The Mechanism of the Mitsunobu Reaction. 11

A~rst.J. Chern., 1983, 36, 557-63

The Mechanism of the Mitsunobu Reaction. 11* Dialkoxytriphenylphosphoranes

Mark von IfzsfeinAand Ian D. J e n k i n ~ ~ , ~ A

School of Science, Griffith University, Nathan, Qld. 41 11. To whom inquiries should be addressed.

Abstract

31P n.m.r. studies indicate that, in the Mitsunobu reaction, alcohols (ROH) react with triphenylphosphine (Ph3P) and dialkyl azodicarboxylates to produce phosphoranes of the type Ph3P(OR),. Mixtures of alcohols produce, in addition, mixed phosphoranes, Ph3P(OR)(OR'). Phosphoranes of the type Ph,P(OR)N(CO,Rf)NHCO,R' are probably intermediates in these reactions but are not observed by ''P n.m.r.

Introduction In the first paper in this series,' it was shown that, although Mitsunobu reactions, utilizing as reagents the combination of triphenylphosphine (PPh,) and diethyl azodicarboxylate [(NCO,Et),], are usually envisaged as proceeding through oxyphosphonium salts, relatively stable phosphoranes are in fact formed as intermediates as evidenced by the high-field (approx. - 55 ppm) shifts in their 31P n.m.r. spectra. It was suggested that these intermediate phosphoranes had the general structure (2) although there was no firm evidence to support this structure over alternative structures such as (3) and (4). This initial work1 was largely carried out at room temperature, with tetrahydrofuran as solvent, and the 31P n.m.r. spectra were recorded at 36.44 MHz with a Bruker HX-90 spectrometer. Under these conditions, the phosphoranes formed from primary alcohols and most secondary alcohols are quite unstable breaking down rapidly to ~ This form triphenylphosphine oxide as the only species observable by 3 1 n.m.r. made any quantitative work extremely difficult. We have now carried out a much more careful study of these systems at lower temperatures and used the more sensitive ~ spectra. Our results now indicate Bruker CXP-300 instrument to record the 3 1 n.m.r. very clearly that the phosphoranes observed during Mitsunobu reactions have the structure (3), not the structure (2) as previously suggested. In line with our new findings, we suggest the mechanism shown in Scheme 1. References to studies on the structure of the initially formed betaine (1) have been given previously.' It can be seen from Scheme 1 that the overall stoichiometry of

* Part I, Aust. J. Chern., 1982, 35, 767. Guthrie, R. D., and Jenkins, I. D., Ausr. J. Chem., 1982, 35, 767.

M, von Itzstein and I. D. Jenkins

/OR P~,P 'OR

(3)

phjp=O

+

R-l

-

P~,P+-OR

I * / P~,P+-0-R

'V

(3)

Scheme 1

RoH

Scheme 2

-OR

Q-

t

Scheme 3

Mechanism of the Mitsunobu Reaction. I1

the reaction is: one mole of betaine (1) reacts with two moles of alcohol (ROH) to give one mole of dialkoxytriphenylphosphorane (3). Scheme 2 shows how these dialkoxyphosphoranes (3) can react further with HX (i.e. the general Mitsunobu reaction2) to give RX with the liberation of triphenylphosphine oxide. It should be noted that one mole of alcohol (ROH) is regenerated in this process, but provided the molar ratio of betaine (1) to alcohol (ROH) is 1 : 1 there will be sufficient betaine remaining for this regenerated ROH to be converted, through Schemes 1 and 2, into the required product RX. Scheme 3 shows how cyclic phosphoranes may be formed with suitable di01s''~ and illustrates how cyclic ethers: especially e p ~ x i d e sare , ~ readily formed from such intermediate phosphoranes. Where stereochemical features prohibit the formation of simple cyclic phosphoranes, polymeric (or cyclic oligomeric) phosphoranes are presumably formed and can undergo analogous epoxide formation as shown. Results and Discussion (a) Variation of the Alcohol Treatment of triphenylphosphine (1 mmol) in chloroform (2 ml) at O°C with diethyl azodicarboxylate (1 mmol) under nitrogen gave a clear, orange solution, the 31P n.m.r, spectrum of which had one major peak at +44.8 ppm corresponding to the betaine (1 ; R' = Et) and one minor peak at +29.7 corresponding to triphenylphosphine oxide as previously described.' Interestingly, the additional minor peak at approximately +20 ppm observed previously' was not detected if mixing was carried out at O°C, but it did appear if the reagents were mixed at room temperature or above. Addition of ethanol (1 mmol) to the cold betaine solution resulted in the appearance of a second major peak at - 53.8, corresponding to the phosphorane (3 ; R = Et). Most importantly, the peak corresponding to the betaine was still present, and the relative intensities of the two peaks was approximately 1 : 1. This result is clearly not consistent with the phosphorane structures (2) or (4) as 1 equiv, of ethanol would consume all of the betaine (I), not just 50 %. The stoichiometry of the reaction is correct for the formation of the phosphorane (3; R = Et), and moreover the 31P n.m.r. chemical shift observed is almost identical to the literature6 value (-54 in dichloromethane; we obtained - 53.5 in this solvent). Similar results were obtained in tetrahydrofuran as solvent, and in this case the chemical shift of the phosphorane (3; R = Et) was - 54.8. We have found that the chemical shift of phosphoranes (3) varies slightly with the solvent (Table l), but that there is very little variation with temperature. We have carried out analogous reactions with a range of primary alcohols (Table I), and in every case the stoichiometry was the same. A second equivalent of alcohol was always required for complete consumption of the betaine (1). The formation of phosphoranes (3; R = CH,RV) was instantaneous at 0-10". Mitsunobu, O., Synthesis, 1981, 1. Guthrie, R. D., von Itzstein, M., and Jenkins, I. D., unpublished data. Carlock, J. T., and Mack, M. P., Tetrahedron Lett., 1978, 5153. Guthrie, R. D., Jenkins, I. D., Yamasaki, R., Skelton, B. W., and White, A. H., J. Chem. Soc., Pevkin Trans. 1, 1981, 2328. Denney, D. B., Denney, D. Z., Chang, B. C . , and Marsi, K. L., J. Am. Chem. Soc., 1969,91,5243.

M. von Itzstein and I. D. Jenkins

Secondary alcohols react far more sluggishly (approximately 30 inin at room temperature for complete reaction) with the betaine (1) than do primary alcohols, and in general the phosphoranes formed are less stable, decomposing rapidly at room temperature to give triphenylphosphine oxide, presumably as a result of an E 2 elimination.' Thus, treatment of the betaine (1; R' = Et) with propan-2-01 in chloroform at O°C showed no phosphorane formation. Only two peaks were present, at + 44.8 corresponding to the betaine and at + 29.7 corresponding to triphenylphosphine oxide (ratio 1 : 2 respectively). The fact that the phosphine oxide peak was the major peak suggests that the phosphorane (3; R = CHMe,) was formed, but that it decomposed at a rate comparable to or greater than its rate of formation. Table 1. 31P n.m.r. chemical shifts of phosphoranes Ph3P(OR)2 in chloroform, tetrahydrofuran (thf) and dichloromethane Negative chemical shifts are in ppm upfield of 85 % phosphoric acid as external standard --

R

CHC13

thf

Me Et Pr Bu CH2(CH2)6Me

-50.2 -53.8 -55.3 -55.2 -55.0

-52.1 -54.8 -55.9 -55.6 -55.6

-

CH2C12 -53.5

R

CHClB

thf

CH2C12

CH2CF3 CHMez CHMeEt menthyl (7)

-58.4

-57.6 -49.6 -49.7 -56.9 -55.0

-57.5

-54.2

After the solution had been standing at room temperature for 1 h, the ratio of peaks changed to 1 : 3 respectively. As we had shown previously' that some phosphoranes are more stable in tetrahydrofuran than in chloroform, we repeated the reaction with an excess of propan-2-01 (2.5 equiv.) in tetrahydrofuran. When the spectrum was recorded at 10°C three major peaks were observed at +44.7 corresponding to the betaine (1; R' = Et), at f 25.3 corresponding to triphenylphosphine oxide, and at -49.6 corresponding to the phosphorane (3; R = CHMe,). In addition, there was a minor peak at -52.4 which we assign to the mixed phosphorane (5; R = Et, R' = CHMe,). The ethanol could be formed by ester exchange with the betaine (1; R' = Et) or by rearrangement of the phosphorane (2; R = CHMe,, ~ the betaine R' = Et). Betaine-catalysed ester exchange has been r e p ~ r t e d . When (1 ; R' = Et) was replaced by the betaine (1 ; R' = CHMe,), only the phosphorane peak at -49.6 was observed. This ethanol-exchange phenomenon giving rise to additional peaks in the 31P n.m.r. spectra plagued some of our early work, but it can easily be overcome by using diisopropyl or di-t-butyl azodicarboxylates instead of the diethyl compound. Similar results were obtained with butan-2-01 and with menthol, phosphorane formation being observed in tetrahydrofuran, but not in chloroform. With the tertiary alcohols 2-methylpropan-2-01 and adamantan-1-01, no phosphorane formation was observed in either solvent. By contrast, the secondary alcohol (6) upon treatment with the betaine (1 ; R' = Et) in chloroform or tetrahydrofuran gave rise to a stable (for at least half a day at room Loibner, H., and Zbiral, E., Helv. Chim. Acfa, 1977, 60, 417. Bittner, S., Barneis, Z., and Felix, S., Tetrahedron Lett., 1975, 3871.


561

temperature) phosphorane (3; R = (7)). The reason for the stability in this case is that S,2 attack at C 3 is extremely difficult for steric and electronic reasons:"0 and the bicyclic ring system makes adoption of an antiperiplanar arrangement between 0 3 and H 4 most unlikely, thereby precluding an E 2 elimination. Once again, the ratio of betaine to phosphorane was approximately 1 : 1 and addition of a second equivalent of (6) caused complete disappearance of betaine signal. By contrast to the stability of (3; R = (7)), the phosphorane (3; R = CH,(CH,),Me) was 80% decomposed after it had been standing at room temperature for 15 min.

(b) Variation of the Azodicarboxylate Although the 1 : 2 stoichiometry of the reaction provides very good evidence for the formation of dialkoxytriphenylphosphoranes, we sought evidence to exclude phosphoranes of the type (2). It was argued that if phosphoranes of type (2) were present, variation of R' (i.e. the azodicarboxylate) should affect the 31Pchemical shift. On the other hand, if the phosphoranes have the structure (3), there should be no change in the ,'P n.m.r. chemical shifts. We have used three azodicarboxylates (R' = Et, CHMe,, CMe,) with triphenylphosphine and the alcohol (6) and in each case, the high-field (phosphorane) peak had an identical chemical shift (-54.2), while the low-field (betaine (I)) peak was different in each case (R' = Et, 44.9; R' = CHMe,, 44.2; R' = CMe,, 42.6). It would be fortuitous if the 31P n.m.r. chemical shift of the betaine (1) were to vary with the ester R' group while the shift of the phosphorane (2) remained invariant. The most likely explanation for the invariance of the phosphorane chemical shift with changes in R' is that the structure does not involve the azodicarboxylate, thus lending further support to the structure (3). Similar results were obtained with the primary alcohols octan-1-01 and 2,2,2-triAuoroethanol. In both cases the phosphorane chemical shifts (- 55.0 and -58.4 respectively) were independent of the azodicarboxylate used. Interestingly, the chemical shift for the phosphorane (3; R = CH,CF,) is quite different from the literature value." We have synthesized (3; R = CH,CF,) by an independent route, by treatment of triphenylphosphine dibromide with 2,2,2-trifluoroethanol in the presence of triethylamine and obtained the same chemical shift (- 58.4), thus casting some doubt on the literature value of -70.3. However, a more recent report12 gives a value of - 58.5 for this phosphorane, in agreement with the present work. Kunz, H., and Schmidt, P., Z . Naturforsch., Teil B, 1978, 33, 1009. Tipson, R. S., Adfi. Carbohydr. Chem., 1953, 8, 107; Ball, D. H., and Parrish, F. W., Adv. Carbohydr. Chem., 1969, 24, 139. l 1 Kubota, T., Miyashita, S., Kitazume, T., and Ishikawa, N., J. Org. Chem., 1980, 45, 5052. l 2 Denney, D. R., Denney, D. Z., Hammond, P. J., and Wang, Y., J. Am. Chem. Soc., 1981,103,1785. lo

M. von Itzstein and I. D. Jenkins

(c) Mixed Phosphoranes A third line of evidence that distinguishes unequivocally between the alternative phosphorane structures (2) and (3) was provided by experiments employing mixtures of alcohols. If the phosphoranes formed have the structure (2), then a mixture of two alcohols should give rise to only two phosphorane peaks in the 31P n.m.r. spectrum. If, on the other hand, the phosphoranes have the structure (3), then a mixture of two different alcohols should give rise to three phosphoranes, one of which is the mixed phosphorane (5). Treatment of triphenylphosphine and diethyl azodicarboxylate with an equimolar mixture of ethanol and propan-1-01 in chloroform at 0°C gave a clear yellow solution whose 31P n.m.r. spectrum showed three phosphorane peaks, at - 53 * 8, - 54.5 and -55.3 in the approximate ratio of 1 : 2 : 1. These correspond to the phosphoranes (3; R = Et), (5; R = Et, R' = Pr) and (3; R = Pr), respectively. Exactly the same result was obtained if the two phosphoranes (3; R = Et) and (3; R = Pr) were prepared separately and the two solutions mixed, confirming6,l2a rapid ligandexchange reaction between alkoxy groups at phosphorus and lending support to the equilibrium between phosphorane and alkoxyphosphonium salt shown in Scheme 1. The fact that discrete signals are obtained for these mixed phosphoranes shows, however, that the rate of exchange, although very fast at O0C, is slow on the 3 1 n.m.r. time scale. Analogous results were obtained with a mixture of ethanol and butan-1-01, and with ethanol and octan-1-01. As expected, the use of a mixture of three alcohols (ethanol, propan-1-01 and 2,2,2-trichloroethanol) gave rise to six phosphorane peaks in the 31P n.m.r. spectrum, corresponding to the three symmetrical phosphoranes of type (3) and the three possible mixed phosphoranes of type (5). The 31P n.m.r. chemical shifts of these mixed phosphoranes are shown in Table 2. To the best of our knowledge, such mixed acyclic phosphoranes have not previously been observed by 31P n.m.r. spectroscopy. Not unexpectedly, the chemical shifts of the mixed phosphoranes Ph3P(OR)(OR1)fall between those of the two symmetrical phosphoranes Ph3P(OR), and Ph,P(OR1), in all cases. Table 2. 31Pn.m.r. chemical shifts of phosphoranes PhjP(OR)(OR') in chloroform Negative chemical shifts are in ppm upfield of 85 % phosphoric acid as external standard

Me Et Et A

Et Pr BU

-51.9 -54.5 -54.4

Et Et Et

CH2(CH&Me CH2CCI3 CHZCF,

-54.3 -56.2 -54.gB

Et Pr

CHMe, CH2CC13

-52.3A -56.7

In CH2C1,. In tetrahydrofuran.

We had hoped initially that using wholly and partially proton-coupled spectra we might be able to distinguish between the phosphorane structures (2) and (3), but all attempts to obtain coupling information proved unsuccessful. This is presumably a result of the rapid intramolecular ligand exchange (pseudorotation) that is occurring at room temperature.12 Isolation of these phosphoranes was not attempted due to the extreme sensitivity of these compounds to moisture.

~


Conclusion

The stoichiometry of the reaction, the values of the 31P n.m.r. chemical shifts and their lack of dependence on the dialkyl azodicarboxylate used, and the formation of mixed phosphoranes, all provide very strong evidence for the formation of dialkoxytriphenylphosphoranes during Mitsunobu reactions with primary and secondary alcohols. This result brings together two important areas of research that were formerly considered to be quite separate and to involve different mechanisms: the use of diethyl azodicarboxylate and triphenylphosphine in synthesis (the Mitsunobu reaction),' and the use of phosphoranes in syi~thesis.~'"~ The formation of symmetrical dialkoxyphosphoranes also provides a simple explanation for the racemization that occurs at phosphorus when a chiral phosphine is employed in the Mitsunobu reaction.14 Experimental All solvents were dried prior to use. 31P n.m.r. spectra were recorded at 121.44 MHz with a Bruker CXP-300 instrument. Solutions (all 0 . 5 M) were made up at O°C under nitrogen immediately prior to recording the spectra.

Acknowledgments

We thank Professor R. D. Guthrie for useful discussions. This work was supported in part by the Australian Research Grants Scheme. We acknowledge the award of a ~ data were Griffith University Postgraduate Scholarship to M.v.1. The 3 1 n.m.r. recorded at the Brisbane N.M.R. Centre, Griffith University.

Manuscript received 29 October 1982

Burger, K., in 'Organophosphorus Reagents in Organic Synthesis' (Ed. J. I. G. Cadogan) Ch. 11 (Academic Press: New York 1979). l4 Heesing, A., and Steinkamp, H., Chem. Bev., 1982, 115, 2854.

l3