot synthesis of vicinal diamines from readily available α-olefins through Rh(III)-catalyzed aziridination and subsequent nucleophilic attack by exogenous amines. The reaction exhibits broad functional group tolerance with good yield and regioselectivity.

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HFIP, Cs2CO3 and 1a, 1b, 1d, 1f, 2a-2i were purchased from Sigma Aldrich and used without further purification. 1c,8 1e,9 1g10 and [Ind*RhCl2]2 catalyst11 were synthesized following literature procedures. 1H and 13C NMR spectra were collected at ambient temperature on Bruker 400 MHz and Bruker Avance III 500 MHz spectrometers. Regioisomeric ratios were measured by integration of 1H NMR spectra of product mixtures prior to purification. Low resolution mass spectra were recorded on a Waters Acquity UPLC-MS or Agilent 5977B GC/MS. Infrared spectra were collected on a Perkin Elmer Spectrum Two FT-IR Spectrometer. Melting point were measured by Stanford Research System MPA160 melting point apparatus.

General Procedures

To a 1 dram vial, [Ind*RhCl2]2 (0.0025 mmol, 2.5 mol%), Ts-NH-OPiv (0.13 mmol, 1.3 equiv) and Cs2CO3 (0.01 mmol, 0.1 equiv) were measured and dissolved in HFIP (0.2 M) and stirred 16 hours at 22 °C. Then, amine (0.3 mmol, 3 equiv) was added to the vial and heated to 80 °C and stirred for additional 16 hours. The mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography either manually on SiliCycle® SilicaFlash® P60 (230-400 mesh) silica gel or automatically using a Teledyne Isco Lumen CombiFlash with RediSep Rf Disposable Flash columns.

4-methyl-N-(1-morpholinohexan-2-yl)benzenesulfonamide (3aa)

Yield: 20.4 mg, 98%, yellow oil.

Rf = 0.35 (EA/Hex 1:1).

1H NMR (500 MHz, CDCl3) δ 7.76 (m, 2H), 7.29 (m, 2H), 3.53 – 3.44 (m, 4H), 3.13 – 3.04 (m, 1H), 2.41 (s, 3H), 2.24 (d, J = 7.4 Hz, 2H), 2.21 – 2.12 (m, 1H), 2.11 – 2.03 (m, 1H), 2.07 (dt, J = 11.0, 4.3 Hz, 2H), 1.67 (ddd, J = 14.4, 9.6, 4.6 Hz, 1H), 1.53 (dddd, J = 14.0, 11.2, 7.3, 4.1 Hz, 1H), 1.29 – 1.18 (m, 3H), 1.17 – 1.08 (m, 1H), 0.84 (t, J = 6.9 Hz, 3H).

13C NMR (126 MHz, CDCl3) δ 143.5, 137.2, 129.7, 127.4, 66.8, 61.1, 53.3, 50.0, 33.1, 26.9, 22.8, 21.6, 14.1.

IR (CDCl3, cm−1) ν 3272, 2954, 2928, 2858, 1598, 1453, 1329, 1302, 1159, 1115, 1092, 815, 665, 550.

LRMS (ESI) m/z [C17/H29N2O3S]+ ([M+H]+ ) calculated 341.2, found 341.1.

4-methyl-N-(1-(pyrrolidin-1-yl)hexan-2-yl)benzenesulfonamide (3ab)

Yield: 25.2 mg, 78%, pale-yellow oil.

Rf = 0.16 (DCM:MeOH 19:1).

1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.43 (s, 1H), 3.01 (ddt, J = 9.4, 7.3, 4.6 Hz, 1H), 2.51 (dd, J = 12.3, 9.6 Hz, 1H), 2.41 (s, 3H), 2.32 – 2.21 (m, 3H), 2.16 (td, J = 8.2, 4.4 Hz, 2H), 1.75 – 1.56 (m, 5H), 1.51 (dddd, J = 14.2, 11.3, 7.2, 4.2 Hz, 1H), 1.31 – 1.02 (m, 3H), 0.83 (t, J = 6.9 Hz, 3H).

13C NMR (126 MHz, CDCl3) δ 143.3, 137.3, 129.6, 127.4, 58.3, 54.0, 52.3, 33.2, 27.0, 23.7, 22.8, 21.7, 14.1.

IR (CDCl3, cm−1) ν 3287, 2958, 2928, 1382, 1320, 1159, 1093, 909, 731, 660, 549.

LRMS (ESI) m/z [C17H28N2O2S]+ ([M+H]+) calculated 325.2, found 325.2.

4-methyl-N-(1-(piperidin-1-yl)hexan-2-yl)benzenesulfonamide (3ac)

Yield: 24.8 mg, 73%, yellow oil.

Rf = 0.27 (EA/Hex 1:1).

1H NMR (400 MHz, CDCl3) δ 7.80 – 7.71 (m, 2H), 7.33 – 7.25 (m, 2H), 3.07 (ddt, J = 10.3, 8.2, 4.2 Hz, 1H), 2.41 (s, 3H), 2.28 (dd, J = 12.7, 10.3 Hz, 1H), 2.19 (dd, J = 12.6, 4.7 Hz, 1H), 2.15 – 2.04 (m, 3H), 1.70 (ddt, J = 10.2, 8.8, 4.1, Hz, 1H), 1.56 – 1.46 (m, 1H), 1.45 – 1.32 (m, 6H), 1.32 – 1.16 (m, 6H), 1.15 – 1.05 (m, 1H), 0.84 (t, J = 7.1 Hz, 3H).

13C NMR [101 MHz, CDCl3) δ 143.2, 137.3, 129.6, 127.4, 60.9, 54.2, 50.1, 38.7, 33.2, 27.3, 26.9, 25.7, 24.1, 22.8, 21.6, 14.1.

IR (CDCl3, cm−1) ν 2930, 2859, 1709, 1597, 1553, 1455, 1404, 1332, 1160, 1093, 664, 550.

LRMS (ESI) m/z [C18H31N2O2S]+ ([M+H]+ ) calculated 339.2, found 339.1.

N-(1-(3,4-dihydroisoquinolin-2(1H)-yl)hexan-2-yl)-4-methylbenzenesulfonamide (3ad)

Yield: 25 mg, 65%, yellow solid.

Rf = 0.65 (EA/Hex 1:1).

M.P.= 94 - 98 (°C)

1H NMR (500 MHz, CDCl3) δ 7.73 – 7.67 (m, 2H), 7.22 – 7.17 (m, 2H), 7.17 – 7.04 (m, 3H), 6.78 – 6.73 (m, 1H), 3.28 (d, J = 14.8 Hz, 1H), 3.23 – 3.11 (m, 2H), 2.85 – 2.76 (m, 1H), 2.69 (dt, J = 16.4, 5.4 Hz, 1H), 2.57 (dt, J = 11.2, 5.5 Hz, 1H), 2.50 (ddd, J = 15.3, 8.0, 4.3 Hz, 1H), 2.47 – 2.41 (m, 2H), 2.41 (s, 3H), 1.80 – 1.71 (m, 1H), 1.64 – 1.54 (m, 1H), 1.35 – 1.14 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H).

13C NMR (126 MHz, CDCl3) δ 143.3, 137.0, 134.0, 129.7, 128.7, 127.3, 126.6, 126.4, 125.7, 60.7, 55.5, 51.1, 50.6, 33.2, 29.1, 27.2, 27.0, 22.9, 21.7, 14.1.

IR (CDCl3, cm−1) ν 3276, 2954, 2926, 2867, 1598, 1454, 1328, 1160, 1093, 903, 813, 741, 666, 550.

LRMS (ESI) m/z [C22H31N2O2S]+ ([M+H]+ ) calculated 387.2, found 387.2.

N-(1-(dibutylamino)hexan-2-yl)-4-methylbenzenesulfonamide (3ae)

Yield: 26.4 mg, 69%, pale-yellow oil.

Rf = 0.31 (DCM:MeOH 19:1).

1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.39 (s, 1H), 2.99 (tt, J = 9.2, 4.6 Hz, 1H), 2.40 (s, 3H), 2.37 – 2.04 (m, 6H), 1.68 (dtd, J = 12.5, 7.2, 6.4, 3.3 Hz, 1H), 1.52 (dddd, J = 14.0, 11.4, 7.3, 4.1, Hz, 1H), 1.34 – 1.18 (m, 6H), 1.13 (m, 6H), 0.90 – 0.80 (m, 9H).

13C NMR (126 MHz, CDCl3) δ 143.3, 137.3, 129.6, 127.5, 57.2, 53.5, 51.1, 32.8, 28.7, 26.9, 22.9, 21.6, 20.7, 14.2, 14.2.

IR (CDCl3, cm−1) ν 3286, 2976, 2863, 1381, 1349, 1118, 1075, 916, 733, 662, 548.

LRMS (ESI) m/z [C21H38N2O2S]+ ([M+H]+) calculated 383.3, found 383.3.

N-(1-(cyclopentylamino)hexan-2-yl)-4-methylbenzenesulfonamide (3af)

Yield: 28 mg, 83%, clear brown oil

Rf = 0.3 (DCM/MeOH 95:5)

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 3.16 (p, J = 6.4 Hz, 1H), 2.85 (p, J = 6.5 Hz, 1H), 2.49 (s, 1H), 2.48 (s, 1H), 2.41 (s, 2H), 1.76 – 1.55 (m, 2H), 1.53 – 1.33 (m, 2H), 1.23 – 1.09 (m, 3H), 0.79 (t, J = 6.9 Hz, 1H).

13C NMR (126 MHz, CDCl3) δ 143.3, 138.0, 129.7, 127.3, 59.6, 53.5, 50.9, 33.0, 32.9, 27.7, 24.0, 23.9, 22.6, 21.6, 14.0.

IR (CDCl3, cm−1) ν 3278, 2953, 2930, 2862, 1598, 1454, 1325, 1157, 1092, 905, 814, 723.

LRMS (ESI) m/z [C18H31N2O2S]+ ([M+H]+ ) calculated 339.2, found 339.2

4-methyl-N-(1-(pentylamino)hexan-2-yl)benzenesulfonamide (3ag)

Yield: 20 mg, 59%, beige solid.

Rf = 0.2 (DCM/MeOH 95:5)

M.P.= 59 - 63 (°C)

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.20 – 3.10 (m, 1H), 2.49 – 2.45 (m, 2H), 2.42 (s, 3H), 2.40 – 2.26 (m, 2H), 1.52 – 1.37 (m, 2H), 1.36 – 1.26 (m, 4H), 1.24 – 1.12 (m, 6H), 0.89 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 6.8 Hz, 3H).

13C NMR (126 MHz, CDCl3) δ 143.3, 138.0, 129.7, 127.3, 53.3, 52.4, 49.8, 33.4, 29.9, 29.5, 27.6, 22.7, 22.6, 21.6, 14.2, 14.0.

IR (CDCl3, cm−1) ν 3278, 2955, 2926, 2857, 1459, 1326, 1159, 1093, 814, 664.

LRMS (ESI) m/z [C18H31N2O2S]+ ([M+H]+ ) calculated 341.2, found 341.2

4-methyl-N-(1-(phenylamino)hexan-2-yl)benzenesulfonamide (3ah)

Yield: 23.0 mg, 66%, 5.0:1 rr, yellow oil.

Rf = 0.30 (EA/Hex 1:4).

Major isomer: 1H NMR [500 MHz, CDCl3) δ 7.80 – 7.76 (m, 2H), 7.31 – 7.26 (m, 2H), 7.18 – 7.13 (m, 2H), 6.76 – 6.69 (m, 1H), 6.52 – 6.46 (m, 2H), 4.84 (d, J = 7.9 Hz, 1H), 3.45 – 3.36 (m, 1H), 3.17 (dd, J = 12.9, 4.7 Hz, 1H), 3.06 (dd, J = 12.9, 7.3 Hz, 1H), 2.44 (s, 3H), 1.55 – 1.47 (m, 1H), 1.45 – 1.38 (m, 1H), 1.22 – 1.06 (m, 4H), 0.79 (t, J = 7.0 Hz, 3H).

Major isomer: 13C NMR (126 MHz, CDCl3) δ 147.7, 143.5, 137.6, 129.7, 129.2, 127.2, 117.7, 112.9, 53.5, 48.1, 33.3, 27.6, 22.4, 21.5, 13.8.

IR (CDCl3, cm−1) ν 3400, 3280, 2954, 2930, 2861, 1602, 1508, 1322, 1157, 1091, 749, 665, 550.

LRMS (ESI) m/z [C19H27N2O2S]+ ([M+H]+ ) calculated 347.2, found 347.1.

N-(1-((4-methoxyphenyl)amino)hexan-2-yl)-4-methylbenzenesulfonamide (3ai)

Yield: 22.0 mg, 58%, 7.0:1 rr, yellow oil.

Rf = 0.77 (EA/Hex 1:1).

Major isomer:

1H NMR (500 MHz, CDCl3) δ 7.76 – 7.72 (m, 2H), 7.28 – 7.24 (m, 2H), 6.78 – 6.70 (m, 2H), 6.46 – 6.41 (m, 2H), 4.79 (d, J = 7.8 Hz, 1H), 3.74 (s, 4H), 3.40 – 3.32 (m, 1H), 3.09 (dd, J = 12.8, 4.6 Hz, 1H), 2.97 (dd, J = 12.8, 7.2 Hz, 1H), 2.42 (s, 3H), 1.53 – 1.33 (m, 2H), 1.28 – 1.20 (m, 1H), 1.20 – 1.02 (m, 4H), 0.77 (t, J = 7.0 Hz, 3H).

Major isomer:

13C NMR (126 MHz, CDCl3) δ 152.5, 144.4, 142.0, 137.8, 129.8, 127.3, 114.9, 113.8, 55.9, 52.8, 50.1, 35.1, 27.7, 22.5, 20.2, 12.3.

IR (CDCl3, cm−1) ν 3278, 2953 2930, 2860, 1512, 1463, 1322, 1236, 1157, 1091, 1037, 903, 817, 725, 664.

LRMS (ESI) m/z [C20H29N2O3S]+ ([M+H]+ ) calculated 377.2, found 377.2.

N-(1-cyclohexyl-3-morpholinopropan-2-yl)-4-methylbenzenesulfonamide (3ba)

Yield: 26 mg, 71%, colorless oil

Rf = 0.30 (EA/Hex 6:4)

1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.21 (bs, 1H), 3.54 – 3.45 (m, 4H), 3.15 (ddt, J = 9.9, 8.1, 5.1 Hz, 1H), 2.42 (s, 3H), 2.29 (dd, J = 12.7, 5.0 Hz, 1H), 2.22 – 2.15 (m, 3H), 2.07 (m, 2H), 1.76 – 1.48 (m, 4H), 1.34 – 1.07 (m, 5H), 0.95 – 0.79 (m, 3H).

13C NMR (126 MHz, CDCl3) δ 143.5, 137.2, 129.7, 127.4, 66.9, 61.9, 53.5, 48.1, 41.7, 34.0, 34.0, 33.1, 29.8, 26.5, 26.2, 21.6.

IR (CDCl3, cm−1) ν 3273, 2921, 2851, 1598, 1448, 1327, 1160, 1117, 1072, 1009, 815.

LRMS (ESI) m/z [C20H33N2O3S]+ ([M+H]+ ) calculated 381.2, found 381.2

N-((1-adamantan-2-yl)-3-morpholinopropan-2-yl)-4-methylbenzenesulfonamide (3ca)

Yield: 34 mg, 79%, colorless oil

Rf = 0.4 (EA/Hex 6:4)

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.51 (t, J = 4.7 Hz, 4H), 3.10 (ddt, J = 9.8, 8.2, 5.0 Hz, 1H), 2.41 (s, 3H), 2.30 (dd, J = 12.7, 5.1 Hz, 1H), 2.26 – 2.15 (m, 3H), 2.10 (dt, J = 11.2, 4.6 Hz, 2H), 2.01 (ddd, J = 13.7, 8.3, 4.9 Hz, 1H), 1.91 (dd, J = 12.6, 2.8 Hz, 1H), 1.79 (tdt, J = 14.5, 5.4, 3.0 Hz, 5H), 1.70 (d, J = 3.3 Hz, 2H), 1.66 – 1.41 (m, 9H).

13C NMR (126 MHz, CDCl3) δ 143.5, 137.2, 129.7, 127.4, 66.9, 61.8, 53.5, 48.7, 40.4, 39.2, 38.3, 37.1, 32.8, 31.6, 31.6, 31.5, 28.2, 28.0, 21.6.

IR (CDCl3, cm−1) ν 3270, 2904, 2851, 1452, 1402, 1329, 1160, 1116, 1092, 906, 727.

LRMS (ESI) m/z [C24H37N2O3S]+ ([M+H]+) calculated 433.3, found 433.3

4-methyl-N-(1-morpholino-3-phenylpropan-2-yl)benzenesulfonamide (3da)

Yield: 16.4 mg, 44%, yellow oil.

Rf = 0.36 (EA/Hex 1:1).

1H NMR [500 MHz, CDCl3) δ 7.86 – 7.74 (m, 2H), 7.33 – 7.29 (m, 2H), 7.28 – 7.23 [m, 2H), 7.23 – 7.18 (m, 1H), 7.17 – 7.11 (m, 2H), 3.51 – 3.40 (m, 4H), 3.34 – 3.24 (m, 1H), 3.17 (dd, J = 13.7, 3.8 Hz, 1H), 2.79 (dd, J = 13.7, 8.1, Hz, 1H), 2.42 (s, 3H), 2.24 – 2.13 (m, 2H), 2.13 – 2.02 (m, 2H), 2.02 – 1.92 (m, 2H).

13C NMR (126 MHz, CDCl3) δ 143.67, 137.06, 136.76, 129.83, 129.80, 128.53, 127.39, 126.70, 66.80, 60.39, 53.15, 50.95, 39.72, 21.64. ff

IR (CDCl3, cm−1) ν 3261, 3060, 3027, 2922, 2854, 2814, 1598, 1453, 1332, 1160, 1115, 1089, 702, 665, 551.

LRMS (ESI) m/z [C20H27N2O3S]+ ([M+H]+ ) calculated 375.2, found 375.2.

N-(6-((tert-butyldiphenylsilyl)oxy)-1-morpholinohexan-2-yl)-4-methylbenzenesulfonamide (3ea)

Yield: 47.1 mg, 79%, colorless oil.

Rf = 0.40 (EA/Hex 2:3).

1H NMR (500 MHz, CDCl3) δ 7.81 – 7.75 (m, 2H), 7.72 – 7.64 (m, 4H), 7.48 – 7.37 (m, 6H), 7.33 – 7.26 (m, 2H), 5.28 (s, 1H), 3.70 – 3.59 (m, 2H), 3.58 – 3.47 (m, 4H), 3.11 (qd, J = 7.4, 4.1 Hz, 1H), 2.42 (s, 3H), 2.25 (d, J = 7.3 Hz, 2H), 2.22 – 2.14 (m, 2H), 2.14 – 2.05 (m, 2H), 1.77 – 1.68 (m, 1H), 1.60 – 1.48 (m, 3H), 1.41 – 1.27 (m, 2H), 1.07 (s, 9H).

13C NMR (126 MHz, CDCl3) δ 143.4, 137.0, 135.6, 134.0, 129.6, 127.6, 127.2, 66.7, 63.6, 60.9, 53.2, 49.9, 33.0, 32.5, 26.9, 21.5, 21.0, 19.3.

IR (CDCl3, cm−1) ν 3267, 2930, 2857, 1427, 1330, 1160, 1109, 1093, 816, 703, 550, 504.

LRMS (ESI) m/z [C33H47N2O4SSi]+ ([M+H]+ ) calculated 595.3, found 595.3.

ethyl 6-((4-methylphenyl)sulfonamido)-7-morpholinoheptanoate (3fa)

Yield: 32.5 mg, 79%, yellow oil.

Rf = 0.43 (DCM:MeOH 19:1).

1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.50 (dt, J = 12.3, 6.1 Hz, 4H), 3.09 (qd, J = 7.1, 4.6 Hz, 1H), 2.42 (s, 3H), 2.29 – 2.21 (m, 4H), 2.11 (m, 4H), 1.74 – 1.50 (m, 4H), 1.35 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.21 (m, 1H).

13C NMR (126 MHz, CDCl3) δ 173.6, 143.5, 137.0, 129.7, 127.3, 66.7, 60.9, 60.3, 53.3, 49.7, 34.1, 32.9, 24.9, 24.1, 21.6, 14.3.

IR (CDCl3, cm−1) ν 3268, 2930, 2858, 1729, 1329, 1302, 1158, 1116, 1092, 666, 551.

LRMS (ESI) m/z [C20H32N2O5S]+ ([M+H]+) calculated 413.2, found 413.2.

N-(6-(1,3-dioxoisoindolin-2-yl)-1-morpholinohexan-2-yl)-4-methylbenzenesulfonamide (3ga)

Yield: 42.0 mg, 86%, yellow oil.

Rf = 0.25 (EA/Hex 2:1).

1H NMR (400 MHz, CDCl3) δ 7.88 – 7.83 (m, 2H), 7.79 – 7.71 (m, 4H), 7.32 – 7.27 (m, 2H), 5.13 (brs, 1H), 3.70 – 3.60 (m, 2H), 3.56 – 3.46 (m, 4H), 3.17 – 3.08 (m, 1H), 2.42 (s, 3H), 2.28 – 2.14 (m, 4H), 2.14 – 2.05 (m, 2H), 1.76 – 1.67 (m, 1H), 1.66 – 1.56 (m, 3H), 1.40 – 1.20 (m, 2H).

13C NMR (101 MHz, CDCl3) δ 168.4, 143.4, 137.1, 133.9, 132.1, 129.6, 127.2, 123.2, 66.7, 61.0, 53.2, 49.7, 37.6, 32.6, 28.5, 21.8, 21.5.

IR (CDCl3, cm−1) ν 3274, 2938, 2859, 2814, 1708, 1397, 1331, 1159, 1116, 721.

LRMS (ESI) m/z [C25H32N3O5S]+ ([M+H]+) calculated 486.2, found 486.1.

Supplementary Material

SI

Scheme 4.

Scheme 4

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Proposed Mechanism

Table 1.

Optimization Table

graphic file with name nihms-1609704-t0006.jpg
entry conc. (M) morpholine (equiv) temp.(°C) reaction time (h) yield (%)a
1 0.1 2 22 8 < 5
2 0.1 2 40 8 19
3 0.1 2 80 8 63
4b 0.1 2 80 8 28
5 0.1 2 80 20 78
6 0.2 2 80 20 87
7 0.2 3 80 24 99
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a

Determined by 1H NMR analysis of unpurified reaction mixture

b

AgSbF6 (1 equiv.) was added.

Acknowledgments

Funding Information

We thank the National Institute of General Medical Sciences (NIGMS, Grant No. GM80442) for support.

Footnotes

Supporting Information

YES (this text will be updated with links prior to publication)

Primary Data

NO (this text will be deleted prior to publication)

Dedicated to Professor Mark Lautens on the occasion of his 70th birthday

Reference

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI
NIHMS1609704-supplement-SI.pdf (2.2MB, pdf)

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