Base- and metal-free decarboxylative aldol reaction of β-ketoacids with glyoxylate hydrates and glyoxal monohydrates in water

Article abstract of DOI:10.1039/c6gc02705a

An environmentally benign decarboxylative aldol reaction of β-ketoacids with glyoxylate and glyoxal monohydrates in water is reported. The reaction proceeds smoothly without any base and metal catalysts, affording the corresponding β-hydroxy ketones in high yields. A preliminary mechanism study of this aldol transformation suggests a stepwise process involving the nucleophilic addition of β-ketoacids to glyoxylate hydrates and glyoxal monohydrates followed by a subsequent decarboxylation reaction.

Full text of DOI:10.1039/c6gc02705a

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Base- and metal-free decarboxylative aldol reaction of β-
ketoacids with glyoxylate hydrates and glyoxal
monohydrates in water
Received 00th January 20xx,
Accepted 00th January 20xx
Nan Ren, Jing Nie and Jun-An Ma*
DOI: 10.1039/x0xx00000x
An environmental benign decarboxylative aldol reaction of βꢀketoacids with glyoxylate and glyoxal monohydrates
in water is reported. The reaction proceeds smoothly without any base and metal catalysts, affording the
correspoding βꢀhydroxy ketones in high yields. A preliminary mechanism studies of this aldol transformation
suggests a stepwise process involving nucleophilic addition of βꢀketoacids to glyoxylate hydrates and glyoxal
monohydrates followed by a subsequent decarboxylation reaction.
www.rsc.org/
ethers reacted with carbonyl compounds in water without
any catalyst to give the aldol products in low yields.
Recently Dash and coꢀworkers7 reported an uncatalyzed
aldol reaction of thiazolidinedione with aromatic
aldehydes to afford the corresponding βꢀhydroxy carbonyl
compounds. However, this method is limited by the scope
and the accessibility of the required nucleophilic
substrates. Thus, the development of new catalystꢀfree
aldol reactions in aqueous medium for the construction of
diverse aldolꢀproducts is still in high demand.
Introduction
The development of practical, atomꢀeconomical, and
environmentally benign chemical reactions has become a
vital consideration in current chemical research1. In this
context, organic reactions in aqueous medium2 have
attracted more and more attention of synthetic chemists,
because water is nonflammable, nontoxic and the most
abundant solvent in nature. Although there are many
potential advantages in terms of cost, safety, and
environmental concerns when common organic solvents
are replaced by water, it is still a challenge that the poor
solubilities and reactivities of reactants in aqueous
medium led to the deleterious effect on many organic
transformations3.
The decarboxylative transformations of βꢀketoacids,
which are catalyzed by enzymes, have proven to be the
key step in the biosynthesis of natural tropinone,
lycopodine alkaloids, and macrophomic acid8. The
decarboxylative reaction of βꢀketoacids provides
a
traceless means of activation with CO2 as the only byꢀ
product for carbonꢀcarbon bondꢀforming process. Inspired
from nature, organic chemists have developed a variety
of efficient carbonꢀcarbon bondꢀforming reactions by
empolying βꢀketoacids as ketone enolate equivalents 9. In
this context, metalꢀ and organcatalytic decarboxylative
aldol reactions of βꢀketoacids with aldehydes and ketones
have been well established (Scheme 1a)10. However, the
use of organic solvents has been the focus of all such
studies. In sharp contrast, the implementation of the
biomimetic decarboxylative aldol reactions in aqueous
media, especially in pure water as a valuable synthetic
tool still remains unexploited.
During our ongoing studies in the field of
decarboxylative transformations of βꢀketoacids11, we have
developed a useful baseꢀ and metalꢀfree decarboxylative
aldol reaction of βꢀketoacids with glyoxylate hydrates and
glyoxal monohydrates in aqueous medium (Scheme 1b).
The notable features of this reaction are its operational
simplicity, readily accessible starting materials, mild
reaction conditions, low cost and ecoꢀfriendliness. Thus,
The aldol reaction is one of the most powerful
methods for the formation of carbonꢀcarbon bonds in
organic synthesis4. Traditionally, the aldol reactions have
been conducted in the presence of strong base or acid.
However, under such conditions, the desired aldol adduct
is afforded along with other side products derived from
dehydration, dimerization, polymerization, or selfꢀ
condensation. Catalytic aldol reactions which avoid
dehydration in aqueous media have been widely studied,
and many methods have been successfully applied to the
synthesis of natural products and compounds of
pharmaceutical significance5. In sharp contrast, examples
of uncatalyzed aldolꢀtype reactions in aqueous medium
are rare. In 1986 Lubineau6 demonstrated that silyl enol
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this protocol highly meets the criteria of Green been prolonged to 18 h, delivering the corresponding
Chemistry12. Herein, we report the results of our studies products 3k
in relatively lower yields (entries 11–14).
–
n
on this subject.
The heteroarylꢀsubstitued βꢀketoacids could also be used
as the nucleophile substrates, thus generating the desired
products 3o and 3p in high yields (entries 15 and16). In
addition, it was found that cyclic, linear, and branched
alkylꢀsubstituted βꢀketoacids were also acceptable
substrates and provided the corresponding aldol products
3q–u in good yields (entries 17–21). This decarboxylative
aldol reaction could also be performed on the decagram
scale without losing efficiency, and the aldol product 3a
could be obtained by direct vacuum distillation (entry 22).
Table 1 Scope of the decarboxylative aldol reaction of βꢀ
ketoacids 1 with ethyl glyoxylate hydrate 2 a
Scheme 1. The decarboxylative aldol reactions of βꢀketoacids
in organic solvents and water.
Results and discussion
Entry
R
Time (h) Product Yield (%) b
We initiated our investigation by conducting the
decarboxylative aldol reaction between 3ꢀoxoꢀ3ꢀ
phenylpropanoic acid 1a and ethyl glyoxylate hydrate
1
2
3
4
5
6
7
C6H5
6
6
6
6
6
6
6
3a
3b
3c
3d
3e
3f
87
85
83
87
81
85
90
2 in
4ꢀMeꢀC6H4
3ꢀMeꢀC6H4
2ꢀMeꢀC6H4
2,4ꢀMe2ꢀC6H3
4ꢀMeOꢀC6H4
3ꢀMeOꢀC6H4
pure water (Scheme 2). To our delight, this aldol
condensation could be carried out at room temperature
for 6 h to afford the desired aldol product 3a in 87%
isolated yield in the absence of any Brønsted bases and
metal complexes. Small amount of side product
acetophenone, formed from a competing decarboxylation
pathway, was observed. Notably the dehydration byꢀ
product was not detected in the reaction system. Next,
when the amount of 1a was reduced to 1.0 equivalent,
the yield of 3a was decreased dramatically to 55%. Thus,
the optimized conditions for this reaction are summarized
3g
3,4,5ꢀ(MeO)3ꢀ
C6H3
8
12
3h
83
9
4ꢀFꢀC6H4
2ꢀFꢀC6H4
4ꢀClꢀC6H4
3ꢀClꢀC6H4
2ꢀClꢀC6H4
4ꢀBrꢀC6H4
2ꢀFuryl
6
3i
3j
82
90
75
73
76
74
92
90
84
80
85
87
87
85
as follows: 1a (0.3 mmol) and
temperature in pure water under air for 6 h.
2 (0.2mmol) at room
10
11
12
13
14
15
16
17
18
19
20
21
22c
6
18
18
18
18
6
3k
3l
3m
3n
3o
3p
3q
3r
Scheme 2. The decarboxylative aldol reaction of βꢀketoacid
1a with ethyl glyoxylate hydrate 2.
3ꢀThienyl
Phenethyl
Cyclopropyl
Cyclohexyl
nꢀPropyl
tꢀButyl
6
12
12
12
12
12
10
With the optimized reaction conditions in hand, the
scope of the decarboxylative aldol reaction was
investigated by using a series of βꢀketoacids, and the
results were summarized in Table 1. The reaction of
orthoꢀ, metaꢀ, and paraꢀsubstitued phenyl βꢀketoacids
3s
3t
3u
with ethyl glyoxylate hydrate
and the aldol adducts 3a could be obtained in 81–90%
2 all proceeded smoothly,
C6H5
3a
–
j
a Reactions were performed with 1 (0.3 mmol) and 2 (0.2
yields (entries 1–10). It should be noted that the
substrates with chlorine or bromine substituents on the
phenyl ring are less reactive as the reaction time has
b
mmol) in water (1.5 ml) at room temperature for 6–18 h.
Isolated yield. c Reaction was performed with 80 mmol of 2.
2 | J. Name., 2012, 00, 1-3
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To further extend this baseꢀ and catalystꢀfree chromatography (FCC). In addition, when this aldol
decarboxylative aldol reaction in water, we also used a reaction was scaled up to the gram scale, the desired
variety of glyoxal monohydrates
4 as the electrophilic product 7 was also obtained in 87% yield by simple
partners under the current reaction conditions. As shown filtration (Scheme 3). We analysed the solutions of these
in Table 2, the reaction of a series of phenylꢀsubstituted aromatic aldehydes in D2O by using 1H and 13C NMR,
glyoxal monohydrates with βꢀketoacid 1a worked well to and found that nicotinaldehyde exists as partial hydrate
afford the corresponding products 5a
yields (entries 1–7). 2ꢀNaphthylꢀ and 2ꢀthienylꢀsubstituted (see ESI). In contrast, for the other three aromatic
glyoxal monohydrates also participated in this aldehydes, the corresponding hydrates were
–g in good to high species (aldehyde/hydrate = 10/1) in aqueous solution
decarboxylative reaction well to give the aldol products 5h undetectable on the timescale of the NMR experiment.
and 5i in the yield of 82% and 87%, respectively (entries These results indicate that the hydrate species of
8 and 9). The aldol reactions of alkylꢀsubstituted glyoxal aldehydes is critically important to this aldol reaction.
monohydrates were also tested (entries 10 and 11). The
desired adducts 5j and 5k were obtained in high yields.
Furthermore, almost the same result was obtained when
the aldol reaction of phenyl glyoxal monohydrate with βꢀ
ketoacid 1a was scaled up to the gram scale (entry 12).
Table 2 The decarboxylative aldol reaction of βꢀketoacid 1a
with a series of glyoxal monohydrates 4 a
Scheme 3. The decarboxylative aldol reaction of βꢀketoacid
1a with nicotinaldehyde 6.
It is of great value to elucidate the mechanism of this
biomimetic decarboxylative aldol reaction in neutral
Entry
1
R
Time (h) Product Yield (%) b
aqueous media, because the chemical environment is
fairly similar to nature. To cast some light on the
mechanism, NMR and ESI/MS methods were used to
study this decarboxylative aldol reaction. It is noteworthy
that the baseꢀ and metalꢀfree aqueous conditions make
NMR spectroscopic analysis of the crude reaction mixture
very reliable and feasible in D2O. By using tertꢀbutyl
C6H5
8
8
5a
5b
5c
5d
5e
5f
85
93
92
90
85
92
75
82
87
92
88
83
2
4ꢀMeC6H4
4ꢀMeOC6H4
4ꢀFC6H4
4ꢀClC6H3
4ꢀBrC6H4
4ꢀNO2C6H4
2ꢀNaphthyl
2ꢀThienyl
Methyl
3
8
4
8
5
16
24
16
16
8
substituted βꢀketoacid 1u and methyl glyoxylate hydrate
8
as substrates, we monitored the current aldol reaction via
13C NMR (Figure 1). In comparison with the spectra of
substrates and product (Figure 1: a, b, and c), an addition
intermediate with new signals at 45.33, 52.77, 69.66,
170.50, 173.74, and 212.78 ppm was observed (Figure 1:
d). However, all attempts to isolate this intermediate were
unsuccessful. An ESI/MS analysis of this aldol reaction
allowed further identification of the addition intermediate
using the highꢀresolution mass data {HRMS (ESI) calcd
for C10H16O6Na [M + Na]+ 255.0839, found 255.0845}
(Figure 1e). In the control experiment, we found that the
corresponding ketone could not react with methyl
6
7
5g
5h
5i
8
9
10
11
12c
8
5j
tꢀButyl
8
5k
5a
C6H5
16
a Reactions were performed with 1a (1 mmol) and 4 (0.67
b
mmol) in water (2 ml) at room temperature for 8–24 h.
Isolated yield. c Reaction was performed with 10 mmol of 4.
glyoxylate hydrate to afford the desired product
9
under
the standard conditions.
Based on these preliminary results,
a stepwise
Subsequently, we also investigated the aldol reaction of
βꢀketoacid 1a with several aromatic aldehydes, including
benzaldehyde, pꢀnitrobenzaldehyde and furaldehyde.
Unfortunately these aromatic aldehydes were found to be
insuitbale for this decarboxylative aldol reaction and no
desired products were observed under the present
process could be involved in this reaction system, in
which nucleophilic addition of the βꢀketoacids to
glyoxylate hydrates and glyoxal monohydrates gave the
addition intermediates, followed by the decarboxylation to
afford the desired aldol products. These interesting
findings may be helpful to further understand the
mechanism of the decarboxylative reactions in biological
systems8.
standard conditions. Interestingly, nicotinaldehyde
react with βꢀketoacid 1a in water to afford the βꢀhydroxy
ketone in excellent yields by flash column
6 could
7
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e)
OH
O
O
O
O
O
CO2
Me
Me
Me
O
OH
O
O
Me
Me
Me
OH
CO2Me
D2O
rt
OH
OMe
Me
Me
Me
Me
OH
OMe
+
OH
CO2Me
HO
HO
HO
Me
Me
9
1u
8
C9H16O4Na : calcd. 211.0941
found 211.0943
C10H16O6Na : calcd. 255.0839; found 255.0845
d)
c): 9
b): 1u
8
a):
Figure 1 13C NMR spectra of the reactants, the aldol product, and the reaction mixture in D2O (a–d) (bottom); the reaction
equation (middle); as well as ESI/MS experiment of the reaction mixture (e) (top).
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chromatography (petroleum ether/ethyl acetate: 6/1–3/1) gave
the expected product.
Conclusions
In conclusion, we have successfully developed a
decarboxylative aldol reaction of βꢀketoacids with
glyoxylate hydrates and glyxoal monohydrates in pure
water. This synthetic protocol proves to be ecoꢀfriendly
and costꢀeffective. In the absence of any base and metal
catalysts, the reaction proceeded smoothly to afford the
aldol adducts in good to high yields. Efforts are currently
underway to elucidate the mechanistic details and to
apply this reaction in bioorthogonal chemistry, the results
of which will be reported in due course.
The scaled-up decarboxylative aldol reaction of β-
ketoacid 1a with ethyl glyoxylate hydrate
Ethyl glyoxylate hydrate 2 (9.6 g, 80 mmol) was added to the
suspension of βꢀketoacid 1a (15.8 g, 96 mmol) in water (20
mL). The ultimate suspension was stirred for 10 h at ambient
temperature. After completion of the reaction, water was
evaporated under reduced pressure. Purification by vaccum
distillation using a Vigreux column gave the desired product as
a bright yellow oil (15.1 g, 85%); bp 153–157 °C/2 mmHg.
Ethyl 2-hydroxy-4-oxo-4-phenylbutanoate (3a)14a: 38.6 mg;
87% yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.96ꢀ
7.92 (m, 2H), 7.60ꢀ7.54 (m, 1H), 7.49ꢀ7.43 (m, 2H), 4.65 (dd, J
= 9.4, 5.3 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.56‒3.41 (m, 3H),
1.26 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 197.66,
173.92, 136.54, 133.74, 128.82, 128.29, 67.32, 61.97, 42.30,
14.24.
Experimental Section
1H, 13C and 19F NMR were recorded at 400 MHz (1H
NMR), 100 MHz (13C NMR), as well as 376 MHz (19F
NMR). Chemical shifts were reported in parts per million
(ppm) from the solvent resonance as the internal
standard (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm).
Multiplicity was indicated as follows:
s (singlet), d
Ethyl 2-hydroxy-4-oxo-4-(p-tolyl)butanoate (3b)14a
: 40.1
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet
of doublet), dt (doublet of triplets), br (broad). Coupling
constants were reported in Hertz (Hz). High resolution
mass spectrometry (HRMS) spectra were obtained on a
micrOTOFꢀQII Instrument. IR spectra were recorded on
an AVATAR 360 FTꢀIR spectrometer. Melting points were
measured on a WRSꢀ1A digital melting point apparatus
and are uncorrected. All commercially available reagents
were used without further purification. Analytical thin layer
chromatography was performed on 0.20 mm silica gel
plates. Silica gel (200‒300 mesh) was used for flash
chromatography. The ethyl glyoxylate and glyoxal
monohydrates were synthesized according to the
literature13. All the βꢀketoacids were prepared according
o
1
mg; 85% yield; white solid; Mp: 51ꢀ52 C; H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H),
4.58 (dd, J = 9.7, 5.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.47ꢀ
3.33 (m, 3H), 2.34 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 196.20, 172.80, 143.54, 132.96, 128.36,
127.28, 66.28, 60.79, 41.01, 20.67, 13.11.
Ethyl 2-hydroxy-4-oxo-4-(m-tolyl)butanoate (3c): 39.2 mg;
1
83% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.76ꢀ7.71
(m, 2H), 7.41ꢀ7.31 (m, 2H), 4.65 (dd, J = 5.6, 4.1 Hz, 1H), 4.25
(q, J = 7.1 Hz, 2H), 3.51ꢀ3.40 (m, 3H), 2.40 (s, 3H), 1.27 (t, J =
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 196.77, 172.80,
137.50, 135.44, 133.37, 127.65, 127.55, 124.40, 66.23, 60.81,
41.20, 20.31, 13.11; IR (KBr, ν, cmꢀ1): 3480, 2982, 2924,
1738, 1682, 1591, 1367, 1273, 1205, 1101, 1039, 788, 690;
HRMS (ESI) found: m/z 259.0944 [M + Na]+; calcd. for
C13H16O4+Na 259.0941.
to the literature11b
.
General procedure for decarboxylative aldol reaction of β-
ketoacids with glyoxylate hydrates
Ethyl 2-hydroxy-4-oxo-4-(o-tolyl)butanoate (3d): 41.1 mg;
87% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.69ꢀ7.65
Glyoxylate hydrates 2 or 8 (0.2 mmol) was added to the
suspension of βꢀketoacid 1 (0.3 mmol) in water (1.5 mL). The
1
(m, 1H), 7.42ꢀ7.37 (m, 1H), 7.30ꢀ7.23 (m, 2H), 4.63 (dd, J =
5.2, 4.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.45ꢀ3.36 (m, 3H),
2.51 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 201.10, 173.94, 138.70, 136.94, 132.12, 131.88,
128.85, 125.78, 67.43, 61.87, 44.83, 21.40, 14.16; IR (KBr, ν,
cmꢀ1): 3486, 2979, 2929, 1739, 1685, 1453, 1368, 1262, 1208,
ultimate suspension was stirred for
6 h at ambient
temperature. The reaction mixture was extracted with ethyl
acetate (15 mL × 3). The combined organic solvent was
washed with saturated sodium bicarbonate (10 mL), brine (10
mL), dried over anhydrous sodium sulfate, and the solvent
evaporated in vacuo. Purification of crude product by flash
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1099, 1037, 760; HRMS (ESI) found: m/z 259.0945 [M + Na]+; 7.85ꢀ7.79 (m, 1H), 7.51ꢀ7.45 (m, 1H), 7.21ꢀ7.14 (m, 1H), 7.11ꢀ
calcd. for C13H16O4+Na 259.0941.
7.04 (m, 1H), 4.55 (dd, J = 9.6, 5.6 Hz, 1H), 4.20 (q, J = 7.1
Hz, 2H), 3.53ꢀ3.45 (m, 1H), 3.45ꢀ3.36 (m, 1H), 3.23 (d, J = 5.7
Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
194.38 (d, J = 3.9 Hz), 172.84, 161.18 (d, J = 241.3 Hz),
134.20 (d, J = 9.2 Hz), 129.64 (d, J = 2.4 Hz), 123.91 (d, J =
12.6 Hz), 123.57 (d, J = 3.4 Hz), 115.73 (d, J = 21.9 Hz),
66.00 (d, J = 2.7 Hz), 60.85, 46.11 (d, J = 8.1 Hz), 13.10; 19F
Ethyl
4-(2,4-dimethylphenyl)-2-hydroxy-4-oxobutanoate
(3e): 40.5 mg; 81% yield; colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.63ꢀ7.59 (m, 1H), 7.09ꢀ7.05 (m, 2H), 4.61 (dd, J =
9.9, 5.6 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.47ꢀ3.35 (m, 3H),
2.49 (s, 3H), 2.35 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 199.30, 172.95, 141.66, 138.27, 132.87,
132.02, 128.44, 125.38, 66.48, 60.77, 43.41, 20.66, 20.38,
13.13; IR (KBr, ν, cmꢀ1): 3488, 2987, 2927, 2360, 1737, 1681,
1610, 1449, 1369, 1264, 1208, 1099, 1037, 762; HRMS (ESI)
found: m/z 273.1099 [M + Na]+; calcd. for C14H18O4+Na
273.1097.
NMR (376 MHz, CDCl3) δ ꢀ108.85～ꢀ108.93 (m); IR (KBr, ν,
cmꢀ1): 3491, 2984, 2935, 1739, 1687, 1609, 1578, 1480, 1452,
1368, 1277, 1211, 1101, 1040, 767, 540, 513; HRMS (ESI)
found: m/z 263.0692 [M + Na]+; calcd. for C12H13FO4+Na
263.0690.
Ethyl
4-(4-chlorophenyl)-2-hydroxy-4-oxobutanoate
56 oC; 1H
(3k)14a: 38.5 mg; 75% yield; white solid; Mp: 55
ꢀ
Ethyl 2-hydroxy-4-(4-methoxyphenyl)-4-oxobutanoate (3f)
o
14a: 42.8 mg; 85% yield; white solid; Mp: 65
ꢀ
66 C; 1H NMR
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.6 Hz, 2H), 7.44 (d, J =
8.5 Hz, 2H), 4.65 (dd, J = 9.3, 5.2 Hz, 1H), 4.26 (q, J = 7.1 Hz,
2H), 3.50 (dd, J = 17.4, 3.8 Hz, 1H), 3.41 (dd, J = 17.4, 6.0 Hz,
1H), 3.33 (d, J = 5.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 196.27, 173.70, 140.15, 134.79,
129.61, 129.06, 67.12, 61.99, 42.14, 14.14.
(400 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8
Hz, 2H), 4.63 (dd, J = 9.5, 5.4 Hz, 1H), 4.24 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 3.50ꢀ3.36 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 196.15, 173.85, 163.92, 130.53,
129.53, 113.85, 67.40, 61.77, 55.53, 41.77, 14.14.
Ethyl
(3g): 45.4 mg; 90% yield; yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.52 7.46 (m, 2H), 7.39ꢀ7.33 (m, 1H), 7.14ꢀ7.09 (m,
1H), 4.64 (dd, J = 5.5, 4.1 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H),
3.83 (s, 3H), 3.55ꢀ3.39 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 197.36, 173.81, 159.87, 137.78,
129.70, 120.87, 120.16, 112.29, 67.22, 61.87, 55.46, 42.32,
14.14; IR (KBr, ν, cmꢀ1): 3490, 2980, 1738, 1683, 1591, 1437,
1262, 1204, 1101, 1038, 866, 789, 686; HRMS (ESI) found:
m/z 275.0894 [M + Na]+; calcd. for C13H16O5+Na 275.0890.
2-hydroxy-4-(3-methoxyphenyl)-4-oxobutanoate
Ethyl 4-(3-chlorophenyl)-2-hydroxy-4-oxobutanoate (3l):
37.4 mg; 73% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
1
ꢀ
7.92 (s, 1H), 7.84ꢀ7.81 (m, 1H), 7.58ꢀ7.54 (m, 1H), 7.45ꢀ7.39
(m, 1H), 4.65 (d, J = 3.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.51
(dd, J = 17.5, 3.6 Hz, 1H), 3.42 (dd, J = 17.5, 5.9 Hz, 1H), 3.29
(d, J = 4.0 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 195.18, 172.67, 136.94, 134.04, 132.50,
129.04, 127.27, 125.27, 66.03, 60.99, 41.29, 13.11; IR (KBr, ν,
cmꢀ1): 3487, 2983, 2931, 1739, 1689, 1571, 1471, 1422, 1262,
1210, 1101, 1043, 789, 681; HRMS (ESI) found: m/z 279.0400
[M + Na]+; calcd. for C12H13ClO4+Na 279.0395.
Ethyl 2-hydroxy-4-oxo-4-(3,4,5-trimethoxyphenyl)butano-
ate (3h): 51.8 mg; 83% yield; yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.19 (s, 2H), 4.63 (dd, J = 4.4, 4.0 Hz, 1H), 4.26 (q, J
= 7.0 Hz, 2H), 3.89 (s, 9H), 3.53ꢀ3.37 (m, 3H), 1.28 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 196.35, 173.81,
153.11, 143.08, 131.66, 105.72, 67.34, 61.90, 60.98, 56.32,
41.93, 14.15; IR (KBr, ν, cmꢀ1): 3474, 2941, 2838, 1735, 1675,
1584, 1457, 1413, 1325, 1233, 1123, 1002, 890, 772; HRMS
(ESI) found: m/z 335.1106 [M + Na]+; calcd. for C15H20O7+Na
2335.1101.
Ethyl 4-(2-chlorophenyl)-2-hydroxy-4-oxobutanoate (3m):
39.0 mg; 76% yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.56ꢀ7.52 (m, 1H), 7.41ꢀ7.30 (m, 3H), 4.61 (dd, J = 5.7, 4.4
Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.51 (dd, J = 17.5, 4.2 Hz,
1H), 3.44 (dd, J = 17.5, 6.0 Hz, 1H), 3.30 (s, 1H), 1.28 (t, J =
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 199.97, 173.70,
138.31, 132.33, 131.26, 130.69, 129.53, 127.05, 67.28, 62.04,
46.52, 14.15; IR (KBr, ν, cmꢀ1): 3487, 2983, 2359, 1738, 1701,
1588, 1432, 1365, 1268, 1206, 1100, 1034, 761; HRMS (ESI)
found: m/z 279.0396 [M + Na]+; calcd. for C12H13ClO4+Na
279.0395.
Ethyl 4-(4-fluorophenyl)-2-hydroxy-4-oxobutanoate (3i)14b
:
o
1
39.3 mg; 82% yield; white solid; Mp: 62ꢀ64 C; H NMR (400
MHz, CDCl3) δ 8.01ꢀ7.95 (m, 2H), 7.17ꢀ7.11 (m, 2H), 4.65 (dd,
J = 8.9, 4.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.51 (dd, J =
17.4, 3.8 Hz, 1H), 3.42 (dd, J = 17.4, 6.0 Hz, 1H), 3.35 (d, J =
4.7 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 195.91, 173.75, 166.04 (d, J = 242.3 Hz), 132.93 (d,
J = 2.9 Hz), 130.90 (d, J = 9.5 Hz), 115.86 (d, J = 20.9 Hz),
67.17, 61.93, 42.08, 14.12; 19F NMR (376 MHz, CDCl3) δ ꢀ
Ethyl
4-(4-bromophenyl)-2-hydroxy-4-oxobutanoate
67 oC; 1H
(3n)14b: 44.5 mg; 74% yield; white solid; Mp: 66
ꢀ
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.61 (d, J =
8.5 Hz, 2H), 4.64 (dd, J = 9.2, 5.1 Hz, 1H), 4.26 (q, J = 7.1 Hz,
2H), 3.49 (dd, J = 17.4, 3.8 Hz, 1H), 3.40 (dd, J = 17.4, 6.0 Hz,
1H), 3.32 (d, J = 5.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 196.45, 173.70, 135.19, 132.02,
129.70, 128.84, 67.09, 61.93, 42.15, 14.13.
104.09～ꢀ104.16 (m).
Ethyl 4-(furan-2-yl)-2-hydroxy-4-oxobutanoate (3o)14c: 39.0
mg; 92% yield; white solid; Mp: 67ꢀ68 C; H NMR (400 MHz,
Ethyl 4-(2-fluorophenyl)-2-hydroxy-4-oxobutanoate (3j):
43.2 mg; 90% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
1
o
1
6 | J. Name., 2012, 00, 1-3
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CDCl3) δ 7.60 (s, 1H), 7.24ꢀ7.21 (m, 1H), 6.56ꢀ6.53 (m, 1H), Ethyl 2-hydroxy-5,5-dimethyl-4-oxohexanoate (3u)14e: 35.2
4.63 (dd, J = 10.0, 5.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.42ꢀ mg; 87% yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.44
3.24 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, (dd, J = 9.9, 4.9 Hz, 1H), 4.21 (q, J = 8.0 Hz, 2H), 3.29 (d, J =
CDCl3) δ 186.15, 173.67, 152.37, 146.89, 117.92, 112.51, 5.5 Hz, 1H), 2.98 (d, J = 4.7 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H),
67.05, 61.95, 42.03, 14.09.
1.11 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 213.70, 173.94,
67.15, 61.68, 44.11, 40.35, 26.07, 14.11.
Ethyl 2-hydroxy-4-oxo-4-(thiophen-3-yl)butanoate (3p):
1
41.1 mg; 90% yield; yellow oil; H NMR (400 MHz, CDCl3) δ Methyl 2-hydroxy-5,5-dimethyl-4-oxohexanoate (9)14i: 72.5
8.08 (s, 1H), 7.55ꢀ7.52 (m, 1H), 7.34ꢀ7.30 (m, 1H), 4.62 (s, mg; 82% yield; yellow oil; 1H NMR (400 MHz, D2O) δ 4.47 (t, J
1H), 4.25 (q, J = 7.1 Hz, 2H), 3.47ꢀ3.31 (m, 3H), 1.27 (t, J = = 5.0 Hz, 1H), 3.63 (s, 3H), 3.08 (d, J = 5.1 Hz, 2H), 1.01 (s,
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 190.65, 172.70, 9H); 13C NMR (101 MHz, D2O) δ 218.06, 175.98, 66.30, 52.62,
140.77, 131.82, 125.76, 125.65, 66.21, 60.89, 42.26, 13.10; IR 43.93, 40.76, 25.15.
(KBr, ν, cmꢀ1): 3473, 3102, 2981, 1736, 1672, 1511, 1412,
General procedure for decarboxylative aldol reaction of
ketoacids with glyoxal monohydrates
β-
1266, 1206, 1101, 1040, 866, 798, 636; HRMS (ESI) found:
m/z 251.0346 [M + Na]+; calcd. for C10H12O4S+Na 251.0349.
A mixture of βꢀketoacid 1a (164.2 mg, 1 mmol) and glyoxal
monohydrate 4 (0.67 mmol) was stirred in water (2 mL) at
room temperature for 8 h. In most cases (except 5j and 5k),
the solid product was directly filtered, washed with saturated
sodium bicarbonate (20 mL) and dried under vacuum to afford
the aldol products. Compounds 5j and 5k were purified by
flash column chromatography (petroleum ether/ethyl acetate:
6/1–4/1).
Ethyl 2-hydroxy-4-oxo-6-phenylhexanoate (3q): 42.0 mg;
1
84% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.23
ꢀ
7.18
(m, 2H), 7.14ꢀ7.08 (m, 3H), 4.40 (dd, J = 5.7, 4.2 Hz, 1H), 4.16
(q, J = 7.1 Hz, 2H), 3.16 (s, 1H), 2.89 2.69 (m, 6H), 1.20 (t, J =
ꢀ
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 207.34, 173.72,
140.70, 128.55, 128.31, 126.21, 66.98, 61.94, 46.09, 44.95,
29.36, 14.14; IR (KBr, ν, cmꢀ1): 3485, 2979, 2933, 2128, 1720,
1450, 1374, 1264, 1211, 1099, 1033, 749, 701; HRMS (ESI)
found: m/z 273.1097 [M + Na]+; calcd. for C14H18O4+Na
273.1097.
2-hydroxy-1,4-diphenylbutane-1,4-dione (5a)14h: 145 mg;
85% yield; white solid; Mp: 90ꢀ92 oC; 1H NMR (400 MHz,
CDCl3) δ 8.01ꢀ7.97 (m, 2H), 7.95ꢀ7.91 (m, 2H), 7.61ꢀ7.53 (m,
2H), 7.52ꢀ7.43 (m, 4H), 5.68 (s, 1H), 4.08 (s, 1H), 3.52ꢀ3.29
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 200.82, 197.19,
136.60, 135.14, 133.99, 133.62, 128.97, 128.76, 128.70,
128.35, 70.06, 43.56.
Ethyl 4-cyclopropyl-2-hydroxy-4-oxobutanoate (3r): 31.6
mg; 85% yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.47
(dd, J = 5.9, 4.0 Hz, 1H), 4.28ꢀ4.20 (m, 2H), 3.25 (s, 1H), 3.11
(dd, J = 17.4, 3.9 Hz, 1H), 3.03 (dd, J = 17.4, 6.1 Hz, 1H),
1.97ꢀ1.90 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.10
ꢀ1.06 (m, 2H),
(5b)14h
:
0.95
ꢀ
0.90 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 208.41,
2-hydroxy-4-phenyl-1-(p-tolyl)butane-1,4-dione
167.2 mg; 93% yield; white solid; Mp: 112ꢀ113 oC; 1H NMR
(400 MHz, CDCl3) δ 7.95ꢀ7.87 (m, 4H), 7.59ꢀ7.53 (m, 1H),
7.47ꢀ7.41 (m, 2H), 7.31ꢀ7.27 (m, 2H), 5.66 (s, 1H), 4.04 (d, J =
5.8 Hz, 1H), 3.44ꢀ3.31 (m, 2H), 2.41 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 200.37, 197.17, 145.11, 136.69, 133.57,
130.90, 129.67, 128.87, 128.68, 128.35, 69.88, 43.87, 21.79.
173.66, 67.04, 61.81, 46.42, 21.06, 14.14, 11.30; IR (KBr, ν,
cmꢀ1): 3496, 2985, 1738, 1698, 1391, 1265, 1205, 1094, 1030,
737; HRMS (ESI) found: m/z 209.0784 [M + Na]+; calcd. for
C9H14O4+Na 279.0784.
Ethyl 4-cyclohexyl-2-hydroxy-4-oxobutanoate (3s): 36.5
1
mg; 80% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 4.45
(s, 1H), 4.26ꢀ4.18 (m, 2H), 3.25 (s, 1H), 2.99ꢀ2.88 (m, 2H),
2-hydroxy-1-(4-methoxyphenyl)-4-phenylbutane-1,4-dione
2.34ꢀ2.31 (m, 1H), 1.85ꢀ1.64 (m, 5H), 1.30ꢀ
1.15 (m, 8H); 13C
o
(5c)14h: 175.3 mg; 92% yield; white solid; Mp: 120ꢀ121 C; 1H
NMR (101 MHz, CDCl3) δ 211.70, 173.80, 67.10, 61.77,
51.03, 43.85, 28.14, 28.06, 25.77, 25.53, 25.49, 14.14; IR
(KBr, ν, cmꢀ1): 3487, 2931, 2856, 2360, 1739, 1712, 1449,
1377, 1260, 1207, 1107, 1032, 758; HRMS (ESI) found: m/z
251.1274 [M + Na]+; calcd. for C12H20O4+Na 251.1276.
NMR (400 MHz, CDCl3) δ 8.01ꢀ7.97 (m, 2H), 7.97ꢀ7.93 (m,
2H), 7.60ꢀ7.55 (m, 1H), 7.49ꢀ7.43 (m, 2H), 6.99ꢀ6.95 (m, 2H),
5.69ꢀ5.65 (m, 1H), 4.08 (d, J = 6.3 Hz, 1H), 3.88 (s, 3H), 3.42
(dd, J = 17.0, 7.9 Hz, 1H), 3.31 (dd, J = 17.0, 2.9 Hz, 1H); 13
C
NMR (101 MHz, CDCl3) δ 199.09, 197.34, 164.26, 136.70,
133.59, 131.18, 128.69, 128.36, 126.12, 114.22, 69.61, 55.60,
44.09.
Ethyl 2-hydroxy-4-oxoheptanoate (3t)14d: 32.7 mg; 87%
1
yield; colorless oil; H NMR (400 MHz, CDCl3) δ 4.45 (dd, J =
9.8, 5.5 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.23 (d, J = 5.2 Hz,
1H), 2.92 (dd, J = 17.3, 4.0 Hz, 1H), 2.86 (dd, J = 17.3, 6.1 Hz,
1-(4-fluorophenyl)-2-hydroxy-4-phenylbutane-1,4-dione
(5d)14h: 164.2 mg; 90% yield; white solid; Mp: 121ꢀ123 C; H
NMR (400 MHz, CDCl3) δ 8.07ꢀ8.03 (m, 2H), 7.95ꢀ7.93 (m,
2H), 7.59ꢀ7.57 (m, 1H), 7.47ꢀ7.44 (m, 2H), 7.19ꢀ7.14 (m, 2H),
5.61 (s, 1H), 4.11 (s, 1H), 3.46 (dd, J = 17.2, 7.1 Hz, 1H), 3.37
(dd, J = 17.2, 3.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
199.08 (s), 197.52 (s), 166.11 (d, J = 257.2 Hz), 136.51 (s),
o
1
1H), 2.41 (t, J = 7.3 Hz, 2H), 1.64ꢀ1.55 (m, 2H), 1.27 (t, J = 7.1
Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
208.57, 173.75, 67.03, 61.85, 45.86, 45.30, 16.97, 14.12,
13.61.
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133.72 (s), 131.61 (d, J = 9.4 Hz), 130.13 (s), 128.74 (s), 7.98ꢀ7.94 (m, 2H), 7.62ꢀ7.56 (m, 1H), 7.50ꢀ7.45 (m, 2H), 5.08
128.34 (s), 116.15 (d, J = 21.2 Hz), 70.17 (s), 43.26 (s); 19F (s, 1H), 3.62 (s, 1H), 3.35 (dd, J = 17.1, 7.2 Hz, 1H), 3.28 (dd,
NMR (376 MHz, CDCl3) δ ꢀ103.13~ꢀ103.27 (m).
J = 17.1, 3.5 Hz, 1H), 1.28 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 215.77, 198.33, 136.68, 133.63, 128.72, 128.29,
69.80, 43.50, 42.44, 26.80. IR (KBr, ν, cmꢀ1): 3422, 1735,
1702, 1450, 1365, 1260, 1205, 1154, 1036, 950, 758; HRMS
(ESI) found: m/z 257.1144 [M + Na]+; calcd. for C14H18O3+Na
257.1148.
1-(4-chlorophenyl)-2-hydroxy-4-phenylbutane-1,4-dione
(5e)14h: 164.1 mg; 85% yield; white solid; Mp: 149ꢀ150 C; H
NMR (400 MHz, CDCl3) δ 7.96ꢀ7.93 (m, 4H), 7.61ꢀ5.56 (m,
1H), 7.48ꢀ7.44 (m, 4H), 5.59 (s, 1H), 4.06 (s, 1H), 3.46 (dd, J =
17.3, 6.9 Hz, 1H), 3.38 (dd, J = 17.2, 3.1 Hz, 1H); 13C NMR
o
1
(101 MHz, CDCl3) δ 199.55, 197.51, 140.42, 136.45, 133.78, Procedure for decarboxylative aldol reaction of β-ketoacid
132.10, 130.25, 129.28, 128.75, 128.34, 70.29, 43.14.
1a with nicotinaldehyde 6
nicotinaldehyde 6 (0.75 g, 7 mmol) was added to the
suspension of βꢀketoacid 1a (1.7 g, 10.5 mmol) in water (15
mL). The ultimate suspension was stirred for 10 h at room
temperature. The white precipitate was directly filtered,
washed with saturated sodium bicarbonate (60 mL), and dried
under vacuum to afford the desired product 7 (1.3 g, 87%)
without further purification.
1-(4-bromophenyl)-2-hydroxy-4-phenylbutane-1,4-dione
(5f)14h: 201.2 mg; 90% yield; yellow solid; Mp: 155ꢀ157 oC; H
NMR (400 MHz, CDCl3) δ 7.95ꢀ7.93 (m, 2H), 7.90ꢀ7.86 (m,
2H), 7.65ꢀ7.63 (m, 2H), 7.61ꢀ7.57 (m, 1H), 7.49ꢀ7.44 (m, 2H),
5.57 (s, 1H), 4.02 (s, 1H), 3.46 (dd, J = 17.2, 6.9 Hz, 1H), 3.38
(dd, J = 17.2, 3.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
199.74, 197.48, 136.47, 133.77, 132.56, 132.26, 130.31,
129.17, 128.75, 128.34, 70.34, 43.11.
1
3-hydroxy-1-phenyl-3-(pyridin-3-yl)propan-1-one (7)14g: 1.3
o
g; 87% yield; white solid; Mp: 89
ꢀ
91 C; 1H NMR (400 MHz,
2-hydroxy-1-(4-nitrophenyl)-4-phenylbutane-1,4-dione
(5g)14h: 150.4 mg; 75% yield; yellow solid; Mp: 143ꢀ145 oC; 1H
NMR (400 MHz, CDCl3) δ 8.34ꢀ8.30 (m, 2H), 8.20ꢀ8.16 (m,
2H), 7.96ꢀ7.92 (m, 2H), 7.63ꢀ7.58 (m, 1H), 7.50ꢀ7.47 (m, 2H),
5.52ꢀ5.48 (m, 1H), 4.09 (s, 1H), 3.54 (d, J = 4.9 Hz, 2H); 13C
NMR (101 MHz, CDCl3) δ 199.41, 198.04, 150.46, 139.23,
136.16, 134.02, 130.03, 128.82, 128.33, 123.91, 71.25, 42.22.
CDCl3) δ 8.60 (s, 1H), 8.48ꢀ8.44 (m, 1H), 7.94ꢀ7.91 (m, 2H),
7.82ꢀ7.78 (m, 1H), 7.59ꢀ7.54 (m, 1H), 7.47ꢀ7.41 (m, 2H), 7.30ꢀ
7.25 (m, 1H), 5.38 (dd, J = 8.8, 3.3 Hz, 1H), 4.63 (s, 1H), 3.41
(dd, J = 17.6, 8.8 Hz, 1H), 3.32 (dd, J = 17.6, 3.4 Hz, 1H); 13
C
NMR (101 MHz, CDCl3) δ 199.52, 148.87, 147.65, 138.90,
136.52, 133.91, 133.88, 128.86, 128.28, 123.67, 67.93, 47.23.
Acknowledgements
2-hydroxy-1-(naphthalen-2-yl)-4-phenylbutane-1,4-dione
o
(5h)14h: 167.2 mg; 82% yield; yellow solid; Mp: 91ꢀ92 C; 1H
This work was supported financially by the National
Natural Science Foundation of China (No. 21225208,
21472137, and 21532008), Tianjin Municipal Science &
Technology Commission (14JCQNJC06200),and the
National Basic Research Program of China (973
Program: 2014CB745100).
NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.04ꢀ8.02 (m, 1H),
7.98ꢀ7.91 (m, 4H), 7.89ꢀ7.85 (m, 1H), 7.64ꢀ7.60 (m, 1H), 7.59ꢀ
7.53 (m, 2H), 7.47ꢀ7.41 (m, 2H), 5.85ꢀ5.81 (m, 1H), 4.11 (d, J
= 6.1 Hz, 1H), 3.52ꢀ3.41 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 200.74, 197.31, 136.64, 135.94, 133.63, 132.43, 130.89,
130.66, 129.75, 129.04, 128.94, 128.70, 128.36, 127.87,
127.12, 124.10, 70.19, 43.79.
Notes and references
2-hydroxy-4-phenyl-1-(thiophen-2-yl)butane-1,4-dione
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Org. Process Res. Dev., 2007, 11, 114.
2 (a) C.ꢀJ. Li, Chem. Rev., 2005, 105, 3095; (b) C.ꢀJ. Li and
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o
(5i)14h: 151.4 mg; 87% yield; white solid; Mp: 114ꢀ116 C; 1H
NMR (400 MHz, CDCl3) δ 7.98ꢀ7.96 (m, 3H), 7.74ꢀ7.72 (m,
1H), 7.61ꢀ7.57 (m, 1H), 7.49ꢀ7.45 (m, 2H), 7.19ꢀ7.16 (m, 1H),
5.45ꢀ5.40 (m, 1H), 4.01 (d, J = 6.6 Hz, 1H), 3.56 (dd, J = 17.3,
7.6 Hz, 1H), 3.45 (dd, J = 17.3, 3.2 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 198.02, 193.15, 139.88, 136.49, 135.04,
133.92, 133.76, 128.75, 128.40, 128.35, 71.54, 43.66.
3-hydroxy-1-phenylpentane-1,4-dione (5j)14f: 36.1 mg; 94%
1
yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.97ꢀ7.93 (m,
2H), 7.62ꢀ7.56 (m, 1H), 7.50ꢀ7.44 (m, 2H), 4.52 (d, J = 3.3 Hz,
1H), 3.85 (d, J = 4.3 Hz, 1H), 3.56 (dd, J = 17.6, 3.7 Hz, 1H),
3.40 (dd, J = 17.6, 6.1 Hz, 1H), 2.33 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 209.71, 198.36, 136.31, 133.84, 128.77,
128.30, 73.91, 41.64, 25.65.
3 (a) U. M. Lindström, Chem. Rev., 2002, 102, 2751; (b) A.
Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725; (c)
M. B. Gawande, V. D. Bonifácio, R. Luque, P. S. Branco
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(a) A. T. Nielsen and W. J. Houlihan, Org. React., 1968, 16,
1; (b) T. Mukaiyama, Org. React., 1982, 28, 203; (c) C. H.
Heathcock, The Aldol Reaction: Acid and General Base
Catalysis in Comprehensive Organic Synthesis, Pergamon
3-hydroxy-5,5-dimethyl-1-phenylhexane-1,4-dione
(5k):
41.2 mg; 88% yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ
8 | J. Name., 2012, 00, 1-3
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