The O-acylation of ketone enolates by allyl 1H-imidazole-1-carboxylate mediated with boron trifluoride etherate - A convenient procedure for the synthesis of substituted allyl enol carbonates

Article abstract of DOI:10.1021/jo7016313

(Chemical Equation Presented) A convenient access to substituted allyl enol carbonates was established through the reaction of ketone enolates with the complex of allyl 1H-imidazole-1-carboxylates and boron trifluoride etherate.

Full text of DOI:10.1021/jo7016313

more highly substituted allyl chloroformates focused our atten-
tion on developing a convenient high yielding process. In
addition, although substituted allyl â-keto esters can be more
readily synthesized by ester exchange reactions of simple â-keto
esters with the corresponding allyl alcohol,4 there is still an
absence of a convenient procedure for the preparation of
substituted allyl enol carbonates from simple ketones. Notably,
the role of allyl â-keto esters and that of allyl enol carbonates
are not completely exchangeable in the Pd-catalyzed decar-
boxylative allylic alkylation reactions.5 Therefore, the develop-
ment of a convenient approach to access substituted allyl enol
carbonates will significantly broaden the scope of the asym-
metric synthesis of R-allyl ketones.
The O-Acylation of Ketone Enolates by Allyl
1H-Imidazole-1-carboxylate Mediated with Boron
Trifluoride EtheratesA Convenient Procedure
for the Synthesis of Substituted Allyl Enol
Carbonates
Barry M. Trost* and Jiayi Xu
Department of Chemistry, Stanford UniVersity, 337 Campus
DriVe, Stanford, California 94305-5080
bmtrost@stanford.edu
ReceiVed July 25, 2007
A convenient access to substituted allyl enol carbonates was
established through the reaction of ketone enolates with the
complex of allyl 1H-imidazole-1-carboxylates and boron
trifluoride etherate.
The regioselectivity in the acylation of metal enolates in
general is dependent on the acylating reagent (acetic anhydride
favors O-acylation better than acetyl chloride), the metal (K
favors O-acylation while Mg favors C-acylation), the solvent
(chelating solvent such as 1,2-dimethoxyethane favors O-
acylation while nonpolar solvent such as toluene favors C-
acylation), and the reaction temperature (higher temperature
favors O-acylation while lower temperature favors C-acylation).6
Allyl enol carbonates and allyl â-keto esters have received
more and more attention as useful precursors in the palladium-
catalyzed synthesis of enantiomeric enriched R-allyl ketones,
which are important building blocks in asymmetric organic
synthesis.1 The preparation of allyl enol carbonates and allyl
â-keto esters can be performed by the treatment of the
corresponding enolates with an acylating agent, usually allyl
chloroformate.2 However, very few substituted allyl chlorofor-
mates are commercially available, and the preparation3 of such
compounds is limited not only by their poor thermal stability
and the use of excess highly toxic phosgene but also by the
hydrogen chloride generated from the reaction, which may not
be compatible with acid-sensitive functional groups on the
molecule. Furthermore, the higher reactivity of the allyl enol
carbonates and the frequently low yields in their synthesis with
(4) Gilbert, J. C.; Kelly, T. A. J. Org. Chem. 1988, 53, 449.
(5) In the reaction of Pd-catalyzed decarboxylative allylic alkylation of
ketones to generate tertiary centers, the reaction mechanisms of allyl enol
carbonates and that of allyl â-keto esters may be different: Intermediate I
from enol carbonates can only undergo decarboxylation to afford Pd enolate
II which recombines to the product. Intermediate III from â-keto esters,
however, may undergo a facile H-shift to generate IV depending on the
acidity of the R-proton. IV recombines to a â-keto acid V, which
decarboxylates to the product. Therefore, allyl â-keto esters cannot
completely replace enol allyl carbonates in this reaction. See: (a) Tsuji, J.;
Minami, I. Acc. Chem. Res. 1987, 20, 140. (b) Tsuji, J.; Yamada, Y.;
Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52,
2988.
(1) For reviews concerning Pd-catalyzed decarboxylative asymmetric
allylic alkylation of ketone enol carbonates and â-keto esters, see: (a) You,
S.-L.; Dai, L.-X. Angew. Chem., Int. Ed. 2006, 45, 5346. (b) Braun, M.;
Meier, T. Angew. Chem., Int. Ed. 2006, 45, 6952. (c) Braun, M.; Meier, T.
Synlett 2006, 5, 661. For recent publications, see: (d) Trost, B. M.; Xu, J.;
Markus, R. J. Am. Chem. Soc. 2007, 129, 282. (e) Schulz, S. R.; Blechert,
S. Angew. Chem., Int. Ed. 2007, 46, 3966. (f) Behenna, D. C.; Stockdill, J.
L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2007, 46, 4077.
(2) (a) Olofson, R. A.; Cuomo, J.; Bauman, B. A. J. Org. Chem. 1978,
43, 2073. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
1793. (c) Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett 1990, 3,
169. (d) Harwood, L. M.; Houminer, Y.; Manage, A.; Seeman, J. I.
Tetrahedron Lett. 1994, 35, 8027.
(3) (a) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1957, 79, 1197.
(b) Young, W. G.; Clement, R. A.; Shih, C. H. J. Am. Chem. Soc. 1955,
77, 3061. (c) Oliver, K. L.; Young, W. G. J. Am. Chem. Soc. 1959, 81,
5811.
(6) (a) House, H. O.; Auerbach, R. A.; Gall, M.; Peet, N. P. J. Org.
Chem. 1973, 38, 514. (b) Olofson, R. A.; Cuomo, J.; Bauman, B. A. J.
Org. Chem. 1978, 43, 2073. (c) Taylor, R. J. K. Synthesis 1985, 4, 364. (d)
Bairgrie, L. M.; Leung-Toung, R.; Tidwell, T. T. Tetrahedron Lett. 1988,
29, 1673. (e) Zhong, M.; Brauman, J. I. J. Am. Chem. Soc. 1996, 118, 636.
10.1021/jo7016313 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/27/2007
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J. Org. Chem. 2007, 72, 9372-9375

Imidazolides have been widely used in the acylation7a of
alcohols,7b amines,7c acids,7d and carbanions.7e The reaction of
ketone enolates with imidazolides favors C-acylation, and it is
a better alternative to the Claisen condensation to synthesize
â-keto esters and 1,3-diketones.8 As we expected, treatment of
the sodium enolate of 1-tetralone in DME at -78 °C with allyl
1H-imidazole-1-carboxylate 1a gave only C-acylation product
3 (eq 1). It is a general notion that reaction of ketone enolates
with “hard” electrophiles favor O-acylation while “soft” elec-
trophiles favor C-acylation.6 We postulated that the complex
of the imidazolide with an azaphilic Lewis acid, such as boron
trifluoride, is a “harder” electrophile than the imidazolide itself
and it should favor O-acylation.9 To our delight, the experi-
mental result supported our proposal, and in contrast to eq 1,
the reaction mediated with BF3‚Et2O cleanly generated only allyl
enol carbonate 4a in 85% yield (eq 2).
TABLE 1. Formation of Allyl Enol Carbonates from Various
Substituted Allyl 1H-Imidazole-1-carboxylates
To investigate the generality of the reaction, we prepared
several substituted allyl 1H-imidazole-1-carboxylates 1 by
simply mixing 1,1′-carbonyldiimidazole with the corresponding
allylic alcohols in a cosolvent of THF and CH2Cl2 at 0 °C for
several hours and then isolated the product by silica gel column
chromatography. The yields are normally very good (Table 1).
As a demonstration, the sodium enolate of 1-tetralone or
2-methyl-1-tetralone was treated with a variety of the BF3
complexes of differently substituted allyl derivatives 1, respec-
tively, and consistently, good yields were obtained in every case.
It is remarkable that, through this procedure, enol carbonates
containing amino groups could be produced in the same manner
(Table 1, entry 10).
The reaction of various sodium enolates with the BF3 complex
of 1 exclusively gave enol carbonates in high yields (Table 2,
entries 7, 9, and 11), while the ones without BF3 gave
exclusively â-keto esters in Table 2, entries 1 and 6, or a mixture
of both in entry 8, possibly because the steric effect of the methyl
group disfavored the C-acylation. There are also some cases in
which the nature of the enolate is such that the regioselectivity
toward the O-acylation is not perfect even with the BF3-activated
electrophile. For instance, the reaction of the sodium enolate
of 1-indanone with the 1d-BF3 complex in DME at -78 °C
yielded a mixture of enol carbonate 8 and â-keto ester 7 in a
3:1 ratio (Table 2, entry 2). By switching to the less coordinated
potassium enolate, generated by use of potassium tert-butoxide
as base, the ratio improved to 17:1 (Table 2, entry 3). In the
presence of 18-C-6, the enolate has even weaker coordination
with the potassium countercation, and in this case, no 7 was
observed (Table 2, entry 4). Since the reactions between enolates
and 1-BF3 complex are fast even at -78 °C, either the
thermodynamic (such as 13 in entry 9) or the kinetic product
(such as 15 in entry 10) can be obtained with excellent selectivity
a Isolated yields of 1 from the reaction of 1,1′-carbonyldiimidazole and
the corresponding allyl alcohol.
by quenching the corresponding enolates generated using
different conditions. Substrates 16 and 17 have been used in
the formal synthesis of (S)-oxybutynin, and they can be
alternatively prepared by this method (Table 2, entry 11).1d
In summary, allyl 1H-imidazole-1-carboxylates are readily
accessible from 1,1′-carbonyldiimidazole and allylic alcohols.
They are normally stable and easy to handle. By tuning their
reactivity with BF3 in the reaction with ketone enolates, we have
developed a convenient procedure for the synthesis of a broad
scope of allyl enol carbonates in high yields and regioselectivity.
The study of Pd-catalyzed asymmetric decarboxylative allylic
alkylation reactions of substituted allyl enol carbonates and their
application in organic synthesis is ongoing.
Experimental Section
(7) (a) For review concerning the application of imidazolides as acylating
agents, see: Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 7, 350. (b)
Bertolini, G.; Pavich, G.; Vergani, B. J. Org. Chem. 1998, 63, 6031. (c)
Vatele, J.-M. Tetrahedron 2004, 60, 4251. (d) Kitagawa, T.; Kuroda, H.;
Sasaki, H. Chem. Pharm. Bull. 1987, 35, 1262. (e) Werner, T.; Barrett, A.
G. M. J. Org. Chem. 2006, 71, 4302.
(8) (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223. (b) Shone, R. L.; Deason, J. R.; Miyano, M. J. Org. Chem. 1986,
51, 268. (c) Tanaka, T.; Okamura, N.; Bannai, K.; Hazato, A.; Sugiura, S.;
Tomimori, K.; Manabe, K. i.; Kurozumi, S. Tetrahedron 1986, 42, 6747.
(9) For reference concerning the much better reactivity of acylimidazo-
lium salts than the corresponding imidazolides, see: (a) Anders, E.; Will,
W. Tetrahedron Lett. 1978, 41, 3911. (b) Oakenfull, D. G.; Salvesen, K.;
Jencks, W. P. J. Am. Chem. Soc. 1971, 93, 188. (c) Grzyb, J. A.; Shen, M.;
Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A. Tetrahedron 2005,
61, 7153.
General Procedures. Procedure A: A clean oven-dried 50 mL
flask was charged 460 mg of sodium bis(trimethylsilyl)amide (2.4
mmol) under nitrogen. The flask was cooled to -78 °C in a dry
ice/acetone bath, and 5 mL of 1,2-dimethoxyethane (DME) was
added through a syringe. The flask was taken out from the bath to
allow it to warm up until the solid completely dissolved. Then it
was cooled to -78 °C. To the solution was added 317 mg of
1-indanone (2.4 mmol) in 2 mL of DME. The solution was stirred
for 30 min before it was transferred into the solution of 384.4 mg
of 1d (2 mmol). After 10 min, the cooling bath was removed and
the reaction was allowed to warm to room temperature and stirred
at room temperature for 1 h. One portion of 10 mL of saturated
aqueous ammonium chloride was poured into the reaction mixture
J. Org. Chem, Vol. 72, No. 24, 2007 9373

TABLE 2. The Reaction of Various Ketone Enolates with 1 or Its BF3 Complex
a A: 1.0 equiv of NaHMDS, DME, -78 °C, then 0.8 equiv of 1; B: 1.0 equiv of NaHMDS, DME, -78 °C, then a mixture of 0.8 equiv of 1 and BF3·Et2O
or, if the product cannot be separated from the starting ketone by silica gel chromatography, 1.2 equiv of NaHMDS, DME, -78 °C, then a mixture of 1.2
equiv of 1 and BF3·Et2O; C: 1.2 equiv of KOtBu, THF, -78 °C, then a mixture of 1.2 equiv of 1 and BF3·Et2O; D: 1.2 equiv of KOtBu, 1.2 equiv of
18-crown-6, THF, -78 °C, then a mixture of 1.2 equiv of 1 and BF3·Et2O. b Combined isolated yield for the reactions with more than one product. c The
enolate was formed by the addition of a solution of 1 equiv of NaHMDS into a solution of the substrate at 0 °C then cooled to -78 °C.
followed by 10 mL of diethyl ether. The aqueous layer was
extracted with 10 mL of diethyl ether. The combined organic
solution was washed with 10 mL of saturated brine and dried over
MgSO4. After concentration, the crude product was isolated with
silica gel column chromatography eluted with 15% diethyl ether
in petroleum ether to afford 323 mg of a white solid as a 5:1 mixture
of 7 and its enol tautomer (63%): mp ) 77-79 °C; Rf ) 0.24
(diethyl ether/petroleum ether 1:9); 1H NMR (400 MHz, CDCl3) δ
) 10.45 (br s, 1H, enol), 7.77 (m, 1H, ketone), 7.62 (m, 1H, enol),
7.62 (m, 1H, ketone), 7.50 (m, 1H, ketone), 7.45 (m, 1H, enol),
7.39 (m, 2H, enol), 7.39 (m, 1H, ketone), 5.98 (m, 1H, enol), 5.98
(m, 1H, ketone), 5.81 (m, 1H, enol), 5.74 (m, 1H, ketone), 5.47
(m, 1H, enol), 5.35 (m, 1H, ketone), 3.71 (m, 1H, ketone), 3.55
(m, 1H, ketone), 3.55 (m, 2H, enol), 3.38 (m, 1H, ketone), 3.38
(m, 1H, enol), 2.20-1.60 (m, 6H, ketone), 2.20-1.60 (m, 6H, enol).
Procedure B: To the solution of 460 mg of NaHMDS in 5 mL
of DME at -78 °C was added 292 mg of 1-tetralone (2 mmol) in
2 mL of DME. The solution was stirred at -78 °C for 30 min.
9374 J. Org. Chem., Vol. 72, No. 24, 2007

Meanwhile, another clean oven-dried 50 mL flask was charged with
365 mg of 1a (2.0 mmol) and 5 mL of DME. The solution was
cooled to -78 °C, and 0.30 mL of boron trifluoride etherate (2.4
mmol) was added dropwise and stirred for 15 min. The above
solution was transferred into the solution of enolate through a
cannula under nitrogen and stirred for 30 min. One portion of 10
mL of saturated aqueous ammonium chloride was poured into the
reaction mixture followed by 10 mL of diethyl ether. The mixture
was taken out from the bath and allowed to warm to ambient
temperature. The organic layer was separated, and the aqueous layer
was extracted once with 10 mL of diethyl ether. The organic layer
was combined and dried over magnesium sulfate. After filtration
and concentration in vacuo, the crude material was purified by silica
gel column chromatography eluted with 10% diethyl ether in
petroleum ether to give 392 mg of 4a as a colorless liquid (85%):
Rf ) 0.39 (diethyl ether/petroleum ether 1:9); IR (film) 3068, 3024,
2941, 2890, 2836, 1760, 1659, 1489, 1452, 1428, 1360, 1293, 1244,
7.25 (m, 1H), 7.15 (m, 2H), 6.05 (m, 1H), 5.87 (m, 1H), 5.23 (m,
1H), 3.32 (s, 2H), 2.03 (s, 3H), 2.20-1.60 (m, 6H); 13C NMR (100
MHz, CDCl3) δ ) 152.4, 144.6, 140.1, 139.6, 134.0, 128.3, 126.3,
124.6, 123.8, 117.3, 112.6, 73.1, 39.1, 28.2, 24.9, 18.6, 12.2.
Procedure D: Follow procedure C, but 18-C-6 was added to
the enolate solution.
Cyclohex-2-en-1-yl 1H-inden-3-yl carbonate (8). Starting from
317 mg of 1-indanone (2.4 mmol) and 384.4 mg of 1d (2 mmol)
by procedure D, 470 mg of a colorless oil was obtained after
purification by silica gel chromatography (92%): Rf ) 0.47 (diethyl
ether/petroleum ether 1:9); IR (film) 3034, 2943, 2835, 1756, 1618,
1603, 1578, 1456, 1398, 1336, 1292, 1227, 1172, 1127, 1050, 1012,
1
918,782, 760, 717 cm-1; H NMR (400 MHz, CDCl3) δ ) 7.41
(m, 2H), 7.30 (m, 1H), 7.24 (m, 1H), 6.34 (t, J ) 2.4 Hz, 1H),
6.04 (m, 1H), 5.86 (m, 1H), 5.25 (m, 1H), 3.40 (d, J ) 2.4 Hz,
2H), 2.20-1.60 (m, 6H); 13C NMR (100 MHz, CDCl3) δ ) 152.3,
149.4, 141.8, 138.7, 134.0, 126.3, 125.7, 124.5, 124.1, 118.2, 114.3,
72.9, 34.9, 28.2, 24.9, 18.6. Anal. Calcd for C16H16O3: C, 74.98;
H, 6.29. Found: C, 75.12; H, 6.11.
1
1225, 1186, 1013, 993, 944, 772, 744 cm-1; H NMR (400 MHz,
CDCl3) δ ) 7.2 (m, 4H), 5.99 (m, 1H), 5.81 (t, J ) 4.6 Hz, 1H),
5.42 (dq, J ) 17.2, 1.3 Hz, 1H), 5.32 (dq, J ) 10.2, 1.3 Hz, 1H),
4.71 (dt, J ) 5.6, 1.3 Hz, 2H), 2.86 (t, J ) 8.2 Hz, 2H), 2.45 (m,
2H).
Procedure C: Follow the details in procedure B, but potassium
tert-butoxide was used as base and THF as solvent.
Acknowledgment. We thank the National Science Founda-
tion and the National Institutes of Health, General Medical
Sciences Grant GM13598, for their generous support of our
programs. J.X. has been supported by Abbott Laboratories
Fellowships in the Stanford Graduate Fellowships Program.
Cyclohex-2-en-1-yl 2-methyl-1H-inden-3-yl carbonate (9).
Starting from 350 mg of 2-methyl-1-indanone (2.4 mmol) and 384.4
mg of 1d (2 mmol) by procedure C, 474 mg of white solid was
obtained after purification by silica gel chromatography (88%): mp
) 66-67 °C; Rf ) 0.30 (diethyl ether/petroleum ether 1:9); IR
(film) 3034, 2944, 1756, 1656, 1397, 1336, 1242, 1165, 1140, 1033,
Supporting Information Available: Full experimental details,
spectral data, and characterization for all new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
1
911, 732 cm-1; H NMR (400 MHz, CDCl3) δ ) 7.34 (m, 1H),
JO7016313
J. Org. Chem, Vol. 72, No. 24, 2007 9375