NMR Spectroscopy of Stereoisomers

Introduction

Nuclear magnetic resonance (NMR) spectroscopy is a very useful tool used widely in modern organic chemistry. It exploits the differences in the magnetic properties of different nuclei in a molecule to yield information about the chemical environment of the nuclei, and subsequently the molecule, in question. NMR analysis lends itself to scientists more easily than say the more cryptic data achieved form ultraviolet or infared spectra because the differences in magnetic properties lend themselves to scientists very well. The chemical shifts that are characteristic of different chemical environments and the multiplicity of the peaks fit well with our conception of the way molecules are structured.

Using NMR spectroscopy, we can differentiate between constitutional isomers, stereoisomers, and enantiomers. The later two of these three classifications require close examination of the differences in NMR spectra associated with changes in chemical environment due to symmetry differences; however, the differentiation of constitutional isomers can be easily obtained.

Constitutional isomerism

Nuclei both posses charge and spin, or angular momentum, and from basic physics we know that a spinning charge generates a magnetic moment. The specific nature of this magnetic moment is the main concern of NMR spectroscopy.

For proton NMR, the local chemical environment makes different protons in a molecule resonate at different frequencies. This difference in resonance frequencies can be converted into a chemical shift (δ) for each nucleus being studied. Because each chemical environment results in a different chemical shift, one can easily assign peaks in the NMR data to specific functional groups based upon president. Presidents for chemical shifts can be found in any number of basic NMR text. For example, Figure 1 shows the spectra of ethyl formate and benzyl acetate. In the lower spectra, benzyl acetate, notice peaks at δ = 1.3, 4.2, and 8.0 ppm characteristic of the primary, secondary, and aromatic protons, respectively, present in the molecule. In the spectra of ethyl formate (Figure 1b), notice that the number of peaks is is the same as that of benzyl acetate (Figure 1a); however, the multiplicity of peaks and their shifts is very different.

Figure 1: ¹H NMR spectra of (a) ethyl formate and (b) benzyl acetate.

The difference between these two spectra is due to geminal spin-spin coupling. Spin-spin coupling is the result of magnetic interaction between individual protons transmitted by the bonding electrons between the protons. This spin-spin coupling results in the speak splitting we see in the NMR data. One of the benefits of NMR spectroscopy is the sensitivity to very slight changes in chemical environment.

Stereoisomerism

Diastereomers

Based on their definition, diastereomers are stereoisomers that are not mirror images of each other and are not superimposable. In general, diastereomers have differing reactivity and physical properties. One common example is the difference between threose and erythrose (Figure 2).

Figure 2: The structures of threose and erythrose.

As one can see from Figure 2, these chemicals are very similar each having the empirical formula of C₄H₇O₄. One may wonder: how are these slight differences in chemical structure represented in NMR? To answer this question, we must look at the Newman projections for a molecule of the general structure (Figure 3).

Figure 3: Newman projections of a general diastereomer.

One can easily notice that the two protons represented are always located in different chemical environments. This is true because the R group makes the proton resonance frequencies v₁(I) ≠ v₂(III), v₂(I) ≠ v₁(II), and v₂(II) ≠ v₁(III). Thus, diastereomers have different vicinal proton-proton couplings and the resulting chemical shifts can be used to identify the isomeric makeup of the sample.

Enantiomers

Enantiomers are compounds with a chiral center. In other words, they are non-superimposable mirror images. Unlike diastereomers, the only difference between enantiomers is their interaction with polarized light. Unfortunately, this indistinguishability of racemates includes NMR spectra. Thus, in order to differentiate between enantiomers, we must make use of an optically active solvent also called a chiral derivatizing agent (CDA). The first CDA was (α-methoxy-α-(trifluoromethyl)phenylacetic acid) (MTPA also known as Mosher's acid) (Figure 4).

Figure 4: The structure of the S-isomer of Mosher's Acid (S-MTPA)

Now, many CDAs exist and are readily available. It should also be noted that CDA development is a current area of active research. In simple terms, one can think of the CDA turning an enantiomeric mixture into a mixture of diastereomeric complexes, producing doublets where each half of the doublet corresponds to each diastereomer, which we already know how to analyze. The resultant peak splitting in the NMR spectra due to diastereomeric interaction can easily determine optical purity. In order to do this, one may simply integrate the peaks corresponding to the different enantiomers thus yielding optical purity of incompletely resolved racemates. One thing of note when performing this experiment is that this interaction between the enantiomeric compounds and the solvent, and thus the magnitude of the splitting, depends upon the asymmetry or chirality of the solvent, the intermolecular interaction between the compound and the solvent, and thus the temperature. Thus, it is helpful to compare the spectra of the enantiomer-CDA mixture with that of the pure enantiomer so that changes in chemical shift can be easily noted.

Bibliography

• H. Günther, NMR Spectroscopy: Basic Principles, Concepts, and Applications in Chemistry, John Wiley & Sons, Chichester (1996).
• F. A. Bovey, Nuclear Magnetic Resonance Spectroscopy, 2^nd Ed, Academic, New York (1988).
• S. Braun, H.-O. Kalinowski, S. Berger, 100 and More Basic NMR Experiments: A Practical Course, VCH, Weinheim (1996).
• A. E. Derome, Modern NMR Techniques for Chemistry Research , Pergamon, Oxford (1987).
• J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.

King, S.; Barron, A. NMR Spectroscopy of Stereoisomers, OpenStax-CNX Web site. http://cnx.org/content/m38355/1.1/, May 16, 2011.

1-benzoylmorpholine

1-benzoylmorpholine

1H NMR (300 MHz, CDCl3):

7.21-7.40 (m, 5 H, ArH), 

3.50 (br, s, 6H, CH2), ortho to oxygen atom

3.29 (br, s, 2H, CH2 ).  ortho to nitrogen atom

13CNMR (75.5 MHz, CDCl3):

169.8 (CH=O), 134.7 (Ar-C_q), 129.3 (Ar-CH), 128.0 (Ar-CH), 126.5 (Ar-CH), 76.6 (CH2), 74.0 (CH2), 66.3 (CH2).

MS (ESI): m/z 191.0 (M+H)+

Anal. Found (calculated for C₁₀H₈N₂O): C 69.47 (69.09). H 6.48 (6.85), N 7.02 (7.32)%.

---

S. Rubino, S. Petruso, R. Pierattelli, G. Bruno, G. C. Stocco, L. Steardo, M. Motta, M. Passerotto, E. Del Giudice and G. Guli, J. Inorg. Biochem., 2004, 98, 2071-2079. http://dx.doi.org/10.1016/j.jinorgbio.2004.09.012

EFINACONAZOLE , Эфинаконазол ,艾非康唑 , إيفيناكونازول

 
Efinaconazole
(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
(2R, 3R) -2 - (2,4 - difluorophenyl) -3 - (4 - methylene-piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - manufacture ol (KP-103)
Efinaconazole is a triazole antifungal. It is approved for use in Canada as 10% topical solution for the treatment of onychomycosis (fungal infection of the nail).^[1][2] Efinaconazole acts as a 14α-demethylase inhibitor.^[3]

Identifiers
CAS number	164650-44-6
PubChem	CID 489181
ChemSpider	428538
Chemical data
Formula	C18H22F2N4O
Mol. mass	348.39 g/mol

SEE AT

PATENT

http://www.google.com/patents/WO2012029836A1?cl=en

Method for producing butanol derivatives - 1 - 2 - triazole Is a (compound described in Example 1 of Patent Document 1) a compound of formula 1 to be effective against fungal diseases of humans and animals are known, the present invention, (2R, 3R) - 2 - (2,4 - difluorophenyl) -3 - (4 - methylene piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - (generic name ol ( The present invention relates to preparation of their salts that Fina et Kona zole (Efinaconazole)), hereinafter abbreviated as "KP-103" or even) in: INN).
Example 1
(2R, 3R) -2 - (2,4 - difluorophenyl) -3 - (4 - methylene-piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - manufacture ol (KP-103)


Was stirred while addition of acetonitrile 80mL, lithium hydroxide 2.859g methylene piperidine hydrobromide (4-MP · HBr) 21.26g and (119.4mmol) and (119.4mmol) - 4 obtained in Production Example 1. Then, (2R, 3S) -2 - (2,4 - difluorophenyl) -3 - methyl -2 - [(1H-1, 2,4 - triazol-1 - yl) methyl] oxirane and 20g (79.6mmol) was added, and the mixture was heated under reflux for 14 hours at (external temperature 100 ℃) oil bath. After completion of the reaction, to precipitate the crystals by the addition of ethanol and distilled water to the reaction solution. Thereafter, the crystals were filtered, washed with ethanol / water mixture 40mL, and naturally dried at room temperature for 12 hours and dried under reduced pressure at 40 ℃, KP-103 24.2g light yellow 87.3% (yield, HPLC purity 95.3 % I got).
¹ H-NMR (500MHz, CDCl ₃₎
δ: 0.96 (3H, dd, J = 2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br) ,2.90-2 .94 (1H, q, J = 7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J = 0.73, 14.39 Hz), 4.87 (1H, dd, J = 0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H , m), 7.51 (1H, dt, J = 6.59, 9.03 Hz), 7.78 (1H, s),
8.02 (1H, s).
FAB-MS m / z: 349 [M ⁺ H] +
:86-89 ℃ melting point
Optical rotation: [α] _D ²⁵ -87 ~ -91 ° (C = 1.0, methanol)




“Drugs at FDA: JUBLIA”. Retrieved 26 June 2014.

NDA Appl No		RLD	Active Ingredient	Dosage Form; Route	Strength	Proprietary Name	Applicant
N203567		Yes	EFINACONAZOLE	SOLUTION; TOPICAL	10%	JUBLIA	DOW PHARM

JUNE6 2014 APPROVED

Patent Data

Appl No	Prod No	US Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N203567	001	7214506	Oct 5, 2021			U – 281
N203567	001	8039494	Jul 8, 2030			U – 281
N203567	001	8486978	Oct 24, 2030		Y

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N203567	001	NCE	Jun 6, 2019

Efinaconazole is a triazole antifungal. It is approved for use in Canada as 10% topical solution for the treatment of onychomycosis (fungal infection of the nail).^[1][2] Efinaconazole acts as a 14α-demethylase inhibitor.^[3]



UPDATED

Efinaconazole

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)-butane-2-ol

EFINACONAZOLE,

KP-103,

cas 164650-44-6, Efinaconazole [INN], UNII-J82SB7FXWB,  AC1LAJ21, Efinaconazole [USAN:INN],

• Efinaconazole
• Jublia
• KP-103
• UNII-J82SB7FXWB

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol

Molecular Formula: C18H22F2N4O   Molecular Weight: 348.390286

efinaconazole

 

1H NMR PREDICT

………………………………………
 13C NMR PREDICT

 COSY PREDICT

HMBC PREDICT

...............................
 ELABORATION

1H NMR PREDICT

13C NMR

PATENT

http://www.google.com/patents/US20130150586

Example 1Production of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (KP-103)21.26 g (119.4 mmol) of the 4-methylenepiperidine hydrobromide (4-MP.HBr) obtained in Production 1 and 2.859 g (119.4 mmol) of lithium hydroxide were added to 80 mL of acetonitrile and stirred for a while. Thereafter, 20 g (79.6 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane was added and the mixture was heated under reflux in an oil bath (external temperature: 100° C.) for 14 hours. After the reaction completed, ethanol and distilled water were added to the reaction mixture, whereupon a crystal was precipitated. Thereafter, the crystal was filtered off, washed with 40 mL of an ethanol/water mixture, dried with air at room temperature and further dried under reduced pressure at 40° C. for 12 hours to give a pale yellow crystal of KP-103 in an amount of 24.2 g (yield, 87.3%; purity on HPLC, 95.3%).

1H-NMR (500 MHz, CDCl3)δ: 0.96 (3H, dd, J=2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br), 2.90-2.94 (1H, q, J=7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J=0.73, 14.39 Hz), 4.87 (1H, dd, J=0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H, m), 7.51 (1H, dt, J=6.59, 9.03 Hz), 7.78 (1H, s), 8.02 (1H, s).

FAB-MS m/z: 349 [M+H]+

melting point: 86-89° C.

optical rotation: [α]D 25 −87 to −91° (C=1.0, methanol)

………………………………….

Journal of Organic Chemistry, 2014 ,  vol. 79,   7  pg. 3272 – 3278

http://pubs.acs.org/doi/abs/10.1021/jo500369y

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Scheme 3. Synthesis of Efinaconazole (Jublia)

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Efinaconazole)

To a solution of 1 (54.2 mg, 0.216 mmol) in EtOH (217 μL) was added 4-methylenepiperidine (147 mg, 1.51 mmol), ……………………deleted………………. see original…………….. was purified using silica gel column chromatography (CHCl3/MeOH = 10:1) to give 67.6 mg ofefinaconazole (90% yield) as a colorless amorphous solid.

[α]D20 −87.8 (c 1.12, CHCl3);

1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.76 (s, 1H), 7.51–7.45 (m, 1H), 6.78–6.68 (m, 2H), 5.50 (brs, 1H), 4.85 (d,J = 14.4 Hz, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.61 (s, 2H), 2.88 (q, J = 6.9 Hz, 1H), 2.66 (br s, 2H), 2.32 (br s, 2H), 2.21–2.17 (m, 4H), 0.93 (dd, J = 6.9, 2.1 Hz, 3H);

13C NMR (150 MHz, CDCl3) δ 162.5 (dd, J = 250, 13 Hz), 158.5 (dd, J = 246, 12 Hz), 151.3, 145.9, 144.4, 130.6 (dd, J = 8.7, 5.8 Hz), 124.7 (dd, J= 14, 3.6 Hz), 111.4 (dd, J = 20, 2.9 Hz), 108.1, 104.1 (dd, J = 28, 25 Hz), 77.7 (d, J = 5.8 Hz), 64.4, 55.9 (d, J = 8.7 Hz), 52.4, 35.2, 7.63 (d, J = 2.9 Hz);

19F NMR (376 MHz, CDCl3) δ −105.8, −110.7;

IR (CHCl3, cm–1) ν 3423, 3073, 2979, 2939, 2899, 2810, 1615, 1498, 1418, 1273, 1138;

HRMS (ESI-TOF) calcd for C18H23ON4F2 [M + H]+ m/z 349.1834, found 349.1828.

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

……………

SYN
http://newdrugapprovals.org/2014/06/10/valeant-pharmaceuticals-announces-fda-approval-of-jublia-for-the-treatment-of-onychomycosis/


updated
1H NMR



get clear pic at........http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

13C NMR

get clear pic at........http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf


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LOPINAVIR

 
LOPINAVIR
(2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide
[1S-[1R*,(R*),3R*,4R*]]-N-[4-[[(2,6-dimethyl-phenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide
(2S,3S,5S)-2-(-2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1 ,6-diphenylhexane
628.8008

Abbott Laboratories

CAS	192725-17-0

AHFS/Drugs.com	International Drug Names
MedlinePlus	a602015
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)

DrugSyn.org
US5914332
SYNONYMS

ABT-378, Aluviran, Koletra, ABT 378, 1mui, 2rkf, 2rkg, A 157378.0, RS-346

Molecular Formula: C₃₇H₄₈N₄O₅   Molecular Weight: 628.80082

Org. Proc. Res. Dev., 2000, 4 (4), pp 264–269

DOI: 10.1021/op990202j

http://pubs.acs.org/doi/abs/10.1021/op990202j
A large scale process for the synthesis of HIV protease inhibitor candidate ABT-378 has been developed which utilizes an intermediate common to the synthesis of ritonavir, Abbott’s first generation compound. The synthesis relies on the sequential acylation of this intermediate which is carried through as a mixture of diastereomers until the penultimate step. A synthesis of acid 5, derived from l-valine, is also reported.

[1S-[1R*(R*),3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide (2).

A 500-mL, three-necked, round-bottomed flask equipped with mechanical stirring, ……………………..DELETED…………………The solid product was washed with 30 mL of 1:1 EtOAc/heptane and dried in vacuo at 70 °C for 60 h, affording 18.8 g (89% yield) of ABT-378 2 as a colorless solid. Before crystallization crude 2 assayed as >93% pure by HPLC; after crystallization >99% purity was achieved.

mp (EtOAc), 124−127 °C. (uncorrected)

IR:  3413, 3335, 3289, 3060, 2966, 1671, 1650, 1624, 1545, 1520, 1453, 1189, 701 cm^-1.

¹H NMR (300 MHz):  δ 7.30−7.13 (m, 10H), 7.02−6.92 (m, 3H), 6.86 (v br s, 1H), 5.68 (br s, 1H), 4.25 (m, 1H), 4.19 (app d, J = 10 Hz, 2H), 4.19 (m, 2H), 3.78 (m, app d sept, 1H), 3.12 (m, 1H), 3.06 (m, 2H), 2.97 (d, J = 7.6 Hz, 2H), 2.88 (m, 1H), 2.81 (app ABX dd, J = 14, 5.2 Hz, 1H), 2.68 (app ABX, dd, J = 14, 9.5 Hz, 1H), 2.23 (m, 1H), 2.18 (s, 6H), 1.83 (s, 1H), 1.74 (m, 2H), 1.53 (m, 1H), 1.28 (m, 2H), 0.83 (app t, J = 7 Hz, 6H).

¹³C NMR (75 MHz):  δ 170.7, 168.8, 156.5, 154.2, 138.1, 138.0, 130.3, 129,3, 129.2, 129.0, 128.4, 128.2, 126.3, 126.0, 124.6, 70.2, 69.7, 63.1, 54.4, 48.7, 41.8, 41.1, 40.8, 40.0, 38.2, 25.4, 21.7, 19.6, 18.7, 16.1,

MS (ESI) 629 (M + H)⁺, 651 (M + Na)⁺.

Anal. Calcd for C₃₇H₄₈N₄O₅:  C, 70.66; H, 7.69; N 8.91. Found:  C, 70.26; H, 7.73; N 8.79.

[α]_d²⁰ = − 22.85 (c 0.4 MeOH).

• Crystallographic studies have shown, to our surprise, that 2 isolated by this crystallization method is not a solvate.
• The determination of the enantiomeric excess (% ee) for ABT-378 (2) can be done indirectly. Compound 17, which results from the acylation of 4 with the enantiomer of acid 5, is known to us, having been detected as an impurity in our process development.¹⁷ Compound 18 can only result from the acylation of the enantiomer of 4 (2R,3R,5R) with 5. The levels of 17/18 observed in 2 are typically <0.1%. Until there is a need for a more definitive assay, we assume this represents an upper limit to the amount of ent-2 present.

Enantiomeric excess is determined by HPLC (Chiracel OD column, elution with hexane: ethanol: trifluoroacetic acid (930:  70:  1). The desired l-isomer has a retention time of approximately 14 min; the d-isomer, 11.5 min.

References

1. “FDA Approved Drug Products: Kaletra”. Retrieved 30 April 2004.
2. KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
3. Capparelli E, Holland D, Okamoto C, et al. (2005). “Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV”. AIDS (London, England) 19 (9).
4. HIV drug used to reverse effects of virus that causes cervical cancer University of Manchester, 17 February 2014.

 

• Abbott: Kaletra (lopinavir/ritonavir) tablets

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US8236991	8-8-2012	PROCESS FOR THE PREPARATION OF SUBSTANTIALLY  PURE (2S,3S,5S)-5-AMINO-2-N,N-DIBENZYLAMINO-3- HYDROXY-1,6-DIPHENYLHEXANE
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Coumarin-3-carboxylic acid

5-benzyl-4-methyl-2-aminothiazolium hydrochloride

5-benzyl-4-methyl-2-aminothiazolium hydrochloride (3) has the following physical and spectroscopic properties: mp = 219–221 °C (decomp.).

 ¹H NMR (500 MHz, DMSO-d₆) 
δ: 2.20 (s, 3 H),........... methyl group
3.44 (bs) (water), Ar-CH2 GP
3.93 (s, 2 H), 
7.23–7.26 (m, 3 H), 
7.33 (t, J = 7.4 Hz, 2 H), 
9.24 (s, 2 H), 
13.37 (bs, 1 H).

¹³C NMR (125 MHz, DMSO-d₆) δ: 11.5, 30.4, 116.8, 126.8, 128.3, 128.7, 131.0, 138.8, 167.8.

IR (neat) cm^-1: 3242, 3192, 3058, 2919, 2652, 1623, 1573, 1453, 1075, 830, 760, 698. 

HRMS (ESI) Exact mass calcd for C₁₁H₁₃N₂S [M+H]⁺: 205.0794, found: 205.0798; 

Anal. Calcd for C₁₁H ₁₃N₂SCl: C, 54.88; H, 5.44; N, 11.64; S, 13.32; Cl, 14.73; Found: C, 54.72; H, 5.63; N, 11.57; S, 13.28; Cl, 14.58

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Compound 1 has the following spectroscopic properties: ¹H NMR (500 MHz, CDCl₃) δ: 1.38 (d, J = 6.4 Hz, 3 H), 1.81 (bs, 1 H), 4.49 (q, J = 6.4 Hz, 1 H), 6.27 (dd, J = 16, 6.4 Hz, 1 H), 6.57 (d, J = 16 Hz, 1 H), 7.23–7.26 (m, 1 H), 7.30–7.33 (m, 2 H), 7.38–7.39 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃) δ: 23.4, 68.9, 126.4, 127.6, 128.5, 129.3, 133.5, 136.7. IR (neat) cm ^-1: 3346, 3026, 2972, 1494, 1449. HRMS (ESI) Exact mass calcd for C₁₀H₁₁ [M-OH]⁺: 131.0855, found: 131.0856.
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 3-chloro-4-phenylbutan-2-one (2) has the following spectroscopic properties: ¹H NMR (500 MHz, CDCl₃ ) δ: 2.29 (s, 3 H), 3.08 (dd, J = 14.3, 8.1 Hz, 1 H), 3.34 (dd, J = 14.3, 6.2 Hz, 1 H), 4.41 (dd, J = 8, 6.2 Hz, 1 H), 7.21–7.33 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃) δ: 26.8, 39.8, 63.8, 127.2, 128.6, 129.3, 136.1, 202.6. IR (neat) cm ^-1: 3030, 2928, 1715, 1357, 1157. HRMS (ESI) Exact mass calcd for C₁₀H₁₁ClONa [M+Na]⁺: 205.0391, found: 205.0394.