I2-catalyzed direct α-hydroxylation of β-dicarbonyl compounds with atmospheric oxygen under photoirradiation

Article abstract of DOI:10.1021/jo401866p

An I₂-catalyzed hydroxylation of β-dicarbonyl moieties using air as the oxidant under photoirradiation has been developed for the easy preparation of α-hydroxy-β-dicarbonyl compounds. The transformation was completed with only 1 mol % of I₂. With α-unsubstituted malonates, the hydroxylated dimerization product was afforded as the predominant product along with a minor product, α,α-dihydroxyl malonate.

Full text of DOI:10.1021/jo401866p

Note
pubs.acs.org/joc
I2‑Catalyzed Direct α‑Hydroxylation of β‑Dicarbonyl Compounds with
Atmospheric Oxygen under Photoirradiation
Chun-Bao Miao,* Yan-Hong Wang, Meng-Lei Xing, Xin-Wei Lu, Xiao-Qiang Sun,* and Hai-Tao Yang
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, People’s Republic of China
S
* Supporting Information
ABSTRACT: An I2-catalyzed hydroxylation of β-dicarbonyl
moieties using air as the oxidant under photoirradiation has
been developed for the easy preparation of α-hydroxy-β-
dicarbonyl compounds. The transformation was completed with
only 1 mol % of I2. With α-unsubstituted malonates, the
hydroxylated dimerization product was afforded as the
predominant product along with a minor product, α,α-
dihydroxyl malonate.
he α-hydroxy-β-dicarbonyl compounds are useful syn-
thetic intermediates and common structural units in many
tates to generate α-ketoesters as the major product
accompanied by the formation of minor α-hydroxylation
products (<10% yield).19 In view of the limitations of the
existing methods, we report here a metal-free and air oxidative
methodology for the α-hydroxylation of β-dicarbonyl moieties
catalyzed by I2 under photoirradiation (Scheme 1).
The use of I2 as an inexpensive and efficient reagent in
organic transformations has been well documented.20 We
recently reported a directly air oxidative α-hydroxylation of α-
substituted diethyl malonates using I2 and NaOAc (0.2 equiv
for each) in THF.21 However, only the Michael adducts of
malonates with enones were used in the research. In
continuation of our research on I2 chemistry,21,22 we attempted
to explore a general methodology to realize the α-hydroxylation
of other common β-dicarbonyl compounds using an I2/NaOAc
system.
T
natural products and pharmaceutical compounds.1 To date, a
number of methods have been developed to prepare the α-
hydroxy-β-dicarbonyl moieties.2 Recently, the asymmetric α-
hydroxylation of β-dicarbonyl compounds has gained increased
attention.3 The commonly used strategy is the direct oxidation
of the corresponding β-dicarbonyl compounds with various
oxidants (i.e., MoOPH,4 OsO4,5 Pb(OAc)4,6 m-CPBA,7 DMD,8
oxaziridines,9 IBX,10 oxone,11 ROOH,3d,12 H2O213), or
molecular oxygen catalyzed by a transition-metal catalyst (i.e.,
Mn,14 Co,15 Cs,16 Ce,17 Pd18) (Scheme 1). Nevertheless, the
Scheme 1
We commenced our investigation of the hydroxylation of β-
ketoester 1a by stirring together at room temperature a mixture
of 1a (1 mmol), NaOAc (0.2 mmol), and iodine (0.2 mmol) in
THF (10 mL). In our initial studies, we noted that the reaction
had poor reproducibility. Sometimes 1a could be completely
transformed to 2a within 12 h, while at other times a low
conversion of 1a to 2a (<25%) was achieved even after stirring
for 4 days. Later on, we determined that conversion was related
to the light intensity. The reaction proceeded better under
strong light than in the dark. When the reaction was carried out
under the irradiation of a 300 W high pressure lamp at 35 °C,
the reaction was completed within 1 h and gave the desired
product 2a in 95% yield. We then proceeded to optimize the
other conditions of the transformation (Table 1).
required stoichiometric amounts of organic oxidants or heavy
metals present disadvantages of high costs of materials and the
need to dispose of toxic byproducts. Thus, from an economical
and ecological point of view, the air oxidation of β-dicarbonyl
compounds catalyzed by Mn, Co, Ce, Cs, and Pd salts is
optimal. However, these reactions are still limited by the
restricted scope of substrates, the requirement for a metal
catalyst loading of at least 5 mol %, and the need for an oxygen
atmosphere (1 atm). Recently, the direct transformation of β-
ketoesters to α-hydroxymalonate with molecular oxygen
catalyzed by CaI2 under photoirradiation through a tandem
oxidation/rearrangement process was reported. In this
procedure, the substrates were limited to the α-unsubstituted
β-ketoesters.2c The combination of I2 and t-BuOK has been
reported to initiate the oxidative degradation of arylacetoace-
The influence of the molar ratio of 1a:I2:base on the reaction
was first investigated (Table 1, entries 1−4). The results
showed that 1 mol % of I2 and 1 mol % of NaOAc were enough
to give a high yield of 2a (94%, entry 4), albeit a longer reaction
Received: August 22, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401866p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of Reaction Conditions for the
Synthesis of 2a
Scheme 2. I2-Catalyzed α-Hydroxylation of 2-Substituted β-
Keto Esters
a
a
b
molar ratio
[1a:I2:base]
time
(h)
yield
(%)
entry
base
solvent
1
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
NaOH
TEA
1:0.2:0.2
THF
1
2
95
2
1:0.05:0.05
1:0.02:0.02
1:0.01:0.01
1:0.01:0.01
1:0:0.01
THF
93
3
THF
3
94
4
THF
4
94
c
5
THF
48
4
trace
0
6
THF
7
1:0.01:0
THF
4
0
8
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
1:0.01:0.01
THF
5
93
9
THF
10
10
10
10
10
10
10
10
10
10
92
10
11
12
13
14
15
16
17
18
THF
trace
trace
19
pyridine
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
THF
dioxane
EtOAc
CHCl3
CH3CN
EtOH
DMF
DMSO
29
15
a
Reaction conditions: 1 (1 mmol), I2 (0.01 mmol), NaOAc (0.01
10
mmol), THF (10 mL), and 300 W high pressure mercury lamp.
13
88
3). The reaction proceeded smoothly to afford the correspond-
ing α-hydroxylated products 4a−4k (except 4f) in moderate to
trace
a
Unless otherwise noted, all the reactions were performed with 1a (1
mmol) and proper additives in 10 mL of solvents, simultaneously
bubbled with air through a capillary column and irradiated with a 300
W high pressure mercury lamp at 35 °C. Isolated yield. The reaction
was carried out under dark conditions.
Scheme 3. I2-Catalyzed α-Hydroxylation of 2-Substituted
Malonates
a
b
c
time (4 h) was needed. Both I2 and NaOAc were essential for
the successful hydroxylation of 1a (Table 1, entries 6 and 7).
Photoirradiation also played an essential role; that is, only a
trace conversion to 2a occurred under dark conditions after 48
h (Table 1, entry 5). Other organic or inorganic bases were also
examined. The inorganic bases such as Na2CO3 or NaOH were
the more efficient base (Table 1, entries 8 and 9). Attempts to
use triethylamine or pyridine were unsuccessful, generating
only traces of 2a (Table 1, entries 10 and 11). Among the
typical solvents, THF was found to be the most effective.
Although DMF afforded an acceptable 88% yield of 2a, the
solvent had a high boiling point and was hard to remove.
Overall, the most efficient and environmentally friendly method
to prepare a high yield of 2a involved using only 1 mol % of I2
and 1 mol % of NaOAc in THF under photoirradiation (Table
1, entry 4). Compared to our previous work,21 the reaction
time was shortened (4 h vs 48 h) and the loading of iodine was
decreased greatly (1% vs 20%).
a
Reaction conditions: 1 (1 mmol), I2 (0.01 mmol), NaOAc (0.01
mmol), THF (10 mL), and 300 W high pressure mercury lamp. b 0.05
mmol of I2 and 0.05 mmol of NaOAc were used.
Under the optimal reaction conditions, we examined the
scope and generality of this kind of transformation using
various β-ketoester compounds (Scheme 2). 2-Alkyl β-
ketoesters 1a−c, 1e, and 1f were efficiently converted to the
corresponding tertiary alcohols 2a−c, 2e, and 2f in excellent
yields within 2−8 h (83−94%). The double bonds were also
tolerated in this reaction (2f). In the case of the product 2d, the
yield was only 51% due to the incomplete conversion of 1d and
formation of some byproducts. Gratifyingly, the cyclic
substrates also gave the alcohol products 2g−2j in good yields
(72−90%).
excellent yields (56−96%). Although a hydroxyl group could be
successively introduced to 2-propargyl malonate 3e to produce
4e in 90% yield, 2-allyl malonate 3f failed to give the expected
product 4f. Alkynyl, carbonyl, nitro, and cyano groups were also
compatible with the reaction conditions (4e and 4g−i).
Furthermore, 2-aminodo substituted malonates 3j and 3k also
gave the α-hydroxyl malonates 4j23 and 4k23 in moderate
yields.
The use of 2-substituted malonates 3 demonstrated the
broad applicability of the I2-catalyzed hydroxylation (Scheme
To demonstrate the further synthetic utility of this
hydroxylation system, more 1,3-dicarbonyl compounds were
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The Journal of Organic Chemistry
Note
tested (Scheme 4). β-Diketones 5a−5d were smoothly
transformed to 6a−6d. As for 3-phenyl acetylacetone 5b, the
Table 2. Aerobic Oxidation of Unsubstituted β-Dicarbonyl
Compounds Catalyzed by I2
a
Scheme 4. α-Hydroxylation of β-Dicarbonyl Compounds
a
Catalyzed by I2
a
A mixture of 7 (1 mmol), I2, and NaOAc in 10 mL of THF was
irrradiated with 300 W high pressure mercury lamp at 35 °C,
b
simultaneously bubbled air through a capillary column. Isolated
yields.
a
was identified as the hydroxylated dimerization product and 9a
was α,α-dihydroxyl diethyl malonate. In comparison to the
Mn(OAc)3-catalyzed dimerization of malonate in HOAc with
the addition of large amounts of Ac2O and KOAc,25 our
procedure was a much greener approach with easier handling.
The dehydration of the alcohol 8a could easily afford the tetra-
acceptor-substituted alkene,25 which possessed unique elec-
tronic properties and was difficult to prepare. Diisopropyl
malonate 7b could also afford the hydroxylated dimerization
product 8b and α,α-dihydroxyl diisopropyl malonate 9b. When
ethyl acetoacetate 7c and acetylacetone 7d were employed in
the reaction, TLC indicated that complete conversion to a
single product had occurred. However, the NMR analysis
showed both of the products were present as complex mixtures.
The reaction mechanism for the generation of α-hydroxy-β-
dicarbonyl compounds 2, 4, and 6 is similar to our previous
research.21 In the presence of I2 and NaOAc, the β-dicarbonyl
compounds 1 are transformed to the crucial intermediate A,
which undergoes homolytic cleavage of the C−I bond to
generate the carbon radical B (Scheme 6). Insertion of
molecular oxygen to the species B followed by coupling with
iodine radical furnishes the iodoperoxide D. Homolytic O−O
bond cleavage of D produces oxygen radical E, and follow-up
trapping by the iodine radical forms hypoiodite F, which acts as
a good electrophonic reagent (I+). F reacts with the β-
dicarbonyl compound 1, 3, or 5 to afford α-hydroxyl product 2,
4, or 6 and the intermediate A, which undergoes the next cycle.
The photoirradiation is favorable to the key step of C−I bond
cleavage, which results in an obvious acceleration effect on the
reaction and low demand of the iodine catalyst. For the α-
unsubstituted malonates, elimination of HOI from D affords G,
which reacts with malonate to generate 8 or water to form 9,
respectively. Reaction of HOI with malonate provides H, which
enters into the next catalytic cycle.
Reaction conditions: 1 (1 mmol), I2 (0.01 mmol), NaOAc (0.01
mmol), THF (10 mL), and 300 W high pressure mercury lamp. b 0.05
mmol of I2 and 0.05 mmol of NaOAc were used.
desired hydroxylated product 6b was obtained in 62% yield
along with the formation byproduct 1024 in 21% yields.
Although the quantitative conversion of 5c and 5d was
observed on TLC, the isolated yields of products 6c and 6d
were relatively low. The cyclic β-diketone 5e and the simple
ketones 5f and 5g, with only one carbonyl group failed to give
the product. Fortunately, α-ethoxycarbonyl cyclic amides 5h
and 5i both produced the corresponding products 6h and 6i in
52% and 62% yields, respectively.
In order to show the practicality of the developed method,
we further performed large-scale I2-catalyzed hydroxylation
with 15 mmol of 1a or 3a in 30 mL of THF (Scheme 5). In
Scheme 5
order to reduce the use of solvent, the concentration was 5
times to that of the 1 mmol scale. An excellent yield of 2a
(92%) and 4a (94%) also could be achieved according to the
same procedure although the complete conversion needed a
longer time (9 and 11 h, respectively).
In the above I2-catalyzed hydroxylation, only the α-
substituted β-dicarbonyl compounds were investigated. We
questioned if the reaction could proceed with α-unsubstituted
β-dicarbonyl compounds under similar conditions. Conse-
quently, we treated the diethyl malonate 7a with 1 mol % of I2
and 1 mol % of NaOAc in THF under the similar conditions
(Table 2). After 4.5 h, complete conversion of 7a was observed
and a main product 8a along with minor product 9a was
isolated. Through NMR and HRMS spectroscopy analysis, 8a
In summary, we have developed an I2-catalyzed air oxidation
of β-dicarbonyl compounds under photoirradiation for the easy
preparation of α-hydroxy-β-dicarbonyl compounds. The
present method shows wide applicability and good functional
group tolerance. It is particularly noteworthy that the method is
C
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The Journal of Organic Chemistry
Note
1
a
2e: Colorless oil, 247.0 mg, 83%. H NMR (300 MHz, CDCl3) δ
7.95−7.99 (m, 2H), 7.59 (tt, J = 7.4, 1.3 Hz, 1H), 7.45 (t, J = 7.6 Hz,
2H), 7.20−7.25 (m, 3H), 7.05−7.11 (m, 2H), 4.21 (q, J = 7.1 Hz,
2H), 4.19 (s, 1H), 3.56 (d, J = 14.1 Hz, 1H), 3.44 (d, J = 14.2 Hz, 1H),
1.17 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.9, 171.6,
134.5, 134.3, 133.6, 130.5, 129.5, 128.7, 128.2, 127.2, 82.5, 62.8, 42.0,
14.0; HRMS-MALDI-TOF m/z: [M+K]+ Calcd for C18H18KO4
337.0842; Found 337.0837.
Scheme 6. Possible Reaction Mechanism
1
2f: Colorless oil, 179.9 mg, 84%. H NMR (300 MHz, CDCl3) δ
5.90 (ddt, J = 17.0, 10.4, 5.8 Hz, 1H), 5.27−5.38 (m, 2H), 4.68 (d, J =
5.8 Hz, 2H), 4.18 (s, 1H), 2.29 (s, 3H), 2.05−2.15 (m, 1H), 1.88−1.98
(m, 1H), 1.15−1.40 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 205.1, 170.7, 131.1, 119.6, 84.4, 66.9, 35.1, 25.3, 24.8,
22.7, 13.9; HRMS-MALDI-TOF m/z: [M+Na]+ Calcd for
C11H18NaO4 237.1103; Found 237.1110.
2g:18a Colorless oil, 155.1 mg, 90%. 1H NMR (300 MHz, CDCl3) δ
4.19−4.34 (m, 2H), 3.68 (s, 1H), 2.43−2.56 (m, 3H), 2.05−2.18 (m,
3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 213.6,
171.7, 79.8, 62.6, 35.9, 34.9, 18.4, 14.1.
2h:18a Colorless oil, 165.1 mg, 89%. 1H NMR (300 MHz, CDCl3) δ
4.33 (s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.52−2.73 (m, 3H), 2.00−2.11
(m, 1H), 1.79−1.93 (m, 2H), 1.63−1.77 (m, 2H), 1.30 (t, J = 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 207.4, 170.1, 80.7, 62.1, 38.9,
37.6, 27.0, 22.0, 14.0.
a
One of the reviewers proposed an alternative mechanism. They
thought that peroxy radical C would abstract a hydrogen atom from
the solvent THF, but not combine with the iodine radical to form
iodoperoxide D (see Supporting Information for the mechanism
discussion).
2i:18b Pale yellow solid, 158 mg, 72%. 1H NMR (300 MHz, CDCl3)
δ 8.05 (dd, J = 7.9, 1.2 Hz, 1H), 7.54 (td, J = 7.5, 1.4 Hz, 1H), 7.35 (t,
J = 7.5 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.38 (s, 1H), 3.75 (s, 3H),
3.07−3.21 (m, 2H), 2.72 (dt, J = 13.6, 5.0 Hz, 1H), 2.25 (ddd, J =
13.6, 8.7, 6.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 194.6, 171.2,
144.1, 134.5, 130.2, 129.0, 128.3, 127.1, 77.8, 53.1, 32.8, 25.6.
2j:17a Colorless oil, 112.7 mg, 78%. 1H NMR (300 MHz, CDCl3) δ
4.54 (ddd, J = 9.0, 8.3, 4.8 Hz, 1H), 4.47 (dt, J = 9.1, 7.3 Hz, 1H), 4.22
(s, 1H), 2.72 (ddd, J = 13.5, 7.3, 4.9 Hz, 1H), 2.41 (ddd, J = 13.5, 8.2,
7.3 Hz, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 205.0,
174.7, 81.3, 66.3, 34.1, 24.7.
consistent with the principles of green chemistry due to its
metal-free conditions, low loading of catalyst, and the use of
atmospheric oxygen as the oxidant, which makes the synthesis
more efficient, economical, and ecologically friendly.
EXPERIMENTAL SECTION
■
4a:2c Colorless oil, 214.8 mg, 93%. 1H NMR (300 MHz, CDCl3) δ
4.26 (q, J = 7.1 Hz, 4H), 3.73 (s, 1H), 2.02 (t, J = 7.8 Hz, 2H), 1.29 (t,
J = 7.1 Hz, 6H), 1.22−1.39 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.8, 79.1, 62.4, 34.4, 25.3, 22.7, 14.1,
14.0.
General Procedure for the I2-Catalyzed Direct α-Hydrox-
ylation of β-Dicarbonyl Compounds. The reaction was performed
on an XPA-7 photochemical reactor (http://www.njxu.com). A
mixture of the β-dicarbonyl compounds (1, 3, 5, or 7, 1 mmol), I2
(0.01 mmol, 10 μL × 1 mol·mL−1 THF solution of I2), and NaOAc
(0.01 mmol, 10 μL × 1 mol·mL−1 aqueous solution of NaOAc) were
stirred in 10 mL of THF in a quartz tube (ø 18 mm × 180 mm) at 35
°C under the irradiation of a 300 W high pressure mercury lamp for a
given time. Simultaneously, the solution was bubbled with an air pump
through a capillary column. Upon completion of the reaction detected
by TLC, the solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether) to provide the corresponding products 2, 4,
6, 8, or 9.
4b:23 Colorless oil, 168.9 mg, 89%. 1H NMR (300 MHz, CDCl3) δ
4.26 (q, J = 7.1 Hz, 4H), 3.77 (s, 1H), 1.63 (s, 3H), 1.29 (t, J = 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 171.0, 76.1, 62.5, 21.6, 14.0.
4c:18a Colorless oil, 251.9 mg, 95%. 1H NMR (300 MHz, CDCl3) δ
7.20−7.30 (m, 5H), 4.25 (q, J = 7.1 Hz, 4H), 3.73 (s, 1H), 3.35 (s,
2H), 1.29 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 170.0,
134.7, 130.4, 128.1, 127.2, 79.3, 62.6, 40.5, 14.1.
4d:18b Colorless oil, 221 mg, 88%. H NMR (300 MHz, CDCl3) δ
1
7.62−7.67 (m, 2H), 7.34−7.41 (m, 3H), 4.34 (s, 1H), 4.35 (dq, J =
10.7, 7.1 Hz, 2H), 4.27 (dq, J = 10.7, 7.1 Hz, 2H), 3.35 (s, 2H), 1.30
(t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 169.9, 136.0, 128.6,
128.0, 126.7, 80.0, 63.0, 14.0.
2a:17b Colorless oil, 189.1 mg, 94%. 1H NMR (300 MHz, CDCl3) δ
4.21−4.31 (m, 2H), 4.17 (s, 1H), 2.29 (s, 3H), 2.04−2.14 (m, 1H),
1.86−1.96 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.18−1.40 (m, 4H), 0.90
(t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.2, 171.1, 84.3,
62.7, 35.0, 25.3, 24.8, 22.8, 14.2, 14.0.
1
4e: Colorless oil, 191.7 mg, 90%. H NMR (300 MHz, CDCl3) δ
4.22−4.38 (m, 4H), 4.04 (s, 1H), 2.98 (d, J = 2.6 Hz, 2H), 2.05 (t, J =
2.7 Hz, 1H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
169.0, 77.8, 77.7, 71.5, 63.0, 26.0, 14.0; HRMS-MALDI-TOF m/z: [M
+Na]+ Calcd for C10H14NaO5 237.0739; Found 237.0741.
2b:18a Colorless oil, 141.2 mg, 88%. 1H NMR (300 MHz, CDCl3) δ
4.26 (q, J = 7.2 Hz, 2H), 4.19 (s, 1H), 2.28 (s, 3H), 1.60 (s, 3H), 1.30
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.0, 171.4, 81.0,
62.7, 24.2, 21.8, 14.0.
4g:21 White solid, 363.5 mg, 95%. H NMR (300 MHz, CDCl3) δ
1
2c:18a Colorless oil, 203.4 mg, 86%. 1H NMR (300 MHz, CDCl3) δ
7.20−7.30 (m, 5H), 4.23 (q, J = 7.2 Hz, 2H), 4.06 (s, 1H), 3.42 (d, J =
14.2 Hz, 1H), 3.18 (d, J = 14.2 Hz, 1H), 2.29 (s, 3H), 1.28 (t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.1, 170.6, 134.7, 130.2,
128.3, 127.2, 84.3, 62.9, 40.8, 25.2, 14.1.
7.90 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 7.3 Hz,
2H), 7.41 (t, J = 7.3 Hz, 2H), 7.21 (t, J = 7.3 Hz, 2H), 7.16 (d, J = 7.2
Hz, 1H), 4.45 (dd, J = 10.2, 2.9 Hz, 1H), 4.23−4.33 (m, 2H), 4.05
(dq, J = 10.7, 7.1 Hz, 1H), 4.01 (s, 1H), 3.98 (dq, J = 10.7, 7.1 Hz,
1H), 3.72 (dd, J = 17.4, 10.2 Hz, 1H), 3.37 (dd, J = 17.4, 3.1 Hz, 1H),
1.29 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 197.5, 170.0, 169.5, 138.6, 137.0, 133.1, 129.6, 128.6,
128.20, 128.18, 127.5, 82.0, 63.0, 62.8, 44.8, 40.3, 14.1, 13.9.
1
2d: Colorless oil, 152.8 mg, 51%. H NMR (300 MHz, CDCl3) δ
7.57−7.61 (m, 2H), 7.37−7.44 (m, 3H), 7.20−7.28 (m, 3H), 7.02−
7.05 (m, 2H), 4.71 (s, 1H), 4.33 (dq, J = 10.7, 7.1 Hz, 1H), 4.24 (dq, J
= 10.7, 7.1 Hz, 1H), 3.86 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 203.3, 170.6, 135.8, 133.8, 129.7, 128.9, 128.6,
128.5, 127.0, 126.7, 84.6, 63.3, 43.9, 14.1; HRMS-MALDI-TOF m/z:
[M+Na]+ Calcd for C18H18NaO4 321.1103; Found 321.1097.
1
4h: Yellow oil, 312.7 mg, 96%. H NMR (300 MHz, CDCl3) δ
7.34−741 (m, 2H), 7.27−7.31 (m, 3H), 4.95 (dd, J = 13.1, 4.4 Hz,
1H), 4.85 (dd, J = 13.1, 10.1 Hz, 1H), 4.48 (dd, J = 10.1, 4.4 Hz, 1H),
4.34 (dq, J = 10.7, 7.1 Hz, 1H), 4.29 (dq, J = 10.7, 7.2 Hz, 1H), 4.06
D
dx.doi.org/10.1021/jo401866p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
(dq, J = 10.7, 7.1 Hz, 1H), 4.04 (s, 1H), 3.97 (dq, J = 10.7, 7.2 Hz,
1H), 1.32 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 168.9, 168.5, 134.5, 129.4, 128.71, 128.67, 80.3, 76.6,
63.4, 63.2, 47.2, 14.0, 13.8; HRMS-MALDI-TOF m/z: [M+Na]+
Calcd for C15H19NNaO7 348.1059; Found 348.1053.
10: Colorless oil, 30.6 mg, 21%. H NMR (300 MHz, CDCl3) δ
8.00−8.03 (m, 2H), 7.65 (tt, J = 7.4, 1.3 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.7, 191.5, 134.7,
131.9, 130.5, 129.0, 26.5.
Large Scale Preparation of 2a and 4a. A mixture of the β-
dicarbonyl compounds (1a or 3a, 15 mmol), I2 (38.1 mg, 0.15 mmol),
and NaOAc (12.3 mg, 0.15 mmol) were stirred in 30 mL of THF in a
quartz tube (ø 28 mm × 180 mm) at 35 °C under the irradiation of a
300 W high pressure mercury lamp for a given time. Simultaneously,
the solution was bubbled with an air pump through a capillary column.
After the reaction was completed, most of the solvent was removed in
vacuo, and 40 mL of water were added. To the mixture was added
saturated Na2S2O3 until the disappearance of umber, and then the
mixture was extracted with dichloromethane (30 mL × 3). The
combined organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (ethyl acetate/petroleum ether) to provide the corresponding α-
hydroxylmalonate 2a (2.78 g, 92%) or 4a (3.26 g, 94%).
1
4i: Colorless oil, 212.2 mg, 93%. H NMR (300 MHz, CDCl3) δ
4.30 (q, J = 7.1 Hz, 4H), 3.91 (s, 1H), 2.47−2.52 (m, 2H), 2.39−2.44
(m, 2H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
169.4, 118.9, 77.2, 63.2, 30.4, 14.0, 11.7; HRMS-MALDI-TOF m/z:
[M+H]+ Calcd for C10H16NO5 230.1029; Found 230.1023.
4j:23 Colorless oil, 205.3 mg, 70%. H NMR (300 MHz, CDCl3) δ
1
8.02 (br, 1H), 7.83−7.86 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J =
7.4 Hz, 2H), 5.27 (s, 1H), 4.36 (q, J = 7.1 Hz, 4H), 1.31 (t, J = 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 167.1, 166.9, 132.6, 132.5, 128.8,
127.4, 80.3, 63.8, 14.0; HRMS-MALDI-TOF m/z: [M+H]+ Calcd for
C14H18NO6 296.1134; Found 296.1131.
4k:23 Colorless oil, 131.2 mg, 56%. 1H NMR (300 MHz, CDCl3) δ
7.40 (br, 1H), 5.20 (s, 1H), 4.32 (q, J = 7.1 Hz, 4H), 2.06 (s, 3H), 1.29
(t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 170.4, 167.0, 80.0,
63.6, 22.8, 13.9; HRMS-MALDI-TOF m/z: [M+H]+ Calcd for
C9H16NO6 234.0978; Found 234.0972.
ASSOCIATED CONTENT
* Supporting Information
■
S
6a:17a Pale yellow oil, 172.9 mg, 84%. 1H NMR (300 MHz, CDCl3)
δ 7.18−7.30 (m, 5H), 4.70 (s, 1H), 3.28 (s, 2H), 2.23 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 206.8, 134.6, 130.1, 128.4, 127.2, 91.1, 41.9,
25.7.
NMR spectra of all the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
6b:23 Pale yellow oil, 118.2 mg, 62%. 1H NMR (300 MHz, CDCl3)
δ 7.46−7.51 (m, 2H), 7.36−7.44 (m, 3H), 5.28 (s, 1H), 2.29 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 206.2, 136.6, 129.1, 129.0, 126.0, 89.1,
26.4.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: estally@yahoo.com.
*E-mail: sunxiaoqiang@yahoo.com.
6c:11 Colorless oil, 94.1 mg, 60%. H NMR (300 MHz, CDCl3) δ
1
4.62 (s, 1H), 2.61−2.78 (m, 2H), 2.40−2.48 (m, 1H), 2.24 (s, 3H),
2.02−2.13 (m, 1H), 1.64−1.96 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 209.1, 207.6, 85.5, 39.5, 38.5, 27.4, 25.6, 21.8.
Notes
The authors declare no competing financial interest.
6d:11 Yellow solid, 94.5 mg, 43%. H NMR (300 MHz, CDCl3) δ
1
ACKNOWLEDGMENTS
■
8.02−8.06 (m, 2H), 7.55 (tt, J = 7.4, 1.3 Hz, 1H), 7.43 (t, J = 7.5 Hz,
2H), 4.82 (s, 1H), 2.69−2.87 (m, 3H), 2.07−2.17 (m, 1H), 1.64−1.84
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 210.2, 198.0, 134.7, 133.3,
129.9, 128.5, 85.2, 40.2, 40.0, 27.6, 22.1.
The authors are grateful for financial support from the National
Natural Science Foundation of China (Nos. 20902039 and
21202011) and the Priority Academic Program Development
of Jiangsu Higher Education Institutions.
1
6h: Colorless oil, 96.9 mg, 52%. H NMR (300 MHz, CDCl3) δ
4.21−4.36 (m, 2H), 3.85 (br, 1H), 3.39−3.55 (m, 2H), 2.93 (s, 3H),
2.59 (ddd, J = 13.5, 7.6, 3.3 Hz, 1H), 2.22 (ddd, J = 13.5, 8.8, 7.3 Hz,
1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8,
171.0, 78.0, 62.7, 46.2, 31.0, 30.5, 14.1; HRMS-MALDI-TOF m/z: [M
+Na]+ Calcd for C8H13NNaO4 210.0742; Found 210.0737.
REFERENCES
■
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1
6i: White solid, 172.8 mg, 62%, mp 137−138 °C. H NMR (300
MHz, CDCl3) δ 7.29 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H),
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8b:25 Colorless oil, 132.4 mg, 68%. 1H NMR (300 MHz, CDCl3) δ
5.03−5.18 (m, 4H), 4.43 (s, 1H), 4.36 (s, 1H), 1.25−1.29 (m, 24H);
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1
9a: Colorless oil, 41.5 mg, 22%. H NMR (300 MHz, CDCl3) δ
4.78 (s, 2H), 4.35 (q, J = 7.1 Hz, 4H), 1.33 (q, J = 7.1 Hz, 6H); 13C
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9b: Colorless oil, 35.6 mg, 16%. H NMR (300 MHz, CDCl3) δ
5.16 (hept, J = 6.3 Hz, 2H), 4.80 (s, 2H), 1.30 (d, J = 6.3 Hz, 12H);
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TOF m/z: [M+H]+ Calcd for C9H17O6 221.1025; Found 221.1018.
E
dx.doi.org/10.1021/jo401866p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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