Efficient One-Step Aldol-Type Reaction of Ketones with Acetals and Ketals Mediated by Dibutylboron Triflate/ Diisopropylethyl Amine

Article abstract of DOI:10.1021/ol030108u

(Equation presented) A highly efficient one-step Mukaiyama aldol-type reaction has been developed for the synthesis of β-alkoxy carbonyl compounds starting from ketones and acetals/ketals. The reaction is mediated by a combination of Bu₂BOTf and i-Pr₂NEt affording the products in high yields. Formation of the two possible diastereoisomers of the β-alkoxy ketones from the chiral acetals shows that the condensation takes place by an S_N1 mechanism, involving prior opening of the acetal to an oxonium ion.

Full text of DOI:10.1021/ol030108u

ORGANIC
LETTERS
2004
Vol. 6, No. 1
127-130
Efficient One-Step Aldol-Type Reaction
of Ketones with Acetals and Ketals
Mediated by Dibutylboron Triflate/
Diisopropylethyl Amine
Lian-Sheng Li, Sanjib Das, and Subhash C. Sinha*
The Skaggs Institute for Chemical Biology and the Department of Molecular
Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
subhash@scripps.edu
Received September 8, 2003
ABSTRACT
A highly efficient one-step Mukaiyama aldol-type reaction has been developed for the synthesis of â-alkoxy carbonyl compounds starting
from ketones and acetals/ketals. The reaction is mediated by a combination of Bu2BOTf and i-Pr2NEt affording the products in high yields.
Formation of the two possible diastereoisomers of the â-alkoxy ketones from the chiral acetals shows that the condensation takes place by
an SN1 mechanism, involving prior opening of the acetal to an oxonium ion.
Mukaiyama aldol-type reaction of a silyl enol ether with an
acetal or ketal providing the corresponding â-alkoxy carbonyl
compound1 has been a subject of extensive investigations.2,3
The reaction requires the preformation of silyl enol ether
from corresponding carbonyl compounds, which then un-
dergoes a Lewis acid-catalyzed coupling to the acetal or ketal
in a separate step (eq 1). In a modified process, both the
enol ether formation and the subsequent addition to an acetal
or ketal have also been realized in a single-step (eq 2).4 In
this communication, we describe a new single-step method
using dibutylboron triflate/diisopropylethylamine (Bu2BOTf/
i-Pr2NEt) for the Mukaiyama aldol-type reaction between
ketones and acetals (or ketals).
Recently, we have described the Bu2BOTf/i-Pr2NEt-
mediated intramolecular cyclization of keto-acetal com-
pounds to afford the cyclic ethers in a single step (eq 3).5 In
this process, the dibutylboron enolate of ketone reacted with
the resident acetal, which was activated by Bu2BOTf. To
check the feasibility of this one-step process for the analogous
(1) (a) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15-16. (b)
Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817 and references
therein.
(2) (a) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980, 102,
3248-3249. (b) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37,
3899-3910. (c) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44,
4259-4275.
10.1021/ol030108u CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/11/2003

intermolecular coupling reaction (eq 2, M ) BBu2), initially,
we examined the condensation of acetone (1a) and hexanone
(1f) with acetal 2c, using a procedure similar to that used in
the intramolecular reaction (procedure A).6 Fortunately, the
reaction proceeded smoothly to afford the desired products,
3a, as its semiketal form, and 3b in 44 and 58% yields,
respectively (Scheme 1). Compound 3b was obtained as a
optimized process (procedure B),8 we preformed the dibutyl
boron-enolate of 1f by treatment with Bu2BOTf/i-Pr2NEt at
-78 °C for 30 min, to complete the enolization,9 and then a
solution of acetal 2c was added slowly. Using a workup
procedure similar to procedure A led to a cleaner reaction,
affording 3b in 78% yield.
The scope of the reaction was explored using a series of
ketones, acetals, and ketals. Condensation of various ketones,
including acetophenone (1b), propiophenone (1c), 2-meth-
ylbutanone (1d), cyclopentanone (1e), and cyclohexanone
(1f), with acetals (2a-g) was examined using procedure B.
In all cases, the desired â-alkoxy ketones were obtained in
good yields (Table 1). The substituted cyclic acetal, 2b,
underwent highly regioselective acetal opening to produce
the â-alkoxy ketone (3d) with a primary alcohol (entry 2,
Table 1). The isomeric secondary alcohol was not detected.
The reaction slightly favored the formation of syn isomer
(entries 8-13, Table 1). The highest syn selectivity was
obtained when propiophenone was used as the ketone
counterpart (entry 9, Table 1). We next investigated reactions
of ketones (1b,c) with various ketals (4a-g) using procedure
B, which also gave satisfactory results (Table 2). Function-
alized ketals such as 4f and 4g also afforded the desired
products with high yields.
Scheme 1a
a Key: (a) 1a (or 1f), 2c, i-Pr2NEt, CH2Cl2, -78 °C, then
Bu2BOTf (procedure A); (b) 1f, i-Pr2NEt, CH2Cl2, -78 °C,
Bu2BOTf, 0.5 h, then 2c (procedure B).
To check the regioselectivity of this reaction with respect
to ketone, two sets of experiments were conducted. In one
experiment, 2-butanone (1g) and acetal 2e were used
(Scheme 2A). The reaction of 1g with 2e (Scheme 2A) using
Bu2BOTf/i-Pr2NEt in CH2Cl2 afforded the two regio-
isomeric compounds, 6 and 7, in a nearly 1.4:1 ratio. Whereas
no change in regioselectivity of the reaction was noticed
when the reaction was conducted in ether, a minor improve-
ment in the stereoselectivity of syn-7 over anti-7 was realized.
In another experiment (Scheme 2B), condensation of 1b with
n-butyl THP ether was investigated, which predominantly
gave the open chain product (8a, 73% yield) and a minor
amount of tetrahydropyran derivative (8b, 7%). Use of
3-methyl-2-butanone, on the other hand, exclusively formed
the open chain product (9a, 72% yield). Therefore, this
method also provides an easy protocol to give 5-alkoxy-7-
keto-alkan-1-ols (such as 8a and 9a).
separable mixture of syn and anti isomers (56:44). In-
terestingly, when other boron-Lewis acids such as BCl3,
c-Hex2BCl, or 9-BBNOTf7 were used, none of them provided
the desired product. Next, we varied the reaction conditions,
including the mode of addition of the substrates. In an
(3) (a) Ishitani, H.; Iwamoto, M. Tetrahedron Lett. 2003, 44, 299-301.
(b) Cossy, J.; Lutz, F.; Alauze, V.; Meyer, C. Synlett 2002, 45-48. (c)
Trehan, A.; Vij, A.; Walia, M.; Kaur, G.; Verma, R. D.; Trehan, S.
Tetrahedron Lett. 1993, 34, 7335-7338. (d) Le Roux, C.; Ciliberti, L.;
Laurent-Robert, H.; Laporterie, A.; Dubac, J. Synlett 1998, 1249-1251 and
references therein. (e) Ooi, T.; Tayama, E.; Takahashi, M.; Maruoka, K.;
Tetrahedron Lett. 1997, 38, 7043-7046. (f) Kamata, M.; Yokoyama, Y.;
Karasawa, N.; Kato, M.; Hasegawa, E. Tetrahedron Lett. 1996, 37, 3483-
3486. (g) Kamata, M.; Nagai, S.; Kato, M.; Hasegawa, E. Tetrahedron Lett.
1996, 37, 7779-7782. (h) Mukaiyama, T.; Kobayashi, S.; Murakami, M.
Chem. Lett. 1984, 1759-1762. (i) Mukaiyama, T.; Iwakiri, H. Chem. Lett.
1985, 1363-1366. (j) Murakami, M.; Minamikawa, H.; Mukaiyama, T.
Chem. Lett. 1987, 1051-1052. (k) Sakurai, H.; Sasaki, K.; Hosomi, A.
Bull. Chem. Soc. Jpn. 1983, 56, 3195-3196. (l) Hosomi, A.; Sakata, Y.;
Sakurai, H. Chem. Lett. 1983, 405-408. (m) Jung, M. E.; Hogan, K. T.
Tetrahedron Lett. 1988, 29, 6199-6202. (n) Kawai, M.; Onaka, M.; Izumi,
Y. Bull. Chem. Soc. Jpn. 1988, 61, 1237-1245.
To extend the scope of the reaction, we briefly studied
the Bu2BOTf/i-Pr2NEt-mediated coupling of ketone and
esters with trialkyl ortho esters and acetals, respectively
(Scheme 3). As shown, ketone 1c reacted with triethyl
orthoformate to afford the corresponding â-keto acetal, 11a.
However, under similar conditions, the reaction did not take
(4) For direct formation of silyl enol ether, see: Kobayashi, S.; Nishio,
K. J. Org. Chem. 1993, 58, 2647-2649. For direct generation of Titanium
enolates, see: (a) Keck, G. E.; Wager, C. A.; Wager, T. T.; Savin, K. A.;
Covel, J. A.; McLaw, M. D.; Krishnamurthy, D.; Cee, V. J. Angew. Chem.,
Int. Ed. 2001, 40, 231-234. (b) Cosp, A.; Romea, P.; Talavera, P.; Urpi,
F.; Vilarrasa, J.; Font-Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615-617.
(c) Cosp, A.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42,
4629-4631. (d) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau,
M. T. J. Am. Chem. Soc. 1990, 112, 8215-8216. For BF3‚OEt2-mediated
reaction, see: Hashigaki, K.; Yoshioka, S.; Yamato, M. Synthesis 1986,
1004-1007.
(7) It has been reported that 9-BBNOTf could catalyze the aldol-type
reaction between silyl enol ether and acetals. Ishihara, K.; Yamamoto, H.;
Heathcock, C. H. Tetrahedron Lett. 1989, 30, 1825-1828.
(8) Procedure B. Bu2BOTf (1.0 M, 1.3 mL, 1.3 mmol) was added
dropwise to a solution of ketone (1 mmol) and i-Pr2NEt (0.2 mL, 1.15 mmol)
in dry CH2Cl2 (5 mL) at -78 °C under argon. The resulting mixture was
stirred for 30 min, and then a solution of an acetal (1 mmol) in dry CH2Cl2
(3 mL) was added slowly. Stirring was continued for 30 min, and then the
reaction was quenched by addition of PBS buffer (1.3 mL), methanol (1.3
mL) and H2O2 (0.5 mL). The resulting mixture was warmed to room
temperature and stirred for 1 hour, extracted with ether, washed with brine
and dried over MgSO4. The crude product was purified by chromatography
on silica gel column.
(5) For the Bu2BOTf/i-Pr2NEt-mediated intramolecular one-step aldol-
type coupling of ketones with acetals and ketals, see: Das, S.; Li, L.-S.;
Sinha, S. C. Org. Lett. 2004, 6, 123-126.
(6) Procedure A. To a solution of acetone (1 mmol) and acetal 2 (1
mmol) in 5 mL of CH2Cl2 at -78 °C was added i-Pr2NEt (1 mmol),
followed by a rapid addition of Bu2BOTf (1.2 mmol). The resulting reaction
mixture was stirred at -78 °C for 30 min, and then buffer (pH ) 7.4, 1.2
mL), methanol (1.2 mL), and H2O2 (0.4 mL) were added. Stirring was
continued for 1 h at room temperature, and then the mixture was worked
up using ether. The organic layer was washed with aqueous NaHCO3 and
brine and dried over MgSO4. Solvents were removed, and the crude product
was purified by column chromatography on silica gel.
(9) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174-
178.
128
Org. Lett., Vol. 6, No. 1, 2004

Table 1. Bu2BOTf/i-Pr2NEt-Mediated Aldol-Type
Table 2. Bu2BOTf/i-Pr2NEt-Mediated Aldol-Type
Condensation of Ketones with Acetals
Condensation between Ketones and Ketals
a Isolated yield. b Ratio of syn and anti isomers was determined by
1HNMR, and the relative configuration was determined by comparing the
corresponding NMR data with the literature. c Performed with 1.2 mol of
ketone.
place when triethyl orthoacetate was used. Esters such as
methylpropionate (10), on the other hand, reacted efficiently
with 2c and 4b to afford 12a and 12b, respectively.10
The Bu2BOTf/i-Pr2NEt-mediated intermolecular aldol-type
reaction of a ketone with acetals ketals can be rationalized
a Isolated yield. b Ratio of syn and anti isomers was determined by
1HNMR, and the relative configuration was determined by comparing the
corresponding NMR data with the literature. c Performed with 1.2 mol of
ketone.
(10) Enolization was carried out at -78 °C for 2 h before the acetal or
ketal was added.
Org. Lett., Vol. 6, No. 1, 2004
129

Scheme 2
Scheme 4
Scheme 3
SN1 mechanism, was evident from an examination of the
reaction of 1b with the chiral acetals, 2h-j. The products
obtained from these acetals were mixtures of both diaster-
eomers of 3p, 3q, and 3r, respectively (eqs 4 and 5). Since
only primary alkoxy is the leaving group, only an SN1
pathway could explain the formation of the diastereoisomeric
mixtures of the products. The SN2 pathway, on the other
hand, would provide only one stereoisomer in each case.
In conclusion, we have developed a highly efficient one-
step intermolecular aldol-type reaction of ketones and acetals
or ketals using Bu2BOTf/i-Pr2NEt. Evidence has been
provided to support the SN1-type mechanism for this one-
pot, operationally simpler method. Further development of
this process to carry out the reaction in a highly stereose-
lective manner is in progress.
as shown in Scheme 4A. Analogous to the TiCl4-mediated
reaction of silyl enol ether with acetal,11 the reaction takes
place via an SN1 mechanism. Presumably, boron enolate (I)
of a ketone reacts with the intermediate II that is generated
by the Bu2BOTf-catalyzed activation to afford the product.
In the overall process, more than 1 equiv of Bu2BOTf is
required for both the enolization of a ketone and activation
of an acetal or ketal. That the reaction takes place by the
Acknowledgment. We thank the Skaggs Institute for
Chemical Biology for financial support.
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915-
7916. (b) Denmark, S. E.; Willson, T. M.; Almstead, N. G. J. Am. Chem.
Soc. 1989, 11, 9258-9260. (c) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki,
K.; Yamamoto, H.; Bartlett, P. A.; Heathcock. C. H. J. Org. Chem. 1990,
55, 6107-6115.
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