Diastereospecific Synthesis of cis- and trans-2,3-~imethyl-1,4-thiamorpholines An Advanced Organic Synthesis and NMR Project Maria Teresa Gallego, Emesto Brunet,' and Jos6 Luis Garcia Ruano Univenidad Aut6noma de Madrid (UAM), Cantoblanco, 28049-Madrid, Spain Ernest L. Eliel University of North Caroilna, Chapel Hill, NC 27599 We describe here a multistep, diastereospecific synthesis that we of cis- and trans-2,3-dimethyl-l,4-thiamorpholines have used as a laboratory exercise for advanced undergraduate students a t UAM. The synthesis, which may alternatively be used as a one-semester project for an individual student, also serves to illustrate certain principles of stereochemistry, conformational analysis, and NMR spectroscopy. Synthetlc Plan Classical syntheses of 1,4-thiamorpholines ( 1 ) by reaction of cysteine or cysteamine hydrochloride, HS-CH'rCH?NH:Ci-, with u-bromoeaters or ketones are nonstereoselectiveand lead to cis-trans mixtures (eq 1)
which are difficult to purify. T o achieve the required diastereoselection, we have followed the route outlined in Figure 1. In aten 1.the known anti addition of iodoisocvanate (eenerated &I s k u from iodine and silver cyanate) olefins(2) is utilized; thus trans- and cis-2-butene are transformed in to R*,S* and R*,R* iodocyanates, 2, respectively. The highly reactive cvanate m o u ~ must next be converted to a t-butvl carbarnate function inorder to avoid side reactions and keep latent the m i n e function, necessary for the formation of the six-membered ring. ~tere&hemist&is controlled in steps 2 and 3, in which iodine is replaced by thioglycolate in two different ways: (i) directly, by a simple SN2 process, with inversion of the reactive stereocenter (Step 2); (ii) in two steps, by prior transformation of 2 into the aziridine 3 and subsequent ring opening (Step 3). Although the aziridine 3 is in fact isolated, step 3 was used to illustrate the concept of neighboring group participation in so far as retention of configuration is concerned. The final step 4 involves deprotection of the m i n e , intramolecular acylation by the ester ..erouD to form the lactam and reduction of the amide with sodium borohydride-acetic acid. Our students wereat~letoobtain an averaeeof 100-200me of diastereornerically pure cis- or trans-2;3-dimethylthic morpholine from 1.8 g of either cis- or trans-butene. (The class was divided into four groups, each following a different stereochemical pathwav. so as to get a meaningful com~arison among the kfficiency and thestereoselectfvity at&ined in every step by the individual students.~
tb
Figure 1. Synthetic route to dlastereomerically pure 2.3dimethyl-1.4-miamorpholines.
RS
BOCN - 8 :
H R'
5a or 5b Me
.
' Author to whom correspondence should be addressed
i'
./H
H R' bans-8 or CIS-8
+
Me
H R' 5b o r 5 a
Figure 2. Competing process In the reaction of 4 wlth miaglycolate.
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Number 6 June 1991
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Table 3. Observed and Calculated (See Text) 13C-NMR Data (CDCI,) 01 Compounds 7
3.60
3.00
2
. PPN
1.80
1.20
60
Table 4.
ShWt Dlfferentlal (In ppm) Engendared by Methyl Subrtltutlon In Cyclohexane ( 6 )
'Of melhyl subatitvent at C(11. *Of ring carbon observed.
Figure 4. 'H
NMR spectra of cis-7 (A) and trans-7 (8).
Cyclization of (R*,S*)-5 [obtained from trans-3 or (R*,R*)-41or (R*,R*)-5 [from cis-3 or (R*,S*)-41 yielded cisand trans-lactams 6, respectively. Students were asked to assign the CH-CH resonances and measure the vicinal coupling in their individual proton spectra. They ascertained the cis (equatorial-axial) or trans (diequatorial) arrangement of methyls in 6 from the observed couplings, 3.4 Hz (gauche CH-CH) and 8.8 Hz (predominant anti-CHCH), respectively. Reduction of cis- and trans-6 gave cis(JCH-CH= 2.6 Hz) and trans-2,3-dimethyl-1.4-thiamorpholine (JCHPCH= 9.1 HZ),respectively. Their 'H-NMR spectra (Fig. 4) are relatively complex hut the pertinent protons were assigned with some help from the instructor. The students were also provided with '3C spectra of the corresponding 2,3-dimethyl-1,4-thiamorpholines(Tahle 3) and asked to assign the signals. T o do that, they were told to calculate the expected values of the 13C chemical shifts of ring carbons (between brackets in Tahle 3) for all possible methyl arrangements, by simply adding the effect of axial or equatorial methyls (Tahle 4) to the unsuhstituted thiamorpholine ring (6c-s = 27.8 ppm, 6c-N = 47.3). Finally, the students were provided with 'H-13C 2DCOSY (7l soectra of both isomers of 7 (each spectrum of Figure 5 hasbeen run in -18 min with a fairly concentrated samole) to show them how this powerful technique makes the assignment of proton signals,khich they found especially difficult in trans-7, almost child's play.
Materials and Methods Reagents were purchased from Aldrich and used as received. THF was dried over sodium-benzophenone. 'H- (200 MHz) and I3CS h l H f50 MHz, spectra ( ~ a b l e2i and 31 were recorded on a Hruker WP-200-SYspecrrnrneter and referenced 10 internal TMS. Elernental analyses (M-H-M'Labs., USA1 of the oxalatea of lactams 6 and
Figure 5. 13C-'H 2D-correlated spectra of
compounds 7.
cis- and tram-7 were correct. Melting points (Gallenkhampapparatus) are uncorrected. 3-Iodo-2-butylisocyanate (2) was prepared (-9 g), following the method described (2), from 1.8 g of cis- or tram-butene, and used without purification. N-t-Butoxycorbonyl-2,3-dimethylaziridine(3). In a 100-mL, round-bottomed flask, equipped with an addition funnel and a reflux condenser with a nitrogen inlet, is placed in a solution of 3 g (27 mmol) of potassium t-butoxide in 25 mL anhydrous THF. The system is flushed withnitrogen and asolution of 4 g (10mmol) of 2 in 25 mL of anhvdrous THF is added with stirrine. - Stinine is eontinued for 30 min at room temperature while maintaining the nitrogen atmosphere, The precipitate is filtered and the filtrate concentrated at reduced pressure. The residue is dissolved in CHC12,which is washed once with brine and dried over anhydrous NazSOn. Removal of the solvent at reduced pressure yields 2.8 g (92%)of crude aziridine, which may be used in the following step without purification. 3-Iodo-2-t-butoxyca1bony1ominobutone(4). In a 50-mL, roundbottomed flask is placed 4g (18mmol) of 2,16mL of t-butyl alcohol and 0.44 rnL of 3 N HCI in ethyl a ~ e t a t eA. ~reflux condenser fitted
Thls solutlon should be prepared by bubbling anhydrous hydrogen chloride gas (see Org. Synth. coll. VI. I, p. 293) through cold ethyl acetate. Volume 68
Number 6
June 1991
519
with a CsC12tube is attached, the mixture stirred overnight at room
temperaturewithamagneticsrirrer.Thesolutionisconcentrated a t
red&ed pressure, and the brownish residue is extracted with hexane. Concentration of the henane solution at reduced pressure yields 4 g (74%)of product, which should be used promptly without further purification. Nucl~ophilieopening of aziridine 3 by thioglycolate. In a 50-mL round-bottomed flask equipped with a reflux condenser fitted with a nitrogen inlet is placed a solution of potassium t-hutuxide [0.3 g (2.7 mmol) or 1.9g (17 mmol) far eis- or tram-3 opening, respectively] in 20 mL of anhydrous t-butyl alcohol. The system is flushed withnitro~enand 1.9 E (17mmol)of methyl thioglycolate (Caution: stench!) isadded with stirring. Stirring is contin"ed for 15 min at room temperature, maintaining the nitrogen atmosphere,then 2.8 g (17 mmol) of aziridine 3 is added, and the mixture is refluxed overnight.After cooling to room temperature, the mixture is poured into 40 mL of water and extracted with 3 X 25 mL portions of CH2CI2.The combined organic layers are dried and concentratedat reduced pressure to yield about 3.8 g (86%) of 5, may be purified by flash chromatography (ethyl acetatehexme 3:7). M.P. (R*,RS)-5,53-54 OC [R',S*-5 is a liquid]. ~
~
Nucleo~hilicd i s ~ t a c e m e n of t iodine bv thioelvcolate in 4. T h e cckditihns are the samk as for t i e trans-aziridine ooenine. T h e crude oroduct 5 is admixed with the corresponding 4,5-dimethyloxazolidin-2-one8 (see text) and should he purified by flash chromatography (ethyl acetate1 hexane 37). T h e yield is 1.tL2.7 g (50-75%). 'H-NMR (CDC13),cis-8 (from 4b): 6 4.83 (dq,J's = 6.6 and 7.8 Hz, 1H, CHO), 4.02 (dq, J's = 6.6 and 7.8 Hz, l H , CHN), 1.37 (d, J =6.6HzIz,3H,CH3), 1.21 (d, J =6.6H2, 3H, CHd; trons-8 (from 48): 64.19 ( d q , S s = 6.3 and 6.3 Hz, l H , CHO), (d, J = 6 . 3 H z , 3.50(dq,Ss =6.3and6.3Hz,lH,CHN),1.37 3H. C H A 1.22 (d. J = 6.3 Hz. 3H. CHd. 5,6-~~~ethj~-2-oxo-l,4-lh;omdrph~line (6). Asolutionof 1.8e (6.5 mmol) of 5 in 30 ml. of 3 h' HCI in ethvlacetate in a 50&L round-bottomed flask is stirred for 30min a t room temperatureand then concentrated at reduced pressure. To the resultingamine hydrochloride (m.p., R',SS, 123-127 O C , R',Ra, 86-89 O C ) 30 mL of anhydrous ethanol and 0.9 g (6.5
520
Journal of Chemical Education
mmol) of anhydrous potassium carbonate are added, and the mixture is refluxed overnight with stirring. The solution is concentrated a t reduced pressure and the resulting solid mass extracted with 30 mL of CH2C12. The solution is filtered, dried over anhydrous NazS04, and concentrated a t reduced pressure. Recrystallization of the crude product from acetone-hexane (111) yields about 0.8 g (85%) product, m.p. c i s 4 112-113 OC, trans-6 130-131 OC. 2,3-Dimethyl-1,4-thiamorpholine (7). T o a solution of 0.8 g (5.5 mmol) of lactam 6 in 30 mL of dioxane in a 50-mL round-bottomed flask eouiooed with a reflux condenser fitboroh&ide ted with a CaClz tube 2 g (52 mmol) of and 3 m~ (52 mmol) of acetic acid are added, ~h~ mixture and then concenovernight trated a t reduced pressure. Hydrochloric acid (10% aqueous) is Slowly added with stirring until the excess sodium borohydride is destroyed, stirring being continued for 2 h a t room temperature. The mixture is then carefully neutralized with small portions of sodium bicarbonate and extracted with 3 X 20 m L portions of CHzClz. The comhined organic layers are dried (anhydrous Na2S04) and concentrated a t reduced nressure to eive 0.6 e (81%) of oroduct. Both isomers mav be iransformei into tge'corresponding oxalates by adding an eouimolecular amount of oxalic acid t o the m i n e dissolved idethanol, stirring and filtering the precipitated derivative and purifying by recrystallization (ethanol). tram-7 Oxalate, m.p. 127-129 "C; cis-7 oxalate, m.p. 150-152 O C .
of
- ..
1. See ersmplc Sekai. K.: Yoneda, N. Chem. Pharrn. Bull. 1981,29,1554. 2. Hassner,A.:Larber,M. E.: Heathmek, C. J. Ow. Chsm. 1367.32.540. 3. Brunet,E.; Carreno, M.C.;GareY Ruano, J. L. Heterocycles 1985,23,1181repat that
4.
5. 6,
7.
the reaction of a similar uic-iodoearbamate (N~meUlo~ycsrbonyl-2-idod.l-~hh"~. lethylamine) with sodium mothyimercaptide occurred with a high percentsge of sriridine formation. See for example Canther, H. NMR Spectroscopy, Wiley: New York, 1980: p 205. See ref 4 p 386. e.g. Stothere, J. B.Corbon-13NMR Spaefrmcopy: Academic: New Yo*. 1972. For sn exhaustive treatise of 2 0 NMR methoda aee Marchand, A. P.. Ed. Methods in Stereochemical Analysis: VCH: New York. 1987; Vol. 9.
