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DOI:10.15227/orgsyn.069.0180

Organic Syntheses, Coll. Vol. 8, p.196 (1993); Vol. 69, p.180 (1990).

DIAZO KETONE CYCLIZATION ONTO A BENZENE RING: 3,4DIHYDRO-1(2H)-AZULENONE[1(2H)-Azulenone, 3,4-dihydro-]

Submitted by Lawrence T. Scott and Chris A. Sumpter1.
Checked by John M. Fevig and Larry E. Overman.

1. ProcedureCaution! Diazomethane is toxic and explosive; all operations should be carried out in a wellventilated hood with adequate shielding. (See (Note 1).)
A. 1-Diazo-4-phenyl-2-butanone. A 1-L Erlenmeyer flask equipped with a two-in. magnetic stirring
bar and a two-hole rubber stopper fitted with a 125-mL Teflon stopcock separatory funnel (Note 2) anda drying tube filled with potassium hydroxide (Note 3) is charged with a solution of 200 mmol (3.4equiv) of diazomethane (Note 4) in 600 mL of dry ether. The solution is cooled to 0°C and stirred athigh speed (Note 5). To this cooled solution, 10.0 g (59 mmol) of hydrocinnamoyl chloride (3phenylpropionyl chloride) (Note 6) diluted to 125 mL with anhydrous ether is added dropwise over a 1hr period. The resulting reaction mixture is stirred cold for an additional 0.5 hr and then at room
temperature for 1 hr. After this period of time the reaction is complete, and excess diazomethane isremoved by evacuating the Erlenmeyer flask with a water aspirator pump in the hood (Note 7). TheErlenmeyer flask is evacuated by connecting the aspirator to a one-hole stopper that has been fitted witha plastic or fire-polished glass tube. After the diazomethane has been removed, the remaining ethereal
solution is concentrated by rotary evaporation to give 10.5–10.6 g (> 100% crude yield) of 1-diazo-4phenyl-2-butanone as a yellow oil (Note 8). This oil is used without purification for the next reaction.
B. 3,4-Dihydro-1(2H)-azulenone. A 250-mL, one-necked, round-bottomed flask is equipped with an
egg-shaped magnetic stirring bar and a high dilution trident (Fig. 1)2 (Note 9). The high-dilution trident
is further equipped with a 100-mL pressure-equalizing addition funnel attached to a nitrogen inlet andan efficient reflux condenser attached to a nitrogen outlet. The round-bottomed flask is charged with
100 mL of dry freshly distilled methylene chloride and 12 mg of rhodium diacetate dimer (Note 10).
This heterogeneous mixture is stirred at high speed (Note 11) and heated to a rapid reflux without
bumping. The addition funnel is charged with a solution of 8.7 g (50 mmol) of 1-diazo-4-phenyl-2butanone (Note 12) diluted to 50 mL with methylene chloride. As soon as the high-dilution trident
reservoir (20 mL) fills up and begins to overflow back into the round-bottomed flask, dropwise additionof the diazo ketone solution is initiated (1:20, one drop of diazo ketone solution to every 20 drops ofsolvent entering the trident reservoir from the condenser). After the addition is complete (2.5–3 hr), thereaction mixture is allowed to reflux for an additional 1 hr. The reaction mixture is then cooled, and theyellow-green solution of the initially formed unstable trienone (Note 13) is suction-filtered through 110
g of neutral alumina (Note 14) in a 250-mL fritted-glass funnel to isomerize the β,γ double bond into
conjugation with the carbonyl group and to remove the rhodium diacetate dimer. The alumina is then

washed with 100 mL of ethyl acetate, and the combined organic filtrates are concentrated by rotary
evaporation to give a yellow oil. Vacuum distillation of this oil through a short-path distillation head
gives 5.5–5.7 g (75–78% yield) of a colorless to slightly green oil that solidifies at 0°C, bp 73–75°C/0.2
mm (Note 15). This material is sufficiently pure for most purposes (Note 16). Recrystallization fromhexane (80 mL per gram of trienone) yields colorless needles, mp 28.5–29.0°C (Note 17).
Figure 1

2. Notes
1. See full warning in Org. Synth., Coll. Vol. II 1943, 165, and Aldrichimica Acta 1983, 16(1), 3–10.
2. Ground glass can cause explosions; therefore, a Teflon stopcock must be used.
3. Potassium hydroxide must be used as the drying agent since calcium sulfate and other drying agentscan react with diazomethane and cause an explosion.
4. Diazomethane is prepared as described in Org. Synth., Coll. Vol. IV 1963, 250, with 50 g of Diazald(from Aldrich Chemical Company, Inc.) in 300 mL of ether added to 15 g of KOH in 25 mL of water,
30 mL of ether, and 50 mL of 2-(2-ethoxyethoxy)ethanol. One equivalent of diazomethane becomesincorporated in the reaction product, and the remainder serves as a scavenger for the HCl produced as areaction by-product. The excess of diazomethane called for in this procedure is necessary to inhibit theundesired formation of 1-chloro-4-phenyl-2-butanone. The submitters report that this reaction can beperformed on twice this scale with comparable results.
5. The high rate of stirring reduces the production of 1-chloro-4-phenyl-2-butanone, a by-product of thisreaction.
6. This compound can be purchased from Aldrich Chemical Company, Inc. or prepared according tostandard methods.3
7. Two hundred milliliters of ether and diazomethane are removed before transfer for rotary
evaporation. Diazomethane in a rotary evaporator can cause explosions.
8. A pure sample of diazo ketone can be obtained by chromatography on silica gel using 15% ethyl

acetate/hexane as an eluent, Rf = 0.37. The checkers estimate the purity of the crude diazo ketone to be
90–91% based on careful column chromatography of 1.0-g aliquots. They further estimate thatapproximately 5–6% of 1-chloro-4-phenyl-2-butanone is also produced in the reaction. The spectral
properties of 1-diazo-4-phenyl-2-butanone are as follows: 1H NMR (300 MHz, CDCl3) δ: 2.59–2.64 (m,2 H), 2.95 (t, 2 H, J = 7), 5.20 (broad s, 1 H), 7.17–7.31 (m, 5 H).
9. The high-dilution trident in this example dilutes the diazo ketone solution to 10−3–10−4 M before it
reaches the reaction mixture.
10. The rhodium diacetate dimer is used in catalytic amounts; 0.132% (weight of dimer/weight of diazoketone) has worked out to be the best ratio for this reaction.
11. The high-speed stirring minimizes undesired bimolecular reactions.
12. The submitters report that this step can be performed on a 0.5-mol scale (87 g of diazo ketone) in
86.5–94.9% yield. This amount of diazo ketone was prepared in multiple batches as described in Step
A. The submitters were reluctant to prepare and handle diazomethane on scale large enough to make 0.5
mol of diazo ketone in one batch.
13. The initially formed trienone isomerizes quantitatively to β-tetralone on treatment with catalytic
amounts of trifluoroacetic acid. This acid sensitivity precludes chromatography of the crude product on
normal silica gel.
14. F20 Alumina (60–200 mesh) from Schoofs, Inc. was used. The checkers used chromatography grade
neutral alumina (100–125 mesh) supplied by Fluka.
15. The oil bath temperature maximum must be maintained below 120°C or the yield of product drops.
16. The checkers found that on this scale a bulb-to-bulb (Kugelrohr) distillation could also be employed.
The distilled product is contaminated with approximately 4–5% of 1-chloro-4-phenyl-2-butanone,
which was produced in Step A. This impurity is easily removed by recrystallization from hexane.
Alternatively, this impurity can be removed at the diazo ketone stage by column chromatography. The
use of purified diazo ketone in Step B affords purer distilled product, but this modification has no
significant effect on the overall yield.
17. The spectral properties of 3,4-dihydro-1(2H)-azulenone are as follows: 1H NMR (300 MHz, CDCl3)
δ: 2.50 (narrow m, 2 H), 2.70 (narrow m, 2 H), 2.78 (apparent d, 2 H, J = 6), 5.38 (dt, 1 H, J = 9.6, 6.3),
6.09 (dd, 1 H, J = 9.2, 6.2), 6.47 (dd, 1 H, J = 11, 5.7), 6.68 (d, 1 H, J = 11); IR (film) cm−1: 1697.

3. Discussion
The cyclopropanation of alkenes, alkynes, and aromatic compounds by carbenoids generated in themetal-catalyzed decomposition of diazo ketones has found widespread use as a method forcarbon−carbon bond construction for many years, and intramolecular applications of these reactions
have provided a useful cyclization strategy. Historically, copper metal, cuprous chloride, cupric sulfate,
and other copper salts were used most commonly as catalysts for such reactions; however, the superior
catalytic activity of rhodium(II) acetate dimer has recently become well established.4 This commerciallyavailable rhodium salt exhibits high catalytic activity for the decomposition of diazo ketones even atvery low catalyst : substrate ratios (< 1%) and is less capricious than the old copper catalysts. We
recommend the use of rhodium(II) acetate dimer in preference to copper catalysts in all diazo ketone
decomposition reactions. The present synthesis describes a typical cyclization procedure.
A special feature of the synthesis described here is the glass apparatus used to achieve high-dilution
reaction conditions (Fig. 1).2 This "trident" is simple but effective and can be fabricated quite easily
from standard parts. The one shown here is designed to accept an overhead mechanical stirrer.
The product of this synthesis is an especially useful, highly functionalized hydroazulene that is notavailable commercially. We have used it as a synthetic precursor to homoazulene,5 6 and to a variety ofhomoazulene derivatives,7 8 bridged homotropylium cations,9 10 and azulene quinones.11 12 It could
undoubtedly serve as a precursor to numerous natural products. The cyclization reaction tolerates
electron-donating substituents4,13,14 but not halogens15 on the aromatic ring.

References and Notes
1. Department of Chemistry and Center for Advanced Study, College of Arts & Science, University

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

of Nevada, Reno, NV 89557–0020.
Vögtle, F.; Wittig, G. J. Chem. Ed. 1973, 50, 650.
Scott, L. T.; Minton, M. A.; Kirms, M. A. J. Am. Chem. Soc. 1980, 102, 6311.
The use of rhodium(II) acetate catalysis in the reaction described here was first reported byMcKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Chem. Commun. 1984, 129.
Scott, L. T.; Brunsvold, W. R.; Kirms, M. A.; Erden, I. Angew. Chem., Int. Ed. Engl. 1981, 20,274;
Scott, L. T.; Brunsvold, W. R.; Kirms, M. A.; Erden, I. J. Am. Chem. Soc. 1981, 103, 5216.
Scott, L. T.; Oda, M.; Erden, I. J. Am. Chem. Soc. 1985, 107, 7213;
Scott, L. T.; Oda, M. Tetrahedron Lett. 1986, 27, 779.
Scott, L. T.; Hashemi, M. M. Tetrahedron 1986, 42, 1823;
Scott, L. T.; Oda, M.; Hashemi, M. M. Chem. Lett. 1986, 1759.
Scott, L. T.; Grütter, P.; Chamberlain, R. E., III J. Am. Chem. Soc. 1984, 106, 4852;
Scott, L. T.; Adams, C. M. J. Am. Chem. Soc. 1984, 106, 4857.
Minton, M. A. Ph.D. Thesis, University of California, Los Angeles, 1977;
Michels, D. G. M. S. Thesis, University of Nevada, Reno, 1980.
Scott, L. T.; Fong, L. K. unpublished observations.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)rhodium diacetate dimer
HCl (7647-01-0)
ethyl acetate (141-78-6)
ether (60-29-7)
cupric sulfate (7758-98-7)
copper (7440-50-8)
calcium sulfate (7778-18-9)
potassium hydroxide,
KOH (1310-58-3)
cuprous chloride (7758-89-6)
methylene chloride (75-09-2)
Diazomethane (334-88-3)hydrocinnamoyl chloride,
3-phenylpropionyl chloride (645-45-4)
hexane (110-54-3)

trifluoroacetic acid (76-05-1)
β-Tetralone (530-93-8)
2-(2-ethoxyethoxy)ethanol (111-90-0)
1-Diazo-4-phenyl-2-butanone (10290-42-3)(5503-41-3)
1-chloro-4-phenyl-2-butanone
3,4-Dihydro-1(2H)-azulenone,
1(2H)-Azulenone, 3,4-dihydro- (52487-41-9)
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