In the Laboratory
W
Organometallic Mediated Organic Synthesis: A Reaction Sequence for an Advanced Integrated Laboratory Course David B. Ball* and Randy Wilson Department of Chemistry, California State University, Chico, Chico, CA 95929-0210; *
[email protected] Rationale In the fall semester 2001, the Chemistry Department at CSU, Chico, will initiate a three-semester integrated laboratory sequence replacing the laboratory portions of our physical, analytical, and inorganic chemistry courses. Having recently acquired a NSF-CCLI-funded high-field NMR spectrometer, we are developing a series of experiments (projects) that incorporate this instrument and overlapping methodology from the subdisciplines of chemistry. The implementation of a threesemester integrated laboratory sequence poses a challenge for any chemistry curriculum. Choosing appropriate experiments that give each subdiscipline thorough and in-depth coverage is paramount in providing our students with an excellent chemical education. Taking advantage of our students’ prior training in organic and analytical chemistry, we have designed a project for the first semester of the sequence that introduces our students to inorganic chemistry via organometallic mediated organic synthesis. Introduction Looking at March’s textbook on advanced organic chemistry (1), one can find 92 different synthetic preparations of alkenes. Unfortunately, almost every method of preparation gives some type of mixture, considering either regiochemistry or stereochemistry. One of the most widely used preparations of alkenes is the Wittig reaction. While it directly produces an alkene of predictable and known regiochemistry, it does not give a specific (E) or (Z) stereochemistry about the double bond for many cases. Even though extensions of the Wittig reaction such as the Horner–Emmons and the Schlosser modifications do improve both the predictability and the actual stereochemical selectivity of E versus Z, the selectivity does not always provide only one stereoisomer. This article describes an interdisciplinary project that utilizes inorganic, analytical, and organic chemistry in a Negishi type Pd(0)-catalyzed coupling of an organometallic reagent and substituted aromatic iodides to produce (E)-disubstituted alkenes. For several decades chemists have utilized palladium (0 and II) complexes to catalyze organic reactions. However, only recently have organic chemists used these catalysts for the synthesis of diversely functionalized organic molecules. It is the melding of inorganic and organic chemistry that has brought about this “revolution” in the application of the techniques and methodologies of organometallic chemistry to organic synthesis.
Start Here Ar-R ArI Reductive Elimination Ar-Pd(II) R
The palladium(0)-catalyzed couplings of aryl and vinyl halides (I > Br >> Cl), triflates and nonaflates with main group and transition metal organometallic reagents (where the metal is Li, Mg, Zn, Zr, B, Al, Sn, Si, Ge, Hg, Tl, Cu, and Ni) are 112
Oxidative Addition
Ar-Pd(II)-I RM Ar-Pd(II)-R
Isomerization
Transmetallation MI
Figure 1. Simplified catalytic scheme for the role of Pd in the coupling reactions of interest.
thoroughly documented in the chemical literature (2). Of these metals, the most useful have been tin (Stille coupling), boron (Suzuki coupling), and zinc or zirconium (Negishi coupling). A broad range of palladium catalysts is available and can be fine tuned for specific applications. Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4, is the most widely used because of its reactivity, availability, and relatively long shelf life. The role of Pd in these coupling reactions is shown in a simplified catalytic scheme (Fig.1) (3). The individual steps are oxidative addition, transmetallation (with retention of stereochemistry of the transferred group), isomerization of organic ligands (trans to cis) about the Pd, and reductive elimination producing the hetero cross-coupled product and the regeneration of the Pd(0) catalyst. Synthetic Scheme Retrosynthetic analysis of the reaction sequence shows the disconnection of the desired disubstituted (E) alkene 1 to aryl iodide 2 and organometallic reagent 3, illustrated in the case of the Negishi-type Pd(0) couplings (Scheme I). The organometallic reagent 3 is generated by two functional group interchanges. I OSiR3
+
3
M
3
OSiR3
G G
1
3
2
M = Zn, Zr
H
M
Palladium(0) Complexes in Organic Synthesis
Pd(0)
3
3
OSiR3
OSiR3 4 H OH 5
Scheme I. Retrosynthetic analysis
Journal of Chemical Education • Vol. 79 No. 1 January 2002 • JChemEd.chem.wisc.edu
In the Laboratory
The synthesis of 1 is initiated by protecting the hydroxyl group of the commercially available 4-pentyn-1-ol, 5, as the tert-butyldiphenylsilyl ether 4 (eq 1).
Table 1. Results from Ar yl Iodides Used in This Study Aryl Iodide
Coupling Product a Yieldb (%) OMe
OMe
95 H
imidazole
+
OH
Cl
Si
DMF, rt
R
I
1a
(1)
5
73 I
H OTBDPS
The conversion of alkyne 4 to the coupling partner 3 involves the use of the hydrozirconating reagent Cp2Zr(H)Cl, known as Schwartz’s reagent. This reagent is made by treating commercially available zirconocene dichloride, Cp2ZrCl2, with LiAlH4 (eq 2) (4 ). Cl Cl
R
1c OMe
OMe
58 I
1d
Zr
THF, rt 68-85%
88 I
Cl
LiAlH4
Zr
NO2
NO2
4
R
1b
(2)
H
aR
R
= (CH2)3OTBDPS. yield.
bIsolated
The purity of this reagent is determined by treating it with an excess of 1-octyne and quenching the reaction with aqueous HCl generating a mixture of 1-octene and 1-octyne (eq 3). This mixture is analyzed by gas chromatography, the amount of 1-octene produced being proportional to the purity of the reagent.W 1. Cp 2Zr(H)Cl 2. 1M HCl
H
+
(3)
H 3
3
3
(excess)
Schwartz’s reagent adds to terminal alkynes regiospecifically (on the basis of steric factors) in a syn fashion, delivering a hydrogen to the internal carbon of the alkyne and the zirconium to the terminal carbon. As vinyl zirconocenes do not transmetallate as well to Pd as do vinyl zinc reagents, the zirconium is exchanged for zinc upon exposure to ZnCl2 in THF (5). The coupling process is completed by adding the oxidative addition product of the aryl iodide 2 and Pd(PPh3)4 to the vinyl zinc solution (eq 4) in prescribed ratios (personal communication with Chris Thompson, Department of Chemistry and Chemical Biology, Harvard University, Apr 4, 2000; 6 ). Workup and flash chromatography give stereospecifically the 100% (E)-disubstituted alkene (100:0 by 1H NMR). 1. 1.5 eq Cp2Zr(H)Cl, rt 2. 2.0 eq ZnCl2
OTBDPS 4
OTBDPS
3. 10 mol % Pd(PPh3)4, 1.0 eq
I
1.5 eq G
2
G
1
(4)
Aryl halides that have been successfully utilized in this study are 3-iodoanisole, 4-iodoanisole, 1-iodo-3,5-dimethylbenzene, and 1-iodo-3-nitrobenzene (see Table 1). Hazards Most of the organic solvents and some of the reagents used in these experiments are flammable or air and moisture sensitive. Caution must be exercised with LiAlH4 in THF, as it is both flammable and moisture sensitive. Column chromatography involves use of fine-mesh SiO2 and large volumes of volatile solvents. Adequate ventilation must be provided in making and using these columns. Appropriate disposal of both the heavy metal zirconium and palladium salts is required. Discussion The major reason for this project is to give students a laboratory experience that allows them to utilize techniques and methodologies that cross over the subdisciplines of organic, inorganic, and analytical chemistry. The synthesis of Schwartz’s reagent (eq 2) provides an avenue for developing experience in the handling of Schlenk glassware, as well as in the preparation, isolation, and use of a light- and air-sensitive organometallic reagent under an inert atmosphere. The analysis of this reagent emphasizes analytical techniques in carrying out the reaction and analyzing the results by capillary gas chromatography. Silylation of the hydroxy group of the alkynol is a classic protection process used in organic chemistry to deal with chemoselectivity of various functional groups (eq 1) (7). The syn addition of the Schwartz’s reagent to the silyl-protected alkynol 4, transmetallation, and subsequent Pd(0)-catalyzed
JChemEd.chem.wisc.edu • Vol. 79 No. 1 January 2002 • Journal of Chemical Education
113
In the Laboratory
Acknowledgments
Table 2. Effect of Various Parameters on Yield Reactiona 1
Alkyne (equiv)
Schwartz (equiv)
ZnCl2 (equiv)
1-Iodo-3,5-dimethylbenzene (equiv)
Yield (%)
1.0
1.1
2.0
1.0
37
2
1.0
1.1
1.33
1.5
41
3
1.5
1.5
2.0
1.0
73
aAll
with 10 mol % Pd(PPh3)4 in THF at RT.
Negishi coupling give the student a research-type experience. Syringe and cannula techniques will be learned, as will the fusing of an inorganic compound, all of which require an inert atmosphere with exclusion of oxygen. Isolation of the product of this hetero-crossed-coupling is accomplished by flash chromatography (8). Determination of the stereochemistry of the alkene via 1H NMR spectroscopy requires the student to calculate coupling constants to determine the trans relationship of the vinyl protons ( J observed is 15.9 Hz, vs J = 6–12 Hz predicted for a cis alkene). Infrared and 13C NMR spectroscopy are needed for full characterization of the products. This reaction sequence also gives the faculty ample opportunity to discuss, among many possible topics, the Pd(0) catalytic cycle, turnover numbers, and the 18-electron rule. A typical discussion might include the following points. It was noted above and in the Lab DocumentationW that specific ratios of reagents are used in the coupling process (eq 4). Table 2 indicates that the yield is affected by changing these parameters. In a large number of Pd(0)-catalyzed coupling processes, the rate-determining step is believed to be transmetallation in the catalytic cycle (see Fig. 1) (9). The relatively high ratio of RM to Ar–Pd(II)–I in reaction 3 would be expected to enhance the reaction rate and lead to greater product formation prior to decomposition of the catalyst. It is also noted that there may be an effect on the observed coupling yields due to the aryl iodide being either electron rich (p-methoxy) or electron poor (m-methoxy or m-nitro) (see Table 1). Oxidative addition of nucleophilic Pd(0) to the aryl iodide should be enhanced by electron-withdrawing groups on the halide, while electron-releasing groups on the aryl ring should have the opposite effect (in fact, 4-iodotoluene gives only 28% cross-coupled material). Using a similar argument, the transmetallation step should be facilitated, with increased electronegativity of Ar–Pd(II)–I afforded by the electronwithdrawing substituent(s) on the aryl ligand.
114
Major financial support of this work by the Chemistry Department at CSU, Chico, and Roche Bioscience is acknowledged. We gratefully acknowledge the support of the National Science Foundation (CCLI 99-50413) and of the College of Natural Sciences and the Provost of CSU, Chico, for funding for the NMR spectrometer used in this work. We also acknowledge the summer internship awarded to RW by Craig Lindsley. The idea for this project derived from an on going collaboration with Bruce Lipshutz at UCSB. W
Supplemental Material
Detailed procedures, analytical results, and notes are available in this issue of JCE Online. Literature Cited 1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th ed.; Wiley: New York, 1992, pp 1273–1274. 2. Hegedus, L. S. In Organometallics in Synthesis, A Manual; Schlosser, M.; Wiley: New York, 1994; pp 383–459. Tsuki, J. Palladium Reagents and Catalysts; Wiley: Chichester, 1995. Heck, R. F. Palladium Reagents in Organic Synthesis; Academic: London, 1985. 3. For a review of reaction types in organometallic chemistry see Schwartz, J.; Labinger, J. A. J. Chem. Educ. 1980, 57, 170–175. For recent applications of Pd(0)-catalysis see Hermann, W. A.; Böhn, V. P. W.; Reising, C. P. J. Chem. Educ. 2000, 77, 92–95. Goodwin, T. E.; Hurst, E. M.; Ross, A. S. A. J. Chem. Educ. 1999, 76, 74–75. Brisbois, R. G.; Batterman, W. G.; Kragerud, S. C. J. Chem. Educ. 1997, 74, 832–833. 4. Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 333. Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M. Org. Synth. 1992, 71, 77–82. 5. Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, 100, 2254–2246. Negishi, E. Acc. Chem. Res. 1982, 15, 340–348. 6. Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 12, 456–457. Hu, T.; Panek, J. S. J. Org. Chem. 1999, 64, 3000–3001. 7. Greene, T. E.; Wuts, P. G. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999, pp 113–148. 8. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. 9. Hegedus, L. S. Op. cit., pp 406–408.
Journal of Chemical Education • Vol. 79 No. 1 January 2002 • JChemEd.chem.wisc.edu
