HMBC Described for (Z)-2-Isopropylimino-3-phenyl-thiazolidin-4-one

(Z)-2-Isopropylimino-3-phenyl-thiazolidin-4-one (3a)

3a as an off-white crystalline solid (4.60 g, 88%), mp 149 °C.

¹H NMR (CDCl₃): δ 1.14 (d, J = 6.3 Hz, 6 H, H2b), 3.52 (hept, J = 6.0 Hz, 1 H, H2a), 3.98 (s, 2 H, H5), 7.27−7.32 (m, 2 H, H3b), 7.37−7.44 (m, 1 H, H3d), 7.45−7.52 (m, 2 H, H3c).

¹³C NMR (CDCl₃): δ 23.35 (C2b), 32.58 (C5), 53.86 (C2a), 128.03 (C3b), 128.41 (C3d), 128.97 (C3c), 135.30 (C3a), 149.30 (C2), 171.39 (C4).

HMBC (CDCl₃): H2a → C2, C2b; H2b → C2, C2a; H3b → C3a, C3d; H3c → C3a, C3d; H3d → C3a, C3b; H5 → C2, C4. LC-LC-MS (ES⁺): t_R0.59 min. m/z: 235 (M + H).

The organic extract containing crude (Z)-3-isopropyl-2-phenylimino-thiazolidin-4-one (4a) was concentrated and the crude byproduct was purified by column chromatography on silica gel eluting with heptane:ethyl acetate 3:1 to give pure 4a as a pale-yellow oil (278 mg, 5%).

¹H NMR (CDCl₃): δ 1.55 (d, J = 7.0 Hz, 6 H, H3b), 3.75 (s, 2 H, H5), 4.90 (hept, J = 6.8 Hz, 1 H, H3a), 6.97 (d, J = 7.5 Hz, 2 H, H2b), 7.16 (t, J = 7.5 Hz, 1 H, H2d), 7.37 (t, J = 7.5 Hz, 2 H, H2c).

¹³C NMR (CDCl₃): δ 18.72 (C3b), 32.50 (C5), 48.04 (C3a), 120.92 (C2c), 124.48 (C2d), 129.10 (C2b), 148.36 (C2a), 154.14 (C2), 171.92 (C4).

HMBC (CDCl₃): H2b → C2a, C2c, C2d; H2c → C2a, C2b, C2d; H2d → C2b, C2c; H3a → C2, C3b, C4; H3b → C3a; H5 → C2, C4. LC-MS (ES⁺): t_R 0.98 min. m/z: 235 (M + H)

(Z)-2-Propylimino-3-phenyl-thiazolidin-4-one (5a) (Method B)

To a solution of phenylisothiocyanate (2.00 g, 14.8 mmol) in dichloromethane (20 mL), n-propylamine (875 mg, 1.23 mL, 14.8 mmol) was added portionwise at 20 °C. The solution was stirred at 20 °C for 15 min. The solution was cooled to 0 °C before bromo-acetyl bromide (2.99 g, 1.29 mL, 14.8 mmol) was added carefully such that the temperature did not rise above 5 °C. The reaction mixture was stirred at 0 °C for 15 min before pyridine (2.40 g, 2.45 mL, 30.3 mmol) was added at 0 °C. The mixture was stirred for another 15 min at 0 °C, then warmed to 20 °C and washed with water (10 mL). The aqueous layer is extracted with dichloromethane (10 mL). The solvent of combined organic extracts was evaporated under reduced pressure to afford 5a(1.84 g, 53%) as an off-white solid, mp 138 °C. This material was sufficiently pure (>90%) for further use in the subsequent condensation step with substituted benzaldehydes. ¹H NMR (CDCl₃): δ 0.92 (t, J = 7.3 Hz, 2 H, H2c), 1.61 (h, J = 7.0 Hz, 2 H, H2b), 3.28 (t, J = 7.0 Hz, 2 H, H2a), 4.00 (s, 2 H, H5), 7.28−7.32 (m, 2 H, H3b), 7.37−7.45 (m, 1 H, H3d), 7.47−7.53 (m, 2 H, H3c). ¹³C NMR (CDCl₃): δ 11.86 (C2c), 23.57 (C2b), 32.56 (C5), 54.29 (C2a), 127.98 (C3b), 128.63 (C3d), 129.17 (C3c), 135.17 (C3a), 151.67 (C2), 171.37 (C4). HMBC (CDCl₃): H2a → C2, C2b, C2c; H2b → C2a, C2c; H2c → C2a, C2b; H3b → C3a, C3d; H3c → C3a, C3b; H3d → C3a, C3b; H5 → C2, C4. LC-MS (ES⁺): t_R 0.60 min. m/z: 235 (M + H)

J. Med. Chem., 2010, 53 (10), pp 4198–4211

DOI: 10.1021/jm100181s

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Cape Maclear, Malawi

With no brine, sharks or jellyfish to be afraid of, this water is simply perfect for diving, snorkelling, kayaking. Peached by the edge of the massive Lake Malawi which feels like an ocean, Cape Maclear forms part of a UNESCO World Heritage Site and the beach is simply the hippie hangout. .

Cape Maclear

Town in Malawi

Cape Maclear or Chembe is a town in the Mangochi District of Malawi's Southern Region. The town, situated on the Nankumba Peninsula, is on the southern shore of Lake Malawi and is the busiest resort on Lake Malawi. Wikipedia

 

 

 

 

 


 

 

 

 

 
 

 
 
 

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Assignment of Heteronuclear NMR Spectra Using HMBC

Although organic chemists typically focus on hydrogen and carbon when analyzing complex molecules, there is an increasing amount of analysis done on other elements such as phosphorous or sulfur. NMR is an underappreciated tool to understand the role of these heteroatoms, especially phosphorous, whose NMR-active isotopes are abundant and have high gyromagnetic ratios.

Adenosine triphosphate (ATP) is ubiquitous in eukaryotic and prokaryotic cells and serves as an energy source. Its three phosphate groups and purine ring serve as a great template for some interesting NMR experiments and demonstration of how heteronuclear and heteronuclear 2-dimensional experiments can be used to elucidate molecular structure.

Figure 1: ¹H NMR spectrum of 10 mg/ml ATP in D₂O.
The ¹H NMR spectrum of ATP is straightforward to acquire as long as one doesn’t mind losing the exchangable protons to the solvent. Water suppression techniques are unnecessary given the relatively sharp solvent signal (more on water suppression in a future post). The small peaks at δ 3.5 and d 1.2 ppm are residual triethylamine from the commercial material. Assignment of the non-aromatic peaks (H-1′, H-2′, H-3′, H-4′, H-5′) can be achieved using COSY but will not be shown here – see previous post on clarithromycin for details on ¹H assignment using COSY.

Figure 2: ¹³C NMR spectrum, with the doublet at δ 84 ppm shown in inset
Likewise, the ¹³C NMR of ATP is straightforward to acquire with an overnight scan. A small amount of line broadening (LB = 1.0 Hz) was applied to improve the signal-to-noise, but limited to keep the maintain resolution of the doublet at δ 84 ppm (which arises due to ¹³C-³¹P coupling).

Figure 3: ¹H-¹³C HSQC spectrum
The alkyl ¹³C resonances can easily be assigned using an HSQC spectrum, which correlates the ¹H spectrum with the ¹³C spectrum. In this phase-sensitive version of the HSQC experiment, red cross-peaks have CH₂ multiplicity (H-5′ / C-5′) while black cross-peaks have CH or CH₃ multiplicity. The ¹³C resonances at δ 142 and d 145 ppm are C-2 and C-8 (but assignment not yet known), while the resonances at δ 118, 148, and 150 ppm do not have protons bonded (C-4, C-5, and C-6; assignment not yet known).

Figure 4: ¹H-¹³C HMBC spectrum
Heteronuclear Multiple Bond Correlation is similar to the HSQC, except that 1-bond correlations are canceled out, and only 2- and 3-bond correlations are shown. The HMBC experiment allows one to identify all of the aromatic resonances, on both the ¹H and ¹³C spectra. The H-1′ (δ 6.0 ppm) signal show correlations to the C-4 (δ 148 ppm) and C-8 (δ 142 ppm) signals. The H-8 (δ 8.5 ppm) signal shows correlations to the C-4 and C-5 (δ 118 ppm) signals. The H-2 (δ 8.3 ppm) signal shows correlations to the C-4 and C-6 (δ 150 ppm) signals, as well as a weak signal to C-5.
Now that the ¹H and ¹³C spectra are fully assigned, we can direct our attention to the ³¹P NMR spectra.

Figure 5: ³¹P NMR spectrum
³¹P has decent sensitivity and high abundance and is a good nucleus to use as an example of heteronuclear spectroscopy. A 1-dimensional ³¹P spectrum shows three signals at δ -10, -11, and -23 ppm. This spectrum is ¹H-coupled, but the 3-bond ¹H-³¹P coupling is too small to see. The observed couplings are ³¹P-³¹P couplings, and based on the multiplicity, it is clear that the middle phosphate gives rise to the signal at δ -23 ppm. The other two signals can be differentiated using HMBC, except this time ¹H-³¹P instead of ¹H-¹³C.
As an internal standard, approximately 0.5 equivalents of trimethylphosphonoacetate were added. The ³¹P signal at δ +26.06 ppm gives strong crosspeaks to the methylene (δ 3.2 ppm) as well as methyl (δ 3.8 ppm) protons and helps calibrate the spectrum along the ³¹P axis.


Figure 6: ¹H-³¹P HMBC spectrum, full (top) and enlarged on the ATP signals (bottom).
In this case, crosspeaks between the ³¹P signal at δ -11.27 ppm and the H-4′ and H-5′ signals from δ 4.15-4.35 ppm were observed. The crosspeaks establish the ³¹P signal at δ -11.27 ppm as the first phosphate, allowing assignment of the ³¹P NMR spectrum as well as confirmation that the triphosphate group is covalently attached to the nucleoside via that 5′-OH.

2- Butanone

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