4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- thioxoimidazolidin-l-yl)butanoic acid

Example 14; 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- thioxoimidazolidin-l-yl)butanoic acid

RU59063 (145 mg, 0.38 mmol) was dissolved in 2 mL DMF, charged with PDC (1.4 g, 3.7 mmol) and stirred for 48 hours, upon which time the mixture was quenched with 10 mL 1 M HCL and extracted into Et₂0 (5 X 25 mL). The combined organic layers were washed with brine (1 X 100 mL), dried with Na₂S0₄ and concentrated down to yield 135 mg (90% yield) pure product.


H NMR (300 MHz, CDC1₃) δ 7.94 (d, J= 8.3, 1H), 7.88 (s, 1H), 7.77 (d, J= 8.2, 1H), 3.82 - 3.65 (m, 2H), 2.50 (s, 2H), 2.14 (s, 2H), 1.59 (s, 6H);


¹³C NMR (126 MHz, CDC1₃) δ 178.6, 177.4, 175.3, 175.2, 137.1, 135.2, 133.5 (q, J = 32.1), 132.1, 127.0 (q, J= 4.7), 121.8 (q, J= 276.2), 114.9, 1 10.1, 65.2, 43.3, 31.7, 23.1 ;


 LRMS (ESI) 421.2
(M+Na)⁺.

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2-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-l-yl)butanamido)ethoxy)ethyl 2-(adamantan-l-yl)acetate

   Example 5; 2-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-l-yl)butanamido)ethoxy)ethyl 2-(adamantan-l-yl)acetate



To a 1 dram vial with stirbar was charged 4-(3-(4-cyano-3-
(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)butanoic acid (10.0 mg, 0.025 mmol), EDC (7.0 mg, 0.038 mmol), HOBt (6.0 mg, 0.375 mmol), and 0.35 mL dichloromethane. After 15 minutes of stirring 2-(2-aminoethoxy)ethyl 2-(adamantan-l-yl)acetate (8.0 mg, 0.027 mmol) was added and the mixture left stir for 16 h upon which the mixture was diluted with 1 mL dichloromethane and washed with 10% aq. citric acid (2 X 1 mL), and saturated a₂C03 (2 X 1 mL). The organic layer was dried with Na₂S0₄ and concentrated down to yield a crude oil which was purified by silica gel chromatography (dichloromethane to 19: 1 dichloromethane: MeOH) to yield 5 mg (30% yield) of pure product as an amber oil.

H NMR (500 MHz, CDC1₃) δ 7.93 (d, J= 8.3, 1H), 7.87 (d, J= 1.7, 1H), 7.75 (dd, J= 1.9, 8.3, 1H), 6.04 (t, J= 5.1, 1H), 4.25 - 4.14 (m, 2H), 3.79 - 3.71 (m, 2H), 3.68 - 3.61 (m, 2H), 3.55 (t, J = 5.0, 2H), 3.49 - 3.40 (m, 2H), 2.32 (t, J = 6.7, 2H), 2.14 (dt, J = 6.8, 14.4, 2H), 2.08 (s, 2H), 1.95 (s, 4H), 1.70-1.66 (m, 4H), 1.65-1.55 (m, 13 H);  


¹³C NMR (126 MHz, CDCI₃) δ 178.6, 175.5, 172.0, 171.8, 137.3, 135.3, 133.6 (q, J = 33.4), 132.3, 127.2 (q, J= 4.7), 121.0 (q, J = 274.0), 115.0, 110.1 (q, J= 2.2), 69.7 69.3, 65.4, 62.7, 49.0, 43.7, 42.5, 39.4, 36.8, 33.0, 33.0, 28.7, 23.7, 23.2;


LRMS (ESI) 662.4 (M+H)⁺.

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1H NMR spectra of the encapsulation of ubiquitin within coordination spheres.

(a) Ubiquitin ligand 2a. (b) Ligand 1a. (c) Ubiquitin-containing sphere 3a after treating ubiquitin ligand 2a with ligand 1a (30 equiv) and Pd(NO3)2 (17 equiv) in D2O/CD3CN (1:1, 0.5 ml) at 45 °C for 3 h. Downfield shifts of the signals of the pyridine rings (Ha, Hb) confirm the formation of Pd-pyridine bonds in coordination sphere 3a, and the simple spectrum indicates the quantitative self-assembly of ubiquitin-containing sphere 3a. All spectra recorded at 500 MHz, inD2O:CD3CN=1:1, at 300 K.http://www.nature.com/ncomms/journal/v3/n10/fig_tab/ncomms2093_F2.html

13 C NMR...One for your eye

Ethanal or AcetaldehydeEthanoic acid or Acetic acidEthanol or Ethyl alcohol

Since all three preceding C-13 spectra are fully proton decoupled, the carbon atoms appear as narrow singlets (single peaks). Note that the carbons in methyl groups (–CH₃, indicated as C2 next to peaks) of all three compounds have a chemical shift rather upfield (close to the right) in the spectra not too far from about 20 ppm. The carbon in themethylene group (–CH₂–, indicated as C1) in ethanol is brought further downfield to 58 ppm because that carbon is bonded directly to the oxygen in the hydroxyl group (–OH). Note that the carbonyl group (–CO–, indicated as C1) carbons in acetaldehyde and acetic acid are downfield at the left side of the spectrum, the carbonyl region between about 160 and 220 ppm.

Synthesis and characterization of maleimide-functionalized polystyrene-SiO2/TiO2 hybrid nanocomposites by sol–gel process Ramesh S, Sivasamy A, Kim JH - Nanoscale Res Lett (2012)

Synthesis and characterization of maleimide-functionalized polystyrene-SiO2/TiO2 hybrid nanocomposites by sol–gel process

Ramesh S, Sivasamy A, Kim JH - Nanoscale Res Lett (2012)http://www.nanoscalereslett.com/content/7/1/350

Nanoscale Research Letters 2012, 7:350  doi:10.1186/1556-276X-7-350

Synthesis of N-chloromethyl maleimide

N-chloromethyl maleimide was prepared in two steps[1-4]. In the first step, N-ethylmaleimide was prepared using a suspension of 24.5 g (0.25 mol) of maleimide in 20.3 ml of 37% formalin at 30°C with the addition of 0.75 ml of 5% NaOH over a period of 30 min and allowing it to stand for 3 h and then filtered. The crude product yield of 75%, m.p = 103°C, was recrystallized using ethyl acetate

1 H NMR (CDCl3), δ (ppm) = 3.45 (S, 1 H), 5.09 (S, 2 H), and 6.76 (S, 2 H)

and 13 C NMR, δ (ppm) = 61.11, 134.71, and 70.25 (C = O).

In the second step, phosphorous trichloride of 4.3 g (0.03 mol) was added to the solution of 10 g (0.08 mol) of N-methyl maleimide in 50 ml of acetone in an ice bath. Then, the solution was stirred for 30 min and then concentrated at the aspirator. The resulting partly crystalline residue was precipitated by adding 50 ml of ice-cold water and filtered. The product N-chloromethyl maleimide was recrystallization from benzene-petroleum ether mixture. The sequence of reaction N-chloromethyl maleimide is presented in Figure1

1HNMR (CDCl3) δ (ppm) = 5.32 (S, 2 H), and 6.84 (S, 2 H);

13 C NMR δ (ppm) = 44.28, 135.27, and 168.17 (C = O).

FTIR spectra. (a) N-methylolmaleimide, (b) N-chloromethyl maleimide, and (c) maleimide-functionalized polystyrene.

Brivanib alaninate  is a new oncology therapy with potential applications against a wide variety of tumor types and several stages of disease progression

Brivanib alaninate ブリバニブアラニンエステル

SYN...........http://newdrugapprovals.org/2014/12/23/brivanib-alaninate-%E3%83%96%E3%83%AA%E3%83%90%E3%83%8B%E3%83%96%E3%82%A2%E3%83%A9%E3%83%8B%E3%83%B3%E3%82%A8%E3%82%B9%E3%83%86%E3%83%AB/

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500126u

http://pubs.acs.org/doi/full/10.1021/op500126u

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanonate (1)

1H NMR (400 MHz, CDCl3) 8.31 (1 H, s), 7.83 (1 H, s), 7.25 (1 H, s), 7.00 (1 H, d, J= 8.6 Hz), 6.95 (1 H, dd, J = 15.4, 8.6 Hz), 6.28 (1 H, s), 5.36–5.30 (1 H, m), 4.08–4.00 (2 H, m), 3.57 (1 H, dd, J = 14.0, 6.9 Hz), 2.47 (3 H, s), 2.40 (3 H, s), 1.66 (3 H, s), 1.38 (3 H, d, J = 6.4 Hz), 1.35 (3 H, d, J = 7.1 Hz).

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-(benzyloxycarbonylamino)propanonate

1H NMR (400 MHz, CDCl3) 8.17 (1 H, br s), 7.84 (1 H, s), 7.41 (1 H, s), 7.35–7.28 (5 H, m), 7.03 (1 H, d, J = 8.6 Hz), 6.95 (1 H, t, J = 7.7 Hz), 6.30 (1 H, s), 5.36–5.32 (2 H, m), 5.11 (2 H, br s), 4.43–4.40 (1 H, m), 4.02–3.99 (2 H, m), 2.46 (3 H, s), 2.41 (3 H, s), 1.44 (3 H, d, J = 7.2 Hz), 1.38 (3 H, d, J = 7.2 Hz).

HSQC - TOCSY 3 Heptanone

One can see the two spin systems on either side of the carbonyl group, color coded in yellow and pink. The second panel shows an expansion of the region within the red square of the first panel. Here we can separate the overlapping quartet and triplet for the methylene protons on either side of the carbonyl group.

 
 
Protons a, b, c and d constitute one spin system, an unbroken network of coupled protons.  The ethyl group, e and f, constitutes a second, separate spin system, because there is no coupling between a and e, across the carbonyl.
In a COSY spectrum, CH₂ a would show a correlation to CH₂ b.   In a TOCSY spectrum, it would also show correlations to CH₂s c and d.  


 








 

 


 
 


RAMAN

 




13 C NMR


 



MASS

 



IR








 







1H NMR









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REGIOMERS

http://www.google.com/patents/US7514563

FIG. 1 is a gHMBC spectrum of the borylation products of 4-chlorobenzonitrile. BELOW
 







FIG. 2 is a gHMBC spectrum of the borylation products of 4-bromobenzonitrile.
 






FIG. 3 is a gHMBC spectrum of the borylation product of 4-iodobenzonitrile.


 





FIG. 4 is a gHMBC spectrum of the borylation products of 4-methoxybenzonitrile.
FIG. 5 is a gHMBC spectrum of the borylation products of 4-thiomethylbenzonitrile.
FIG. 6 is a gHMBC spectrum of the borylation product of 4-dimethylaminobenzonitrile.
FIG. 7 is a gHMBC spectrum of the borylation product of methyl 4-cyanobenzoate.
FIG. 8 is a gHMBC spectrum of the borylation product of 4′-cyanoacetanilide.
FIG. 9 is a gHMBC spectrum of the borylation products of 1,5-dimethyl-2-pyrrolecarbonitrile.
FIG. 10 is a gHMBC spectrum of the borylation products of 5-methyl-2-furonitrile.



Regioisomer Assignment by NMR Spectroscopy:

From gHMBC NMR experiments, the two regioisomers for the borylation of 4-substituted benzonitriles can be distinguished unambiguously as in FIGS. 1 to 10. In isomer A, carbon atoms represented as C1 and C4 on the benzene ring, as well as C7 (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C3 is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H), which can be observed using gHMBC spectroscopy. In the gHMBC spectrum, carbon atoms C1 and C7 should show one cross peak each to proton H_c, whereas carbon atom C4 should show two cross peaks to protons H_a and H_b. Therefore the resulting number of cross peaks for C1, C4, and C7 should be 1, 2, and 1, respectively.
In Isomer B, carbon atoms represented as C1′, C4′, on the benzene ring, as well as C7′ (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C2′ is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H). In the gHMBC spectrum, carbon atoms C1′ and C7′ should show two cross peaks each, to protons H_d and H_e, whereas carbon atom C4′ should show only one cross peak to proton H_f. Therefore the resulting number of cross peaks for C1′, C4′, and C7′ should be 2, 1, and 2, respectively. Hence isomers A and B can be unambiguously assigned from gHMBC data.
For isomer A, with proton H_c unambiguously assigned by gHMBC, H_a and H_b can be assigned from their multiplicities. Proton H_a appears as a doublet, coupled to proton H_b with J≈2-3 Hz. Proton H_b appears as a doublet of doublets due to coupling to protons H_a and H_c. Carbon atoms C2, C6, and C5 were then assigned from the correlations in the gHMQC spectra. Carbon atom C7 (nitrile carbon) usually appears around δ 119. Depending on the substituent, carbon atom C1 was usually found shifted downfield around δ 130-170 (except in 4-iodobenzonitrile for which it appears around δ 100). Carbon atom C4 is shifted upfield, and was usually found around δ 100-115. Similarly, all the carbons of isomer B can be assigned.
In the five membered heterocycles, the ⁴J_H-H coupling was used together with gHMBC and NOESY1D spectroscopy to identify the major isomer. Regioisomers in the fluorine containing benzonitriles were assigned by ¹³C spectroscopy (with the help of the fact that the boron bearing carbon is not observed due to broadening from and coupling with boron). In the case of 1,3-dicyanobenzene, ¹H NMR spectroscopy was employed to assign the major and minor isomers.
Experimental Details and Spectroscopic Data EXAMPLE 1 Borylation of 4-fluorobenzonitrile

General procedure A was applied to 4-fluorobenzonitrile (242 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 8 h. The ratio of the two isomers in the crude reaction mixture by GC was 11:89. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (88.5 mg, 72%) as a white solid. The ratio of the two isomers in the isolated product by GC was 8:92. ¹³C NMR spectroscopy was used to assign the major isomer as 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. ¹H NMR (CDCl₃, 500 MHz): δ (major isomer) 8.04 (dd, ⁴J_H-F=5.4 Hz, J=2.2 Hz, 1H, H_d), 7.7 (ddd, J=8.5, 2.2 Hz, ⁴J_H-F=4.9 Hz, 1H, H_e), 7.1 (t, J=8.5 Hz, 1H, H_f), 1.32 (br s, 12H), (minor isomer) 7.67 (dd, J=8.8 Hz, ⁴J_H-F=4.9 Hz, 1H, H_c), 7.52 (dd, ³J_H-F=8.5 Hz, J=2.9 Hz, 1H, H_a), 7.17 (dt, J=8.3, 2.9 Hz, 1H, H_b) 1.34 (br s, 12H); ¹³C NMR {¹H} (CDCl₃, 125 MHz): δ (major isomer) 169.0 (d, ¹J_C-F=261.3 Hz, C1′), 141.6 (d, ³J_C-F=9.6 Hz, C3′), 137.0 (d, ³J_C-F=10.5 Hz, C5′), 117.9 (nitrile C7′), 116.7 (d, ²J_C-F=25.6 Hz, C6′), 108.2 (d, ⁴J_C-F=3.8 Hz, C4′), 84.5 (C8′), 24.7 (C9′), (minor isomer) 164.2 (d, ¹J_C-F=257.1 Hz, C1), 135.9 (d, ³J_C-F=8.8 Hz, C5), 122.8 (d, ²J_C-F=21.0 Hz, C2), 118.5 (d, ²J_C-F=22.2 Hz, C6), 118.1 (nitrile C7), 113.1 (C4), 85.1 (C8), 24.7 (C9); ¹¹B NMR (CDCl₃, 96 MHz): δ 29.92; ¹⁹F NMR (CDCl₃, 282 MHz): δ (major isomer) −92.62 (m), (minor isomer) −104.84 (m); FT-IR (neat): 3076, 2982, 2934, 2231, 1608, 1487, 1429, 1412, 1373, 1350, 1236, 1143, 1070, 964, 852, 835, 571 cm⁻¹; LRMS (% rel. int.): m/e (major isomer) 247 M⁺ (26), 232 (100), 205 (12), 188 (20), (minor isomer) 247 M⁺ (29), 232 (97), 206 (100), 189 (74), 148 (97), 121 (25); Anal. Cacld for C₁₃H₁₅BFNO₂: C, 63.20; H, 6.12; N, 5.67. Found: C, 63.52; H, 6.20; N, 5.56. HRMS Calcd for C₁₃H₁₅BFNO₂: 247.1180. Found: 247.1171.





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