The reaction of β-ketoacids with allylboronates

Article abstract of DOI:10.1081/SCC-100000576

Allylboronates react with β-ketoacids to yield tertiary homoallylic β-hydroxycarboxylic acids. The reaction presumably proceeds via a bicyclic transition state. The β-carboxylic substituent enhances the rate of the reaction.

Full text of DOI:10.1081/SCC-100000576

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THE REACTION OF β-KETOACIDS WITH
ALLYLBORONATES
a
a
b
George W. Kabalka , Kathy Yang & Zhe Wang
a
Departments of Chemistry & Radiology, The University of Tennessee, Knoxville, TN,
7996-1600, U.S.A.
3
b
DuPont Pharmaceuticals, Chambers Works, Deepwater, NJ, 08023, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: George W. Kabalka, Kathy Yang & Zhe Wang (2001): THE REACTION OF β-KETOACIDS WITH
ALLYLBORONATES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:4, 511-517
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SYNTHETIC COMMUNICATIONS, 31(4), 511–517 (2001)
THE REACTION OF β-KETOACIDS WITH
ALLYLBORONATES
George W. Kabalka,1 Kathy Yang, and Zhe Wang
,∗
1
2
1Departments of Chemistry & Radiology, The University
of Tennessee, Knoxville, TN 37996-1600
2
DuPont Pharmaceuticals, Chambers Works, Deepwater,
NJ 08023
ABSTRACT
Allylboronates react with β-ketoacids to yield tertiary homo-
allylic β-hydroxycarboxylic acids. The reaction presumably pro-
ceeds via a bicyclic transition state. The β-carboxylic substituent
enhances the rate of the reaction.
Allylmetallic reagents have been of synthetic, mechanistic, and biochemical
importance for more than 70 years because of their well-defined stereo- and regio-
chemistry (1,2). Aldol condensation (3,4) and aldol-like carbon-carbon coupling
reactions (5,6) have played fundamental roles in the synthesis of natural products
of propiogenic/acetogenic biosynthetic origins (7). Over the last decade, the reac-
tion of allyl- and crotyl-metal reagents with carbonyl compounds has proven to be
especially important in acylic diastereoselective syntheses (8).
In earlier studies, we discovered remarkable rate and diastereoselectivity
enhancements brought about by the hydroxyl group in allyl- and crotylbo-
rations involving α-hydroxyketones (9), α-oxocarboxylic acids (10,11), and
∗
Corresponding author.
511
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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5
12
KABALKA, YANG, AND WANG
β-hydroxyaldehydes and ketones (12). These reactions are assumed to proceed via
a rigid bicyclic transition state. In a study of the allylboration of β-ketoacids, we
found that allylboronate 1 reacts with β-ketoacids 2 to produce tertiary homoallylic
β-hydroxycarboxylic acids 3 in good yields (Tab. 1).
OiPr
B
O
O
R
OH O
−10 °C H2O
OiPr + R
OH
OH
1
2
3
The allylboration of ethyl phenylacetate does not occur under the reaction
conditions. The hydroxyl group in the carboxylic acid moiety evidently plays an
important role. The reaction presumably proceeds through a bicyclic transition
state such as 4 (Scheme 1).
Table 1. Reaction of β-Ketoacids with B-Allyldiisopropoxyborane
β-Ketoacids (2)
Products (3)
Yielda
O
O
OH
O
PhCH2
PhCH2
C6H13
OH
OH
(2a)
(2b)
(3a)
(3b)
65.0%
79.8%
OH
OH
O
O
6 13
CH H
O
OH
O
O
OH
O
OH
(2c)
(3c)
80.8%
OH
O
O
O
OH
OH
(
2d)
(3d)
(3e)
(3f)
83.3%
70.1%
89.0%
OH
O
O
OH
O
OH
(
2e)
2f)
OH
O
O
OH
O
OH
(
OH
aIsolated yields.

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β-KETOACIDS WITH ALLYLBORONATES
513
O
B
1
+
2
O
O
OiPr
3
R
Scheme 1. Proposed transition state of allylboration of β-Ketoacids.
Unlike other neighboring group-assisted allylborations that require Et3N as
the catalyst (9–11), preliminary investigations revealed that the allylboration of
β-ketoacids can be carried out in the absence of base. In fact, the presence of Et3N
results in the decarboxylation of the β-ketoacid. A solvent study revealed that the
formation of the decarboxylated product could be minimized if the reactions were
run in ether or THF rather than dichloromethane.
EXPERIMENTAL
All glassware was oven-dried prior to use. Reactions were run under an
1
13
inert atmosphere. H and C NMR were recorded at either 250 or 300 MHz
and referenced to TMS. Diisopropoxy allylboronate was prepared according to
literature procedures (13).
Preparation of β-Ketoacids (2)
β-Ketoacids were prepared according to literature procedures (14). Butyl-
lithium (20 mmol, 12.5 mL of a 1.6 M in hexane solution) was added over 10 min
to a stirred solution of bis(trimethylsilyl)malonate (20 mmol, 5.0 g) in dry ether
◦
(
20 mL) under a nitrogen atmosphere at −78 C. The mixture was then allowed
◦
to warm to 0 C and a solution of the appropriate acid chloride (10 mmol) was
added in one portion. The mixture was stirred for 10 min at 0 C and then shaken
◦
thoroughly with cold aqueous 5% sodium bicarbonate (50 mL) for 5–10 min. The
aqueous layer was acidified to pH 1 ∼ 2 with cold 4 N sulfuric acid and extracted
with ethyl acetate (3 × 30 mL). The extracts were combined, dried over anhydrous
magnesium sulfate, and the solvent removed under reduced pressure. The product
was recrystallized from hexane.
3-Oxo-4-phenylbutanoic Acid (2a)
The reaction was carried out as described in the general procedure using
◦
phenylacetyl chloride (10 mmol, 1.6 g). The yield was 1.6 g (91%); m.p. 69 C (lit.
◦
1
70 C). H NMR (CDCl3): δ 7.20–7.42 (m, 5H), 3.82 (s, 1H), 3.47 (s, 1H).

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-Oxononanoic Acid (2b)
KABALKA, YANG, AND WANG
3
The reaction was carried out as described in the general procedure using
◦
heptanoyl chloride (10 mmol, 1.5 g). The yield was 1.6 g, (93%); m.p. 69.5 C (lit.
7
◦
1
0.5 C) (15). H NMR (CDCl3): δ 3.52 (s, 1H), 2.59 (t, 2H), 1.60 (m, 2H), 1.29
(
m, 6H), 0.90 (t, 3H).
4-Methyl-3-oxopentanoic Acid (2c)
The reaction was carried out as described in the general procedure using
◦
isobutyryl chloride (10 mmol, 1.1 g). The yield was 1.1 g (85%); m.p. 73 C.
1
H NMR (CDCl3): δ 3.55 (s, 2H), 2.83 (m, 1H), 1.15 (d, 6H). Literature values:
δ 3.45 (s, 2H), 2.55 (m, 1H), 1.09 (d, 6H) (16).
3
-Oxo-3-p-toluoylpropanoic Acid (2d)
The reaction was carried out as described in the general procedure using
◦
p-toluoyl chloride (10 mmol, 1.6 g). The yield was 1.6 g (91%); m.p. 84.2 C
(
◦ ◦
1
lit. 84 –86 C) (17). H NMR (CDCl3): δ 7.92 (d, 2H), 7.28 (d, 2H), 3.98 (s, 2H),
2.42 (s, 2H).
3-Cyclohexyl-3-oxopropanoic Acid (2e)
The reaction was carried out as described in the general procedure using
cyclohexylcarbonyl chloride (10 mmol, 1.5 g). The yield was 1.6 g (92%); m.p.
◦
1
8
5 C. H NMR (CDCl3): δ 3.56 (s, 2H), 2.44 (m, 1H), 1.75–1.95 (m, 4H), 1.10–
.42 (m, 6H). Literature values: δ 3.55 (s, 2H), 2.71–0.94 (m, 11H) (18).
1
3-Oxo-3-phenylpropanoic Acid (2f)
The reaction was carried out as described in the general procedure using
◦
benzoyl chloride (10 mmol, 1.4 g). The yield was 1.5 g (90%); m.p. 108 C (lit.
◦
1
110 C) (14). H NMR (CDCl3): δ 7.98 (d, 2H), 7.45 (t, 3H), 3.98 (s, 2H).
Allylboration of β-Ketoacids—General Procedure
In a typical procedure, diisopropyl allyboronate (3 mmol in 20 mL of ether)
was added to a nitrogen-flushed round-bottomed flask containing a β-ketoacid

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β-KETOACIDS WITH ALLYLBORONATES
515
◦
(
3mmol)inether(20mL)at−10 C. Thereactionwaswarmedtoroomtemperature
and stirred overnight. Aqueous NaHCO3 (5%, 50 mL) was added to the reaction
mixture. The aqueous layer was separated and then acidified with HCl until a
pH of ∼1 was attained. The acidified mixture was extracted with ethyl acetate
(
3 × 15 mL). The combined organic extracts were dried over anhydrous MgSO4,
the solvent removed under reduced pressure, and the product purified by column
chromatography.
3-Benzyl-3-hydroxy-5-hexenoic Acid (3a)
The reaction was carried out as described in the general procedure using
-oxo-4-phenylbutanoic acid (2a) (3.0 mmol, 0.73 g). The yield was 0.41 g (65%).
C (CDCl3): δ177.5, 136.7, 133, 130.6, 128.2, 127.0, 119.8, 73.1, 45.5, 44.0, 41.8.
H (CDCl3): δ 7.25 (m, 5H), 5.92 (m, 1H), 2.9 (s, 2H), 2.5 (m, 2H), 2.28 (m, 2H).
3
1
1
3
HRMS (EI) calcd for C13H16O3: 220.1099; found 179.071 (M-C3H5).
3-Hexyl-3-hydroxy-5-hexenoic Acid (3b)
The reaction was carried out as described in the general procedure using
1
3
3
(
(
-oxononanoic acid (2b) (3.0 mmol, 0.52 g). The yield was 0.51 g (80%).
C
1
CDCl3): δ 177.0, 132.5, 119.8, 73.0, 44.1, 43.0, 39.6, 32.2, 24, 23.2, 14.2. H
CDCl3): δ 5.80 (m, 1H), 5.15 (m, 2H), 2.42 (s, 2H), 2.25 (d, 2H), 1.50 (t, 2H),
1
1
.30 (m, 8H), 0.90 (t, 3H). HRMS (EI) calcd for C12H22O3: 214.1569; found
73.118 (M-C3H5).
3-Hydroxy-3-isopropyl-5-hexenoic Acid (3c)
The reaction was carried out as described in the general procedure using
4
-methyl-3-oxopentanoic acid (2c) (3.0 mmol, 0.32 g). The yield was 0.42 g (81%).
C (CDCl3): δ 178.2, 132.7, 119.8, 74.4, 41.0, 40.0, 36.1, 17.2, 17.0. H (CDCl3):
1
3
1
δ 5.91 (m, 1H), 5.17 (m, 2H), 2.45 (m, 2H), 2.27 (m, 2H), 1.92 (m, 1H), 0.98 (m,
6H). Analysis calcd for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.68; H, 9.28.
3-Hydroxy-3-p-tolyl-5-hexenoic Acid (3d)
The reaction was carried out as described in the general procedure using
3
(
-oxo-3-p-tolylpropanoic acid (2d) (3.0 mmol, 0.53 g). The yield was 0.55 g
83%). 13C (CDCl3): δ 175.5, 143, 136.2, 133.6, 129.0, 125.0, 118.5, 74.2, 48.1,
1
44.0, 21.6. H (CDCl3): δ 7.0–7.3 (m, 5H), 5.56 (m, 1H), 5.0 (m, 2H), 2.65 (m, 1H),

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KABALKA, YANG, AND WANG
2.4(m, 1H), 2.21(s, 2H). HRMS(EI)calcdforC13H16O3:220.1099;found179.071
(
M-C3H5).
3-Cyclohexyl-3-hydroxy-5-hexenoic Acid (3e)
The reaction was carried out as described in the general procedure using
3
-cyclohexyl-3-oxopropanoic acid (2e) (3.0 mmol, 0.51 g). The yield was 0.42 g
(
70%). 13C (CDCl3): δ 176.0, 134.2, 118.0, 74.2, 46.0, 42.2, 41.0, 28.0, 27.1, 26.6.
H (CDCl3): δ 5.9 (m, 1H), 5.1 (m, 2H), 2.3 (m, 2H), 2.4 (m, 2H). 3.8 (m, 4H),
1
1.5 (m, 1H), 1,1 (m, 6H). Analysis calcd for C12H20O3: C, 67.89; H, 9.50. Found:
C, 67.59; H, 9.45.
3-Hydroxyl-3-phenyl-5-hexenoic Acid (3f)
The reaction was carried out as described in the general procedure using
3
-oxo-3-phenylpropanoic acid (2f) (3.0 mmol, 0.49 g). The yield was 0.55 g
13
(
89%). C (CDCl3): δ 177.0, 144.2, 133.0, 128.4, 127.2, 125.3, 199.8, 74.2, 47.8,
1
44.1. H (CDCl3): δ 7.2–7.4 (m, 5H), 5.6 (m, 1H), 5.1 (m, 2H), 2.9 (m, 2H), 2.7
(m, 2H). HRMS (EI) calcd for C12H14O3 206.0943; found 165.055 (M-C3H5).
ACKNOWLEDGMENTS
We thank the US Department of Energy and the Robert H. Cole Foundation
for support of this research.
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Received in the USA May 22, 2000

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