Phosphorus(III)-mediated reductive condensation of α- Keto esters and protic pronucleophiles

Full text of DOI:10.15227/orgsyn.092.0267

HHS Public Access
Author manuscript
Organic Synth. Author manuscript; available in PMC 2018 August 23.
Published in final edited form as:
Organic Synth. 2015 ; 92: 267–276. doi:10.15227/orgsyn.092.0267.
Phosphorus(III)-Mediated Reductive Condensation of α-Keto
Esters and Protic Pronucleophiles
Wei Zhao and Alexander T. Radosevich
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania
16802, United States
Graphical abstract
Procedure
A. Methyl 2-(N-Benzyl-4-Methylphenylsulfonamido)-2-Phenylacetate (3). 4-Methyl-N-
(phenylmethyl)benzenesulfonamide (2) (8.49 g, 32.5 mmol, 1.1 equiv) was placed in an
oven-dried 1-L 2-neck round bottom flask equipped with a magnetic stir bar (3/8 × 1 ½”,
Teflon-coated, octagon). The center neck of the reaction flask was fitted with a rubber
septum-capped 60-mL pressure-equalizing addition funnel, and the side neck was fitted with
a rubber septum with nitrogen inlet (as shown in the image below). The reaction vessel was
then purged with nitrogen atmosphere by three evacuation-backfill cycles (Notes 1). Dry
dichloromethane (296 mL, 0.1 M) was added to the round bottom flask via cannula transfer
from an oven-dried 1-L Schlenk Flask (Notes 2). Methyl benzoylformate (1) (4.20 mL, 4.85
g, 29.6 mmol, 1.0 equiv) was added to the solution through the side neck (Notes 3). The
addition funnel was then charged with tris(dimethylamino)phosphine (5.90 mL, 5.30 g, 32.5
mmol, 1.1 equiv) through the septum on top (Notes 4). Dichloromethane (33 mL) was added
to the addition funnel in the same way using a 60-mL syringe and an oven-dried steel
needle. The reaction flask was cooled to –78 °C with a dry ice-acetone bath in a 3-L Dewar
flask (Notes 5). The tris(dimethylamino)phosphine solution was added dropwise to the flask
over 20-30 min while stirring (Notes 6 and 7). Upon complete addition of the
tris(dimethylamino)phosphine solution, the cooling bath was removed and the reaction
mixture was stirred for 2 h, during which time it warmed to ambient temperature (Notes 8).

Zhao and Radosevich
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When the reaction reached completion as determined by TLC (Notes 9), the dropping funnel
was removed and distilled water (300 mL) was added to the reaction mixture in one portion.
The biphasic mixture was then transferred to a 1-L separatory funnel. The organic layer was
separated, washed with saturated aqueous sodium chloride solution (3 × 400 mL), dried over
anhydrous sodium sulfate (150 g) for 15 minutes (Notes 10). The sodium sulfate was filtered
and the solution was concentrated in vacuo using a rotary evaporator (ca. 100 mmHg, water
bath temperature 30 ˚C). The crude residue was purified by silica gel flash column
chromatography using EtOAc and hexanes as eluent (Notes 11, 12, 13 and 14), yielding the
title compound as an air and moisture stable white solid (9.44 – 10.09 g, 78 – 83 %, picture
shown below).
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Zhao and Radosevich
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Notes
4-Methyl-N-(phenylmethyl)benzenesulfonamide was synthesized according to
1.
2.
the known procedure: Coste, A.; Couty, F.; Evano, G. Org. Synth. 2010, 87, 231.
Dichloromethane was purchased from Fischer Scientific (Product Number:
D138-4) and degassed by bubbling argon for 1.5 h before passed through an
activated alumina column using a Glass Contour solvent system. The solvent is
collected using an oven-dried 1-L Schlenk flask as receiving flask, which was
purged with argon atmosphere by three evacuation-backfill cycles.
Methyl benzoylformate (>97.0%) was purchased from TCI (Product Number:
B1033) and used as received.
3.
4.
5.
Tris(dimethylamino)phosphine (97%) was purchased from Alfa Aesar (Product
Number: A12571) and used as received.
4-Methyl-N-(phenylmethyl)benzenesulfonamide may not be completely
dissolved at this temperature.
The rate of the addition was held at approximately 2 drops per second.
The mixture was stirred at 600 rpm throughout the reaction.
6.
7.
8.
The reaction should remain colorless to faint yellow. A bright yellow color
usually indicates the formation of side products.
Thin layer chromatograph was performed on silica gel 60 F TLC plate (EMD
9.
254
Millipore TLC Silica Gel 60 Glass Plates, purchased from Fischer Scientific,
Product Number: M1057150001) with 1:6 EtOAc:Hexanes as eluent. The
following R values were observed (visualized under 254 nm UV light): R
f
f
(methyl benzoylformate): 0.40; R (4-methyl-N-
f
(phenylmethyl)benzenesulfonamide): 0.14; R (product): 0.22. Picture of TLC
f
plate is shown below (lane “SM”: methyl benzoylformate; lane “R”: reaction
mixture; lane “Nu”: 4-methyl-N-(phenylmethyl)benzenesulfonamide):
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Zhao and Radosevich
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Sodium chloride and sodium sulfate were purchased from VWR and used as
10.
11.
12.
13.
received.
Silica gel (230-400 mesh) was purchased from SiliCycle (Product Number:
R12030B) and used as received.
Ethyl acetate and hexanes were purchased from Fischer Scientific and used as
recived.
Dichloromethane (5 mL) was added to the crude mixture. The crude product was
loaded onto a column packed with silica gel slurry in 1:10 EtOAc:Hexanes
(column is 9 cm in diameter, height of silica gel was 25 cm). After 1 L of initial
elution, 1:8 EtOAc:Hexanes was used as eluent and 150 mL fractions were
collected.
1
The product has the following spectral characteristics: H NMR (360 MHz,
14.
CDCl ) δ 7.62 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.3, Hz, 2H), 7.19-7.16 (m, 3H),
3
7.15-7.10 (m, 2H), 7.02 (dd, J = 5.0 Hz, J = 1.6 Hz, 3H), 6.87-6.85 (m, 2H), 5.79
(s, 1H), 4.64 (d, J = 16.3 Hz, 1H), 4.41 (d, J = 16.3 Hz, 1H), 3.57 (s, 3H), 2.40 (s,
13
3H); C NMR (100 MHz, CDCl ) δ 170.5, 143.5, 137.5, 137.0, 133.5, 129.5,
3
129.4, 128.9, 128.7, 128.0, 127.8, 127.5, 126.8, 63.2, 52.2, 49.4, 21.6; IR (neat):
2950, 2500, 2160, 2024, 1741, 1598, 1493, 1449, 1335, 1290, 1200, 1141, 1092,
−1
1046, 979, 927, 862, 815, 744, 692, 661 cm ; mp 96-98 °C; HRMS (EI): m/z
calcd for C H NO S [M+H] 410.1426, found 410.1429; Anal. Calcd for
23 24
4
C H NO S: C 67.46, H 5.66, N 3.42, O 15.63 S 7.83, found: C 67.64, H 5.97,
23 23
4
N3.48, O 15.60, S 7.88.
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Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper
training in experimental organic chemistry. All hazardous materials should be handled using
the standard procedures for work with chemicals described in references such as “Prudent
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full text can be accessed free of charge at http://www.nap.edu/catalog.php?
record_id=12654). All chemical waste should be disposed of in accordance with local
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Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red
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caution note does not imply that no significant hazards are associated with the chemicals
involved in that procedure. Prior to performing a reaction, a thorough risk assessment should
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and experimental operation on the scale that is planned for the procedure. Guidelines for
carrying out a risk assessment and for analyzing the hazards associated with chemicals can
be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and are conducted
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to the procedures herein.
Discussion
Phosphorus(III) reagents are known to undergo reaction with 1,2-dicarbonyl compounds to
2
give adducts of formal P-addition to the carbonyl oxygen (Kukhtin-Ramirez reaction). We
have shown that these Kukhtin-Ramirez adducts further react to incorporate a range of N-,
3,4
O-, and C-based protic pronucleophiles with expulsion of a phosphine oxide by-product.
The process likely proceeds in stepwise fashion, initiated by proton transfer from the protic
pronucleophile to the Kukhtin-Ramirez adduct, followed by Arbuzov-like displacement of
the phosphine oxide leaving group. This reaction sequence therefore represents a convenient
one pot process for access to a range of α–functionalized carbonyl compounds from readily
3,4
available reagents and precursors.
The synthetic method is exemplified in the above procedure, which demonstrates the
synthesis of methyl 2-(N-benzyl-4-methylphenylsulfonamido)-2-phenylacetate (3), an α–
5
amino ester derivative. By direct reductive construction of the α-C-N bond, our approach
takes advantage of the wide available α–keto esters as starting materials, and provides an
operationally simple and chemoselective alternative to transamination and reductive
6,7
amination strategies. Furthermore, since this method does not involve the intermediacy of
imine equivalents, useful C-N bonds from N-pronucleophiles that do not form imines (e.g.
7
azoles) can be successfully synthesized using this method (Table 1).
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Zhao and Radosevich
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The reaction is tolerant of a range of solvents (CH Cl , THF, PhMe), but the use of
2
2
dichloromethane reliably provides the highest yields and streamlines the aqueous workup on
the laboratory scale. The use of commercially available P(NMe ) results in the formation of
2 3
O=P(NMe ) (i.e. HMPA), a water soluble byproduct that is readily eliminated by aqueous
2 3
extraction. In view of potential handling concerns resulting from the toxicity of HMPA, we
note that the use of alternative phosphorous triamide reagents, specifically tris(1-
pyrrolidinyl)phosphine (which generates a less toxic phosphorus(V) oxide by-product),
8
provide similarly satisfactory results (Scheme 1, 1.8 mmol scale).
As noted in our previous studies, the scope of the reaction with respect to protic
pronucleophile includes diverse O-based (phenols, carboxylic acids and some alcohols) and
C-based (readily enolizable 1,3-dicarbonyls and related derivatives). The selection of protic
pronucleophile is bracketed by pK , with only those species capable of proton transfer to the
a
Kukhtin-Ramirez adduct (pK ca. 25-27 in DMSO) being reactive under these conditions
a
(Table 2).
Appendix Chemical Abstracts Nomenclature (Registry Number)
4-Methyl-N-(phenylmethyl)benzenesulfonamide: Benzenesulfonamide, 4-methyl-N-
(phenylmethyl)-; (1576-37-0)
Dichloromethane: Methane, dichloro-; (75-09-2)
Methyl benzoylformate: Benzeneacetic acid, α-oxo, methyl ester; (15206-55-0)
Tris(dimethylamino)phosphine: Phosphorus triamide, N,N,N,N′,N′,N′-hexamethyl-;
(1608-26-0)
Sodium Chloride: sodium chloride; (7647-14-5)
Sodium Sulfate: sulfuric acid sodium salt (1:2); (7757-82-6)
Biographies
Wei Zhao is from Jinan, Shandong Province, P. R. China. He completed his BSc at Xiamen
University, working with Prof. Pei-Qiang Huang and Prof. Xiao Zheng. In fall 2010 he
joined Penn State Chemistry working with Prof. Alexander Radosevich. He is now a senior
graduate student with research focused on redox catalysis at geometrically constrained
organophosphorus compounds.
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Zhao and Radosevich
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Alex Radosevich is from Waukegan, IL and received his B.S. from Notre Dame (2002). He
obtained a Ph.D. from UC Berkeley (2007) working with Prof. Dean Toste. Following
postdoctoral research at MIT with Prof. Dan Nocera, he joined the department of chemistry
at Penn State in 2010 as an assistant professor, where his research has focused on the design,
development, and implementation of new synthetic methodology.
References
1. Department of Chemistry, Pennsylvania State University, University Park, PA 16802,
radosevich@psu.edu. We thank NIGMS (GM114547), Alfred P. Sloan Foundation, and the
Pennsylvania State University for funding.0
2. Osman FH, El-Samahy FA. Chem Rev. 2002; 102:629–678. [PubMed: 11890753]
3. Miller EJ, Zhao W, Herr JD, Radosevich AT. Angew Chem Int Ed. 2012; 51:10605–10609.
4. Zhao W, Fink DM, Labutta CA, Radosevich AT. Org Lett. 2013; 15:3090–3093. [PubMed:
23738614]
5. Williams RM. Synthesis of Optically Active α-Amino Acids. Pergamon; Oxford: 1989.
6. Genet JP, Greck C, Lavergne D. Modern Amination Methods. Ricci A, editorWiley-VCH;
Weinheim, Germany: 2000. Chapter 3
7. (a) Abel-Magid AF, Mehrman SJ. Org Proc Res Devel. 2006; 10:971–1031.(b) Gomez S, Peters JA,
Maschmeyer T. Adv Synth Catal. 2002; 344:1037–1057.(c) Baxter EW, Reitz AB. Organic
Reactions. 2002; 59:1.
8. (a) Coste J, Le-Nguyen D, Castro B. Tetrahedron Lett. 1990; 31:205–208.(b) Coste J, Frerot E,
Jouin P. Tetrahedron Lett. 1991; 32:1967–1970.(c) Kang FA, Sui Z, Murray WV. J Am Chem Soc.
2008; 130:11300–11302. [PubMed: 18665598]
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Scheme 1
Phosphorus(III)-mediated synthesis of α-amino esters.
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Table 1
Scope of the phosphorus(III)-mediated α-amino ester synthesis.a
a
2
Yield under literature reported conditions.
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Table 2
Additional examples of Phosphorus(III)-mediated carbonyl functionalization with O- and C- pronucleophiles.
Organic Synth. Author manuscript; available in PMC 2018 August 23.