The Synthesis of An Undergraduate Organic Laboratory Experiment and Class Project R. M. Letcher and M. P. Sammes University of Hong Kong, Hong Kong Descri~tionsof heterocvcle suitable for uu- .nrenarations . dergraduite organic laboratory classes have appeared in numerous texts and journals ( I ) , hut very few, if any, include the preparation of an isoquiuoline. The chemistry of the isoquinoline ring system is nevertheless invariahlv included in undergraduate-lecture courses on heterocycles and especially natural products, where, in the form of the l-benzyl-tetrahydro derivatives, it dominates alkaloid chemistry and biosynthesis. This experiment endeavors to fill this gap by describing the synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinolines via the well-known Pictet-Spengler route; and it gives students an opportunity to carry out a total synthesis from simple starting materials, and also to study the spectra and properties of alkaloid-like materials. A 1-phenyl-1,2,3,4-tetrahydroisoquinoline (I) has actually been found to occur in nature (2).
This four-stage synthesis is outlined below and involves such basic reactions as an aldol condensation, a lithium aluminium hydride (LAH) reduction, Schiff base formation, and concludes with a Pictet-Spengler (or Mannich) cyclization, all of which give readily isolable products. The experiment, suitable for either the intermediate- or final-year organic course, requires three or four, three-hour laboratory periods for completion and has been successfully performed by our students for the past three years. A noteworthy aspect of the experiment is that the procedure can accommodate a variety of starting materials (I1 and V), thus enabling independent project work to he carried out by each student (3).The possible substituents for compound V are given in Table 1.The spectra of the products also lend themselves to ready interpretation and make interesting correlations possihle, especially when numerous related products are prepared in a class. A shortened form of the experiment, which could be designed to focus on these spectral characteristics, is possihle by starting with the Schiff base formation.' In this way the experiment requires as little as four hours of laboratory time.
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If the sequence is considered to be too long for the time available. or the LAH reduction too hazardous for a particular class, ,j-(3,4dimethoxyphenyl)eihylamine(IV) may be ptuchased commercially relatively cheaply.
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Reaction Sequence
Table 1. Substituentstor Compound V and the Resultant Products Sub~tit~ent~ R
('4 me (Ref.)
R'
(vv
(VIII)
me (Ref.)
me
described; this feature, which can he exploited further, provides considerahle motivation for students. Spectroscopy Mass Spectrometry
The isoquinoline hydrochlorides (VII) listed in Table 1, all exhibit the molecular ion and two fragment ion peaks in their mass spectra, viz. an M - l and M-Ar peak, both resultingfrom classic textbook fission of the carhon-carbon or carbon-hydrogen bond a to the N-atom:
The first step involves a high yielding aldol condensntion between 3.4-dimethoxvhenzaldehvde(11) and nitromrthane. to give the crystalline"&nitrostyr&e (111). which is reduced to the 2-arvlethvlamine (IV) hv inverse addition to excess I.AH, the aikene-double bond also heing reduced under these conditions ( 4 ) . Students are also introduced to a very useful technique for the slow addition of a reactant, by making use of a Soxhlet extractor and the sparingly soluble nature of the reactant [the styrene (Ill)]in THF. The reaction is also high vieldina and kves the product as aviscous oil, which, for the prepar&on 2 the suhitanccs listed in Tnhle 1, need not he further purified.' The third srep readily yields crysralline Schiff hases (see Table 1 I in over 7000;vield. The r\vli7ation step is probably the most challenging part of the synthesis, but for the compounds in Tahle 1,goes readily with student yields of purified hydrochlorides in the range of 4&70%. These oroducts are all nonhverosconic and are best characterized .?or purity by means of their 'H NMR spectra. A further step involves the conversion of the hvdrochloride to the free base which in all cases was found to be crystalline; the free hases have not previously been reported. Variety of Starting Materials We have found that the experimental procedure described below readily yields the desired isoquinoline (VII) for a variety of suhaituted henzaldrhydes (Vj.Some ot'thesesubstituents are shown in Tnhle 1. Benznldehvdes (11and V),different from those used in Tahle 1 may also be employed, as has been shown in the review by Waley and Govindachari (51,thus making a large number of different syntheses possible. I t should he noted that the cyclization procedure described below may not he suitable for all other substituents, and for these, slightly modified procedures (e.g., use of anhydrous HCl) have been suggested (6). From our list of compounds prepared, i t can he seen that the 4'-methyl- and the two bromoisoquinolines are new and have not been previously
m/e 192
' H NMR
Spectra of the hydrochlorides (VII) [(CDd2SO]or the free hases (VIII) (CDCld are very simple to interpret, with signals for H-1, NH, H-5, H-8, and the methoxy groups of the isoquinoline ring each giving separate singlets (respectively near
65.65.9,10.3,6.25,6.9,3.5,and3.8inthesalts,and65.0-5.15, 2.0,6.2,6.65,3.65, and 3.85 in the free bases for the compounds listed). 1 3 C NMR and Project Aspect
With a minimum of three or four compounds, and using proton-noise decoupled and off-resonance decoupled spectra together with empirical substituent parameters for substituted benzenes, all signals, including those in the aromatic Table 2. Approximate 'F Chemical Shifls (6)for lsoquinoline Ring Carbon Atoms In Salts (VII) and Free Bases (VIII) Carbon atom
Salts (VII) [(CDdrSOI
C-48 C-5 C-6 C-7 C-8 C-8a Me0
125.2 111.7 148.7 147.8 110.9 122.5-123.08 55.6'
Free Base (VIII) (CDCld
127.8 111.9 148.0 147.4 111.1 128.3-130.2' 56.0b
Obswved ranges b U ~ ~ a lnot l y resolved
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region c a n be assigned q u i t e easily (Table 2). T h i s is a useful s exercise for s t u d e n t s to carry out, a n d for t h e c o r n ~ o u n dwe have studied, gives highly consistent results. W e have found additionally that t h e signal for C-Sa i n the free bases (VIII) shows a good linear correlation with (combined) urna n d o, H a m m e t t constants for t h e L a w 1 ring substituents. For a series of seven a m p o u n d s we find p = -2.01 and n correlation T h e corresponding signnl in t h e salts coc.fficient r = 0.99-. IVIIl shows n o useful correlations: neither d o siennls for C - l in either compounds (VII) o r (VIII).
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Experimental
3,4-~imethoxy-p-nitrostyrene(111) A mixture of 3,4-dimethoryhenzaldehyde(11) (16.6 g, 0.1 mol), nitromethane (7 ml, 0.13 mol), ammonium acetate (3.1 g, 0.04 mol) and glacial acetic acid (30 ml) is heated under reflux for 1h. In a fume hood, the hot product is poured with stirring into an ice and water mixture (400 g), and the solid precipitate filtered under suction and recrystallized from ethanol (3 mllg). This should yield 17.7 g (85%) of the nitrostyrene (III), mp 140-141'C. pi3.4-Dimethoxyphenyf)ethylamine(IV)
CAUTION: LAH reacts violently and inflames on contact with moisture; the dust is also harmful by inhalation and skin contact. All weighings and transfer operations of this substance must he carried out in a fume hood with careful exclusion of moisture, the student wearing protective gloves and goggles. Full safety precautions (&) should he reviewed before commencing this experiment. T o a dry2 500-ml two-necked round-bottomed flask containing dr)r? tetrahydrofuran (THF) carefully transfer LAH (7.0 g, 0.19 mol). Close the side neck with a stopper, and in the central neck place a Soxhlet extractor fitted with an efficient douhle-surface reflux condenser and a CaC12 drying tube. Remove the condenser, and place in the extractar a Soxhlet thimble containing the nitrostyrene(lI1) (8.4 g, 0.04 mol) both previously oven-dried at 105 T!for 1h. Refit the condenser, cool the flask in ice and water, remove the drying tube, and pour enough dry T H F down the condenser to cause the contents of the Soxhlet extractor to siphon. When the vigorous reaction has subsided, repeat with a second addition of dry THF. The mixture is now stirred under gentle reflux using an oil bath (magnetic stirrer-hotplate) until all of the nitro-compound has been extracted (1-2 h). The flask is cooled in an icelsalt hath, and the two necks fitted respectively with a 100ml tap funnel containing water and an efficient double surface reflux condenser. With vigorous stirring, water is added dropwise until all remaining LAH has been destroyed (-. 25 ml is needed). The mixtwe is filtered under suction (fume hood), the residue is blended thoroughly with diethyl ether (100 ml) in a conical flask using a spatula and is refiltered. The filtrates are combined, and the ether, THF, and some water are removed on a rotary evaporator. The residual aqueous solution is extracted with diehloromethane (4 X 30 ml), the combined extracts are dried (MgS04), the mixture filtered, and the solvent evaporated under reduced pressure. The residual oil (IV) (5.4 g, 75%) is used direct19 in the next step, and should not he exposed to the atmosphere for any length of time as it readily reacts with carhon dioxide to form a carbonate. The m i n e (IV) may, however, he stored in a well-stoppered flask indefinitely. Schiff B a s e s ( VI)
Method A for Liquid Aldehydes ( V ) :A mixture of theamine (IV) (5.4 g, 0.03 mol) and the assigned aldehyde (V) (0.03 mol) is stirred . the mixture manuallv in a 100-ml conical flask,. usine-a s ~ . a t u l auntil sets to adry, hard, colorless or pale yellow mass, with evolution of heat. If, however, no reaction takes place, the mixture should first he heated, with stirring, on a boiling water hath. The product is best recrystallized from aqueous ethanol. Method R for Solid Aldehydes ( V ) :The aldehyde (V) (0.03 mol) is dissolved in absolute ethanol (30 ml; heated if necessary) in a 100-ml conical flask, and the amine (IV) (5.4 g, 0.03 mol) is added. The so-
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lution is boiled gently on a water bath (fume hood) until most of the ethanol has evaporated, and the residue is allowed to cool. The product which sets as a solid mass is recrystallized as for Method A. 1-Afyl- 1,2,3,4-tetrahydroisoquinolineHCI salts (VII) This method works well for the compounds (VII) listed in Tahle 1; when aldehydes (11 and V) are employed which are different from those used for Tahle 1,modifications (6)may he necessary. Working in the hood, the Schiff base (VI) (0.01 mol) dissolved in the minimum volume of dichloromethane (--3 ml), is slowly added to a vigorously stirred solution of 24% hydrochloric acids (20 ml) in a 100-ml round-bottomed flask maintained a t between 80 and 90'. The addition, which should take approx. 5 min, is accompanied by a yellow coloration which usually fades fairly rapidly. A white crystalline mass of the isoquinoline hydrochloride often begins to form before the addition is aver. The reaction is then finally completed by refluxing the mixture for 20 min. After cooling in ice, the solution is filtered. If, however, no product has separated, the solution is evaporated to dryness under reduced pressure, the residue is dissolved in the minimum amount of hot absolute ethanol, anhydrous diethyl ether is added dropwide to give a slight cloudiness, and the mixture is cooled, with scratching. The product may be recrystallized in the same way. A simple test to ensure that the isolated product is, in fact, the ismuinoline hvdroehloride and not the hvdroehloride of the Schiff base. ra carried our as fdluwa: t o n d u t i o n 01' the rpcryrtnlliwd product 1-20 m g ~d~rsalvedin three dnlps of warm iOo> aqueous ethanol, is added ru,o drops of Bradg's reaxent (2,-l-dinrtrophenylhydrazine). If a copiuu~yellow orange precipitate is forrntd, the product is the hydrochloride of the Schiff base, a compound which readily hgdruIy8.e~under theor conditions. The isoquinuline hydrochluridr give3 n o precipitate. The Free B a s e ( VIII) The hydrochloride (VII) (0.01 mol) is dissolved in 5% aqueous sodium hydroxide solution (15 ml), and the mixture is extracted with dichloromethane (2 X 20 ml). The extracts are washed with water (10 ml), dried (MgSOA and after filtration, the solution is evaporated yielding the free base (VIII) as a colorless solid which is best recrystallized by dissolving in the minimum volume of dichloromethane or ethyl acetate and adding light petroleum (hp 60-809) before cooling. The free hases, which are obtained virtually quantitatively, appear not to he hveroscooic and mav be keot in the atmomhere without deterioration. Melting points of some examples of compounds (VI), (VII) and (VIII) are given in Tahle 1. NMR spectra were recorded using a Jeol FX 90Q Fourier Transform speWometer employing tetramethylsilane as internal standard. I3C NMR spectra were recorded at 22.53 MHz with digital resolution hettar than i0.05 ppm and 'H NMR were recorded at 89.6 MHz with a digital resolutionbetter than i0.005 ppm.
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Literature Cited (1) WolthuisE., J.C"e~.Eouc.,56.343 (1979).
(2) Leander K.,and Lllning B., TeLrohadronLeffwa. ,393 (1968). (3) LeteherR.M., J . C ~ e ~ . E D ~ ~ . . 5 8 . 1 0 2 0 ( 1 9 8 1 ) . (4) Ramires F. A.,and Burger A,, J. Amar. Cham. Soc., 72,2781 (19501. (5) Whsley W. M., end Govindechari T. R., Ormnic Reocfionr, 6.152 (1951). (6) Weinbach E. C..and Hartung W. H., J. Org. Chem., 15,676(1950). (7) Vie1 C., Dorma R., and Rumpf P., Bull. Soc. Chim. Flanre, 1956 (1966). (81 ( 8 ) Fieser L. F.,and Fieser M.. "Reagents for Omnic Synthesis,.l uol. 1. John 1967. p 583. (b) "Reagents for Organic Synthosis,"p. 1140
All glassware should be ovendried beforehand. A method for drying THF is given in reference (8b). For its reaction with certain aldehydes, not included in Table 1, e.g. 4-methoxybenzaidehyde. it was found necessary to distill the amine (IV) (bp 188'115 mm). Commercial concentrated acid contains approximately 36% HCI by weight.
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