Novel one-pot three-component coupling reaction with trimethylsilylmethyl- phosphonate, acyl fluoride, and aldehyde through the horner-wadsworth-emmons reaction

Article abstract of DOI:10.1021/ol301879a

A novel three-component coupling between trimethylsilylmethylphosphonate, acyl fluoride, and aldehyde has been developed. A sequential nucleophilic addition of lithio-trimethylsilylmethylphosphonate to the acyl fluoride and Horner-Wadsworth-Emmons reaction of an aldehyde with the lithio-β- ketophosphonate generated in situ by desilylation at the α-position of the α-silyl-β-ketophosphonate by fluoride took place cleanly in a one-pot operation. Various E- and Z-enones were obtained in high yields with high stereoselectivities by this one-pot procedure.

Full text of DOI:10.1021/ol301879a

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4206–4209
Novel One-pot Three-component Coupling
Reaction with Trimethylsilylmethyl-
phosphonate, Acyl Fluoride, and
Aldehyde through the HornerÀ
WadsworthÀEmmons Reaction
Taiki Umezawa,* Tomoya Seino, and Fuyuhiko Matsuda
Division of Environmental Materials Science, Graduate School of Environmental
Science, Hokkaido University, Sapporo 060-0810, Japan
umezawa@ees.hokudai.ac.jp
Received July 9, 2012
ABSTRACT
A novel three-component coupling between trimethylsilylmethylphosphonate, acyl fluoride, and aldehyde has been developed. A sequential
nucleophilic addition of lithio-trimethylsilylmethylphosphonate to the acyl fluoride and HornerÀWadsworthÀEmmons reaction of an aldehyde
with the lithio-β-ketophosphonate generated in situ by desilylation at the R-position of the R-silyl-β-ketophosphonate by fluoride took place
cleanly in a one-pot operation. Various E- and Z-enones were obtained in high yields with high stereoselectivities by this one-pot procedure.
The HornerÀWadsworthÀEmmons reaction (HWE
reaction) is a reliable and powerful method for carbonÀ
carbon bond formation via coupling between a β-ketopho-
sphonate and an aldehyde, giving an R,β-unsaturated
compound with high stereoselectivity.1 The HWE reaction
has been broadly utilized for the synthesis of various
compounds including natural products. In general, the
β-ketophosphonate used as the HWE reaction precursor A is
synthesized from a readily accessible compound. Representa-
tive examples for the synthesis of A are shown in Scheme 1.
An aldehyde is often transformed into A in 2 steps through
addition of commercially available methylphosphonate,
(1) Review of HWE reaction: (a) Maryanoff, B. E.; Reitz, A. B.
Chem. Rev. 1989, 89, 863–927. (b) Boutagy, J.; Thomas, R. Chem. Rev.
1974, 74, 87–99.
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(2) (a) Traore, M.; Maynadier, M.; Souard, F.; Choisnard, L.; Vial,
H.; Wong, Y.-S. J. Org. Chem. 2011, 76, 1409–1417. (b) Nicolaou, K. C.;
Jiang, X.; Lindsay-Scott, P. J.; Corbu, A.; Yamashiro, S.; Bacconi, A.;
Fowler, V. M. Angew. Chem., Int. Ed. 2011, 50, 1139–1144. (c) Nicolaou,
K. C.; Aversa, R. J.; Jin, J.; Rivas, F. J. Am. Chem. Soc. 2010, 132, 6855–
6861. (d) Crimimins, M. T.; Zuccarello, J. L.; McDougall, P. J.; Ellis,
J. M. Chem.;Eur. J. 2009, 15, 9235–9244. (e) Sparling, B. A.; Simpson,
G. L.; Jamison, T. F. Tetrahedron 2009, 65, 3270–3280. (f) Frankowski,
(3) (a) Coppola, G. M. Synthesis 1988, 81–84. (b) Evans, M. A.;
Morken, J. P. Org. Lett. 2005, 7, 3371–3373. (c) Rodriquez, M.; Bruno,
I.; Cini, E.; Marchetti, M.; Taddei, M.; Gomez-Paloma, L. J. Org. Chem.
2006, 71, 103–107. (d) Milburn, R. R.; McRae, K.; Chan, J.; Tedrow, J.;
Larsen, R.; Faul, M. Tetrahedron Lett. 2009, 50, 870–872. (e) Nilson,
M. G.; Funk, R. L. Org. Lett. 2010, 12, 4912–4915.
(4) (a) Ezquerra, J.; Mendoza, J.; Pedregal, C.; Ramırez, C. Tetra-
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Chem. 2000, 65, 2163–2171. (c) Tchabanenko, K.; Chesworth, R.;
Parker, J. S.; Anand, N. K.; Russell, A. T.; Adlington, R. M.; Baldwin,
J. E. Tetrahedron Lett. 2005, 61, 11649–11656.
(5) (a) Balczewski, P.; Mikolajczyk, M. Org. Lett. 2000, 2, 1153–1155.
(b) Motoyoshiya, J.; Miyajima, M.; Hirakawa, K.; Kakurai, T. J. Org.
Chem. 1985, 50, 1326–1327. (c) Savignac, P.; Mathey, F. Tetrahedron
Lett. 1976, 17, 2829–2832.
130, 6018–6024. (g) Torihata, M.; Nakahara, T.; Kuwahara, S. Org.
Lett. 2007, 9, 2557–2559. (h) Fujiwara, K.; Aki, Y.; Yamamoto, F.;
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r
10.1021/ol301879a
Published on Web 07/31/2012
2012 American Chemical Society

followed by oxidation of the resultant alcohol (eq 1).2
Carboxylic acid derivatives, such as esters,3 imides,4
or acyl chlorides,5 are also employed as precursors by
addition of methylphosphonate (eq 2). The MichaelisÀ
Arbuzov reaction, that is, substitution of an R-halocar-
bonyl compound by a trialkyl phosphite, also affords A
(eq 3).6 However, these procedures sometimes encounter
problems in purification due to side products or the high
polarity of A.
Scheme 2. Proposed One-pot Reaction
Accordingly, we planned to develop the one-pot synthe-
sis of the R,β-unsaturated ketone through the formation
Scheme 1. Synthesis of β-Ketophosphonates
Table 1. Optimization of Reaction Conditions
entry
base
time (h)
X
Y
Z
yielda
1
2
3
4
5
6
7
n-BuLi
2
20
20
20
20
2
2.0
2.0
2.0
2.0
2.0
2.0
1.8
2.0
2.0
2.0
2.0
2.0
2.0
2.5
1.8
1.8
1.8
1.8
1.8
1.8
1.8
54%
57%
56%
76%
99%
80%
99%
of A accompanied by the instantaneous generation of its
enolateandsubsequentHWE reaction. Weenvisionedthat
the sequential reactions illustrated in Scheme 2 would be
suitable for this purpose. The R-silyl-β-ketophosphonate 4
would be formed by the nucleophilic substitution reaction
between the acyl fluoride 3 and the enolate 2 produced by
treatment of the trimethylsilylmethylphosphonate 1 with
a base. The acyl fluoride 3 can be obtained from the
corresponding carboxylic acid and (diethylamino)sulfur
trifluoride (DAST)7 with high purity by simple extraction
and is stable for several days. We expected that the fluoride
ion liberated during the substitution would induce the in
situ generation of the corresponding enolate 5 via desilyla-
tion at the R-position of 4.8 Subsequent addition of the
aldehyde 6 to the reaction mixture would afford the HWE
product 7. Herein, we would like to describe the novel one-
pot three-component coupling reaction.
n-BuLi
NaHMDS
KHMDS
LHMDS
LHMDS
LHMDS
20
a Isolated yield after column chromatography.
Table 1 summarizes the optimization of reaction condi-
tions using dimethyl trimethylsilylmethylphosphonate (1a),9
5-phenylvaleryl fluoride (3a), and benzaldehyde (6a).
At first, the reactions were carried out by employing 2.0
equiv (to 6a) of 1a, 2.0 equiv (to 6a) of the base, and 1.8
equiv (to 6a) of 3a. When n-BuLi or NaHMDS was used as
the base, the three-component coupling reaction pro-
ceeded successfully in one-pot to give the E-enone 7a in
54À57% yields with complete stereoselectivity (entries
1À3). The reaction with KHMDS improved the yield to
76% (entry 4). An almost quantitative yield of 7a was
obtained with LHMDS (entry 5). In the coupling reaction
with LHMDS, a shorter reaction time resulted in a de-
crease in the yield of 7a (entry 6). When the amount of
(6) (a) Taber, D. F.; Bai, S.; Guo, P. Tetrahedron Lett. 2008, 49, 6904–
6906. (b) Pietruszka, J.; Witt, A. Synthesis 2006, 4266–4268.
(7) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578. (b)
Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis 1973,
787–789.
(8) Desilylation from R-silylphosphonate or R-silylester by fluoride,
see: (a) Latouche, R.; Texier-Boullet, F.; Harnelin, J. Tetrahedron
Lett. 1991, 32, 1179–1182. (b) Kita, Y.; Sekihachi, J.; Hayashi, Y.; Da,
Y.-Z.; Yamamoto, M.; Akai, S. J. Org. Chem. 1990, 55, 1108–1112. (c)
Kawashima, T.; Ishii, T.; Inamoto, N. Bull. Chem. Soc. Jpn. 1987, 60,
1831–1837. (d) Kawashima, T.; Ishii, T.; Inamoto, N. Tetrahedron Lett.
1983, 24, 739–742.
(9) (a) Hamada, A.; Braunstein, P. Organometallics 2009, 28, 1688–
1696. (b) Aboujaoude, E. E.; Lietje, S.; Collignon, N. Synthesis 1986,
934–937.
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Org. Lett., Vol. 14, No. 16, 2012
4207

Table 2. One-pot Reaction with Various Substrates
a Isolated yield after column chromatography. b Stirred for 48 h. c LHMDS (2.0 equiv) was used. d Stirred for 48 h; 2.5 equiv each of 1b and 3a, and 3.0
equiv of n-BuLi as a base were used.
1a was reduced to 1.8 equiv (to 6a), 2.5 equiv (to 6a) of
LHMDS was necessary to obtain 7a with excellent yield
(entry 7). In stark contrast, the same reaction with the
anion generated from LHMDS and dimethyl methylpho-
sphonate [MeP(O)(OMe)2], 3a, and 6a did not take place
at all and any formation of 7a or the corresponding
β-ketophosphonate was not observed.10
As mentioned above, 7a was quantitatively derived from
6a with complete stereoselectivity under the optimized
conditions (Table 1, entry 7). Next, the scope of substrates
for the coupling reaction was examined.11 As shown in Table
2, a wide variety of aldehydes and acyl fluorides participated
in the one-pot procedure, providing the E-enones as the sole
stereoisomers in high yields. In the coupling reactions of 3a,
the aromatic aldehydes 6bÀf with electron-donating or
-withdrawing groups on the benzene ring afforded the
E-enones 7bÀf in high yields, although longer reaction times
were needed with the electron-donating aldehyde 6b and
sterically demanding aldehyde 6d (entries 1À5). The alkyl
aldehydes, octanal (6g) and 2,2-dimethylpropanal (6h), were
also converted into the E-enones 7g and 7h (entries 6, 7).
ꢀ
(10) Berte-Verrando, S.; Nief, F.; Patois, C.; Savignac, P. J. Chem.
Soc., Perkin Trans. 1 1994, 821–824.
(11) To a solution of 1a (35.3 mg, 0.180 mmol) in THF (1 mL) was
added LHMDS (1.0 M in THF, 250 μL, 0.250 mmol) at À78 °C under Ar
atmosphere. After 20 min, a solution of 3a (32.4 mg, 0.180 mmol) in
THF (0.5 mL) was added to the mixture. The mixture was warmed to
room temperature and stirred for 1 h, after which 6a (10.2 μL, 0.100
mmol) was added to the mixture. The mixture was stirred for 20 h,
quenched with saturated NaHCO3, extracted with AcOEt (Â3), washed
with brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatography (AcOEt/
Hexane = 1:99) to give 7a (26.0 mg, 0.0990 mmol, 99%) as colorless oil.
4208
Org. Lett., Vol. 14, No. 16, 2012

6f and 6g successfully occurred in a completely stereoselective
manner using n-BuLi as the base instead of LHMDS to yield
the trisubstituted E-enones 7o and 7p (entries 14, 15).
Table 3. Z-Selective One-pot Reaction
Z-R,β-Unsaturated ketones have often been constructed
in several steps (e.g., addition of acetylide to aldehyde,
partial reduction of triple bond to Z-olefin, and oxidation
of the resultant alcohol).13 For rapid access to this unit, the
Z-selective three-component coupling reaction was examined
according to the reports by Still14a and Ando.14b,c Among
the phosphonates and the bases tested, the combination of
bis(2,2,2-trifluoroethyl) trimethylsilylmethylphosphonate
(1c)15 and NaHMDS in the presence of TDA-116 afforded
the best selectivity (E:Z = 7:93) with 3a and 6f, giving the
Z-enone 7q in good yield (Table 3, entry 1).17 The acyl
fluoride 3b also reacted with 6f in high selectivity to afford
the Z-enone 7r (entry 2). The coupling reactions of the
alkyl aldehyde 6g with 3a and 3b gave the Z-enones 7s and
7t as the major stereoisomers (entries 3, 4).
yielda
(E:Z)b
entry
solvent
R1
R2
In summary, we have developed a novel three-component
coupling reaction with trimethylsilylmethylphosphonate,
acyl fluoride, and aldehyde. Nucleophilic substitution of
lithio-trimethylsilylmethylphosphonate with acyl fluoride
and subsequent HWE reaction of the aldehyde with the
lithio-β-ketophosphonate generated in situ through desilya-
tion of the R-silyl group of the R-silyl-β-ketophosphonate by
the fluoride ion proceeded smoothly in a one-pot operation.
Various substrates participated in the one-pot coupling
reaction to give E- or Z-enones stereoselectively in high
yields. To the best of our knowledge, the present reaction is
the first example of this type of one-pot coupling reaction.
This new synthetic method will allow rapid access to
R,β-unsaturated ketones with high stereoselectivities.
1
2
3
4
THF
THF
(CH2)4Ph (3a) p-CNC6H4 (6f) 84% (7:93)
(CH2)5OBn (3b) p-CNC6H4 (6f) 65% (16:84)
PhMe-HMPA (CH2)4Ph (3a) n-C7H15 (6g) 67% (25:75)
PhMe-HMPA (CH2)5OBn (3b) n-C7H15 (6g) 95% (37:63)
a Isolated yield of EZ mixture after column chromatograpohy.
b Ratio was determined by analysis of crude 1H NMR spectra.
Functional groups such as carbamate, epoxide, and PMB
ether were compatible with the one-pot reaction and the
highly functionalized E-enones 7i and 7j were obtained
(entries 8, 9). Various acyl fluorides were also good substrates
for the present reaction. Benzyl ether, acetate, and olefin
were tolerated to give the E-enones 7kÀm (entries 10À12).
Furthermore, the branched acyl fluoride 3e bearing a chiral
center at the R-position afforded the optically pure E-enone
7n without racemization (entry 13).12 Trisubstituted E-R,
β-unsaturated ketones were also readily accessed by the one-
pot procedure. Attempts to synthesize the trisubstituted
olefins were conducted with diethyl 1-trimethylsilylethylpho-
sphonate (1b).9b The three-component couplings of 3a with
Acknowledgment. This work was partially supported
by a Grant-in-Aid for Young Scientists (B) from the Japan
Society for the Promotion of Science (JSPS).
Supporting Information Available. Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra of
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Confirmation of optical purity of 7n, see Supporting Information.
(13) (a) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim, J. H.;
Genovino, J.; Maltas, P.; Moessner, C. Angew. Chem., Int. Ed. 2008, 47,
3021–3025. (b) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2008, 73, 3638–
3641. (c) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Louiseleur, O. Org.
Lett. 2005, 7, 4125–4128. (d) Stampfer, W.; Kosjek, B.; Faber, K.;
Kroutil, W. Tetrahedron Asymmetry 2003, 14, 275–280.
(14) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408. (b) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108. (c) Ando, K.
J. Syn. Org. Chem. Jpn. 2000, 58, 869–876.
(15) Preparation of 1c, see Supporting Information.
(16) Touchard, F. P. Tetrahedron Lett. 2004, 45, 5519–5523.
(17) Optimization for Z-selective HWE reaction, see Supporting
Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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