the microjcole Ioborotory Microscale Syntheses of Heterocyclic Compounds Rlma Al-awar' and George H. Wahl, Jr2 N m h Carolina State University Raleigh. N C 27695
Several coIlections of microscale experiments currently exist for t h e organic chemistry laboratory (1-4). b u t new experiments, particularly nontraditional syntheses, are always of interest. W e wish t o report microscale syntheses of fo& heterocyclic compounds for which large-scale versions were described previouslv in the Journal (5). As with almost all of the other experiments we have converted t o microscale, we found little trouble in adapting several of Wolthuis's syntheses of heterocycles. Thus, it is quite likely t h a t many other reactions will be easily converted to microscale, or "micronized". This approach offers so many advantages t h a t all undergraduate laboratory programs, including the large freshman programs (6, 7) should consider making t h e conversion. Not only are costs minimized, b u t most importantly the risks of working with chemicals are greatly diminished while the opportunities of trying new reactions t h a t require "exotic" reagents are increased. T h e few disadvantages such a s the use of nontraditional equipment are minor and can b e overcome by incorporating a few standard-size experiments t h a t employ the supplanted equipment such a s the separatory funnel. Procedures for the microscale preparation of four heterocyclic compounds (14) are described below.
edited by ARDEN P. ZIPP
uousatirring.The hot solution was poured intoa5.mLthin-wall \,ial equipped with a magnetic stir bar. The residue in the original vial was rinsed into the thin-wall vial with 0.10 mL of ethanol followed by 1.65 mL of hot water. The solution was then allowed to cool without agitation until crystals began w iurm. At that point the mixturewascooled 105-10% withatirring. (lithe mixture is turhid uoon addition of the hot water, it is heated to 50-60 O C before it is nilowed to cool.l The ervstals were filtered on e Hirsch funnel and washed with a total of i m l . of a chilled ethanol water mrxture (11 1.7) (v t,). After rerryatalli7ation from ShDi ethanol, 0.285 c r j 2 " o l of culorlesa cr).stals of mp 81-9,i "C lit. mp 92-94 'C) tdl were obtained ~
Preparation of 25Dirnethyl- l-phenylpyrrole (2) In a 5-mL reaction vial equipped with a magnetic stir bar and a water condenser, 303 pL of aniline, 391 pL of acetonylacetone (2.5hexanedione), and 1 drop of conc. HCI were refluxed gently with stirring for 30 min. The hot solution was then poured into another 5mL reaction vial containing 200 pL of cone. HC1 and about 3.0 mL of water. The oroduct was filtered through - a Hirsch funnel and washed with ahout 10 mL of water to give brown crystals ttJtR2 C, b4.651. After recrystallization from 95-0 methand using a Craig tube, brown crystalsoimp 47-49 O C were obrain~d.(Lit. rnp 50-51 TI15,. ~~
~
~
Preparation of .I-Methylcarbostyrll(3) In a 5-mL thin-wall vial equipped with a magnetic stir bar, 400 pL of conc. HzS04was stirred and warmed to 75 'C. Over a period of about 5 min, 0.1770 g of acetoacetanilide was added in small quantities while the temperature was maintained between 70 and 90 "C. After the addition of the solid, the mixture was maintained in the same temperature range for an additional 30 min and then allowed to cool to about 60 OC. The warm mixture was carefully poured into another thin-well vial containing 5 mL of water. The resulting suspension was cooled to 20 OC and filtered through a Hirsch funnel. The crystals were washed with 4 mL of cold water and then 1mL of cold methanol to produce 0.134 g (84.5%) of a colorless solid which was recrystallized from 95% ethanol (Craig tube) to produce colorless crystals mp 222-223 OC. (Lit. mp 222-224 "C) (9). Preparation of Benzofurazan- I-oxide ( 4 ) In a 5-mL thin-wall vial equipped with a magnetic stir bar, 875 pL of methanol was placed, followed by 150uL of a 50%NaOH solution. To this solution 0.05 g of o-nitroaniline was added, and the mixture warmed gently to dissolve the amine. The flask was then transferred to an ice and water bath with a temperature between 0 and 5 OC. While the solution was being stirred, 2.0 mL of bleach (Clorox) were added dropwise (-1 drop every 5 s) and finally the solution was allowed to stir for 10 min under the same temperature conditions. The crystals that form were filtered on a Hirsch funnel and washed with 3.0 mL of water followed by 0.5 mL of 1-2% HCI solution and again with 1.0 mL of water. The 0.033 g (67.3%)of orange crystals were recrystallized from methanol to yield a product with mp 64-67 "C (lit. 72-73 'C) (5).
Experimental Preparation of 3-Carbethoxycournarin (1) An equimalar mixture of salicylaldehyde(266 pL) and diethylmalonate (417 pL) was placed in a 5-mL reaction vial equipped with a water condenser and magnetic stir bar. Then 1 mL of ethanol, 5 drops of piperidine, and 1drop of glacial acetic acid were successively added, and the resulting solution was refluxed for 2 h with eontinI
1. Wshl, G.
H., Jr. Micro~caleExperiments in Organic Chamisfry, 3rd ed.: KINKO:
Rsieigh 1989. 2. May0.D. W.;Pike.R.M.;Butcher.S.S.Mieroscole 01gonicLaborato~.2ndod.:Wiley
New York.1989. 3. Williamson. K. W. Moerascoi~and Microsrola 01ganir Experimenb; Heath: Lorington,MA, 1989. 4. pavia, D. :.I Lampman. G. M ; Kli.. G. S.; Engel: R. G. Introduction Lo 0,ganic Laborofor" Techniouas-A Microscale Amroach: Saunden: Philadebhia. 1989.
5. W o l ~ i u s , ~ . ~ ~ . C h e m . 1919,66,363-$4. '~d~e. 6. Mills. J. L.: Hamoton. M. D. Mlcrosrol~Laborslory Monvol for Cemrai Chemlalry:
Undergraduate honors research student 1987-1988. Author to whom correspondence should be addressed. Volume 67
Number 3 March 1990
265
