The mechanism of stereoselectivity in the cycloaddition reactions of a-hydroxy- ortho-quinodimethanes with the fumarate of methyl lactate and mandelate

JAMES L. CHARLTON' AND SHAWN MADDAFORD Department of Chemistry, University of Manitoba, Winnipeg, Man. Canada R3T 2N2

Received November 17, 1992

JAMES L. CHARLTON and SHAWN MADDAFORD. Can. J. Chem. 71, 827 (1993). The Diels-Alder cycloaddition reaction of the fumarate of methyl lactate or methyl mandelate with a-hydroxy-ortho-

quinodimethane produces an unexpected exo product with very high asymmetric induction. Experiments and calcula- tions have been carried out that show that the origin of the stereoselectivity in these reactions is related to hydrogen bonding between the a-hydroxy-o-quinodimethane and the lactate or mandelate group in the dienophile.

JAMES L. CHARLTON et SHAWN MADDAFORD. Can. J. Chem. 71, 827 (1993). La reaction de cycloaddition de Diels-Alder du fumarate du lactate de mCthyle ou du mandelate de methyle avec l'a-

hydroxy-ol-tho-quinodimethane conduit a un produit exo inattendu, avec une induction asymCtrique trks ClevCe. On a effectuC des experiences et des calculs qui montrent que l'origine de la stCrCosClectivitC de ces rkactions est relike a la liaison hydrogkne entre 1'a-hydroxy-ortho-quinodimethane et le groupe lactate ou mandClate du dienophile.

[Traduit par la redaction]

Introduction We recently published several accounts of the stereose-

lective and asymmetric Diels-Alder reactions of a-hy- droxy-ortho-quinodimethanes (a-hydroxy-o-QDMs) with the fumarate of methyl lactate or methyl mandelate (1-5).

While these reactions are proving useful in asymmetric synthesis (1, 3, 6 ) , a satisfactory explanation of the stereo- selectivity observed has not yet been proposed. Such an ex- planation would have to account for both the absolute stereoselectivity and the unusual relative stereoselectivity observed. The relative stereoselectivity is unusual in that all previous accounts of Diels-Alder reactions of a-hydroxy or a-alkoxy-o-QDMs with dienophiles have shown that the re- actions produce cis-l,2 adducts via endo transition states (A) (7-1 1). This is in contrast to the reactions of a-hydroxy-o- QDMs with the fumarates of lactate or mandelate, where predominantly trans- 1,2 adducts are formed via exo transi- tion states (B).

- yx \ '.. mx *a/

B x

' ~ u t h o r to whom correspondence may be addressed.

FIG. 1. Possible transition state for the Diels-Alder reaction of a-hydroxy-o-QDM with the acrylate of methyl (S)-lactate.

The absolute stereochemistry of the products is that pro- duced from exo addition of the o-QDM to the re face of the fumarate of methyl @)-lactate 1 (as in transition state B, see also Fig. 1). The observed addition to the re face of the dienophile is similar to results of previous Diels-Alder studies on this dienophile by Helmchem and co-workers (12, 13), who attributed this absolute stereoselectivity to steric block- ing of the si face of the dienophile. While steric factors could be used to explain facial selectivity with respect to the di- enophile when reaction occurs with an a-hydroxy-o-QDM, it would not explain the unusual preference for the exo tran- sition state geometry B. It seemed possible, given the posi- tion of the hydroxyl group on the o-QDM, that hydrogen bonding between the hydroxyl group and the lactyl car- bony1 might be responsible for this preferred exo reaction geometry as illustrated in Fig. 1.

Models show that a similar hydrogen-bonded transition state is sterically unlikely for the endo transition state. Al- though controlling stereoselectivity by such a long-range hydrogen bond may seem implausible, a similar type of nine- membered ring hydrogen bond has been found to be re- sponsible for facial selectivity in the Diels-Alder reaction shown in Fig. 2 (14).

Even if one accepts the hypothesis of a hydrogen-bonded exo transition state for the reaction of the fumarate of methyl (S)-lactate with an a-hydroxy-o-QDM, it is not immedi- ately obvious how the S chiral auxiliary directs addition to the re face of the dienophile (as is shown in Fig. 1). The steric crowding appears to be similar for both the S and R chiral

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CAN. J. CHEM. VOL. 71, 1993

selectivity in the title reactions, we have studied the effect of variation in o-QDM structure, solvent, and dienophile structure. We have also carried out molecular orbital cal- culations (GAUSSIAN-86 AM1) on possible transition states for the reaction of the acrylate of methyl @)-lactate with

Q a-hydroxy-o-QDM.

FIG. 2. Hydrogen bonding control of facial selectivity in Diels- Results and discussion

Alder reaction (14). As a probe of structural effects on stereoselectivity we have studied the reactions of a-hydroxy-o-QDM 1 with several new dienophiles, 5, 6, 10,-and 11, and the reactions of

auxiliaries when reaction occurs at the re face of the dieno- a-methoxy-o-QDM 2 with 7 and 10. The stereoselectivity phile. of these reactions was compared to the stereoselectivity of

In an attempt to determine the mechanism of the stereo- reactions previously reported.2

Dienophiles 5, 6, 10, and 11 were all synthesized by an uncatalysed reaction of the acid chloride with an excess of the appropriate alcohol, followed by chromatography on silica gel.

o-QDMs 1 and 2 were generated by heating either ben- zocyclobutenol 12 (16) or 1-methoxybenzocyc~obutene 13 (16) in toluene containing the dienophile and 4A molecular sieves.

Cycloadducts were separated by flash chromatography on silica gel using ethyl acetate - hexanes as solvent. In some cases separation and characterization of all of the individual isomers was not possible. Determination of isomer ratios was carried out using either 'H nmr (300 or 500 MHz) or hplc (ODs-2, methanol-water as eluent). The assignment of rel- ative stereochemistry within the tetralin ring of the cycload- ducts (endo vs. exo) was made using 'H nrnr. For all

cycloadducts H1 appear between 4.6 and 5.2 ppm (in CDCl,) and endo (cis-1,2) coupling constants, J , , , are 2-5 Hz, while exo (trans-1,2) coupling constants are 7-12 Hz (for pre- vious examples see refs. 2-6, 17). The results of the prod- uct study are shown in Table 1.

In the case of cycloadducts from dienophiles 3-8, there are four possible diastereomeric products (two endo and two exo) for each absolute configuration of the chiral center in the dienophile. These four possible diastereomers are illus- trated in Fig. 3 for 1 reacting with the acrylate of methyl (3- lactate, 3.

As mentioned above, it has been shown that the major product from the reaction of 1 with 3 is the exo-re cycload- duct (4). The exo-re cycloadduct is also the major cycload- duct from the reaction of 1 with (S)-4, (S)-7, and (S)-8 (2, 4). Racemic material was studied in the case of dienophiles 5 and 6 and, although the endo isomers could be distin- guished from the exo isomers by 'H nmr, no attempt was

h he preparation of dienophiles 3 and 7 is given in ref. 4 while that of 8 is given in ref. 1. The preparation of dienophile 4 is described by K.K.S. Koh (15).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CHARLTON AND MADDAFORD

TABLE 1. Diastereoselectivity of Diels-Alder reactions of o-QDMs 1 and 2

o-QDM Dienophile Yield (%) Facial selectivitya endo; exo Ref.

955 exo >90: 10 exo

33:17 endo, 34:16 exo -

exo only 5 >90% exo 2

5050 exo only exo only 5 exo only 2

74:26 16 60:40 20:80

endo only endo only 15

88:12

"Ratio of exo and (or) endo diastereorners for cases in which the dienophile carries a chiral auxiliary.

exo-si exo-re

endo-re endo-si

FIG. 3. Possible products from the reaction of a-hydroxy-o-QDM, 1, with the acrylate of methyl @)-lactate.

made to determine the configuration of the tetralin ring car- bons relative to the center in the chiral auxiliary.

Reaction of 1 with dienophile 5 gave a mixture of four diastereomers as evidenced by the number of doublets in the H1 region of the 'H spectrum. Correct elemental composi- tion was confi ied by elemental analysis of the mixture. The 'H nmr at 500 MHz in 20% CDCl, in deuterobenzene al- lowed integration of the four H1 signals of isomers exo-l, e-xo-2, endo-1, and endo-2, giving the ratio of 34: 16:33: 17, respectively (J = 9.1, 8.9, 3.25, and 3.45, respectively). The hplc separation of the mixture on ODs-2 using a methanol- water mixture as eluent resulted in the isolation of three of the four isomers (in order of elution, exo- 1, endo- 1, endo- 2) and their individual 'H nmr spectra are reported in the experimental.

Reaction of 1 with dienophile 6 gave only a single exo cycloadduct in 45% yield after chromatography. No signals consistent with other diastereomers could be observed in the nmr of the crude product.

The product mixture from dienophile 11 was more com- plicated. An 'H nmr spectrum of the crude product mixture showed doublets at 5.43 (J = 5.17), 5.12 (J = 3.65), and 4.86 (J = 9.53) ppm (CDCl,). Chromatography on silica gel resulted in the isolation and characterization of only one of the three compounds. Based on its ir spectrum (1788 cm-I) and comparison of its 'H nmr spectrum to that of a similar compound (4), it was assigned structure 14.

The doublet appearing at 5.43 ppm in the nmr spectrum of the crude product comes from compound 14 and the remaining two doublets at 5.13 and 4.86 ppm were ten- tatively assigned to the endo and exo cycloadducts, respec- tively, on the basis of the coupling constants. Presumably the exo cycloadduct readily closes to the lactone 14 as has been noted in similar cycloadducts (4). The endolexo ratio given in Table 1 for dienophile 11 is calculated using the ratio of the nrnr integration for the presumed endo doublet at 5.13 ppm to the sum of the other two doublets.

Dienophile 9 has been reported to give a mixture of endo (major) and exo (minor) isomers in good yield on reaction with o-QDM 1, produced by irradiation of o-methylbenzal- dehyde (18).

The reaction of di-tert-butyl fumarate, 10, with 1 gave a mixture of the endo (major) and e-xo (minor) cycloadducts, which were separated by chromatography and character- ized.

In the case of a-methoxy-o-QDM 2, primarily endo prod-

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

830 CAN. J . CHEM. VOL. 7 1 , 1993

ucts were formed with dienophiles 7, 9, and 10. Reaction with 7 gave two diastereometric endo adducts, which were both isolated and characterized. Reaction with 9 was re- ported previously to give only an endo cycloadduct (32%) with no indication of the presence of other isomeric cy- cloadducts (18). Reaction of o-QDM 2 with di-tert-butyl fumarate 10 gave primarily an endo cycloadduct, which was isolated by chromatography and characterized. The 'H nmr spectrum of the crude reaction mixture also exhibited a doublet at 4.74 ppm (J = 8. l ) , which was assumed to be the exo cycloadduct. The integration of this peak relative to that assigned to H1 of the etzdo cycloadduct (4.53 ppm, J = 3.39) gave the etzdo/exo ratio of 88: 12 reported in Table 1.

From the above results a pattern of reactivity can be seen. Only o-QDM 1, with an a-hydroxyl group, gives exo cy- cloadducts with high stereoselectivity. o-QDM 2, with an a-methoxy group, gives primarily endo adducts. Steric bulk of the ester group in the dienophile makes little difference to the endo/exo ratio as evidenced by the comparison of di- methyl and di-tert-butyl fumarate, 9 and l l . Only dieno- philes with a strong hydrogen-bonding acceptor group give exo cycloadducts, with the exception of 5.

~ l l of the above facts suggest that a hydrogen-bonded transition state, perhaps similar to that depicted in Fig. 1, directs the endolexo stereoselectivity of the cycloaddition reaction of 1 with dienophiles 3, 4, 6, 7, 8, and 11. In the case of dienophile 5 , it appears that the linear geometry of the nitrile function makes it sterically impossible for it to form a hydrogen bond to the hydroxyl group of the o-QDM. For dienophiles 9 and 10 and (or) reactions involving o-QDM 2, the expected endo products are predominantly formed.

If the proposed hydrogen bonding theory is correct, it should be easily disrupted by solvent effects. Just such an effect was found for the reaction of o-QDM 1 with the fu- marate of methyl (S)-lactate 7. When 1 (from 12 at 100°C) was reacted w~th 7 in toluene containing 30% dimethyl sulfoxide (DMSO) by volume, a mixture of four products was formed. Their ratios, measured by hplc, were 9:15:34:42 (presumed exo-si, exo-re, endo-1, and endo-2 respectively. The exo-re isomer was identified by comparison to an au- thentic sample (4, 5). The two endo adducts were both sep- arated and characterized, although it could not be determined - which was the erzdo-re and which was the endo-si isomer. The remaining minor product could not be isolated in suf-

ficient quantity for characterization but was assumed to be the remaining exo-si diastereomer. As expected, DMSO ap- pears to interfere with the normal diastereoselectivity by hydrogen bonding to the hydroxyl group of the o-QDM, thereby preventing the formation of a hydrogen-bonded transition state similar to that illustrated in Fig. 1. This re- sults in the formation of more endo products and a loss in asymmetric induction for both endo and exo products.

Molecular orbital calculations If the hydrogen-bonded transition state shown in Fig. 1 is

correct it must also be able to account for the high facial se- lectivity observed with respect to the dienophile. For ex- ample, the reaction of a-hydroxy-o-QDM 1 with the acrylate of methyl (S)-lactate 3 gives the exo-re cycloadduct with higher than 90% de. To test the validity of the model, mo- lecular orbital calculations have been carried out on the exo- re transition state for the acrylate of both methyl @)-lactate and methyl (R)-lactate. Such a calculation is equivalent to comparing the exo-re-(S) transition state to the exo-si-(S) transition state since exo-si-(S) is the mirror image of exo- re-(R). If the model is correct, the energy of the exo-re-(S) transition state should be lower than that of the exo-re-(R) (exo-si-(S)). By using geometry optimization it should also be possible to confirm that a hydrogen bond, similar to that depicted in Fig. 1, is possible for a conformationally re- laxed transition state.

Molecular orbital calculations were carried out at the semiempirical level (AM1) with geometry optimization using the program GAUSSIAN-86 (19). To model the transition State the calculations were started at the cycloadduct stage with the saturated tetralin ring in a boat conformation, typical of the final state of Diels-Alder reactions. The lactyl side chain was twisted into a conformation for which hydrogen bond- ing to the OH group was possible. The initial atom coordi- nates for the starting structure were obtained from a model constructed, and conformationally relaxed (molecular me- chanics minimization), using the computer program PC-MODEL (20 ) .~ The dienophile and diene were then iteratively sepa- rated by elongation of the l ,2 an$ 3,4 bonds until a separa- tion (diene-dienophile) of 2.0 A was reached, a distance close to the Diels-Alder reaction transition state (21). At each stage of the iterative dissociation of the adduct, the 1,2 and 3,4 bond lengths were fixed and the rest of the geometry optimized.

The calculations confirmed that it is possible to have a correspond to the s-cis and the s-trarzs dienophile confor- conformationally relaxed transition state with hydrogen mations. The s-cis conformation is shown in the diagram bondiqg between the OH group and the lactyl carbonyl(2.14- 2.3 1 A). The calculations also showed that there are two low- energy conformations of the lactyl side chain that allow for 3Calculations carried out on a Silicon Graphics IRIS 4D70/GT hydrogen bonding and that these two conformations roughly workstation.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CHARLTON A N D MADDAFORD

Analytical VG 7070E-HF instrument. melting points were mea- sured on a hot stage instrument and are uncorrected.

Acrylate of rac-lactonitrile. 5 Acryloyl chloride (5.9 g, 5.3 mL, 65 mmol) and lactonitrile

(2.95 g, 3 mL, 37.8 mmol) were refluxed inomethylene chloride (50 mL) over dry molecular sieves (6.7 g, 4 A) for 68 h. The SO-

lution was filtered and the solvent evaporated, leaving a light yel- low liquid. The liquid was fractionally distilled (bp 160"C, l atm (1 atm = 101.3 kPa)) to remove the lower boiling acryloyl chlo- ride and methylene chloride. The distillate was chromatographed on silica gel (5% ethyl acetate/hexanes) to give a colourless liq- uid (1.4 g, 11.3 mmol, 30%): ir (CH2Cl,): 1739 cm-I; 'H nrnr (CDC1,) 6: 6.52 (dd, lH, J = 1.29, 17.21), 6.15 (dd, IH, J = 10.44, 17.14), 5.98 (dd, lH, J = 1.29, 10.5), 5.47 (q, lH, J = 6.9), 1.69 (d, 3H, J = 6.97); 13C nrnr (CDCI,) 6 : 164.06, 133.29, 126.64, 117.46, 57.39, 18.79; mass spectrum, ammonia ioniza- tion tn/e (rel. %): 143 (M + NH4', l l ) , 126 (M + H+, 1.1), 99 (2.2), 72 (12), 70 (S), 55 (loo), 46 (4). Exact Mass (EI) calcd. for C6H,02N: 125.0477; found: 125.0484.

Acrylate of rac-3-hvdroq~-2-blitanone, 6 Acryloyl chloride (5 mL, 61.5 mmol) and 3-hydroxy-2-butan-

one (5.46 g, 61.9 mmol) were refluxed in CHICII (5 mL) over dry molecular sieves (4 A, 8 g) for 4 days. The solution was filtered and the solvent evaporated to leave an oil. The crude oil was chro-

F , ~ , 4 , oRTEP diagram of the ero-re-s-cis-~ transition state, matographed on silica (10% ethyl acetate/hexanes) to give a col- ourless oil (5.7 g, 66%): ir (CH2C1,): 1730 cm-'; 'H nmr (CDCl,) 6: 6.41 (dd, lH, J = 1.35, 17.34), 6.13 (dd, lH, J = 10.40,

although calculations were carried out for both the s-cis and 17.33), 5.85 (dd, IH, J = 1.36, 10.40), 5.09(q, IH, J = 7.05), 2.12 (s, 3H), 1.38 (d, 3H, J = 7.06); I3C nrnr (CDCI,) 6: 205.61,

the conformations (for both the and dieno~hile) . 165.37, 13 1 ,go, 127.67, 75.07, 25.58, 16.02; mass spectrum m/e The relative energies of the exo-re transition state with the (rel, 142 (M+, 0.41, 100 (1.81, 99 (7.71, 98 (13), 87 (2.41, 55 s-cis-S, s-cis-R, s-trans-s, and s-trans-R dienophile were (loo), 43 (36). Exact Mass calcd. for C , H ~ ~ O ~ : 142.0630; found: foundtobe0.0(reference),8.51,10.6,and5.79kJ/mol, 142.0646. respectively. An ORTEP (22) plot of the conformationally minimized exo-re-s-cis-S transition state is shown in Fig. 4.

The calculations are consistent with the experimental results since the calculated lowest energy transition state, exo-re-S, leads to the observed product. It is interesting to note that the correct prediction of asymmetric induction can be achieved only if the dienophile is in the s-cis conforma- tion.

It was hoped that the calculated optimized geometries of the exo-re-S and exo-I-e-R transition states would give some hint as to the mechanism of the asymmetric control exerted by the chiral auxiliary. However, there was very lit- tle difference in the geometries of the two diastereotopic transition states, indicating that the effect of the auxiliary on reaction diastereoselectivity is very subtle and not simply due to sterically induced changes in reaction geometry.

The calculations do confirm that a hydrogen-bonded transition state leading to the preferred product is structur- ally and energetically feasible. Large rate enhancements have been observed as a result of hydrogen bonding in other Diels- Alder reactions involving dienolic substrates such as 9-hy- droxyanthracene (23). A similar rate enhancement in the re- actions described here may explain the preference for the hydrogen-bonded transition state leading to the exo cy- cloadducts.

Experimental The 'H nrnr spectra were recorded on a Bruker AM-300 or AMX-

500 instrument using tetramethylsilane as internal standard. The ir spectra were recorded on a Perkin-Elmer 88 1 spectrometer. Aldrich silica gel (28,859-4) was used for all chromatography. Elemental analyses were performed by Guelph Chemical Laboratories Ltd., Guelph, Ontario. Exact Mass/mass spectra were obtained on an

Di-tert-bug11 fumarate, 10 Fumaryl chloride (5.1 g, 0.033 mol) was dissolved in benzene

(50 mL) and tert-butyl alcohol (15 mL, 4.8 mol-equdv.) was added at room temperature. Molecular sieves (5.01 g, 4 A, flame-dried under nitrogen) were added and the solution refluxed for 38 h. The resulting solution was filtered through a short column of silica (EtOAc) and the filtrate washed with aqueous NaHCO, solution (5%, 3 x 20 mL). The solution was dried (MgS04) and evapo- rated, giving a yellow oil (2.99 g, 42%) that crystallized on stand- ing. Flash chromatography on silica (eluent 20% ethyl acetate/ hexanes) yielded a colourless solid (1.74 g, 24%) a sample of which was crystallized from ethyl acetate/hexanes; mp 62-63°C; ir (CH?C12): 1709 cm-l; 'H nrnr (60 MHz, CDCl,) 6: 6.73 (s, 2H), 1.53 (s, 18H); I3C nrnr (75.47 MHz, CDC1,) 6: 164.38, 134.53, 8 1.64, 27.99; mass spectrum m/e (rel. %): 155 (IS), 99 (53), 57 (loo), 56 (30). Anal. calcd. for C12H2,,04: C 63.14, H 8.83; found: C 63.41, H 8.91.

Di-(2-hyclro,~yethyl)$lmcc.rate, 11 Fumaryl chloride (I mL, 1.40 g, 9.16 mmol) and ethylene gly-

col (5.2 mL, 10 mol-equiv.) were stirred at 27OC for 24 h. The so- lution was diluted with water (25 mL) and extracted with EtOAc (3 X 25 mL). The organic phase was dried (Na2S04) and the sol- vent evaporated, leaving a viscous oil (1.51 g). The oil was chro- matographed on silica (80% ethyl acetate/hexanes) to give a semicrystalline product (1 .Ol g, 54%); mp 52-53°C; ir (CH2Cl2): 1728 cm-I; 'H nrnr (300 MHz, CDCI,) 6: 6.92 (s, 2H), 4.33 (m, 4H), 3.87 (m, 4H), 2.79 (bs, 2H); ',c nrnr (75.47 MHz, CDCI,) 6: 165.06, 133.64, 66.87, 60.67; mass spectrum m/e (rel. 5%): 144 (15), 143 (loo), 117 (12.5), 99 (65.9), 85 (23), 82 (26). 57 (29). Anal. calcd. for CRHI2O6: C 47.06, H 5.92; found: C 46.99, H 5.77.

Reactions of bet~zocyclobsctenol 12 with diet~ophiles 5, 6, 10, and 11

Reactiot~ of 1 with 5 Benzocyclobutenol (0.125 g, 1.04 mmol) and acrylate 5

(0.439 g, 3.5 1 mmol, 3.36 mol-equiv.) were refluxed in toluene

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

832 CAN. J CHEM. VOL. 71, 1993

(anhydrous, 5 mL) in the presence of 4A molecular sieves (0.92 g) under nitrogen for 11 h. The solution was filtered and the solvent removed in vacuo to leave a yellow oil (0.260 g). The oil was chromatographed on silica (20% ethyl acetate/hexanes) to give a colourless oil (148 mg, 58%), which on examination by 'H nmr appeared to be a mixture of four diastereomers: ir (CH,Cl,): 3604, 2309, 1748, 1734 cm-I. Anal. calcd. for C,4Hl,-N03: C 68.56, H 6.16, N 5.71; found: C 68.52, H 6.57, N 5.45. Three of the four isomers were isolated by hplc on ODs-2 using a methanol-water eluent (4456 to 70:30 over 36 min) and their 'H nmr and mass spectral data are given below in order of their elution.

exo-1: 'H nrnr (CDCl,) 6: 7.59 (d, lH, J = 9.4), 7.14-7.3 (m), 7.10 (m, lH), 5.49 (q, lH, J = 6.94), 5.09 (dd, lH, J = 8.7, 6.6), 2.68-3.0 (m, 3H), 2.49 (d, lH, J = 6.6), 2.89-2.2 (m, lH), 2.03- 1.88 (m, lH, J = 6.0), 1.68 (d, 3H, J = 6.92); mass spectrum m/e (rel. %): 227 (M' - H20, 19), 191 (7), 173 (24), 145 (16), 129 (loo), 81 (12), 69 (54).

endo-1: 'H nmr (CDCl,) 6: 7.41-7.38 (m, lH), 7.26-7.10 (m, 3H), 5.51 (q, lH, J = 6.90), 5.10 (bs, 1 H), 3.00-2.75 (m, 3H), 2.46 (d, lH, J = 5.9), 2.31-2.03 (m, 2H), 1.69 (d, 3H, J = 6.93); mass spectrum m/e (rel. %): 227 (M' - HZO, 14), 191 (3.2), 173 (12), 145 (1 l), 130 (27), 129 (100), 128 (26.4), 119 (20), 115 (16), 91 (15).

endo-2: IH nrnr (CDC1,) 6: 7.41-7.38 (m, lH), 7.27-7.22 (m, 2H), 7.17-7.14 (m, lH), 5.52 (q, lH, J = 6.97), 5.07 (d, lH, J = 3.18), 3.12-2.75 (m, 3H), 2.29-2.10 (m, 2H), 1.71 (d, 3H, J = 6.98); mass spectrum m/e (rel. %): 227 (M' - H,O, 21), 173 (8), 155 (2.9), 145 (8), 130 (39), 129 (loo), 128 (34), 119 (20), 115 (161, 91 (13).

Reaction of 1 with 6 Benzocyclobutenol 12 (0.219 g, 1.82 mmol) and acrylate 6

(0.268 g, 1.89 mmol, 1.04 mol-equiv.) were r~fluxed in toluene (10 mL) in the presence of molecular sieves (4A, 0.5 g) for 19 h. The solution was filtered through silica gel (EtOAc) and the sol- vent evaporated under reduced pressure to leave a yellow oil (0.471 g). The oil was chromatographed on silica (40% ethyl ace- tate/hexanes) and recrystallized from ethyl acetate/hexanes to give long, colorless crystals (0.215 g, 45%); mp 65-69°C; ir (CH,Cl,): 1721 cm-'; 'H nmr (300 MHz, CDCI,) 6: 7.65 (d, lH, J,,, = 7.19), 7.22 (m, 2H), 7.08 (d, 1H,J5,6 = 7.06), 5.26 (q, lH, J = 7.19), 4.98 (d, lH, J1., = 9.32), 3.68 (d, 1 H, J = 2.82), 2.88-2.77 (m, 3H), 2.21 (s, 3H), 2.20-2.12 (m, lH), 2.07-1.92 (m, lH), 1.48 (d, 3H, J = 7.19); I3c nmr (75.47 MHz, CDCl,) 6: 205.88, 174.35, 137.44, 135.32, 128.22, 127.28, 126.93, 126.38, 75.23, 70.52, 48.77, 28.13, 25.68, 23.69, 15.80; mass spectrum m/e (rel. %): 244 (2.2), 191 (17), 173 (25), 157 (30), 146 (27), 129 (loo), 105 (43), 91 (27). Exact Mass calcd. for ClsHl,O,: 262.1205; found: 262.1203.

Reactiorl of1 with di-tert-butyl furnarate, 1 0 Benzocyclobutenol (63.5 mg, 0.529 mmol) and di-tert-butyl

fumarate (242 mg, 1.12 mmol, 2.12 mol-equiv.) were heated in toluene (5 mL) at 110°C in the presence of molecular sieves (1.0 g, 4 A, dried under vacuum) for 19 h. The solution was fil- tered through a short silica gel column using EtOAc as eluent and the solvent evaporated to leave a yellow oil. An 'H nmr spectrum (300 MHz) of this crude product exhibited two doublets at 6 4.88 (J = 8.88) and 5.03 (J = 3.57) in a ratio of 1.5 : 1 (endolexo). The two isomers were separated by chromatography on silica (15% ethyl acetate/hexanes) in a combined yield of 45%.

exo Adduct: mp 91-92°C; ir (CH2Cl2): 1731 cm-'; 'H nrnr (CDC13)6:7.65(d, lH, J = 7.2), 7.27-7.18(m, 2H),7.08(d, IH, J = 7.03), 4.88 (dd, lH, J = 8.88, 5.6), 2.8-3.1 (m, 5H), 2.81 (d, lH, J = 5.6), 1.50 (s, 9H), 1.46 (s, 9H); I3c nrnr (CDCI,) 6: 172.90, 172.58, 137.20, 133.57, 128.00, 127.58, 126.78, 81.85, 81.05, 70.35, 51.58, 42.07, 31.74, 28.07, 28.01; mass spectrum m/e (rel. %): 257 (4.3), 218 (5.4), 189 (9.8), 172 (lo), 129 (15), 97 (28), 83 (36), 69 ( 5 7 , 57 (100). Anal. calcd. for C20H2805: C 68.94, H 8.10; found: C 68.62, H 8.10.

endo Adduct: mp 99-102°C; ir (CH2Cl,): 1733 cm-'; 'H nmr (CDCl,) 6: 7.39-7.35 (m, lH), 7.27-7.20 (m, 2H), 7.15-7.1 1 (m, lH), 5.03 (dd, lH, J = 4.63, 3.57), 3.23-3.12(m, 2H), 2.99 (dd, lH, J = 11.05, 3.57), 2.82(dd, lH, J = 18.10, 12.99),2.17 (bd, lH), 1.50 (s, 9H), 1.48 (s, 9H); ',c nmr (CDCl,) 6: 173.83, 171.78, 136.44, 134.19, 129.33, 128.60, 128.47, 126.74, 81.39, 80.68, 68.52, 48.87, 38.30, 3 1.99, 28.08; 28.01 ; mass spectrum m/e (re]. 5%): 236 (3.8) 235 ( l l ) , 217 (13), 189 (27), 173 (18), 172 (19), 145 (19), 129 (26), 69 (14), 57 (100). Anal. calcd. for C20H2805: C 68.94, H 8.10; found: C 68.98, H 8.23.

Reaction of 1 with 11 The fumarate of ethylene glycol (330 mg, 1.62 mmol) and ben-

zocyclobutenol (214 mg, 1.78 mmol, 1.1 mol-equiv.) were re- fluxed in toluene (10 rnL) in the presence of molecular sieves ( 4 4 for 18 h. The solution was filtered through a short column of si- cila (eluent, ethyl acetate) and the solvent evaporated in vacuo. The 'H nmr spectrum of the crude product revealed the presence of three doublets at 65.43 (J = 5.18), 5.12 (J = 3.65), and4.86(J = 9.53). The crude oil was chromatographed on silica (eluant 70% ethyl acetate/hexanes) to give only one pure fraction (93 mg, 22%); mp 114-1 15°C; ir (CH,CI2): 3600, 1788, 1745 cm-I; 'H nmr (CDCI,) 6:7.35 (dd, lH, J = 1.71,7.3),7.29-7.16(m,3H),5.46(d, lH, J = 5.18), 4.18 (ddd, lH, J = 3.08, 6.04, 9.13), 3.94 (m, lH), 3.84 (t, lH, J = 5.19), 3.51 (dd, lH, J = 17.9, 5.28), 3.46 (bm, 2H), 3.35 (m, lH, J = 1.14, 5.34), 3.09 (d, lH, J = 17.9); 13C nrnr (CDCl,) 6: 176.52, 167.37, 133.84, 126.80, 78.06, 66.38, 60.72, 47.64, 39.04, 27.32; mass spectrum m/e (rel. %): 262 (M', 7.0), 200 (12), 173 (5.7), 172 (8.2), 156 (5.9), 129 (loo), 128 (77), 127 (16). Exact Mass calcd. for C,,H,,O,: 262.0841; found: 262.0845.

Reactions of 1 -methoxybenzocyclobutene 13 with dienophiles 7 and 1 0

Reaction of 2 with 7 The fumarate of methyl (S)-lactate, 7 (1 15 mg, 0.397 mmol),

and 1-methoxybenzocyclobutene (66.6 mg, 0.496 mmol) were re- fluxed together in toluene (10 mL) for 3 days. The solution was filtered through a short column of silica gel (eluent EtOAc) and evaporated to leave a yellow oil (185 mg). The 'H nmr spectrum exhibited two doublets at 6 4.75 ( J = 2.96) and 4.56 (J = 3.33) in a ratio of 1.57 : 1 ; hplc (ODs-2, acetonitrile-water-methanol) exhibited two peaks in a ratio of 1.56: 1. Chromatography of the crude oil on silica gel (eluent 5% EtOAC-benzene) gave adduct endo-1 (62.6 mg) and adduct endo-2 (27.1 mg) (combined yield 62%).

endo-1: ir (CH,Cl,): 1746 cm-I; 'H nmr (CDCl,) 6: 7.18-7.32 (m, 4H), 5.24 (q, lH, J = 7.04), 5.16 (q, lH, J = 7.10), 4.68 (d, lH, J = 3.00), 3.77 (s, 3H), 3.75 (s, 3H), 3.65 (m, lH), 3.44 (dd, lH, J = 7.04, 17.16), 3.34 (s, 3H), 3.17 (dd, lH, J = 11.62, 3.00), 2.94(dd, lH, J = 10.94, 17.16), 1 .54 (d ,3H, J=7 .11 ) , 1.53 (d, 3H, J = 7.04); "C nrnr (CDCl,) 6: 174.85, 171.34, 171.24, 134.49, 133.13, 129.63, 129.14, 128.87, 125.66, 77.19, 68.65, 56.67, 52.24, 47.12, 36.24, 31.17, 17.20, 16.87; mass spectrum m/e (rel. %): 422 (M', 1. l), 359 (2 l), 258 (25), 187 (42), 186 (33), 185 (34), 159 (86), 155 (loo), 128 (46). Exact Mass calcd. for CZIH2609: 422.1577; found: 422.1582.

endo-2: ir (CH2C12): 1745 cm-'; 'H nrnr (CDCl,) 6: 7.19-7.35 (m,4H),5.26(q, lH , J=7 .02 ) ,5 .13 (q , lH , J=7 .08 ) ,4 .66 (d , lH, J = 3.31), 3.75 (s, 3H), 3.74 (s, 3H), 3.63-3.54 (m, lH), 3.36-3.26 (m, 2H), 3.28 (s, 3H), 3.01 (dd, lH, J = 10.49, 16.92), 1.55 (d, 3H, J = 7.04), 1.48 (d, 1 H, J = 7.05); I3C nrnr (CDCI,) 6: 173.52, 171.12, 170.96, 170.87, 134.60, 132.91, 129.63, 129.03, 128.89, 125.75,77.43,68.86, 68.64, 56.73,52.26,52.22, 47.04, 37.26, 52.22, 47.04, 37.10, 31.11, 17.05, 16.72; mass spectrum m/e (rel. %): 422 (M', 0.5), 359 (1.0), 258 ( 2 3 , 187 ( 4 3 , 186 (31), 185 (9) 155 (loo), 128 (39). Exact Mass calcd. for C21H2609: 422.1577; found: 422.1559.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CHARLTON AND MADDAFORD 833

Reaction of 2 with I0 Di-tert-butylfumarate (108 mg, 0.474 mmol) and l-methoxy-

benzocyclobutene (1 11 mg, 0.825 mmol, 1.74 mol-equiv.) were heated in toluen~ (5 mL) at reflux for 16 h in the presence of mo- lecular sieves (4A, 0.19 g). The solution was filtered through a short silica gel column (eluent EtOAc) and the solvent evaporated at re- duced pressure to leave a yellow oil. Further evaporation at 0.5 Torr (1 Torr = 133.3 Pa) for 4 h (20°C) left an oil (168 mg, 98%). The 'H nmr spectrum of this crude product exhibited two doublets at 6 4.53 (J = 3.39) and 4.74 ( J = 8.1) in the ratio of 7.7: 1. Only the major cycloadduct could be characterized; ir (CH2Cl2): 1734 cm-', 'H nmr (CDCI,) 6: 7.28-7.13 (m, 4H), 4.53 (d, lH, J = 3.39), 3.36-3.19 (m, 2H), 3.31 (s, 3H), 2.95 (dd, lH, J = 11.29, 3.39), 2 28 (dd, lH, J = 16.16, 10.4), 1.50(s, 9H), 1.47 (s, 9H); "C nmr (CDCI,) 6: 174.52, 171.17, 135.05, 133.69, 129.59, 128.92, 128.60, 125.58, 80.69, 80.24, 78.29, 56.99, 48.37, 38.01, 3 1.80, 28.1 1, 27.99; mass spectrum m/e (rel. %): 200 (62), 172 (35), 156 (24), 155 (32), 129 (80), 128 (loo), 127 (58), 126 (20). Anal. calcd. for C2,H3,O5: C 69.58, H 8.34; found: C 69.46, H 8.37.

Reaction of berzzocyclobutenol I2 with the futnarate of methyl (S-lactate 7 in DMSO/toluene

Benzocyclobutenol (42 mg, 0.35 mmol) and fumarate 7 (83 mg, 0.29 mmol) were heated at 100°C in 3 0 F DMSO-tol- uene (by volume, 10 mL), over molecular sieves (4A, 300 mg), for 21 h. The solution was filtered through a short silica gel column (eluant EtOAc), diluted with benzene, and extracted with water. The organic fraction was dried (MgSO,) and the solvent evapo- rated. Residual solvent was removed at high vacuum (0.5 Torr, 30°C) to leave an oil (109 mg, 72%). The major isomers were separated using reverse phase hplc (ODs-2, 53% water- 41% methanol: 6% acetonitrile increasing to 100% methanol). The identity of the fourth eluted peak was established as the e.ro-re ad- duct by comparison to an authentic sample ( 4 3 . The two major adducts, eluting second and third, were isolated and character- ized.

endo Adduct I: 'H nmr (CDCl,) 6: 7.13-7.42 (m, 4H), 5.22 (q, lH, J = 7 . 1 9 , ca. 5.14 (m, lH), 5.13 (q, lH, J = 7.01), 3.78 (s, 3H), 3.75 (s, 3H), 3.63 (dt, lH, J = 5.82, 11.6), 3.43 (d, lH, J=4.03),3.19(dd, l H , J = 3.06, 11.54),3.30(dd, 1 H , J = 11.7, 16.8),2.96(dd, l H , J = 5 . 8 2 , 16.82), 1 .56 (d ,3H, J=7 .2 ) , 1.52 (d, 3H, J = 7.1); mass spectrum m/e (rel. %): 408 (Mf, 0.34), 172 (19), 155 (50), 145 (38), 129 (loo), 128 (64). Exact Mass calcd. for C20H1809: 408.1432; found: 408.1440.

endo Adduct 2: 'H nmr (CDCI,) 6: 7.45-7.40 (m, IH), 7.27- 7 24 (m, 2H), 7.14-7.20 (m, lH), 5.35 (d, lH, J = 3.49), 5.28 (q, lH, J = 7.17), 5.17 (q, lH, J = 7.1), 3.93 (bs, lH), 3.80 (s, 3H), 3.77 (s, 3H), 3.48 (dt, lH, J = 6.0, 12.3), 3.36 (dd, lH, J = 6.0, 16.6), 3.22(dd, lH, J = 3.49, 11.7),2.89(dd, lH, J =

12.3, 16.6), 1.57 (d, 3H, J = 7.2), 1.55 (d, 3H, J = 7.1); mass spectrum m/e (rel. %): 408 (M', 0.31), 287 (2.5), 276 (6), 258 (7), 173 (9), 172 (15), 155 (34), 129 (loo), 128 (60), 127 (14). Exact Mass calcd. for C2,HL809: 408.1432; found: 408.1434.

Acknowledgments We gratefully acknowledge the financial support of this

project by the Natural Sciences and Engineering Research Council of Canada. The technical assistance of Wayne Buchannon in recording mass spectra is also gratefully ac- knowledged.

1. J.L. Charlton and K. Koh. J. Org. Chem. 57, 1514 (1992). 2. J.L. Charlton and K. Koh. Synlett, 333 (1990). 3. J.L. Charlton, G.L. Plourde, K. Koh, and A.S. Secco. Can.

J. Chem. 68, 2022 (1990). 4. J.L. Charlton, G.L. Plourde, K. Koh, and A.S. Secco. Can.

J. Chem. 67, 574 (1989). 5. J.L. Charlton, K. Koh, and G.L. Plourde. Tetrahedron Lett.

30, 3279 (1989). 6. J.L. Charlton, K. Koh, and G.L. Plourde. Can. J. Chem. 68,

2028 (1990). 7. J.L. Charlton and M.M. Alauddin. Tetrahedron, 43, 2873

(1987), and references cited (1- 13). 8. M. Pfau, J.E. Rowe, Jr., and N.D. Heindel. Tetrahedron, 34,

3469 (1978). 9. P.G. Sammes. Tetrahedron, 32, 405 (1976).

10. M.B. Glinski and T. Durst. Can. J. Chem. 61,573 (1983). 11. E. Block and R. Stevenson. J. Chem. Soc. Perkin Trans. 1,

308 (1973). 12. G. Helmchen, R. Karge, and J . Weetman. In Modem syn-

thetic methods. Vol. 4. Edited by R. Scheffold. Springer- Verlag, New York. 1986. p. 261.

13. H. Hartmann, A.F.A. Hady, K. Sartor, J. Weetman, and G. Helmchen. Angew. Chem. Int. Ed. Engl. 26, 1 143 (1987).

14. R. Tripathy, P.J. Carrol, and E.R. Thornton. J. Am. Chem. SOC. 113, 7630 (1991).

15. K.K.S. Koh. Ph.D. Thesis, University of Manitoba, Winnipeg. 1991.

16. W.A. Bubb and S. Sternhell. Aust. J. Chem. 29, 1685 (1965). 17. T. Durst, E.C. Kozma, and J.L. Charlton. J. Org. Chem. 50,

4829 (1985). 18. G.L. Plourde. Ph.D. Thesis, University of Manitoba,

Winnipeg. 1990. 19. M.J. Frisch, J.S. Binkley, H.B. Schlegel, K. Raghavachari,

C.F. Melius, R.L. Martin, J.J.P. Steward, F.W. Bobrowicz, C.J. Whiteside, D.J. Fox, E.M. Fluder, and J.A. Pople. Carnegie-Mellon Publishing Unit, Pittsburg, Pa. 1984.

20. PCMODEL V. 4.0, Serena Software, Box 3076, Bloomington, Ind. 1990.

21. R.J. Loncharich, F.K. Brown, and K.N. Houk. J. Org. Chem. 54, 1129 (1989).

22. C.K. Johnson. ORTEP 11: Report ORNL-TM-306-5138. Oak Ridge National Laboratory, Oak Ridge, Tenn. 1976.

23. M. Koerner and B. Rickbom. J. Org. Chem. 55,2662 (1990).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

HA

RB

OR

BR

AN

CH

OC

EA

NO

GR

APH

IC o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.