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Org. Synth. 1996, 73, 134
DOI: 10.15227/orgsyn.073.0134
DETRIFLUOROACETYLATIVE DIAZO GROUP TRANSFER: (E)-1-DIAZO-4-PHENYL-3-BUTEN-2-ONE
[3-Buten-2-one, 1-diazo-4-phenyl-]
Submitted by Rick L. Danheiser, Raymond F. Miller, and Ronald G. Brisbois1.
Checked by Cameron Clark and Stephen F. Martin.
1. Procedure
Caution! Diazo compounds are presumed to be toxic and potentially explosive and therefore should be handled with caution in a fume hood. Although in carrying out this reaction numerous times we have never observed an explosion, we recommend that this preparation be conducted behind a safety shield.
A 500-mL, three-necked, round-bottomed flask is equipped with a mechanical stirrer, nitrogen inlet adapter, and 150-mL pressure-equalizing dropping funnel fitted with a rubber septum (Note 1). The flask is charged with 70 mL of dry tetrahydrofuran (Note 2) and 15.9 mL (0.075 mol) of 1,1,1,3,3,3-hexamethyldisilazane (Note 3), and then cooled in an ice-water bath while 28.8 mL (0.072 mol) of a 2.50 M solution of butyllithium in hexane (Note 4) is added dropwise over 5–10 min. After 10 min, the resulting solution is cooled at −78°C in a dry ice-acetone bath, and a solution of 10.0 g (0.068 mol) of trans-4-phenyl-3-buten-2-one (Note 5) in 70 mL of dry tetrahydrofuran is added dropwise over 25 min. The dropping funnel is washed with two 5-mL portions of tetrahydrofuran and then replaced with a rubber septum. The yellow reaction mixture is allowed to stir for 30 min at −78°C, and then 10.1 mL (0.075 mol) of 2,2,2-trifluoroethyl trifluoroacetate (TFEA, (Note 6)) is added rapidly in one portion via syringe (over ~5 sec). After 10 min, the reaction mixture is poured into a 1-L separatory funnel containing 100 mL of diethyl ether and 200 mL of 5% aqueous hydrochloric acid. The aqueous layer is separated and extracted with 50 mL of diethyl ether. The combined organic layers are washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to afford 18.61 g of a yellow oil. This yellow oil is immediately dissolved in 70 mL of acetonitrile (Note 7) and transferred to a 500-mL, one-necked flask equipped with a magnetic stirring bar and a 150-mL pressure equalizing dropping funnel fitted with a nitrogen inlet adapter. Water (1.2 mL, 0.069 mol), triethylamine (14.3 mL, 0.103 mol) (Note 8), and a solution of 4-dodecylbenzenesulfonyl azide2 (35.74 g, 0.103 mol) (Note 9) in 10 mL of acetonitrile are then sequentially added (each over ~1–2 min) via the dropping funnel. The resulting yellow solution is allowed to stir at room temperature for 6.5 hr and then is poured into a 1-L separatory funnel containing 100 mL of diethyl ether and 200 mL of aqueous 5% sodium hydroxide (NaOH). The organic layer is separated, washed successively with three 200-mL portions of 5% aq NaOH, four 200-mL portions of water, 200 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure using a rotary evaporator to yield 23.17 g of crude reaction product as a light brown oil. The crude reaction product is purified by column chromatography on 230–400 mesh silica gel (30 times by weight, elution with 5–10% diethyl ether-hexane) to furnish 9.54–9.80 g (81–83%) of (E)-1-diazo-4-phenyl-3-buten-2-one (mp 68–69°C) as a bright yellow solid (Note 10), (Note 11)).
2. Notes
1. The apparatus is flame-dried under reduced pressure and then maintained under an atmosphere of nitrogen during the course of the reaction.
2. Tetrahydrofuran was distilled from sodium benzophenone ketyl immediately before use.
3. 1,1,1,3,3,3-Hexamethyldisilazane was purchased from Aldrich Chemical Company, Inc., and was distilled from calcium hydride prior to use.
4. Butyllithium was purchased from Aldrich Chemical Company, Inc., and was titrated prior to use according to the the method of Watson and Eastham.3
5. trans-4-Phenyl-3-buten-2-one was purchased from Aldrich Chemical Company, Inc., and used without further purification.
6. 2,2,2-Trifluoroethyl trifluoroacetate was purchased from Aldrich Chemical Company, Inc., and used without further purification.
7. Acetonitrile was distilled from calcium hydride immediately prior to use.
8. Triethylamine was purchased from Fisher Chemical Company and distilled from calcium hydride before use.
9. The submitters originally used methanesulfonyl azide,4 5 6 but the Board of Editors of Organic Syntheses requested substitution of the much less shock sensitive reagent 4-dodecylbenzenesulfonyl azide. The use of methanesulfonyl azide has previously been recommended,4 since excess reagent as well as certain formamide by-products can be easily separated from the desired diazo ketone product during workup by extraction into dilute aqueous base.
10. The product has the following spectral properties: IR (CCl4) cm−1: 3150–3000, 2090, 1645, 1600, 1445, 1360, 1180, 1140, 1095, 1070, 970, 690; 1H NMR (300 MHz, CDCl3) δ: 5.54 (s, 1 H), 6.60 (d, 1 H, J = 15.8), 7.30–7.34 (m, 3 H), 7.46–7.49 (m, 2 H), 7.57 (d, 1 H, J = 15.8); 13C NMR (75 MHz, CDCl3) δ: 55.8, 123.5, 127.8, 128.5, 129.9, 134.0, 140.1, 184.0; Anal. Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found: C, 69.65; H, 4.84; N, 16.32.
11. When 4-dodecylbenzenesulfonyl azide is used for the diazo transfer reaction, the crude reaction product is contaminated with by-products that cannot be separated during basic workup, and consequently column chromatography is required for the purification of the diazo ketone. Use of mesyl azide for the diazo transfer reaction allows purification of the crude reaction product by recrystallization from diethyl ether-pentane to obtain 10.11 g (86%) of the desired diazo ketone.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior 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 Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The importance of α-diazo ketones as synthetic intermediates has led to the development of a number of general methods for their preparation.7 8 Particularly popular approaches include the acylation of diazo alkanes and the base-catalyzed "diazo group transfer" reaction of sulfonyl azides with β-dicarbonyl compounds.9 10 11,12 13 14 While direct diazo transfer to ketone enolates is usually not a feasible process,15,16diazo transfer to simple ketones can be achieved in two steps by employing an indirect "deformylative diazo transfer" strategy in which the ketone is first formylated under Claisen condensation conditions, and then treated with a sulfonyl azide reagent such as p-toluenesulfonyl azide.9,11,16,17 18 19 20,21 22
Unfortunately, several important classes of α-diazo ketones cannot be prepared in good yield via these standard methods. α'-Diazo derivatives of α,β-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.22,23 24 25 26 27 The acylation of diazomethane with α,β-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain α,β-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones.
The detrifluoroacetylative diazo transfer procedure described here28 is more general than the classical deformylative strategy, and as indicated in the Table, gives superior results when applied to a variety of ketone substrates. The new method has proved particularly valuable in the preparation of diazo derivatives of α,β-enones. In the case of saturated ketones such as 4-tert-butylcyclohexanone, both methods give comparable results, although the new procedure is more convenient to carry out, and has the advantage of providing a regioselective means of effecting diazo transfer to unsymmetrical ketones.
TABLE
SYNTHESIS OF α-DIAZO KETONES

Diazo Transfer Procedurea (Isolated Yield, %)

Entry

α-Diazo Ketone

via Formylation

via Trifluoroacetylation


1

73

95

2

57

92

3

56

81

4

71

63, 90b

5

17

83c, 86

6

45

87

7

44

84

8

68

61


aDiazo transfer reactions were carried out using methanesulfonyl azide unless otherwise indicated. bThe yield is corrected for recovered propiophenone. c4-Dodecylbenzenesulfonyl azide was employed for this diazo transfer reaction.

A key feature of the new procedure is the activation of the ketone starting material as the corresponding α-trifluoroacetyl derivative. To our knowledge, the use of TFEA to activate ketones in this fashion has not previously been reported, although Doyle has employed a similar strategy to achieve diazo transfer to a base sensitive N-acyloxazolidone derivative.29 In our experience, TFEA has proved superior to other trifluoroacetylating agents [e.g. CF3CO2Et, (CF3CO)2O] for this transformation; the reaction of ketone enolates with this ester takes place essentially instantaneously at −78°C. By contrast, the formylation of ketone enolates with ethyl formate is usually carried out using sodium hydride or sodium ethoxide as base and generally requires 12 to 48 hr at room temperature for complete reaction.
Only one equivalent of base is required for the trifluoroacetylation step; apparently the chelated tetrahedral intermediate is stable at −78°C and the β-dicarbonyl product is not generated until workup. Crucial to the success of the trifluoroacetylation reaction in some cases is the selection of lithium hexamethyldisilazide (LiHMDS) for the generation of the ketone enolate; under otherwise identical conditions diazo transfer to several aryl ketones proceeds in dramatically reduced yield when lithium diisopropylamide is employed as base.
In summary, the method described here provides an efficient and convenient route to a variety of α-diazo ketones including unsaturated derivatives that were not previously available by diazo transfer. α-Diazo ketones serve as key intermediates in a number of important synthetic methods including the Arndt-Eistert homologation, the photo-Wolff ring contraction strategy, and the carbenoid-mediated cyclopropanation reaction. We anticipate that improved access to α-diazo ketones will serve to enhance the utility of these valuable synthetic strategies.
This preparation is referenced from:

References and Notes
  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139. We thank the National Institutes of Health (GM 28273) for generous financial support. R. F. M. was supported in part by NIH training grant CA 09112.
  2. Hazen, G. G.; Bollinger, F. W.; Roberts, F. E.; Russ, W. K.; Seman, J. J.; Staskiewicz, S. Org. Synth., Coll. Vol. IX 1998, 400.
  3. Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
  4. Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. Org. Chem. 1986, 51, 4077;
  5. Lowe, G.; Ramsay, M. V. J. Chem. Soc., Perkin Trans. I 1973, 479;
  6. Stork, G.; Szajewski, R. P. J. Am. Chem. Soc. 1974, 96, 5787.
  7. For reviews of methods for the synthesis of α-diazo ketones, see (a) Regitz, M.; Maas, G. "Diazo Compounds: Properties and Synthesis"; Academic Press: New York; 1986;
  8. Regitz, M. In "The Chemistry of Diazonium and Diazo Groups"; Patai, S., Ed.; Wiley: New York, 1978; Part 2, Chapter 17, pp. 751–820.
  9. For reviews of diazo group transfer, see (a) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733;
  10. Regitz, M. Synthesis 1972, 351;
  11. Chapter 13 of ref. 7.
  12. Recent methods for diazo group transfer include: (a) Koskinen, A. M. P.; Munoz, L. J. Chem. Soc., Chem. Commun. 1990, 652;
  13. McGuiness, M.; Shechter, H. Tetrahedron Lett. 1990, 31, 4987;
  14. Popic, V. V.; Korneev, S. M.; Nikolaev, V. A.; Korobitsyna, I. K. Synthesis 1991, 195.
  15. Diazo transfer from 2,4,6-triisopropylphenylsulfonyl azide to the enolate derivatives of hindered cyclic ketones can be achieved by using phase transfer conditions: Lombardo, L.; Mander, L. N. Synthesis 1980, 368.
  16. Evans and co-workers have reported successful diazo transfer from p-nitrobenzenesulfonyl azide (PNBSA) to the enolate derivatives of an N-acyloxazolidinone and a benzyl ester: (a) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. However, we have not been able to achieve efficient diazo transfer to ketone enolates employing these conditions. For example, exposure of the lithium enolate of acetophenone to 1.2 equiv of PNBSA in THF at −78°C for 15 min gave α-diazoacetophenone in only 21% yield.
  17. Regitz, M.; Menz, F. Chem. Ber. 1968, 101, 2622;
  18. Hendrickson, J. B.; Wolf, W. A. J. Org. Chem. 1968, 33, 3610;
  19. Rosenberger, M.; Yates, P.; Wolf, W. Tetrahedron Lett. 1964, 2285;
  20. Regitz, M.; Rüer, J.; Liedhegener, A. Org. Synth. Coll. Vol. VI 1988, 389.
  21. Other indirect diazo transfer routes to α-diazo ketones have been reported involving initial activation of the ketone by benzoylation and acylation with diethyl oxalate: (a) Metcalf, B. W.; Jund, K.; Burkhart, J. P. Tetrahedron Lett. 1980, 21, 15;
  22. Harmon, R. E.; Sood, V. K.; Gupta, S. K. Synthesis 1974, 577.
  23. For discussion and examples, see (a) pp 498–99 of ref. 4;
  24. Fink, J.; Regitz, M. Synthesis 1985, 569;
  25. Itoh, M.; Sugihara, A. Chem. Pharm. Bull. 1969, 17, 2105;
  26. Regitz, M.; Menz, F.; Liedhegener, A. Justus Liebigs Ann. Chem. 1970, 739, 174;
  27. Rosenquist, N. R.; Chapman, O. L. J. Org. Chem. 1976, 41, 3326 and references cited therein.
  28. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959.
  29. Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse; R. A. J. Org. Chem. 1985, 50, 1663.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

sodium benzophenone ketyl

lithium hexamethyldisilazide (LiHMDS)

hydrochloric acid (7647-01-0)

diethyl ether (60-29-7)

acetonitrile (75-05-8)

sodium hydroxide (1310-73-2)

sodium chloride (7647-14-5)

sodium sulfate (7757-82-6)

nitrogen (7727-37-9)

Acetophenone (98-86-2)

sodium ethoxide (141-52-6)

ethyl formate (109-94-4)

lithium (7439-93-2)

benzyl (2154-56-5)

diazo

butyllithium (109-72-8)

Tetrahydrofuran (109-99-9)

sodium hydride (7646-69-7)

hexane (110-54-3)

diethyl oxalate (95-92-1)

triethylamine (121-44-8)

calcium hydride (7789-78-8)

α-diazoacetophenone (3282-32-4)

diethyl ether-pentane

lithium diisopropylamide (4111-54-0)

4-tert-Butylcyclohexanone (98-53-3)

p-toluenesulfonyl azide (941-55-9)

diethyl ether-hexane

1,1,1,3,3,3-hexamethyldisilazane (999-97-3)

methanesulfonyl azide,
mesyl azide

(E)-1-Diazo-4-phenyl-3-buten-2-one

3-Buten-2-one, 1-diazo-4-phenyl- (24265-71-2)

trans-4-phenyl-3-buten-2-one

2,2,2-trifluoroethyl trifluoroacetate (407-38-5)

4-Dodecylbenzenesulfonyl azide (79791-38-1)

2,4,6-triisopropylphenylsulfonyl azide (36982-84-0)

p-nitrobenzenesulfonyl azide