4-(2-(difluoromethyl)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino-N-( 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)- 1 ,3 ,5-triazin-2-amine

Synthesis of 4-(2-(difluoromethyl)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino-N-( 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)- 1 ,3 ,5-triazin-2-amine Al

Al
[00224] Compound Al was prepared according to Scheme 1, where compound 1 (l-[4- chloro-6-(4-morpholinyl)-l,3,5-tianzin-2-yl]-2-(difluoromethyl)-lH-benzimidazole) was synthesized according to the procedure as described in U.S. Pat. Appl. Publ. No.
2007/244110, the disclosure of which is incorporated herein by reference in its entirety.

[00225] A mixture of compound 1 (184 mg, 0.502 mmol) and 1,2,3,4-tetrahydro-l- naphthylamine (221 mg, 1.50 mmol) in dioxane (10 mL) was refluxed for 1 hr. The mixture was poured into ice-water (5 mL) to give a white precipitate, which was recrystallised from ethanol/water to give 65 mg (27% yield) of compound Al as a white solid: purity: 96.7% (HPLC);

MS m/z: 478.2 (M+l);

1H NMR (CDC1₃, 500 MHz) (rotamers) δ 8.45 (t, J= 7.5 Hz, 1H), 7.90 (t, J= 9.0 Hz, 1H), 7.71 and 7.60 (2t, J_HF = 53.5 and 53.5 Hz, 1H), 7.45-7.33 (m, 3H), 7.23-7.12 (m, 3H), 5.94 and 5.77 (2d, J= 8.0 and 8.5 Hz, 1H), 5.34(d, J= 5.5 Hz, 1H), 3.94-3.82 (m, 8H), 2.82-2.77 (m, 2H), 2.18-1.81 (m, 4H) ppm.


Example 2
Synthesis of (5)-4-(2-(difluoromethyl)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino-N-( 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)- 1 ,3 ,5-triazin-2-amine A2

A2
[00226] Compound A2 was synthesized according to the procedure for compound Al substituting (5)-l,2,3,4-tetrahydro-l-naphthylamine in place of 1,2,3, 4-tetrahydro-l- naphthylamine to give the product in 61% yield: 98.2% purity (HPLC);

MS m/z: 478.1 (M+l);

1H NMR (CDCls, 500 MHz) δ 8.48-8.40 (m, 1H), 7.91 (t, J= 8.0 Hz, 1H), 7.67 and 7.66 (2t, J_HF ⁼ 53.5 and 54.0 Hz, 1H), 7.45-7.35 (m, 3H), 7.27-7.14 (m, 3H), 5.57 (m, 1H), 5.36 (m, 1H), 3.94 (m, 4H), 2.82 (m, 4H), 2.85 (m, 2H), 2.25-2.11 (m, 1H), 2.08-1.86 (m, 3H) ppm.


Example 3
Synthesis of (i?)-4-(2-(difluoromethyl)-lH-benzo[<i]imidazol-l-yl)-6-morpholino-N-(l, 2,3,4- tetrahydronaphthalen- 1 -yl)- 1 ,3 ,5-triazin-2-amine A3

A3
[00227] Compound A3 was synthesized according to the procedure for compound Al substituting (i?)-l,2,3,4-tetrahydro-l-naphthylamine in place of 1,2,3, 4-tetrahydro-l- naphthylamine to give the product in 60% yield: 95.5% purity (HPLC);

MS m/z: 478.3 (M+l);

1H NMR (DMSCW, 500 MHz) (rotamers) δ 8.63 (d, J= 8.0 Hz, 0.6H), 8.42 (d, J= 9.0 Hz, 0.6H), 8.33 (d, J= 8.0 Hz, 0.4H), 8.28 (d, J= 9.0 Hz, 0.4H), 7.97 (t, J_HF = 52.5 Hz, 0.6H), 7.85-7.81 (m, 1H), 7.75 (t, J_HF = 52.5 Hz, 0.4H), 7.48-7.37 (m, 2H), 7.29-7.24 (m, 1H), 7.21- 7.09 (m, 3H), 5.31 (m, 1H), 3.82 (m, 4H), 3.65 (m, 4H), 2.86-2.72 (m, 2H), 2.09-1.93 (m, 2H), 1.93-1.84 (m, 1H), 1.82-1.93 (m, lH) ppm.






 http://www.google.com/patents/WO2012135166A1?cl=en
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Nucleophilic Aromatic Substitution of 5-fluoro-1-indanone with morpholine ......5-morpholino-1-indanone

5-Morpholino-1-indanone

.

Nucleophilic Aromatic Substitution of 5-fluoro-1-indanone with morpholine

 The synthesis was performed using standard Schlenk techniques under a nitrogen atmosphere.  To a dried and nitrogen flushed glass microwave reaction vial was added  5-flouro-1-indanone (0.101 g, 0.67 mmol).  The vial's atmosphere was cycled four times. Morpholine (2.0 mL, 0.023 mol, 3.47 equivs.) was added, The reaction was then sealed and heated to 100 ^oC for 20 hours under variable watt microwave heating.  At the completion of the reaction the crude material was transferred to a 50 mL round bottom flask using 3.5 mL ethyl acetate. Silica and ethyl acetate (4.5 mL) were added to the flask and the solvent was removed under reduced pressure to yield a free flowing dry load.  The crude product was then subjected to purification via flash chromatography (75 : 25 ethyl acetate : hexanes) to yield a red solid (144 mg, 98.7%).

¹H NMR:  (CDCl₃) δ ppm 2.59-2.62 (m, 2H), 3.01 (t, J=5.7 Hz, 2H), 3.30 (t, J=5.0 Hz, 4H), 3.83 (t, J=4.7 Hz, 4H), 6.78 (m, 6.78-6.79, 1H), 6.83-6.86 (m, 1H), 7.61 (d, J=8.8 Hz, 1H).

¹³C NMR:  (CDCl₃) δ ppm 25.8, 36.3, 47.6, 66.4, 109.7, 114.0, 124.9, 128.2, 155.8, 157.7, 204.9

GCMS EI [M⁺]  Predicted: 217.2, Actual: 217


see


5-morpholino-1-indanone-1H.pdf
5-morpholino-1-indanone-13C.pdf
GCMS Data 5-morpholino-1-indanone.pdf

GCMS EI [M+]  Predicted: 217.2, Actual: 217

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HELP TO INTERPRET USING RELATED 

MOLECULES.....U CAN LEARN

SOME OTHER INDANONES

Chern, C.-Y.; Yek, Y.-L.; Chen, Y.-L.; Kan, W.-M. J. Chin. Chem. Soc. 2008, 55, 846–853.

Dinges, J.; Albert, D.H.; Arnold, L.D.; Ashworth, K.L.; et al J. Med Chem. 2007, 50, 2011-2029

 

 

 

The resonance assignment of 2-ethyl-1-indanone 

References

Chern, C.-Y.; Yek, Y.-L.; Chen, Y.-L.; Kan, W.-M. J. Chin. Chem. Soc. 2008, 55, 846–853.

Dinges, J.; Albert, D.H.; Arnold, L.D.; Ashworth, K.L.; et al J. Med Chem. 2007, 50, 2011-2029

O-Methylation of Temazepam

 

 

[(3RS)-7-chloro-3-methoxy-1-methyl-5-phenyl-1,3-dihydro-2h-1,4-benzodiazepin-2-one]

.

 Temazepam (20 g; 0.067 mol) and  methanol (120 ml) was added to a 0.5 Lt, 4 necked flask bearing a mechanical stirrer, addition flask and thermometer, set up on a cooling tub at room temperature. Perchloric acid (70%; 2mL (10%/vol.) was added slowly through a dropping funnel keeping the reaction temperature between 20-25°C in 1-2 h. The reaction mixture was allowed to come to room temperature and was stirred overnight. Then distilled complete methanol under reduced pressure and residue adding to 50% Na₂CO₃ solution (200 ml). The reaction mass was extracted with CH₂Cl₂ (2 X 200 ml) and dried over Na₂SO₄. The dichloromethane was concentrated under reduced pressure to obtain a light yellow oily liquid which on forced scratching with glass rod gives light yellow solid (18 g, 86%).  

IR (cm-1): 1680.00 ([C=O]), 1608.00 ([HCOCH₃]) (ether).

¹H NMR (CDCl₃; 400MHz):
δ 7.68-7.66(d;2H;ArH),7.56-7.47(m;2H;ArH),7.44-7.40(t;2H;ArH),7.35-7.32(t;2H;ArH), 4.67(s;1H,COCH),3.63(s;3H;NCH₃),3.43(s;3H;OCH₃).


¹³C NMR (CDCl₃; 100 MHz):167.40, 163.92, 141.57, 137.17, 131.88, 130.97, 130.20, 129.63, 129.53, 129.42, 128.38, 122.89, 90.02, 55.38, 35.19.

IR graph

 1H NMR GRAPH

 13 C NMRGRAPH

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NMRanalyst's AssembleIt workwindow contains the FindIt, VerifyIt, and AssembleIt components.

.
 ScienceSoft, LLC
www.ScienceSoft.net

 NMRanalyst's AssembleIt workwindow contains the FindIt, VerifyIt, and AssembleIt components.

 http://www.sciencesoft.net/NMRanalyst_Manual/HTML/overview.html

 NMRanalyst automates the analysis of one to three dimensional NMR spectra. It reduces experimental multidimensional NMR data to a list of detected spin systems, eliminating the tedious manual interpretation of raw NMR data. NMRanalyst's AssembleIt workwindow contains the FindIt, VerifyIt, and AssembleIt components. The FindIt component identifies the best matching structures for analysis results. It contains over 15.9 million common molecular structures and further ones can be added. The VerifyIt component rates a specified structure by its agreement with NMR results. It can compare the rating with all the FindIt structures for further confirmation of the specified structure. The AssembleIt component performs the structure elucidation. It combines the analysis results of several spectra and derives the most likely molecular skeletons from this often incomplete and ambiguous information.

The NMRplot program displays experimental, simulated, and residual spectra as contour, surface, and isosurface plots. The NMRgraph program displays and allows editing molecular structures. It predicts proton and carbon chemical shifts. It completes determined molecular skeletons by adding likely bond multiplicities and NMR unobserved heteroatoms.
The NMRanalyst spectral analysis software is based on a mathematical spin system model. NMRanalyst analyzes all acquired phase components simultaneously for maximum sensitivity. This provides maximum sensitivity for various types of multidimensional spectra. This approach contrasts with other computerized analysis strategies, such as peak picking, which ignore valuable spectral information. By using this novel mathematical approach, NMRanalyst often excels compared to even an experienced spectroscopist in the sensitivity, reliability, accuracy, and speed of the data analysis.
The software supports the analysis of the following and equivalent spectrum types:

• Adequate sensitivity DoublE-QUAnTum spEctroscopy (ADEQUATE),
• Double-Quantum Filtered COrrelation SpectroscopY (DQF-COSY),
• HETeronuclear CORrelation (HETCOR),
• Heteronuclear Multi-Bond Connectivity (HMBC),
• Heteronuclear Single Quantum Coherence (HSQC, HMQC),
• Incredible Natural Abundance DoublE-QUAntum Transfer Experiment (INADEQUATE),
• Nuclear Overhauser Effect SpectroscopY (NOESY),
• Rotating frame Overhauser Effect SpectroscopY (ROESY),
• TOtal Correlation SpectroscopY (TOCSY), and
• 3D spectra.

1.1 The Automated Spectral Analysis

The first application of NMRanalyst was for 2D INADEQUATE spectra. The schematic explains this application for a >CH-CH₂-CH₃ molecular fragment. Its 1D proton decoupled ¹³C spectrum is shown at the back of the schematic. In the 2D spectrum, a pair of bonded carbons (e.g., CH-CH₂) gives rise to a pair of anti-phase doublets, centered at the chemical shifts of the two carbons (v_A and v_B), and split approximately by the carbon-carbon coupling constant (J). Each of these AB spectral patterns is displaced along the F1 axis by the sum of the two relevant chemical shifts, v_A+v_B.
This spin system results in a bond pattern for each pair of bonded carbons symmetrically disposed about the diagonal as shown. Because the double-quantum frequency (in F1 direction) is the sum of the chemical shifts of the two coupled carbons, an initial analysis of a proton decoupled 1D carbon spectrum can be used to identify the regions of the 2D INADEQUATE spectrum which may contain correlation signals. For each pair of resonances identified in the 1D spectrum, two small regions of the spectrum are defined by the small rectangles shown in the figure above. In case of a bond between the two carbons under consideration, the characteristic pattern is contained within this "fitting area". Here, the AB and BC fitting areas contain the required patterns, but the AC fitting area does not, consistent with the bonding of the three-carbon fragment shown. The objective of NMRanalyst is to examine the fitting area appropriate for each pair of carbon resonances and to determine whether or not it contains a correlation (bond) signal.

This analysis strategy extends to other spectrum types by using the appropriate spin-system model. Shown in this schematic is the DQF-COSY spin system. The spectrum contains an active coupling of two protons. Each correlation (coupling) signal is composed of 16 anti-phase transitions. The spectral diagonal is normally overly crowded and NMRanalyst only examines the off-diagonal transitions in the two shown fitting areas. What can be improved by using this automated spectral analysis?

1. A major limitation of NMR is its lack of sensitivity. A phase sensitive 2D dataset is acquired with four phase components and each phase sensitive 3D dataset with eight. Half of the phase components are acquired sequentially and hence their noise content is uncorrelated. NMRanalyst evaluates all phase components simultaneously by nonlinear regression analysis, making full use of the acquired data.
2. The visual spectrum analysis can be described as "pattern recognition". What sticks out of the noise level and looks like an expected signal? Can this signal be assigned to other signals in the same or other spectra or is it perhaps a spectral artifact?NMRanalyst looks for the whole spin system, potentially consisting of several transitions. NMRanalyst starts with 1D resonance information and only searches the areas in the multidimensional spectrum which could contain spin systems. The automated analysis is more selective than the visual pattern recognition. It is also more sensitive as it can reliably detect signals even for signal-to-noise challenged spectra where resonances are not visible.
3. The molecular structure determination using NMR remains labor intensive. Why not automate the steps which don't require the creative capabilities of a spectroscopist? "Spectroscopist-In-A-Box" is our goal for NMRanalyst. Things remain to be improved, but NMRanalyst already effectively supports using NMR as a structure elucidation tool.

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GEOMETRICAL ISOMERISM IN β-NITROSTYRENES: PREFERRED CONFORMATIONS OF (E)- AND (Z)- 1-(4-METHYLTHIOPHENYL)-2-NITROBUTENES

.

 Condensation of 4-methylthiobenzaldehyde with 1-nitropropane unexpectedly afforded separable amounts of both (E)- and (Z)-1-(4-methylthiophenyl)-2-nitrobutene. The ¹H and ¹³C NMR spectra allowed the unequivocal assignment of all signals and their correlation with the preferred conformations adopted by these compounds as determined by NOESY experiments. Hartree Fock theory optimizations at the 6-311G(d,p) level were carried out for the stereoisomeric 4-methylthionitroethene, -nitropropene, and -nitrobutene pairs, and the relative energy differences between isomers were calculated in order to estimate approximate E/Z equilibrium constants. These energy differences decrease with the increasing number of side chain carbon atoms, explaining the possibility of separating (E)- and (Z)-nitrobutenes and the failure to isolate the (Z) isomers of the lower homologues under the usual thermodynamically controlled reaction conditions.

Fig. 1. Structures and numbering of the (E)- and (Z)-1-(4-methylthiophenyl)-2-nitroalkenes mentioned in this study: 1a, R² = CH₂CH₃; 1b, R² = CH₃; 1c, R² = H.

 
J. Chil. Chem. Soc., 49, N 3 (2004): 257-260
GEOMETRICAL ISOMERISM IN β-NITROSTYRENES: PREFERRED CONFORMATIONS OF (E)- AND (Z)- 1-(4-METHYLTHIOPHENYL)-2-NITROBUTENES

CLAUDIO HURTADO-GUZMÁN, PATRICIO ITURRIAGA-VÁSQUEZ, GERALD ZAPATA-TORRES AND BRUCE K. CASSELS*
Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, and Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile. E-mail:bcassels@uchile.cl.
(Received: November 4, 2003 - Accepted: July 12, 2004)

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ABSTRACT
Condensation of 4-methylthiobenzaldehyde with 1-nitropropane unexpectedly afforded separable amounts of both (E)- and (Z)-1-(4-methylthiophenyl)-2-nitrobutene. The ¹H and ¹³C NMR spectra allowed the unequivocal assignment of all signals and their correlation with the preferred conformations adopted by these compounds as determined by NOESY experiments. Hartree Fock theory optimizations at the 6-311G(d,p) level were carried out for the stereoisomeric 4-methylthionitroethene, -nitropropene, and -nitrobutene pairs, and the relative energy differences between isomers were calculated in order to estimate approximate E/Z equilibrium constants. These energy differences decrease with the increasing number of side chain carbon atoms, explaining the possibility of separating (E)- and (Z)-nitrobutenes and the failure to isolate the (Z) isomers of the lower homologues under the usual thermodynamically controlled reaction conditions.
Keywords: β-nitrostyrene geometrical isomers; preferred conformations; NMR studies; RHF/6-311G(d,p) calculations.

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INTRODUCTION
β-Nitroolefins are widely used as substrates for nucleophilic additions.^1,2 β-Nitrostyrenes are commonly prepared en route to β-phenylalkylamines, and nitro cycloalkenes have been reviewed as very versatile synthetic intermediates.^3,4 The steric outcome of nucleophilic additions to these compounds depends on the configuration of the starting material, but both stereoisomers are seldom readily available, and β-nitrostyrenes and 1-nitroprop-2-enes obtained by the usual Knoevenagel sequence show a strong predominance of the (E)-isomer which is generally the sole isolated product. Only one literature reference reports obtaining (Z)-β-nitroolefins in good yield by dehydration of the corresponding nitro alcohol when the reaction is carried out at a very low temperature.⁵ A related example reports the elimination reaction of a 2-alkylthio-1-nitropropane with potassium fluoride to produce a mixture of both isomers with the (Z)-isomer predominating.⁶
We now report the separation and complete NMR spectroscopic characterization of both -ethyl-β-nitrostyrene isomers, (E)-1a and (Z)-1a (Figure 1), obtained by Knoevenagel condensation of 4-methylthiobenzaldehyde and 1-nitropropane as an approach to novel monoamine oxidase inhibitors and possible serotonin releasers.⁷ NOESY experiments provided evidence for the preferred conformations of the products. In addition, we computed the relative energy differences at the RHF/6-311G(d,p) level for this (E)- and (Z)-1-(4-methylthiophenyl)-2-nitrobutene pair and the corresponding nitropropenes (1b) and ­ethenes (1c).

Fig. 1. Structures and numbering of the (E)- and (Z)-1-(4-methylthiophenyl)-2-nitroalkenes mentioned in this study: 1a, R² = CH₂CH₃; 1b, R² = CH₃; 1c, R² = H. 


 
RESULTS AND DISCUSSION
The (E) and (Z) isomers of 1-(4-methylthiophenyl)-2-nitrobutene were formed in the reaction mixture of 4-methylthiobenzaldehyde and 1-nitropropane in refluxing toluene, using N,N-dimethylethylenediamine as catalyst, in an approximately 92:8 molar ratio, judging from the ¹H NMR spectrum of the crude product. Both products [(E)-1a and (Z)-1a, respectively] were separated chromatographically and fully characterized by ¹H- and ¹³C-NMR spectroscopy, using HMBC, HMQC and NOESY experiments for complete assignment of the signals. Tables 1 and 2 allow direct comparison of the ¹H and ¹³C chemical shifts of stereoisomers (E)-1a and (Z)-1a.

The ¹H-NMR spectrum of (E)-1-(4-methylthiophenyl)-2-nitrobutene [(E)-1a] (Figure 2a) shows the H1 resonance shifted further downfield (7.98 ppm) than either of the aromatic ring proton resonances (7.29 and 7.36 ppm), while in the (Z) isomer [(Z)-1a] (Figure 2b) the H1 nucleus resonates upfield (6.29 ppm) from the aromatic ring protons (7.16 ppm). This striking difference prompted us to study the two isomers in detail.

Fig. 2a. NOESY spectrum of (E)-1-(4-methylthiophenyl)-2-nitrobutene [(E)-1a] (CDCl₃).

Fig. 2b. NOESY spectrum of (Z)-1-(4-methylthiophenyl)-2-nitrobutene [(Z)-1b] (CDCl₃).

(E)-1-(4-Methylthiophenyl)-2-nitrobutene [(E)-1a] and (Z)-1-(4-Methylthiophenyl)-2-nitrobutene [(Z)-1a].
A mixture of 4-methylthiobenzaldehyde (1.3 ml, 0.010 mol), N,N-dimethylethylenediamine (1.3 ml, 0.010 mol), 1-nitropropane (4.5 ml, 0.041 mol) and toluene (10 ml) was refluxed for 24 h with continuous water removal under a Dean-Stark trap. All volatiles were removed under reduced pressure and the residue was fractionated chromatographically over silica gel, eluting with CHCl₃, to afford the E [(E)-1a] (1.08 g, 92% in the mixture) and Z isomers [(Z)-1a] (0.096 g, 8% in the mixture) as viscous orange colored liquids.
(E)-1a: ¹H-NMR (CDCl₃) δ 1.28 (t, 3H, J = 7.4 Hz, CH₂CH₃), 2.52 (s, 3H, S-CH₃), 2.88 (q, 2H, J = 7.4 Hz, CH₃CH₂C=CH), 7.29 (d, 2H, J = 8.5 Hz, H3' and H5'), 7.36 (d, 2H, J = 8.5 Hz, H2' and H6'), 7.98 (s, 1H, Ar-CH=C). HREIMS m/z (M⁺) = 223.06621; calc. for C₁₁H₁₃NO₂S = 223.06670.
(Z)-1a: ¹H-NMR (CDCl₃) δ 1.20 (t, 3H, J = 7.4 Hz, CH₂CH₃), 2.46 (s, 3H, S-CH₃), 2.67 (q, 2H, J = 7.4 Hz, CH₃CH₂C=CH), 6.29 (s, 1H, Ar-CH=C), 7.16 (apparent s, 4H, J = 9.2 Hz, Ar-H). HREIMS m/z (M⁺) = 223.06622; calc. for C₁₁H₁₃NO₂S = 223.06670.

Journal of the Chilean Chemical Society

versión On-line ISSN 0717-9707

J. Chil. Chem. Soc. v.49 n.3 Concepción sep. 2004

http://dx.doi.org/10.4067/S0717-97072004000300013 

J. Chil. Chem. Soc., 49, N 3 (2004): 257-260 GEOMETRICAL ISOMERISM IN β-NITROSTYRENES: PREFERRED CONFORMATIONS OF (E)- AND (Z)- 1-(4-METHYLTHIOPHENYL)-2-NITROBUTENES CLAUDIO HURTADO-GUZMÁN, PATRICIO ITURRIAGA-VÁSQUEZ, GERALD ZAPATA-TORRES AND BRUCE K. CASSELS* Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, and Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile. E-mail:bcassels@uchile.cl. (Received: November 4, 2003 - Accepted: July 12, 2004)

 http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-97072004000300013
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COSY Spectrum of m-dinitrobenzene

COSY Spectrum of m-dinitrobenzene




 

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