2-Diazopropane

[2684-60-8]  · C3H6N2  · 2-Diazopropane  · (MW 70.11)

(reagent for the cyclopropanation of alkenes2)

Physical Data: the reagent is a gas at rt.

Solubility: the reagent is most commonly prepared and used as a solution in ether.

Analysis of Reagent Purity: titration with benzoic acid has been used to estimate the concentration of 2-diazopropane solutions; however, this method underestimates the yield by as much as 50% since the reaction of benzoic acid with the reagent is not quantitative. Spectrophotometric determination by measuring the absorbance at 500 nm has also been used; however, the ε value for this band is not precisely known.

Preparative Method: 2-diazopropane is most commonly prepared by the oxidation of Acetone Hydrazone with Mercury(II) Oxide in the presence of base.1 The reaction is carried out in ether and the product is codistilled with the ether to provide an ethereal solution of the reagent which is used immediately. The reagent is unstable and undergoes a first-order decay with a half-life of 3 h at 0 °C. Diazo compounds are potentially explosive (especially on contact with objects containing rough or jagged surfaces such as ground glass) and for this reason extreme care must be observed in the synthesis and use of this compound with all operations being conducted behind a blast shield in a hood. Furthermore, the use of glassware which does not contain ground glass joints is essential.

Handling, Storage, and Precautions: in addition to the previously mentioned explosion hazard which this reagent presents, there are health related hazards that must also be considered. Diazo compounds, as a class, are toxic and irritating and can be sensitizers. They must be used in a well-ventilated fume hood and not come in contact with skin. For a description of the hazards associated with this class of compounds, see the handling and storage precautions listed for Diazomethane.

Cyclopropanation of Alkenes.

2-Diazopropane is most commonly used to prepare gem-dimethylcyclopropyl derivatives. Like most diazoalkanes, this reagent will readily undergo cycloadditions with alkenes to provide the corresponding pyrazolines which can be induced to lose N2 to provide the desired cyclopropanes. As with other dipolar cycloadditions, this reaction occurs most readily with electron-deficient alkenes. Extrusion of N2 from these species can be accomplished photochemically, either by direct irradiation or with the aid of a triplet sensitizer such as benzophenone.2 Photochemical reactions without the sensitizer are typically slower, and can provide two side products, the retro cycloaddition to give the starting alkene, and the product of insertion into the vinylic C-H bond to provide the isopropyl-substituted alkene.3 In some systems, thermal extrusion of N2 also provides a substantial amount of the insertion product (eq 1). This is not always observed, however, and in certain cases thermal reactions can provide the desired cyclopropane in high yield.

The regiochemistry of the addition step of the reaction depends on the sterics of the system but, typically, the carbon of the diazoalkane adds to the more electrophilic b-carbon of the alkene. However, if this carbon is disubstituted, then the opposite regiochemistry can be observed, but frequently with diminished yields (eq 2).4 Ultimately, the regiochemistry is inconsequential to the overall reaction because extrusion of N2 provides the same cycloalkane in either case.

It is possible to cyclopropanate an electron-deficient alkene in the presence of an isolated alkene. Thus treatment of the steroid derivative shown in eq 3 with 2-diazopropane provided only addition to the conjugated alkene.5 Photolysis of this compound provided the dimethylcyclopropane in 50% yield. Furthermore, differentiation between two electron-deficient alkenes on steric grounds is possible with this reagent. Thus addition of 2-diazopropane to the steroid derivative shown in eq 4 provided only the product of addition to the alkene containing a single substituent at the b-carbon. Photolysis again provided the desired cyclopropane, but in only 25% yield.

Strained alkenes will also undergo cycloadditions with 2-diazopropane (eq 5).6 This particular case is interesting because the reagent adds predominantly to the more hindered face of the alkene, suggesting that the reaction is directed7 by the acetate groups. In reactions with diazomethane the preference for addition to the more hindered face is even greater.

Additions of 2-diazopropane to chiral bicyclic lactams have also been explored (eq 6).8 These reagents are known to add nucleophiles from the more hindered endo face of the alkene. Thus cyclopropanation with diphenylsulfonium isopropylide provided the expected endo product in a greater than 200:1 ratio. However, addition of 2-diazopropane provided a 1:1 mixture of endo and exo products. This difference in behavior has been explained on the basis of frontier molecular orbital theory.

A similar loss in stereoselectivity was observed in the cyclopropanation of menthyl fumarates. Thus cyclopropanation with isopropylidenetriphenylphosphorane provided an 87:13 ratio of diastereomers while the use of 2-diazopropane provided a 53:47 mixture (eq 7).9

The synthesis of a-cyclopropyl amino acids from suitably protected dehydro amino acids has been accomplished using 2-diazopropane.10 The overall transformation is stereospecific with the (Z)-alkene isomer providing the corresponding cis-cyclopropane (eq 8). The regiochemistry in the cyclopropanation of tropone derivatives has been controlled by first converting the tropone to the dieneiron tricarbonyl complex. The uncomplexed alkene then reacts with 2-diazopropane to provide the pyrazoline which undergoes thermal extrusion of N2 to give the desired cyclopropane (eq 9).11

Cyclopropanation of Allenes.

Allenes are also suitable substrates for cyclopropanation by 2-diazopropane, with the most reactive substrates being those that are conjugated to an electron-withdrawing group. As with alkenes, the regiochemistry of the pyrazoline that is formed depends on the sterics of the system. With allenes that contain one or fewer carbon substituents at the g-carbon, the carbon of the diazopropane will add to the more electron-deficient carbon of the double bond (eq 10). If the g-carbon is disubstituted, then the opposite regiochemistry is observed (eq 11).12

An interesting example of a cyclization to an allene which is not electron deficient has been reported.13 Addition of 2-diazopropane to the allene shown in eq 12 provided the pyrazoline shown, which upon photolysis provided a 2:1 mixture of the two cyclopropanes in the equation. This synthesis was used to disprove an erroneous structure for the sex attractant of the American cockroach.

Cyclopropenation of Alkynes.

Alkynes can be converted to the corresponding cyclopropene via the pyrazole with 2-diazopropane. As with other systems, the reaction works best with electron-deficient alkynes, and the regiochemistry of the pyrazole that is formed depends on the sterics of the alkyne. Thus terminal alkynes provide the usual regiochemistry, whereas internal alkynes provide the opposite regiochemistry (eq 13).14 Photolysis of the pyrazoles induces a rearrangement to a diazoalkene species which then undergoes photochemical extrusion of N2 to give a carbene which inserts into the p-bond of the alkene to provide the cyclopropene (eq 14).

Evidence for the intermediacy of the diazoalkene has been obtained by trapping this species with acetic acid.15 An interesting side reaction has been observed in reactions with trimethylsilyl-substituted alkynes. Irradiation of the pyrazole derived from these alkynes provides the expected carbene which, rather than inserting into the p-bond, inserts into the s-bond of the acyl group to provide the product of a 1,2-acyl shift in high yield (eq 15).16 The generality of this reaction has not yet been established. Other substrates that do not provide the cyclopropene are those that provide products which are sterically hindered. Thus irradiation of the pyrazole shown in eq 16 provides the product of insertion into the tertiary C-H bond rather than the alkene.17

The cyclopropenes produced in this reaction have been used in the synthesis of cis-chrysanthemic methyl ester.18 The key step involves cyclopropenation of the ene-yne shown in eq 17. Addition of 2-diazopropane to the alkyne occurs in preference to the alkene to give both regioisomeric pyrazoles. Photochemical extrusion of N2 from both isomers provides the desired cyclopropene. This was converted to cis-chrysanthemic methyl ester by diimide reduction of the more reactive cyclopropene alkene.

Another use for these cyclopropene reagents is a formal [3 + 2] annulation reaction which provides cyclopentenols. The process involves [2 + 2] cycloaddition of the cyclopropene with an eneamine to provide a strained bicyclic product which undergoes ring opening with acid and water to provide a cyclopentenol (eq 18).19 This strategy has been employed in the synthesis of several natural products including hirsutene,20 silphenene,21 and dihydroilludine M.22

A disadvantage of this strategy is that with certain substrates, the cycloaddition product is accompanied by a substantial amount (at times the major product) of the product of Michael addition of the eneamine to the cyclopropylcarboxylate. A related annulation has therefore been developed which avoids this problem. This strategy involves the addition of 2-diazopropane to a cyclobutene to provide a similar bicyclic intermediate to that obtained previously. This species can also undergo acid-catalyzed ring opening with water (eq 19) to provide the cyclopentenol.23

Insertion into Vinylic C-H Bonds.

A common side reaction which occurs during attempted cyclopropanation of alkenes with diazopropane is an overall insertion into a C-H bond of the alkene. This reaction is favored by thermal extrusion of N2 and, for this reason, photolysis is the preferred method of decomposing pyrazolines to cyclopropanes (eq 1). However, it has been observed that alkenes which bear two electron-withdrawing groups will exclusively provide the insertion product upon reaction with 2-diazopropane with mild or no heating. The reaction has been used to introduce an isopropyl residue into 3-cyanocoumarins24 and iron tricarbonyl complexes of acetyltropone25 in excellent yield (eqs 20 and 21). Furthermore, it has been used in diminished yield to alkylate alkenes with a single electron-withdrawing group, as previously discussed.26

Miscellaneous Reactions.

Interestingly, 2-diazopropane is not commonly used to esterify carboxylic acids. The reaction has been studied with excess acetic acid and has been shown to proceed in 35%-52% yield based on the diazo compound, with the major byproduct being tetramethylethylene.27 This should not be a serious problem to utilizing the reaction with other carboxylic acids since the byproduct is volatile. The reagent has been used to selectively esterify the more hindered carbonyl of a vinylogous acid when other reagents failed (eq 22).28

2-Diazopropane has also been used in the synthesis of episulfides from thioketones. The reaction works even for very hindered substrates (eq 23). Extrusion of sulfur with triphenylphosphine provides the corresponding alkene, thus rendering this a method for the synthesis of hindered alkenes.29

Related Reagents.

Diazomethane.


1. Andrews, S. D.; Day, A. C.; Raymond, P.; Whitting, M. C. OSC 1988, 6, 392.
2. Franck-Neumann, M. AG(E) 1968, 7, 65.
3. This reaction is most common with highly electron-deficient alkenes, such as those bearing two electron-withdrawing groups, and is discussed in more detail later in this article.
4. Andrews, S. D.; Day, A. C.; McDonald, A. N. JCS(C) 1969, 787.
5. Bladon, P.; Rae, D. R.; Tait, A. D. JCS(P1) 1974, 1468.
6. Burdisso, M. B.; Gamba, A.; Gandolfi, R.; Toma, L. JOC 1990, 55, 3311. For a related reaction, see: Franck-Neumann, M. TL 1968, 9, 2979.
7. For a review of directed reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. CRV 1993, 93, 1307.
8. Meyers, A. I.; Romo, D. TL 1989, 30, 1745. Romo, D.; Romine, J. L.; Midura, W.; Meyers, A. I. T 1990, 46, 4951.
9. De Vos, M. J.; Kreif, A. TL 1983, 24, 103. For a related example, see: Walborski, H. M.; Sugita, T.; Ohno, M.; Inouye, I. JACS 1960, 82, 5255.
10. Zhu, Y-F.; Yamazaki, T.; Tsang, J. W.; Lok, S.; Goodman, M. JOC 1992, 57, 1074. Srivastava, V. P.; Roberts, M.; Holmes, T.; Stammer, C. H. JOC 1989, 54, 5866.
11. Saha, M.; Bagby, B.; Nicholas, K. M. TL 1986, 27, 915.
12. Andrews, S. D.; Day, A. C.; Inwood, R. N. JCS(C) 1969, 2443.
13. Day, A. C.; Whitting, M. C. JCS(C) 1966, 464. Day, A. C.; Whitting, M. C. JCS(B) 1967, 991.
14. Day, A. C.; Inwood, R. N. JCS(C) 1969, 1065.
15. Day, A. C.; Whitting, M. C. JCS(C) 1966, 1719.
16. Padwa, A.; Wannamaker, W. T 1990, 46, 1145.
17. Dietrich-Buchecker, C.; Franck-Neumann, M. T 1977, 33, 751.
18. Franck-Neumann, M.; Dietrich-Buchecker, C. TL 1980, 21, 671.
19. Franck-Neumann, M.; Miesch, M.; Kempf, H. S 1989, 820.
20. Franck-Neumann, M.; Miesch, M.; LaCroix, E. TL 1989, 30, 3529.
21. Franck-Neumann, M.; Miesch, M.; LaCroix, E. TL 1989, 30, 3533.
22. Franck-Neumann, M.; Miesch, M.; Barth, F. TL 1989, 30, 3537.
23. Franck-Neumann, M.; Miesch, M.; Gross, L. TL 1990, 31, 5027.
24. Clinging, R.; Dean, F. M.; Houghton, L.; Park, B. K. TL 1976, 17, 1227. Dean, F. M.; Park, B. K. JCS(P1) 1980, 2937.
25. Franck-Neumann, M.; Martina, B. D. TL 1978, 19, 5033.
26. For an additional example, see: McMoriss, T. C.; Ramakrishnan, S.; Arunachalam, T. JOC 1974, 39, 669.
27. Applequist, D. E.; Babad, H. JOC 1962, 27, 288.
28. Solas, D.; Wolinsky, J. JOC 1983, 48, 670.
29. Bushby, R. J.; Pollard, M. D. TL 1977, 18, 3671.

Tarek Sammakia

University of Colorado, Boulder, CO, USA



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