1. Estado de la cuestión 1 Pretexto
1.3 La alianza terapéutica
Reactions were performed under nitrogen using oven-dried glassware. Air- and moisture- sensitive solutions were handled under nitrogen and transferred via syringe. Dry THF was freshly distilled from Na/benzophenone ketyl. Toluene was drawn from a Grubbs column. 1,4-Dioxane was commercially available anhydrous stabilized Acro Seal quality. Unless otherwise stated, reagents were commercially available and used as purchased without further purification. Chemicals were obtained from Sigma- Aldrich, Acros, or Strem, and used as received; solvents were purchased from Fisher Scientific. Reactions were monitored by thin-layer chromatography using Whatman Partisil® K6F 250 µm precoated 60 Å silica gel plates and visualized by short-wave ultra-violet light as well as by treatment with potassium permanganate (KMnO4) or ceric ammonium molybdate (CAM) stain. NMR spectra were
recorded in CDCl3 on either a Bruker 300 MHz or 500 MHz Fourier-transform spectrometer. Chemical
shifts are reported in ppm referenced to tetramethylsilane (TMS) or the CHCl3 solvent residual peak at
7.26 ppm for 1H and 77.23 ppm for 13C{1H}; 19F peaks were referenced to an external standard of
trifluoroacetic acid in CDCl3 at −76.55 ppm. Infrared spectra were obtained on NaCl plates using a
Perkin-Elmer Spectrum 100 Series FTIR spectrometer. Optical rotations were recorded in HPLC-grade CHCl3 using a JASCO DIP-370 digital polarimeter and values were averaged over a minimum of 3 runs.
Chromium-complexed masses were recorded with Electrospray + (ES+) HRMS methods to within 5 ppm, and [M]+, [MH]+, [M – (CO)3]+, or [M – C4H8NO]+ was confirmed by the presence of the
characteristic chromium isotope pattern. Non-chromium-complexed mass was recorded with Chemical Ionization + (CI+) HRMS methods to within 5 ppm, and [M]+ was observed. Where necessary,
microanalysis for C, H, N composition was obtained and accurate to within 0.5%.
Compounds 27272727, 53535353, 545454, and 5654 565656 were prepared according to general literature procedure for the synthesis of arene tricarbonylchromium complexes from Cr(CO)6 and parent arene.35,36 Aryl
trifluromethanesulfonates were prepared in good to excellent yield from the corresponding phenol according to the general literature procedure.37,38
Caution: Caution: Caution:
Caution: Care should be taken to avoid direct light exposure of reactions, as arene tricarbonylchromium complexes can decompose in solution under bright light and air. In crystalline solid form, complexes are reasonably stable to light and can be stored at room temperature in air.
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General procedure 2-A for the synthesis of benzylamine tricarbonylchromium complexes
Complexes were prepared according to general literature procedure for the synthesis of arene tricarbonylchromium complexes from Cr(CO)6 and parent arene35,36 and were crystallized from
dichloromethane and hexanes at -20 ºC or purified by flash column chromatography eluting in methylene chloride or diethyl ether in hexanes to afford yellow crystalline solids. The following procedure is representative.
27 2727
27 –––– MeMeMeMe2222NCHNCHNCHNCH2222((((ηηηη6666----CCCC6666HHHH5555))))Cr(CO)Cr(CO)Cr(CO)Cr(CO)3333: An oven-dried 50 mL round-bottom flask was
charged with Cr(CO)6 (1.54 g, 0.70 mmol, 1.0 equiv), fitted with a straight reflux
condenser, and flushed with dry nitrogen for 30 minutes. N,N-
Dimethylbenzylamine (2.1 mL, 14 mmol, 2.0 equiv), dry THF (1 mL), and dry 1,4- dioxane (2.5 mL) were added by syringe through the reflux condenser, and the mixture was refluxed in a 115 – 120 ºC oil bath for 2 days. The yellow-orange solution was allowed to cool, and completion of the reaction was verified by the absence of solid Cr(CO)6 on the sides of the
flask (from sublimation) after refluxing subsided. The reaction was opened to air, diluted with methylene chloride (5 mL) and filtered over a pad of Celite and MgSO4. The clear yellow solution was
concentrated under vacuo, layered with hexanes, and crystallized at -20º. After filtration, rinsing with cold hexanes and collecting a second crop of crystals, 27272727 (1.57 g, 5.8 mmol, 83% yield) was obtained as a bright yellow crystalline solid. Spectral data is consistent with existing characterization.39
53 53 53
53 –– –– NNNN----(C(C(C(C5555HHHH10101010N)CHN)CHN)CHN)CH2222((((ηηηη6666----CCCC6666HHHH5555)Cr(CO))Cr(CO))Cr(CO))Cr(CO)3333: Using General procedure 2-A, Cr(CO)6
(0.44 g, 2.0 mmol, 1.0 equiv) was reacted with N-benzyl piperidine (0.52g, 3.0 mmol, 1.5 equiv) in 2.3 mL dioxane and 0.7 mL THF at 100-110 ºC for 5 days. Crystallization at -20 ºC yielded 53535353 (0.46 g, 1.5 mmol, 74% yield) as a bright yellow solid. 1111H NMR H NMR H NMR H NMR (300 MHz, CDCl3) δ: 5.42 - 5.29 (m, 4H), 5.25 -
5.21 (m, 1H), 3.18 (s, 2H), 2.45 - 2.42 (m, 4H), 1.64 - 1.51 (m, 4H), 1.49 - 1.39 (m, 2H) ppm; 11131333C{C{C{C{1111H} NMRH} NMR (75 MHz, CDClH} NMRH} NMR 3) δ: 233.2, 109.0, 94.2, 93.3, 91.5, 62.7, 54.7, 26.1,
24.3 ppm; IRIRIRIR: 3087, 2937, 2853, 2800, 2686, 1966 and 1878 (strong CO stretches), 1455, 1343, 1153, 1110, 995, 861, 662, 630, 533 cm-1. HRMSHRMSHRMS (ES+) calc’d for CHRMS 15H18CrNO3 312.0692, found
312.0687 [MH]+.
54 54 54
54 –– ––NNNN----(C(C(C(C4444HHHH8888NO)CHNO)CHNO)CHNO)CH2222((((ηηηη6666----CCCC6666HHHH5555)Cr(CO))Cr(CO))Cr(CO))Cr(CO)3333: Using General procedure 2-A, Cr(CO)6
(0.44 g, 2.0 mmol, 1.0 equiv) was reacted with N-benzyl morpholine (0.5 mL, 3 mmol, 1.5 equiv) in 1.5 mL dioxane and 0.8 mL THF at 120 ºC for 2 days. Crystallization at -20 ºC yielded 54545454 (0.59 g, 1.9 mmol, 94 % yield after 2nd
Cr OC
COCO N
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crop) as a bright yellow crystalline solid. 1111H NMRH NMR (300 MHz, CDClH NMRH NMR 3) δ: 5.41 - 5.34 (m, 4H), 5.27 - 5.23
(m, 1H), 3.72 - 3.69 (m, 4H), 3.24 (s, 2H), 2.53 - 2.50 (m, 4H) ppm; 13131313C{C{C{C{1111H} NMRH} NMRH} NMRH} NMR (75 MHz, CDCl3) δ:
233.0, 107.7, 94.0, 93.2, 91.6, 67.1, 62.2, 53.7 ppm; IR IR IR 3066, 2971, 2867, 2817, 1961 and 1877 IR (strong CO stretches), 1458, 1285, 1115, 1007, 865, 662, 630, 531 cm-1. HRMSHRMSHRMSHRMS (ES+) calc’d for
C14H16CrNO4 314.0484, found 314.0497 [MH]+.
56 56 56
56 –– –– NNNN----(C(C(C(C5555HHHH10101010N)CHN)CHN)CHN)CH2222((((ηηηη6666----CCCC6666HHHH5555)Cr(CO))Cr(CO))Cr(CO))Cr(CO)3333: Using General procedure 2-A, Cr(CO)6
(0.44 g, 2.1 mmol, 1.0 equiv) was reacted with N,N-benzyl methylpiperazine (0.59 mL, 3.0 mmol, 1.5 equiv) in 1.5 mL dioxane and 0.5 mL THF at 105- 115 ºC for 4 days. Crystallization at -18 ºC yielded 1d1d1d1d (0.64 g, 1.9 mmol, 93% yield) as a yellow powdery solid. 1111H NMR H NMR H NMR H NMR (300 MHz, CDCl3) δ: 5.39 - 5.33 (m,
4H), 5.26 - 5.21 (m, 1H), 3.24 (s, 2H), 2.6 - 2.4 (br m, 8H), 2.28 (s, 3H) ppm;
13 13 13
13C{C{C{C{1111H} NMR (75 MHz, CDClH} NMRH} NMRH} NMR 3) δ: 233.0, 108.1, 94.1, 93.3, 91.6, 61.8, 55.1, 53.1, 46.2 ppm; IRIRIRIR:
(strong CO stretches), cm-1. HRMSHRMSHRMSHRMS (ES+) calc’d for C15H19CrN2O3 327.0795, found 327.0799 [MH]+.
General procedure 2-B for racemate synthesis
The following procedure is representative of the synthesis of racemic product standards used for HPLC and SFC analysis of asymmetric reactions and reaction screens:
28 28 28
28ffff –– Me––MeMeMe2222NNCHNNCHCHCH(4(4----C(4(4CCC6666HHHH4444----CHCHCHCH3333))))((((ηηηη6666----CCCC6666HHHH5555)Cr(CO))Cr(CO))Cr(CO))Cr(CO)3333:::: Racemic 282828ffff was prepared as a 28
chromatography reference following the literature procedure for related compounds:40 An oven-dried glass reaction tube was charged with a small
magnetic stirbar and 27272727 (52 mg, 0.19 mmol, 1.0 equiv), sealed with a septum, and purged with nitrogen. PdCl2(PPh3)2 (7 mg, 0.01 mmol, 5 mol %) and LiHMDS (68 mg, 0.4
mmol, 2 equiv) were dissolved in dry THF (1.5 mL) under a nitrogen atmosphere, forming an orange solution, to which neat 4-bromotoluene (38 µl, 0.3 mmol, 1.5 equiv) was added. The catalyst, base, and aryl bromide solution was taken up by syringe and added to 272727, which turned red-orange. The 27 reaction mixture was heated with stirring for 20 h at 43 ºC, then allowed to cool. The orange solution was quenched with two drops of aqueous 2N HCl and allowed to stir for 5 min. The solution was opened to air and diluted with 4 mL diethyl ether, then filtered over a pad of MgSO4 and silica. The
pad was rinsed with an additional 1 mL diethyl ether and the solution was concentrated in vacuo, loaded directly onto a short silica gel column, and eluted with 50% diethyl ether in hexane. Racemic 28
28 28
28ffff (53.8 mg, 0.15 mmol, 78% yield) was obtained as a yellow-orange solid. 1111H NMRH NMRH NMRH NMR (300 MHz,
CDCl3) δ: 7.15 (appar. s, 4H), 5.91 (dt, J = 6.2, 1.0 Hz, 1H), 5.35 - 5.26 (m, 2H) 5.24 (d, J = 6.7 Hz, Cr OC COCO 1d N N CH3
105
2H), 5.16 (dd, J = 5.7, 1.3 Hz, 1H), 4.17 (s, 1H), 2.34 (s, 3H), 2.23 (s, 6H) ppm; 13131313CCCC{{{{1111H}H} NMRH}H}NMRNMR (125 NMR
MHz, CDCl3) δ: 233.1, 137.8, 136.8, 129.3, 129.1, 114.5, 94.7, 94.3, 93.3, 91.3, 91.0, 72.9, 44.2,
21.3 ppm. IRIRIR:::: 2924, 2867 2825, 2780, 1963 and 1876 (strong CO stretches), 1610, 1454, 1412, IR 1150, 116, 802, 662, 631, 531 cm-1.