Dichotomous reactivity in the reaction of triethyl- and triphenylphosphane HBr salts with dimethyl acetals: A novel entry to α-alkoxy-functionalized ylides and general synthesis of vinyl ethers and alkoxy dienes

Article abstract of DOI:10.1002/ejoc.201000601

The discovery of dichotomous reactivity in the reaction of trialkyl- vs. triphenylphosphane HBr salts with acetals allows entry to functionalized α-methoxy phosphonium salts and a novel process for tertiary phosphane methylation. The new protocol opens a general entry to the synthesis of vinyl ethers and differentially substituted 1,3-dienes via Wittig reactions of the functionalized ylides derived from the α-methoxy phosphonium salts.

Full text of DOI:10.1002/ejoc.201000601

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000601
Dichotomous Reactivity in the Reaction of Triethyl- and Triphenylphosphane
HBr Salts with Dimethyl Acetals: A Novel Entry to α-Alkoxy-Functionalized
Ylides and General Synthesis of Vinyl Ethers and Alkoxy Dienes
Priyabrata Das[a] and James McNulty*[a]
Keywords: Alkenes / Wittig reactions / Enol ethers / Acetals
The discovery of dichotomous reactivity in the reaction of
trialkyl- vs. triphenylphosphane HBr salts with acetals allows
entry to functionalized α-methoxy phosphonium salts and a
novel process for tertiary phosphane methylation. The new
protocol opens a general entry to the synthesis of vinyl ethers
and differentially substituted 1,3-dienes via Wittig reactions
of the functionalized ylides derived from the α-methoxy
phosphonium salts.
Enol ethers (A, Figure 1) and alkoxy-functionalized 1,3- duction.[3i] A direct Wittig-type entry toward the synthesis
dienes (B and C, Figure 1) play significant roles in synthetic of functionalized vinyl ethers using simple α-alkoxy-func-
organic chemistry as components in a variety of cyclo- tionalized ylides E derived from phosphonium salts D (RЈ
addition and other reactions.[1] In addition, enol ethers are = alkyl, aryl) appears attractive, given the potential applica-
occasionally found as constituent functional groups in bio- tions that can be envisioned (Figure 1, equations i and ii).
active natural products and analogs.[2] The classic approach Such a Wittig-type process has been realized in only limited
to vinyl ether synthesis involved thermolysis and alcohol cases. The use of ylides E derived from methoxymethyl
elimination from dialkyl ketals. Although of limited scope, phosphonium salts E (RЈ = H), prepared from the reaction
a range of milder variants have been developed for this pro- of a tertiary phosphane with chloromethyl methyl ether has
cess.[3a–3e]
been most often employed to prepare terminal methyl vinyl
ethers and homologous aldehydes through their hydroly-
sis.[4]
The synthesis of α-alkoxy phosphonates and phospho-
nium salts has also been achieved from the reactions of α-
halo ethers such as 2-chlorofuran and 2-chloropyran with
a phosphite or triphenylphosphane respectively,[4d,4e] and
also via strong acid promoted addition of triphenylphos-
phane to tetrahydropyran and ethyl vinyl ether.[4f,4g] A ge-
neral preparation of α-alkoxy phosphonium salts of type D
from the reaction of dimethyl acetals has not been reported.
In this paper we report on the remarkable dichotomous re-
activity of triphenylphosphane and triethylphosphane hy-
drobromide salts in their reactions with dimethyl acetals.
Triphenylphosphane hydrobromide was found to react with
dimethyl acetals, but the reaction proceeds to give the corre-
sponding quaternary methyl(triphenyl) phosphonium salt
(Figure 2). Remarkably, the reaction of triethylphosphane
hydrobromide with dimethyl acetals was found to give the
corresponding α-methoxy phosphonium salt. This new pro-
cess is shown to be general allowing the synthesis of a range
of α-methoxy functionalized phosphonium salts in high
yield, under mild conditions. We also report the Wittig ole-
fination of a range of examples with various aldehydes –
see Figure 1, reactions i) and ii) – and the synthesis of struc-
turally diverse enol ethers and alkoxy-substituted 1,3-
dienes.
Figure 1. Synthesis and reactivity of α-alkoxy phosphonium salts.
Other general methods for vinyl ether synthesis include
the Tebbe ester olefination reaction,[3f] metathesis reac-
tions,[3g] Peterson olefination with α-alkoxysilanes,[3h] and
the Greene method involving α-alkoxyphosphonate re-
[a] Department of Chemistry and Chemical Biology, McMaster
University,
1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada
Fax: +1-905-522 2509
E-mail: jmcnult@mcmaster.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000601.
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P. Das, J. McNulty
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Figure 2. Dichotomous reactivity of dimethyl acetals with tri-
phenyl- vs. triethylphosphane hydrobromide.
We have recently been exploring Wittig[5] reactions of
trialkylphosphane-derived semi-stabilized ylides, prepared
from allylic or benzylic alcohols or halides.[6] The reaction
of a benzylic or allylic alcohol with anhydrous triethylphos-
phane hydrobromide was shown to proceed thermally to
give the necessary phosphonium salt in high yields. In view
of the problems and limitations described in the literature
on the preparation and reactivity of α-alkoxy phosphonium
salts,[4d,4e,4f,4g] we decided to explore a potential synthesis
of α-alkoxy phosphonium salts from the reaction of trieth-
ylphosphane hydrobromide with a dimethyl acetal.
The reaction of benzaldehyde dimethyl acetal 1a with tri-
ethylphosphane hydrobromide in a 1:1 ratio was found to
proceed thermally, without solvent at 80 °C and was com-
plete in under one hour. The product was determined to be
the α-methoxy phosphonium salt 2a. In contrast, the reac-
tion of triphenylphosphane hydrobromide with 1a, under
identical conditions, yielded triphenyl(methyl)phosphonium
bromide in essentially quantitative yield, a result we will
return to momentarily. The successful synthesis of this ini-
tial α-methoxy phosphonium salt 2a prompted us to ex-
plore the generality of the reaction of various dimethyl ace-
tals with triethylphosphane hydrobromide. The reaction
was found to proceed in identical fashion with all dimethyl
acetals so far investigated providing access to the desired α-
methoxy phosphonium salts in high yield. The synthesis of
a selection of such salts, prepared from dimethyl acetals de-
rived from aromatic aldehydes and α,β-unsaturated alde-
Scheme 1. Synthesis of α-methoxy phosphonium salts via direct
thermolysis of dimethyl acetals with Et3P·HBr.
hydes, is summarized in Scheme 1. The reaction requires an- relatively stable. Efficient olefination occurred in all cases
hydrous conditions as both starting dimethyl acetals and upon addition of anisaldehyde and the corresponding vinyl
resulting α-methoxy phosphonium salts are water-sensitive. ethers were purified by silica gel chromatography. The vinyl
The α-alkoxy phosphonium salts 2a–2h were isolated with- ethers 4 were isolated in 90–95% yields and with moderate
out need of chromatographic purification through simply to good (E)-configurational selectivity. Notably, this places
removing methanol under high vacuum. Tripropylphos- the two aryl rings in a “cis” relationship as is found in the
phane and tributylphosphane hydrobromide salts reacted combretastatin series of anticancer stilbenes, a derivative of
likewise with benzaldehyde dimethyl acetal producing the which is currently in human clinical trials.[7] The overall
corresponding α-methoxyphosphonium salts.
process described above (α-methoxyphosphonium salt syn-
We next investigated α-methoxy ylide formation and ole- thesis, ylide formation and olefination) proceeded smoothly.
fination of the range of substituted phosphonium salts 2a The reactivity of α-alkoxy ylides prepared from vinyl ethers
to 2h in reaction with one equivalent of the aromatic alde- and equivalents has been reported to be problematic,
hyde anisaldehyde (Scheme 2). Dark red solutions of the with ylide decomposition and low yields of vinyl ethers ob-
ylides were generated in THF at 0 °C using lithium bistri- tained.[4d,4e,4f] These problems have usually been circum-
methylsilylazide (LHMDS, Scheme 2) and appeared to be vented by switching to Horner phosphonate chemis-
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General Synthesis of Vinyl Ethers and Alkoxy Dienes
try.[4d–4g,8] Triethylphosphane HBr is only mildly acidic sponding functionalized 2-methoxy-1,3-butadienes. Overall,
(pKa = 8.69) and appears to provide the ideal chemoselec- the results shown in Schemes 2 and 3 indicate that all com-
tivity required for the success of this Wittig approach.
binations of the general reactivity outlined in Figure 1 (see
equations i and ii) are possible and the synthesis of a wide
range of vinyl ethers and functionalized 1,3-butadienes can
be contemplated using this method.
Scheme 3. Olefination reactions of the ylide from α-methoxyphenyl
phosphonium bromide with various aldehydes.
Scheme 2. Olefination reactions of α-methoxy phosphonium salts
with anisaldehyde.
In returning to the unprecedented dichotomous chemo-
We next investigated the scope of the Wittig reactions of selectivity outlined in Figure 2, it was of interest to investi-
the ylide derived from α-methoxyphenyl-triethyl phospho- gate the scope of this unusual process. Trialkyl(methyl)-
nium bromide 2a with a range of aldehydes 3a to 3i, sum- phosphonium salts are frequently used as phase-transfer
marized in Scheme 3. In all cases, the methoxy vinyl ethers catalysts and are components of commercial ionic liquids.[9]
4a to 4i were isolated by silica gel chromatography in yields In addition, they are employed in industrial processes such
of 75 to 95% with moderate to high (E)-stereocontrol. The as the Monsanto acetic acid process and Eastman acetic
reaction was successful with electron rich and electron de- anhydride process, both of which involve the carbonylation
ficient aromatic aldehydes, as well as an enolizable aliphatic of methanol.[10] Their synthesis generally involves quat-
aldehyde (entry 9). The success of the reaction with the α,β- ernization of a tertiary phosphane with toxic and reactive
unsaturated aldehyde (E)-cinnamaldehyde (Scheme 3, entry methylating agents such as iodomethane, methyl tosylate or
4) allows entry to functionalized 1-methoxy-1,3-butadienes. dimethyl sulfate. We decided to investigate this dichotomy
In contrast, the use of the α-methoxy ylide derived from further and now report a remarkably simple green approach
(E)-cinnamaldehyde in reaction with an aldehyde towards the methylation of tertiary phosphanes that em-
(Scheme 2, entries 6 and 7) provides access to the corre- ploys only trimethyl orthoformate as the electrophilic meth-
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P. Das, J. McNulty
SHORT COMMUNICATION
ylating agent. Protonation and loss of methanol from the
dimethyl acetal is expected to generate the oxonium cation
shown (i), Figure 3.
Figure 3. Dichotomous reactivity of Et3P and Ph3P with oxonium
intermediates i and ii.
The dichotomy observed in the phosphane alkykylation
is very clear cut. Triphenylphosphane attacks the methyl
group rather than forming the α-alkoxy phosphonium salt,
a result that can be ralionalized in view of both steric con-
siderations and the soft nature of the nucleophile/electro-
phile. Conversely, the strongly nucleophilic triethylphos-
phane directly attacks the cationic site producing the alkoxy
phosphonium salt. Triphenylphosphane hydrobromide was
found to react with any dimethyl acetal, yielding the P-
methyl phosphonium salt. These results prompted us to in-
vestigate the reaction with trimethyl orthoformate, which
would be expected to generate the softer bis-methoxy-
substituted oxonium ion shown (ii). Reaction with tri-
phenylphosphane hydrobromide and triethylphosphane hy-
drobromide both now generated the corresponding P-
methyl phosphonium salts, with no α-alkoxy salts being ob-
served. It appears that either the reversibility of the α-alk-
oxy phosphonium salt formation with cation (ii) or de-
creased hard nature of the cation, in conjunction with steric
effects, direct alkylation to the methyl termini rather than
central cation. Interestingly, triphenylphosphane hydrobro-
mide did not enter into reaction with triisopropyl orthofor-
mate under the same conditions, indicating that the reaction
is in fact subject to a considerable steric effect. The present
P-methylation appears to be restricted to methoxy contain-
ing acetals. In view of the importance of trialkylmethyl and
triarylmethyl phosphonium salts described above, we inves-
tigated the generality of this reaction and now report that
any tertiary phosphane hydrobromide salt can be readily
methylated in this fashion to yield the desired quaternary
salt, summarized in Scheme 4. Increasing the steric de-
mands around the tertiary phosphane had no impact on
the course of the methylation (from ii) as even tri-tert-butyl-
phosphane (entry 5) and the hindered cyclic phosphorinane
(entry 6) HBr salts reacted to deliver the P-methyl quater-
nary salt in very high yield. This general method for P-
methylation using inexpensive, readily available trimethyl
orthoformate is a very attractive alternative to the use of
toxic, methylating agents (CH3I, DMS etc), alkylating
agents that are the subject of strict regulations in many ju-
risdictions.
Scheme 4. Quaternization reactions of tertiary phosphane hydro-
bromide salts using trimethyl orthoformate as electrophilic methyl-
ating agent.
Ylide formation/olefination reactions from the α-methoxy
phosphonium salts so formed allowed for the synthesis of
a wide range of vinyl ethers and variously functionalized
1,3-dienes. These studies led to the discovery of a novel,
general P-methylation process for the production of useful
quaternary phosphonium salts that avoids the use of toxic,
regulated alkylating agents. Further investigations into the
preparation and reactivity of these salts and applications
of the vinyl ether products are under investigation in our
laboratory.
Supporting Information (see also the footnote on the first page of
this article): General experimental details, synthetic protocols for
acetal formation, α-alkoxy phosphonium salt formation and Wittig
reactions and characterization of the salts, enol ether and 1,3-diene
products reported in the tables.
Acknowledgments
We thank Natural Sciences and Engineering Research Council of
Canada (NSERC) and Cytec Canada Inc. for financial support of
this work.
[1] a) P. De Mayo, Acc. Chem. Res. 1971, 4, 41–47; b) S. J. Danish-
efsky, Acc. Chem. Res. 1981, 14, 400–406; c) D. P. Curran,
D. H. Singeleton, Tetrahedron Lett. 1983, 24, 2079–2082; d) F.
Effenberger, K. H. Schonwalder, Chem. Ber. 1984, 117, 3270–
3279; e) S. Kobayashi, K. A. Jorgensen, Cycloaddition Reac-
tions in: Organic Synthesis Wiley-VCH, Weinheim, Germany,
2002; f) S. E. Denmark, V. Guagnano, J. A. Dixon, A. Stolle,
J. Org. Chem. 1997, 62, 4610–4628; g) A. Deagostino, C.
Prandi, C. Zavattaro, P. Venturello, Eur. J. Org. Chem. 2006,
2463–2483.
In conclusion, we have discovered the dichotomous reac-
tivity of triethylphosphane hydrobromide in its reaction
with dimethyl acetals as a general reaction leading to α-
methoxy phosphonium salts. In contrast, triphenylphos-
phane hydrobromide is methylated under these conditions.
3590
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General Synthesis of Vinyl Ethers and Alkoxy Dienes
[2] a) J. C. Liermann, H. Kolshorn, T. Opatz, E. Thines, H. Anke,
J. Nat. Prod. 2009, 72, 1905–1907; b) Y. Sun, L. Tian, J. Huang,
H. Y. Ma, Z. Zheng, A. L. Lv, K. Yasukawa, Y. H. Pei, Org.
Lett. 2008, 10, 393–396; c) W. E. Steinmetz, B. L. Shapiro, J. J.
Roberts, J. Med. Chem. 2002, 45, 4899–4902.
reochem. 1994, 21, 1–157; d) B. E. Maryanoff, A. B. Reitz,
Chem. Rev. 1989, 89, 863–927; e) K. C. Nicolau, M. W. Harter,
J. L. Gunzer, A. Nadin, Liebigs Ann./Recueil 1997, 1283–1301.
a) J. McNulty, P. Das, Eur. J. Org. Chem. 2009, 4031–4035; b)
J. McNulty, P. Das, Tetrahedron Lett. 2009, 50, 5737–5739; c)
J. McNulty, P. Das, D. McLeod, Chem. Eur. J., in press.
R. Siles, F. Ackley, M. B. Hadimani, J. J. Hall, B. E. Mugabe,
R. Guddneppanavar, K. A. Monk, J. C. Chapuis, G. R. Pettit,
D. J. Chaplin, K. Edvardsen, M. L. Trawick, C. M. Garner,
K. G. Pinney, J. Nat. Prod. 2008, 71, 313–320.
a) L. Horner, H. Hoffmann, H. G. Wippel, G. Klahre, Chem.
Ber. 1959, 92, 2499–2505; b) A. F. Kluge, Tetrahedron Lett.
1978, 39, 3629–3632; c) C. Earnshaw, C. J. Wallis, S. Warren,
J. Chem. Soc. Perkin Trans. 1 1979, 3099–3106.
a) B. Cornils, W. A. Herrmann, I. T. Horvath, W. Leintner, S.
Meckling, H. Olivier-Bourbigoi, D. Vogt, Multiphase Homoge-
nous Catalysis, vol. 1–2, Wiley-VCH, Weinheim, 2005; b) C. J.
Bradaric, A. Downard, C. Kennedy, A. J. Robertson, Y. Zhou,
Green Chem. 2003, 5, 143–152.
a) M. J. Howard, M. D. Jones, M. S. Roberts, S. A. Taylor, Ca-
tal. Today 1993, 18, 325–354; b) H. Erpenbach, R. Gradl, E.
Jagers, A. Seidel, N. Weferling, DE 4014073 A1, 1990; c) L.
Magna, H. Olivier-Bourbigou, S. Harry, D. Commereuc, US
Pat. 0059153 A1, 2004.
[6]
[7]
[3] a) M. Marsi, J. A. Gladysz, Organometallics 1982, 1, 1467–
1473; b) R. B. Miller, D. R. McKean, Tetrahedron Lett. 1982,
23, 323–326; c) P. G. Gassman, S. J. Burns, J. Org. Chem. 1988,
53, 5574–5576; d) A. R. Katritzky, S. I. Bayyuk, S. Rachwal,
Synthesis 1991, 279–283; e) G. Cabrera, R. Fiaschi, E. Napo-
liutano, Tetrahedron Lett. 2001, 42, 5867–5869; f) S. H. Pines,
Org. React. 1993, 43, 1–91; g) K. C. Nicolaou, M. H. D. Post-
ema, C. F. Claiborne, J. Am. Chem. Soc. 1996, 118, 1565–1566;
h) S. Kanemasa, J. Tanaka, H. Nagahama, O. Tsuge, Bull.
Chem. Soc. Jpn. 1985, 58, 3385–3386; i) F. Charbonnier, A.
Moyano, A. E. Greene, J. Org. Chem. 1987, 52, 2303–2306.
[4] a) S. G. Levine, J. Am. Chem. Soc. 1958, 80, 6150–6151; b) G.
Wittig, W. Boll, K. H. Kruck, Chem. Ber. 1962, 95, 2514–2525;
c) H. Schlude, Tetrahedron 1975, 31, 89–92; d) C. G. Kruse,
E. K. Poels, A. van der Gen, J. Org. Chem. 1979, 44, 2911–
2915; e) D. R. Coulson, Tetrahedron Lett. 1964, 5, 3323–3326;
f) S. V. Ley, B. Lygo, H. M. Organ, A. Wonnacott, Tetrahedron
1985, 41, 3825–3836; g) W. W. Epstein, M. Garrosian, Phospho-
rus Sulfur 1988, 35, 349–351.
[8]
[9]
[10]
[5] a) G. Wittig, G. Geissler, Justus Liebigs Ann. Chem. 1953, 580,
44–57; b) T. Takeda, Modern Carbonyl Olefination, Wiley-
VCH, Weinheim, 2004; c) E. Vedejs, M. J. Peterson, Top. Ste-
Received: April 29, 2010
Published Online: June 1, 2010
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