First general method for direct formylation of kinetically-generated ketone enolates

Article abstract of DOI:10.1021/ol990781c

(matrix presented) 2,2,2-Trifluoroethyl formate reacts rapidly at -78°C with preformed ketone enolates to give α-formyl ketones in good yields. In addition, this procedure allows for complete reversal of the regioselectivity of the classical Claisen react

Full text of DOI:10.1021/ol990781c

ORGANIC
LETTERS
1
999
Vol. 1, No. 7
89-991
First General Method for Direct
Formylation of Kinetically-Generated
Ketone Enolates†
9
Gregory H. Zayia
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
ghzayia@midway.uchicago.edu
Received July 2, 1999
ABSTRACT
2,2,2-Trifluoroethyl formate reacts rapidly at −78 °C with preformed ketone enolates to give r-formyl ketones in good yields. In addition, this
procedure allows for complete reversal of the regioselectivity of the classical Claisen reaction and provides a superior method for the r′-
formylation of r,â-unsaturated ketones.
R-Formyl ketones (hydroxymethylene ketones) are critically
important and versatile synthetic intermediates. Nonetheless,
gives a more stablized anion (e.g., γ-deprotonation of an R,â-
unsaturated ketone), and complete failure in the formylation
of tertiary R-carbons where the requisite salts cannot form.
R-Formylation under conditions of kinetic control would
overcome each of these limitations but has been heretofore
impracticable due in large part to the poor reactivity between
ketone enolates and typical formate esters (e.g., ethyl
formate). To date, formylation remains the only condensation
which has not yet been successfully applied to kinetically-
1
the method introduced by Ludwig Claisen in 1888 (i.e., base-
induced condensation of a ketone and a formate ester)
2
remains the only general method for their preparation. The
classic Claisen formylation reaction is always run under
equilibrating conditions and succeeds, ultimately, only
because the resonance-stabilized salt of the R-formyl ketone
product forms. The fact that success has always been
contingent on such thermodynamic control imposes several
serious limitations on the scope of the reaction including the
inability to use strong base (e.g., LDA) to stereoselectively
preform desired enolates of unsymmetrical ketones, poor
yields when deprotonation at a site other than an R-positon
3
generated ketone enolates.
We present herein the first general method for achieving
kinetic formylation of ketones, the success of which does
not depend on formation of a salt. The key is use of a very
reactive formate ester. 2,2,2-Trifluoroethyl formate (TFEF)
4
is a known, stable compound which can be easily prepared
†
Presented, in part, at the 216th National Meeting of the American
in about 67% yield from 2,2,2-trifluoroethanol and formic
Chemical Society in Boston, MA, on August 27, 1998 (paper ORGN 692).
acid, commercially available and inexpensive precursors.5
(
1) (a) As precursors to R-diazo ketones, see: Doyle, M. P.; McKervey,
We have found that TFEF reacts rapidly at -78 °C with
preformed ketone enolates to give R-formyl ketones in good
M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides; Wiley: New York, 1998; pp
1
1-14 and references therein. (b) As precursors to enol thioethers, enamino
6
yields. The enolates can be generated either directly from
ketones, enol ethers, R-formyl-R,â-unsaturated ketones, R-methylene
ketones, and hydroxymethyl ketones, see: Davis, B. R.; Garratt, P. J. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 837-838 and references
therein.
(3) Successful condensations include esterifications (Mander, L. N.; Sethi,
S. P. Tetrahedron Lett. 1983, 24, 5425-5428), acylations (Howard, A. S.;
Meerholz, C. A.; Michael, J. P. Tetrahedron Lett. 1979, 1339-1340), and
trifluoroacetylations (Danheiser, R. L.; Miller, R. F.; Brisbois, R. G. Org.
Synth. 1995, 73, 134-143).
(
2) For reviews, see: (a) Hauser, C. R.; Swamer, F. W.; Adams, J. T.
Org. React. 1954, 8, 59-196. (b) House, H. O. Modern Synthetic Reactions,
nd ed.; Benjamin: Menlo Park, 1972; Chapter 11.
2
(4) Blackburn, G. M.; Dodds, H. L. H. J. Chem. Soc. B 1971, 826-831.
1
0.1021/ol990781c CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/08/1999

the ketones using LDA or indirectly from silyl enol ethers
using methyllithium.
75% yield using the new method, essentially no reaction
occurred (<4%) when either ethyl formate or 4-nitrophenyl
formate was used as the electrophile under otherwise identical
conditions. When hexafluoroisopropyl formate was used in
place of TFEF, a complicated mixture resulted, but the
desired 2a was not among the many compounds formed.
The R-formyl ketone products in entries 1-6 are acidic
All major types of ketones have been examined (Table
7
1
); the reaction is quite general. The yields given in the
Table 1. R-Formylation of Kinetically-Generated Ketone
Enolates with 2,2,2-Trifluoroethyl Formate.
enough (pK
a
∼10) to protonate starting enolate essentially
irreversibly under the kinetic conditions employed. However,
an excess of base is not required. To account for this, we
believe that the rate of formation of the initial tetrahedral
intermediates is faster than the rate of their subsequent
collapse; as a result, the acidic proton of a product is not
revealed until all (or most) of the enolate has already been
consumed.
The R′-formylation of R,â-unsaturated ketones using
classical Claisen methodology is generally a difficult, low-
yielding affair. Few examples are documented, and even
2a
fewer are satisfactory. Thermodynamically favored γ-depro-
tonation probably confuses the issue. However, because the
R′-carbon is the kinetically-favored site of deprotonation,9
our methodology using kinetically-generated enolates pro-
vides an attractive solution to this problem. Thus, formylation
of 3-methyl-2-cyclohexen-1-one (entry 6) gave R-formyl
ketone 2f in 83% isolated yield, whereas the classical method
7
f
gave this product in only about 35% yield.
Using our method, it is possible to completely reverse the
regioselectivity of the classical Claisen and attach a formyl
(6) Representative Experimental Procedure: Synthesis of hydroxym-
ethylenemethyl 1-adamantyl ketone (2b). A solution of n-BuLi in hexanes
(
3.88 mL, 1.60 M, 6.21 mmol) was cooled to -40 °C in a 100-mL, three-
necked, round-bottomed flask equipped with a stir bar, N2 inlet, and septum.
Ether (7.3 mL) was added followed by the dropwise addition of diisopro-
pylamine (0.870 mL, 6.21 mmol). After 15 min, the solution was cooled to
-
78 °C. A solution of 1b (Aldrich, 99%, 1.00 g, 5.62 mmol) in ether (6
mL) was added dropwise over ca. 4 min. The solution was stirred at -78
C for an additional 45 min. Neat TFEF (3.22 mL, 33.7 mmol) was added
°
rapidly (ca. 2 s), and the mixture was stirred at -78 °C for 2 h. Neat
H2SO4 (1.10 g, 11.2 mmol) was added at -78 °C in 1 portion. The mixture
was transferred to a separatory funnel with ether (20 mL) and water (20
mL). The layers were separated, and the aqueous phase was extracted with
ether (1 × 20 mL). The combined organic extract was washed with saturated
aqueous NH4Cl (1 × 25 mL), dried (MgSO4), and concentrated in vacuo.
The residual yellow oil was dissolved in ether (50 mL) and extracted with
a
2
e rapidly trimerizes to give 1,3,5-tribenzoylbenzene and is isolated in
b
comparable yields of 40-50% using classical methodology. Yield also
includes LiAlH4 reduction of the crude as the resultant diols were more
easily purified.
1
% aqueous NaOH (6 × 10 mL). The yellow extract was kept cold in an
ice/water bath. The cooled extract was acidifed to pH ) 1 by dropwise
addition of 10% hydrochloric acid and then extracted with CH2Cl2 (5 × 20
mL). The combined organic extract was dried (MgSO4) and concentrated
in vacuo to furnish 2b as a yellow, sweet-smelling oil (871 mg, 75%), a
table are of pure products obtained after appropriate
purificationseither extraction into dilute aqueous base
1
1
8
mixture of enol (93%) and keto (7%) isomers by H NMR: H NMR (400
(entries 1-6) or silica gel chromatography (entry 7).
MHz, CDCl3, TMS, enol) δ 15.02 (bs, 1H, CdCOH), 8.13 (d, J ) 4.4 Hz,
Typically, a 6-fold excess of TFEF was employed to
achieve high conversions, although this is probably more than
necessary.
To put the reactivity of TFEF into a useful perspective,
we note that while cyclododecanone (1a) was formylated in
1H, CdCHsOH), 5.63 (d, J ) 4.4 Hz, 1H, HCdCOH), 2.05 (m, 3H, CH),
1
1
.83-1.68 (m, 12H, CH2); H NMR (keto) δ 9.77 (t, J ) 2.8 Hz, 1H,
HCdO), 3.56 (d, J ) 2.8 Hz, 2H, CH2sCHdO), highfield absorptions
13
same as for enol; C NMR (100.6 MHz, CDCl3, enol) δ 203.9 (CdO),
178.5 (CHdCOH), 97.6 (CHdCOH), 42.0, 38.8, 36.6, 28.1.
(7) All products are known compounds. (a) 2a: Wilson, S. R.; Misra,
R. N.; Georgiadis, G. M. J. Org. Chem. 1980, 45, 2460-2468. (b) 2b:
Fisnerova, L.; Nemecek, O.; Musil, V. Collect. Czech. Chem. Commun.
1968, 33, 2681-2689. (c) 2c: Bansal, R. C.; Browne, C. E.; Eisenbraun,
E. J. J. Org. Chem. 1988, 53, 452-455. (d) 2d: Johnson, W. S.; Shelberg,
W. E. J. Am. Chem. Soc. 1945, 67, 1745-1754. (e) 2e: Pasteur, A.; Rivi e` re,
H.; Tchoubar, B. Bull. Soc. Chim. Fr. 1965, 2328-2332. (f) 2f: Labidalle,
S.; Jean, E.; Moskowitz, H.; Miocque, M. Tetrahedron Lett. 1981, 22, 2869-
2870. Boyer, F.; D e´ combe, J. Bull. Soc. Chim. Fr. 1967, 281-285. (g) 2g:
Tsuboi, S.; Ono, T.; Takeda, A. Heterocycles 1986, 24, 2007-2014.
(8) R-Formyl ketones are sensitive materials (many extremely so). Careful
handling, particularly in the workup and purification is essential.
(9) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry Part B:
Reactions and Synthesis, 3rd ed.; Plenum: New York, 1990; p 7.
(
5) The procedure is a modification of that given in ref 4. 2,2,2-
Trifluoroethanol (Aldrich, 99.5%, 101 g, 1.01 mol) and formic acid (Aldrich,
6%, 186 g, 4.04 mol) were reluxed under N2 for 24 h in a 500-mL, round-
9
bottomed flask equipped with an Allihn condenser and stir bar. The mixture
was cooled to room temperature and the condenser replaced with a 24-cm
Vigreux column and distillation head. A colorless distillate (120 g, bp 55-
6
1 °C) was collected. This was redistilled twice from P2O5 to remove starting
1
1
materials giving TFEF (86.6 g, 67%), pure by H NMR: bp 60 °C; H
NMR (400 MHz, CDCl3, TMS) δ 8.11 (s, 1H, HCdO), 4.56 (q, J ) 8.4
1
3
Hz, 2H, CH2); C NMR (100.6 MHz, CDCl3) δ 159.0 (CdO), 122.9 (q,
J ) 277.0 Hz, CF3), 59.6 (q, J ) 37.1 Hz, CH2).
990
Org. Lett., Vol. 1, No. 7, 1999

+
moiety to the more highly substituted R-carbon of an
unsymmetrical ketone. The formylation of 2-methylcyclo-
hexanone under thermodynamic conditions (e.g., NaOMe and
ethyl formate) is an oft-cited example used to illustrate the
strict regioselectivity of the classical Claisen: 2-formyl-6-
methylcyclohexanone forms exclusively.10 We have found
that the regioisomeric product 2g was obtained instead by
treating 1g with MeLi and reacting the resultant enolate with
TFEF under conditions of kinetic control (entry 7). 2g, unlike
associated K cation (generated with potassium bis(trimeth-
ylsilyl)amide). Further, the poorly-coordinating solvent di-
ethyl ether was significantly better than THF which was
better, in turn, than DME. And finally, virtually none of the
desired R-formyl ketones were formed when the polar
additive HMPA was added to the reaction mixture.
2,2,2-Trifluoroethyl esters merit investigation in other areas
of condensation chemistry. For example, the reaction of
TFEF and anions derived from substrates other than ketones
(e.g., esters, acids, imines, nitriles, â-dicarbonyls) should be
examined. In addition, 2,2,2-trifluoroethyl alkanoates, less
toxic alternatives to acyl cyanides, might hold promise as
reagents for the acylation of kinetically-generated enolates.
2-formyl-6-methylcyclohexanone, cannot form a resonance-
stabilized salt and thus violates the essential criterion of the
thermodynamic reaction.
We have examined variations in base and solvent and
found, in general, that the yields of R-formyl ketones
increased and the reaction became cleaner as the enolates
Acknowledgment. I gratefully acknowledge the receipt
of a GAAN fellowship and intellectual and financial support
from my Ph.D. advisor, Professor Philip E. Eaton. This work
was funded by the U.S. Army Research Office (ASSERT
program).
+
were made less “naked”. Thus, enolates with a Li counterion
(formed by LDA) were superior to ones with a less tightly
(10) Boatman, S.; Harris, T. M.; Hauser, C. R. Org. Synth. 1968, 48,
4
0-44.
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