(Diacetoxyiodo)benzene-Mediated Reaction of Ethynylcarbinols: Entry to α,α'-Diacetoxy Ketones and Glycerol Derivatives

Article abstract of DOI:10.1021/acs.joc.5b00740

Efficient access to α,α'-diacetoxy ketones has been developed from ethynylcarbinols and PhI(OAc)₂. A plausible mechanism for this was proposed on the basis of experimental studies. The usefulness of α,α'-diacetoxy ketone products has been documented, and glycerol derivatives can be easily synthesized in good yields via a one-pot reaction.

Full text of DOI:10.1021/acs.joc.5b00740

Note
pubs.acs.org/joc
(Diacetoxyiodo)benzene-Mediated Reaction of Ethynylcarbinols:
Entry to α,α′-Diacetoxy Ketones and Glycerol Derivatives
Qing-Rong Liu, Cheng-Xue Pan, Xiao-Pan Ma, Dong-Liang Mo,* and Gui-Fa Su*
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Education of China and School of
Chemistry & Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China
S
* Supporting Information
ABSTRACT: Efficient access to α,α′-diacetoxy ketones has
been developed from ethynylcarbinols and PhI(OAc)2. A
plausible mechanism for this was proposed on the basis of
experimental studies. The usefulness of α,α′-diacetoxy ketone
products has been documented, and glycerol derivatives can be
easily synthesized in good yields via a one-pot reaction.
mong the most useful intermediates and key building
blocks in organic synthesis have been α,α′-diacetoxy
simple and efficient conversion method for preparing α,α′-
diacetoxy ketones would be an important step in organic
synthesis and medicinal chemistry. Meanwhile, much attention
has been paid to hypervalent iodine(III) reagents in recent
years due to their interesting activity, ready availability, and ease
of handling.10,11 In 1989, Ochiai and co-workers documented
that α-acetoxy ketones can be synthesized by conjugate
addition of acyloxy groups to alkynylphenyliodonium under
both basic and acidic conditions (Scheme 1A).12 Phenyliodine
A
ketone compounds. They are easily transferred into acetoxy α-
ketols,1 α,α′-dihydroxy ketones,2 or glycerol derivatives,3 which
are common structural motifs in natural products and
biologically active compounds such as fluocinonide,4 pirar-
ubicin,5 betamethasone,6 and disaccharides7 (Figure 1). The
Scheme 1. Oxidation of Alkynes by Hypervalent Iodine(III)
Compounds
Figure 1. Selected examples for α,α′-dihydroxy ketones or related
natural products.
bistrifluoroacetate (PIFA)-promoted intramolecular electro-
philic cyclization of alkynyl amides or alkynyl carboxylic
acids, leading to the formation of pyrrolidinone and lactone
skeletons, has been developed by Tellitu and co-workers in
2005 (Scheme 1B).13 In these reactions, the attack of the
alkynyliodonium salt intermediate by the nucleophiles was the
key step.14 When ethynylcarbinols were used as substrates, we
methods for synthesizing α,α′-diacetoxy ketone from ketone
starting material have been studied, most of which proceeded
through an acetoxy acetone as a key intermediate and a
sequence of bromination followed by acetolysis.8 It has also
been prepared by different routes involving the lead tetraacetate
oxidation of an enamide intermediate.9 Although such a
method gives a satisfactory overall yield, it requires many
steps and the use of toxic mercuric oxide or lead tetraacetate
and thus suffers from environmental problems. Therefore, a
Received: April 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00740
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
reasoned that the OH group might go through an intra-
molecular Michael-type addition to the alkynyliodonium salt
intermediate following attack by other nucleophiles, which
would introduce two nucleophiles into two α-positions of the
carbonyl (Scheme 1C). Herein, we report our results for this
new transformation in the preparation of α,α′-diacetoxy
ketones from ethynylcarbinols with PhI(OAc)2.
Table 2. Substrate Scope for the Preparation of α,α′-
Diacetoxy Ketone by the Reaction of Ethynylcarbinols 1 with
PhI(OAc)2
a b
,
Initially, 1-ethynylcyclopentanol 1a was treated with PhI-
(OAc)2 in toluene at 80 °C under an air atmosphere. α,α′-
Diacetoxy ketone 2a was isolated in 28% yield, accompanied by
the recovery of some starting material (Table 1, entry 1). The
Table 1. Optimizations for the Reaction of 1-
a
Ethynylcyclopentanol 1a with PhI(OAc)2
b
entry
oxidants
solvent
toluene
T (°C)
2a (%)
1
2
3
4
5
6
7
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
80
26
30
15
11
21
16
39
51
61
68
59
<5
71
75
74
0
MeCN
DMSO
DMF
80
80
80
CF3CH2OH
THF
80
80
DCE
80
c
8
DCE
80
9
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
80
10
11
12
100
60
a
rt
Reaction conditions: ethynylcarbinols 1 (0.5 mmol), PhI(OAc)2
b
c
d
13
100
100
100
100
(3.0−4.0 equiv), HOAc (1.5 mL), 24 h. Isolated yields. Run at 60
°C. PhI(OAc)2 (3.75 equiv).
d
e
14
f
15
g
16
corresponding α,α′-diacetoxy ketones 2a and 2b in good
yields. The reaction ran smoothly to furnish the desired
products in high yields when both R1 and R2 were aromatic-
substituted ethynylcarbinols (Table 2, 2c−2e). The reaction
was also tolerated with ethynylcarbinols in which R1 is an
aromatic group and R2 is an aliphatic group (Table 2, 2f−2n).
Having an electron-donating group at the 4-position of the
phenyl group gave higher yields, whereas an electron-
withdrawing group gave lower yields (Table 2, 2j vs 2h−2k).
The presence of meta-substituted groups on the phenyl ring
also afforded the desired products in high yields (Table 2, 21
and 2m). It is noted that when using a substrate with a methyl
group substituted on the aryl ring the reaction must run at 60
°C to provide higher yields (Table 2, 2d and 2l). When R1 and
R2 were acyclic aliphatic groups, the desired products were
obtained in high yields (Table 2, 2o and 2p). We were pleased
to observe that aryl groups with chlorine, bromide, and iodine
were tolerated under the reaction conditions because these
substituents further enhance the potential synthetic utility of
these functionalized products (Table 2, 2e, 2h, 2i, and 2m).
To understand the mechanism better, the reaction was
carried out with 1,1-diphenyl ethanol 3 under the standard
conditions; no desired acetate product 4 was observed,
affording only benzophenone and acetophenone in 46 and
32% yields, respectively (Scheme 2-1). This result revealed that
the OH group of ethynylcarbinol could not be converted to the
acetate intermediate first and that the alkynyl acetate was
oxidized by PhI(OAc)2 to form product 2. When compound 5
a
Reaction conditions: 1-ethynylcyclopentanol 1a (0.5 mmol), PhI-
b
c
(OAc)2 (0.6 mmol), solvent (1.5 mL), 24 h. Isolated yield. HOAc
(5.0 equiv) was added. PhI(OAc)2 (2.0 equiv). PhI(OAc)2 (3.0
equiv). PhI(OAc)2 (4.0 equiv). Only starting material was recovered.
d
e
f
g
influence of the solvent on the reaction was then evaluated.
Performing the reaction in DCE (1, 2-dichloroethane) afforded
2a in 39% yield (Table 1, entry 7), whereas the yield dropped
sharply when MeCN, DMSO, DMF, CF3CH2OH, or THF was
used as solvent (Table 1, entries 2−6). Product 2a increased to
51% yield when 5.0 equiv of HOAc was added to DCE (Table
1, entry 8). To our delight, when HOAc was used as the
solvent, the yield of product 2a was improved to 68% due to
HOAc playing roles as both nucleophile and solvent (Table 1,
entry 9). Studies of the effect of temperature showed that
product 2a was obtained in higher yield at 100 °C, whereas no
reaction occurred and the substrate was recovered for reactions
at room temperature (Table 1, entries 9−12). The amount of
PhI(OAc)2 used also greatly impacted the yield of α,α′-
diacetoxy ketone 2a. Using 3.0 equiv of PhI(OAc)2 proved to
be optimal for the transformation (Table 1, entries 10 and 13−
15). No desired product was observed in the absence of
PhI(OAc)2 after 24 h (Table 1, entry 16).
To examine the scope of present protocols, a variety of
ethynylcarbinols 1 were subjected to the standard conditions.
The results are summarized in Table 2. Treatment of cyclic
ethynylcarbinols 1a and 1b with PhI(OAc)2 provided
B
DOI: 10.1021/acs.joc.5b00740
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The Journal of Organic Chemistry
Note
Scheme 2. Mechanism Studies
Scheme 4. Usefulness of α,α′-Diacetoxy Ketones
was used in the presence or absence of PhI(OAc)2 at 100 °C
for 24 h, no α,α′-diacetoxy ketone 2b was observed, with only
starting material recovered (Scheme 2-2). This demonstrated
that α,α′-diacetoxyketone 2 might not be obtained directly
from compound 5. When substrate 1c was used in DCE/D2O
(3:1) instead of HOAc (Scheme 2-3), desired product D-2c
was obtained in 30% yield with a D/H ratio of 99:1 at the α-
position of the carbonyl group. When chiral ethynylcarbinol 1f
was subjected to the reaction conditions, only racemic product
2f was afforded in 70% yield (Scheme 2-4).
of this direct oxidative process on a gram scale, 1,1-diphenyl
ethynylcarbinol 1c was used as substrate at 5 mmol (1.0 g). To
our delight, α,α′-diacetoxy ketone 2c was isolated in 67% yield
(Scheme 4-2). When commercial (−)-Norgestrel 1q was
subjected to the reaction, desired product 2q was obtained in
43% yield with a 0.9:1 diastereoisomeric ratio, which is one of
the most important steroids (Scheme 4-3). When α,α′-
diacetoxy ketone 2c was treated with diluted HCl in MeOH,
α,α′-dihydroxylketone 7c was obtained in 73% yield.
Interestingly, the glycerol product 8c was isolated in 92%
yield by reduction of 2c with excess NaBH4 (Scheme 4-4).
Because glycerine product 8c was obtained easily by
reduction of NaBH4, we anticipated that we could obtain
glycerine product 8 from ethynylcarbinol 1 by a one-pot
reaction (Scheme 5). To our delight, an efficient process was
observed for the transformation in good yields by two steps
with no formal purification of the intermediates; this approach
required only the removal of HOAc prior to reduction. It is
worth noting that when ethynylcarbinol 1n was subjected to
On the basis of the literature12,14d and our observations, a
plausible mechanism is proposed in Scheme 3. The terminal
Scheme 3. A Plausible Mechanism for the Formation of
Product 2
Scheme 5. Synthesis of Glycerol Derivatives by a One-Pot
a
Reaction
alkyne could be oxidized to form the alkynyliodonium salt (Int-
A) by PhI(OAc)2 first; then, a Michael-type addition of the
ortho-OH group to the alkynyliodonium salt in Int-A provides
Int-B. A carbocation in Int-C could be obtained from the
epoxide in Int-B in the presence of HOAc. Then, Int-C can be
trapped by −OAc to form Int-D. Reductive elimination or
substitution of the phenyliodonium salt provides α,α′-diacetoxy
ketone 2.
The potential value of α,α′-diacetoxy ketones in organic
synthesis and their possible reaction mechanism inspired us to
investigate the possibility of using other trapping reagents and
exploring their synthetic utility. When 1,1-diphenyl ethynylcar-
binol 1c was treated with EtCO2H as the solvent in the
presence of PhI(OAc)2, desired products 6 was obtained in
82% yield (Scheme 4-1). To demonstrate the synthetic utility
a
Reaction conditions: (1) ethynylcarbinol 1 (0.5 mmol), PhI(OAc)2
(3.0−4.0 equiv), HOAc (1.5 mL), 24 h; (2) NaBH4 (22 equiv),
MeOH (3 mL).
C
DOI: 10.1021/acs.joc.5b00740
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The Journal of Organic Chemistry
Note
197.1, 169.9, 169.7, 136.5, 134.9, 129.6, 129.5, 129.0, 128.9, 128.8,
128.5, 87.9, 64.5, 21.4, 20.3; IR (KBr) 3010, 2953, 1741, 1592, 1489,
1368, 1231, 819 cm−1; HRMS (ESI) m/z for C19H16O5Cl2Na (M +
Na)+: calcd, 417.0272; found, 417.0286.
the same procedure the desired product 8n was obtained in
78% yield with a 4:1 diastereoisomeric ratio value.
In summary, we have shown that α,α′-diacetoxy ketones can
be synthesized in good to excellent yields from ethynylcarbinols
in one step through oxidation by PhI(OAc)2. Studies of the
mechanism revealed that the OH group might attack the
hypervalent iodinium salts to form a carbocation intermediate
under HOAc. The glycerol derivatives were easily synthesized
from ethynylcarbinols by a one-pot reaction. This new method
provides a facile entry into the study of the reactivity of α,α′-
dihydroxyketone or glycerol products.
2f, 101.6 mg, yield: 77%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.44−7.42 (m, 4H), 7.39−7.35 (m, 1H), 4.80 (d, J = 16.5
Hz, 1H), 4.72 (d, J = 16.5 Hz, 1H), 2.27 (s, 3H), 2.08 (s, 3H), 1.92 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 198.9, 170.1, 170.0, 137.9,
128.9, 128.5, 124.7, 86.4, 64.3, 23.2, 21.3, 20.4; IR (KBr) 3062, 2940,
2866, 1743, 1599, 1447, 1373, 1229, 762, 701 cm−1; HRMS (ESI) m/z
for C14H16O5Na (M + Na)+: calcd, 287.0895; found, 287.0911.
2g, 123.7 mg, yield: 89%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.32 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.79 (d, J
= 17.0 Hz, 1H), 4.72 (d, J = 17.0 Hz, 1H), 2.35 (s, 3H), 2.26 (s, 3H),
2.09 (s, 3H), 1.90 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 199.0,
170.0, 169.9, 138.3, 135.0, 129.5, 124.6, 86.3, 64.2, 23.1, 21.3, 21.0,
20.3; IR (KBr): 3062, 2940, 2866, 1743, 1599, 1447, 1373, 762, 701
cm−1; HRMS (ESI) m/z for C15H18O5Na (M + Na)+: calcd, 301.1052;
found, 301.1050.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under an
atmosphere of air. Commercially available reagents were used without
1
further purification. H and 13C NMR spectra were recorded at 500
MHz in CDCl3. 13C NMR spectra were recorded at 125 MHz in
CDCl3. IR spectra were recorded on a FT-IR spectrometer, and only
major peaks are reported in cm−1. HRMS were measured in EI or ESI
mode, and the mass analyzer of the HRMS was TOF. Flash column
chromatography was performed on silica gel (200−300 mesh).
Alkynols 1o, 1p, and 1q were purchased from Aldrich. 1a−1n,15
3,16 and 517 were prepared according to literature methods, and their
spectral data matched literature values.
2h, 136.8 mg, yield: 80%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.54 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.78 (d, J
= 16.5 Hz, 1H), 4.72 (d, J = 16.5 Hz, 1H), 2.26 (s, 3H), 2.10 (s, 3H),
1.89 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.7, 170.0, 169.8,
137.1, 132.0, 126.5, 122.8, 86.0, 64.3, 23.3, 21.3, 20.4; IR (KBr): 3003,
2942, 2872, 1743, 1412, 1372, 1229, 1020, 817 cm−1; HRMS (ESI) m/
z for C14H15O5BrNa (M + Na)+: calcd, 365.0001; found, 364.9994.
2i, 155.9 mg, yield: 80%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.74 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.77 (d, J
= 16.5 Hz, 1H), 4.71 (d, J = 16.5 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H),
1.87 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.7, 169.9, 169.8,
138.0, 137.8, 126.7, 94.5, 86.1, 64.3, 23.2, 21.3, 20.3; IR (KBr): 3001,
2940, 1743, 1585, 1484, 1373, 1228, 823 cm−1; HRMS (ESI) m/z for
C14H15O5INa (M + Na)+: calcd, 412.9862; found, 412.9848.
2j, 71.9 mg, yield: 51%. Colorless oil; 1H NMR (500 MHz, CDCl3):
δ 7.43 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 4.77 (d, J = 16.5
Hz, 1H), 4.73 (d, J = 16.5 Hz, 1H), 2.25 (s, 3H), 2.09 (s, 3H), 1.89 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 198.9, 170.0, 169.9, 163.5 (d, J
= 246.4 Hz), 133.8, 126.8 (d, J = 9.0 Hz), 115.8 (d, J = 21.7 Hz), 85.9,
64.3, 23.2, 21.2, 20.3; IR (KBr): 3005, 2944, 1744, 1510, 1373, 1223,
1015, 833 cm−1; HRMS (ESI) m/z for C14H15O5FNa (M + Na)+:
calcd, 305.0801; found, 305.0801.
General Procedure for the Synthesis of α,α′-Diacetoxyke-
tone 2 from Ethynylcarbinol 1 with PhI(OAc)2. In a Teflon-sealed
reaction flask, ethynylcarbinol 1 (0.5 mmol) and PhI(OAc)2 (1.5
mmol, 3.0 equiv) were dissolved in HOAc (1.5 mL) under air, and the
reaction vessel was sealed with a Teflon cap. The reaction mixture was
stirred at 100 °C until substrate 1 disappeared (monitored by TLC).
At this time, the reaction was diluted with H2O (10 mL) and extracted
with Et2O (3 × 10 mL). The combined organic layers were washed
with saturated NaHCO3 solution (1 × 10 mL) and brine (1 × 10 mL),
dried over Na2SO4, and filtered. The solvent was then removed under
vacuum. The crude product mixture was purified by flash
chromatography on silica gel (1:20−1:5; ethyl acetate/petroleum
ether) to give product 2.
2a,8a 85.5 mg, yield: 75%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 4.77 (s, 2H), 2.29−2.24 (m, 2H), 2.14 (s, 3H), 2.09 (s,
3H), 1.95−1.92 (m, 2H), 1.79−1.70 (m, 4H); 13C NMR (125 MHz,
CDCl3): δ 200.8, 171.0, 170.3, 92.7, 65.1, 36.1, 24.8, 21.0, 20.4; IR
(KBr): 2960, 2877, 1738, 1432, 1373, 1236, 1177, 799 cm−1; HRMS
(ESI) m/z for C11H16O5Na (M + Na)+: calcd, 251.0895; found,
251.0887.
2k, 112.8 mg, yield: 68%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.66 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 4.80 (d, J
= 16.5 Hz, 1H), 4.72 (d, J = 16.5 Hz, 1H), 2.27 (s, 3H), 2.08 (s, 3H),
1.91 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.6, 170.0, 169.8,
142.0, 130.8 (q, J = 32.7 Hz), 125.9 (q, J = 2.6 Hz), 125.3, 124.9 (q, J
= 270.7 Hz), 86.0, 64.4, 23.4, 21.2, 20.2; IR (KBr): 3004, 2947, 1745,
1412, 1374, 1328, 1103, 844, 799 cm−1; HRMS (ESI) m/z for
C15H15O5F3Na (M + Na)+: calcd, 355.0769; found, 355.0757.
2l, 100.0 mg, yield: 72%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.29 (s, 1H), 7.23−7.23 (m, 2H), 7.16 (d, J = 7.0 Hz, 1H),
4.80 (d, J = 16.5 Hz, 1H), 4.70 (d, J = 16.5 Hz, 1H), 2.38 (s, 3H), 2.27
(s, 3H), 2.09 (s, 3H), 1.90 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
199.0, 170.1, 170.0, 138.6, 137.8, 128.2, 128.7, 125.3, 121.7, 86.4, 64.3,
23.2, 21.5, 21.4, 20.4; IR (KBr): 3001, 2942, 2855, 1743, 1414, 1373,
1233, 1029, 706 cm−1; HRMS (ESI) m/z for C15H18O5Na (M + Na)+:
calcd, 301.1052; found, 301.1063.
2b,8a 73.8 mg, yield: 61%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 4.83 (s, 2H), 2.15 (s, 3H), 2.13 (s, 3H), 1.74−1.65 (m,
5H), 1.54−1.52 (m, 2H), 1.33−1.26 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 202.0, 170.5, 170.3, 84.3, 64.3, 31.1, 24.9, 21.1, 21.0, 20.4;
IR (KBr): 2940, 2864, 1737, 1449, 1373, 1271, 1137, 710 cm−1;
HRMS (EI) m/z for C12H18O5Na (M + Na)+: calcd, 265.1052; found,
265.1042.
2c, 148.3 mg, yield: 91%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.49 (d, J = 7.0 Hz, 4H), 7.35−7.33 (m, 6H), 4.88 (s, 2H),
2.21 (s, 3H), 2.10 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 197.6,
170.0, 169.8, 138.3, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.6,
89.0, 64.8, 21.4, 20.4; IR (KBr): 3062, 3031, 2942, 2850, 1748, 1595,
1446, 1372, 1231, 755, 701 cm−1; HRMS (EI) m/z for C19H18O5Na
(M + Na)+: calcd, 349.1052; found, 349.1047.
2m, 159.0 mg, yield: 93%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.64 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.31−7.25 (m, 2H),
4.78 (d, J = 16.5 Hz, 1H), 4.71 (d, J = 16.5 Hz, 1H), 2.28 (s, 3H), 2.09
(s, 3H), 1.89 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.6, 170.0,
169.9, 140.2, 131.6, 130.4, 127.8, 123.5, 123.1, 85.7, 64.4, 23.4, 21.3,
20.4; IR (KBr): 3077, 3005, 2941, 1744, 1415, 1373, 1227, 1026, 697
cm−1; HRMS (ESI) m/z for C14H15O5BrNa (M + Na)+: calcd,
365.0000; found, 364.9985.
2d, 106.2 mg, yield: 60%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.35 (d, J = 8.5 Hz, 4H), 7.15 (d, J = 8.5 Hz, 4H), 4.87 (s,
2H), 2.34 (s, 6H), 2.19 (s, 3H), 2.11 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 197.7, 170.1, 169.9, 138.3, 135.5, 128.9, 128.8, 128.4, 128.2,
128.1, 128.0, 89.1, 64.8, 21.5, 21.1, 21.0, 20.4; IR (KBr): 3029, 2925,
2872, 1747, 1413, 1371, 1231, 1013, 813, 766 cm−1; HRMS (ESI) m/z
for C21H22O5Na (M + Na)+: calcd, 377.1365; found, 377.1377.
2e, 177.3 mg, yield: 90%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.40 (d, J = 8.5 Hz, 4H), 7.33 (d, J = 8.5 Hz, 4H), 4.84 (s,
2H), 2.21 (s, 3H), 2.11 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
2n, 136.0 mg, yield: 80%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.38−7.32 (m, 3H), 7.29 (d, J = 6.5 Hz, 2H), 7.17−7.09
(m, 3H), 6.63 (d, J = 7.5 Hz, 2H), 4.69 (d, J = 17.0 Hz, 1H), 4.65 (d, J
= 17.0 Hz, 1H), 3.93 (d, J = 14.5 Hz, 1H), 3.59 (d, J = 14.5 Hz, 1H),
2.21 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 199.1,
D
DOI: 10.1021/acs.joc.5b00740
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
170.1, 169.9, 135.8, 134.5, 130.1, 128.7, 128.5, 127.9, 126.8, 125.4,
88.6, 64.6, 40.7, 21.2, 20.4; IR (KBr): 3033, 2940, 1744, 1495, 1375,
1226, 1059, 754, 702 cm−1; HRMS (ESI) m/z for C20H20O5Na (M +
Na)+: calcd, 363.1208; found, 363.1202.
Synthesis of Glycerol Derivatives from Ethynylcarbinol 1 by
a One-Pot Reaction. In a Teflon-sealed reaction flask, ethynylcarbi-
nol 1 (0.5 mmol) and PhI(OAc)2 (483 mg, 1.5 mmol) were dissolved
in HOAc (1.5 mL) under air. The reaction mixture was stirred at 100
°C until substrate 1 disappeared (monitored by TLC). At this time,
the reaction was diluted with H2O (10 mL) and extracted with Et2O
(3 × 10 mL). The combined organic layers were washed with
saturated NaHCO3 solution (1 × 10 mL) and brine (1 × 10 mL),
dried over Na2SO4, and filtered. The solvent was then removed under
vacuum and used in next step directly.
In a round bottom flask, the above crude products 2 were dissolved
in MeOH (3 mL), and NaBH4 (418 mg, 11 mmol) was added under
air. The reaction mixture was stirred at room temperature for 4 h. At
this time, the reaction was diluted with H2O (10 mL), MeOH was
removed, and the mixture was extracted with DCM (3 × 10 mL). The
combined organic layers were washed with brine (1 × 10 mL), dried
over Na2SO4, and filtered. The solvent was then removed under
vacuum, and the crude product mixture was purified by flash
chromatography on silica gel (1:20−1:1; ethyl acetate/petroleum
ether) to give product 8.
2o,18 91.9 mg, yield: 91%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 4.86 (s, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 1.55 (s, 6H); 13C
NMR (125 MHz, CDCl3): δ 201.8, 170.4, 170.2, 82.8, 64.3, 23.6, 21.1,
20.4.
2p, 75.6 mg, yield: 70%. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 4.91 (d, J = 16.5 Hz, 1H), 4.83 (d, J = 16.5 Hz, 1H), 2.16
(s, 3H), 2.09 (s, 3H), 2.00−1.94 (m, 1H), 1.92−1.86 (m, 1H), 1.55 (s,
3H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 202.0,
170.3, 170.2, 85.9, 85.0, 29.8, 21.1, 20.4, 20.1, 7.3; IR (KBr): 2983,
2946, 2888, 1741, 1423, 1374, 1239, 1048, 943 cm−1; HRMS (ESI) m/
z for C10H16O5Na (M + Na)+: calcd, 239.0895; found, 239.0892.
1
2q, 67.0 mg, yield: 43%. Colorless oil; one isomer: H NMR (500
MHz, CDCl3): δ 5.82 (s, 1H), 5.26 (d, J = 18.0 Hz, 1H), 4.91 (d, J =
18.0 Hz, 1H), 2.50−2.46 (m, 2H), 2.25−2.20 (m, 2H), 2.17 (s, 3H),
2.16 (s, 3H), 2.08−2.05 (m, 3H), 1.86−1.81 (m, 2H), 1.69−1.66 (m,
5H), 1.53−1.46 (m, 5H), 1.13 (t, J = 7.0 Hz, 3H), 1.04−0.97 (m, 2H),
0.82−0.80 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 208.7, 199.9,
171.3, 170.6, 166.0, 124.8, 97.0, 67.9, 49.5, 49.1, 48.1, 42.3, 40.4, 36.5,
35.4, 34.0, 30.6, 29.2, 26.5, 26.1, 23.7, 21.2, 20.6, 20.3, 9.6; another
isomer: 1H NMR (500 MHz, CDCl3): δ 5.82 (s, 1H), 4.90 (d, J = 17.0
Hz, 1H), 4.69 (d, J = 17.0 Hz, 1H), 2.85−2.79 (m, 1H), 2.38−2.36
(m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 2.08−2.05 (m, 3H), 1.86−1.81
(m, 2H), 1.69−1.66 (m, 5H), 1.53−1.46 (m, 5H), 1.13 (t, J = 7.0 Hz,
3H), 1.04−0.97 (m, 2H), 0.82−0.80 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 202.5, 199.8, 171.3, 170.3, 166.3, 124.7, 92.3, 66.7, 49.5,
48.3, 47.7, 42.4, 40.6, 37.2, 35.3, 34.0, 30.5, 28.6, 26.5, 26.3, 23.5, 21.1,
20.6, 20.3, 9.6; IR (KBr): 3271, 2940, 2876, 1736, 1667, 1449, 1371,
1234, 1049, 888 cm−1; HRMS (ESI) m/z for C25H35O6 (M+H)+:
calcd, 431.2433; found, 431.2425.
Synthesis for Product 6. In a Teflon-sealed reaction flask,
ethynylcarbinol 1c (104 mg, 0.5 mmol) and PhI(OAc)2 (483 mg, 1.5
mmol) were dissolved in EtCO2H (1.5 mL) under air. The reaction
mixture was stirred at 100 °C until substrate 1c disappeared
(monitored by TLC). At this time, the reaction was diluted with
H2O (10 mL) and extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with saturated NaHCO3 solution (1 × 10
mL) and brine (1 × 10 mL), dried over Na2SO4, and filtered. The
solvent was then removed under vacuum, and the crude product
mixture was purified by flash chromatography on silica gel (1:20−1:5;
ethyl acetate/petroleum ether) to give product 6 as a colorless oil:
145.2 mg, yield: 82%. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 7.0
Hz, 4H), 7.36−7.32 (m, 6H), 4.88 (s, 2H), 2.53 (q, J = 7.5 Hz, 2H),
2.42 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 197.7, 173.5, 173.1, 138.5,
128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.6, 88.8, 64.6, 28.1, 27.1,
8.99, 8.85; IR (KBr): 3062, 3029, 2984, 2944, 2884, 1745, 1449, 1368,
1173, 1081, 753, 700 cm−1; HRMS (ESI) m/z for C21H22O5Na (M +
Na)+: calcd, 377.1365; found, 377.1378.
8c, 69.5 mg, 57% yield. Colorless oil; 1H NMR (500 MHz, MeOD):
δ 7.60 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 7.31−7.26 (m,
4H), 7.20−7.16 (m, 2H), 4.62−4.60 (m, 1H), 3.55−3.49 (m, 2H),
3.32 (s, 1H) (the two −OH resonances were not observed in MeOD);
13C NMR (125 MHz, MeOD): δ 145.7, 145.1, 127.6, 127.4, 126.5,
126.3, 126.2, 125.6, 79.2, 75.2, 63.0; IR (KBr): 3541, 3479, 3324, 3060,
2995, 2941, 1494, 1177, 752, 699 cm−1; HRMS (ESI) m/z for
C15H16O3Na (M + Na)+: calcd, 267.0997; found, 267.0991.
8e, 124.8 mg, 80% yield. Colorless oil; 1H NMR (500 MHz,
CDCl3): δ 7.50 (d, J = 8.5 Hz, 2H), 7.35−7.24 (m, 6H), 4.58−4.56
(m, 1H), 3.84 (s, 1H), 3.67 (dd, J = 11.5 Hz, 6.0 Hz, 1H), 3.57 (dd, J
= 11.0 Hz, 3.0 Hz, 1H), 3.00 (s, 1H) (one −OH resonance was not
observed in CDCl3); 13C NMR (125 MHz, CDCl3): δ 143.2, 141.8,
133.4, 133.2, 128.6, 128.5, 127.8, 126.7, 79.2, 73.5, 62.9; IR (KBr):
3324, 2925, 2851, 1756, 1490, 1404, 1092, 814, 788 cm−1; HRMS (EI)
m/z for C15H14O3Cl2Na (M + Na)+: calcd, 335.0218; found, 335.0206.
1
8n, 100.6 mg, 78% yield, dr = 4:1. Colorless oil; major isomer: H
NMR (500 MHz, CDCl3): δ 7.34 (d, J = 7.5 Hz, 2H), 7.32−7.31 (m,
2H), 7.29−7.22 (m, 2H), 7.15−7.12 (m, 2H), 6.83−6.82 (m, 2H),
3.99−3.98 (m, 1H), 3.85−3.84 (m, 1H), 3.74−3.73 (m, 1H), 3.39 (d, J
= 13.5 Hz, 1H), 3.27 (d, J = 13.5 Hz, 1H), 2.86 (s, 2H) (one −OH
resonance was not observed in CDCl3); 13C NMR (125 MHz,
CDCl3): δ 142.5, 135.5, 130.7, 128.2, 127.2, 126.7, 126.0, 125.4, 78.2,
76.0, 62.9, 44.2; minor isomer: 1H NMR (500 MHz, CDCl3): δ 7.45 (d,
J = 7.5 Hz, 2H), 7.35−7.31 (m, 2H), 7.30−7.26 (m, 2H), 7.22−7.12
(m, 2H), 7.01−7.00 (m, 2H), 3.91−3.90 (m, 1H), 3.83−3.82 (m, 1H),
3.77−3.75 (m, 1H), 3.34 (d, J = 13.5 Hz, 1H), 3.20 (d, J = 13.5 Hz,
1H), 2.71 (s, 2H) (one −OH resonance was not observed in CDCl3);
13C NMR (125 MHz, CDCl3): δ 142.3, 135.5, 130.6, 128.1, 127.1,
126.8, 126.0, 125.4, 79.4, 75.1, 63.2, 45.5; IR (KBr): 3382, 3030, 2925,
2854, 1495, 1450, 1191, 1060, 702 cm−1; HRMS (EI) m/z for
C16H18O3Na (M + Na)+: calcd, 281.1154; found, 281.1152.
Hydrolysis of 2c with HCl (Synthesis of Product 7c). In a
round bottom flask, 2c (163 mg, 0.5 mmol) was dissolved in MeOH
(5.0 mL), and HCl (1.0 mL, 36%) was added. The reaction mixture
was stirred at room temperature until substrate 2c disappeared
(monitored by TLC). At this time, the reaction was diluted with H2O
(10 mL) and extracted with Et2O (3 × 10 mL). The combined organic
layers were washed with saturated NaHCO3 solution (1 × 10 mL) and
brine (1 × 10 mL), dried over Na2SO4, and filtered. The solvent was
then removed under vacuum, and the crude product mixture was
purified by flash chromatography on silica gel (1:20−1:1; ethyl
acetate/petroleum ether) to give product 7c as a colorless oil: 88 mg,
73% yield. 1H NMR (500 MHz, CDCl3): δ 7.38−7.36 (m, 6H), 7.34−
7.28 (m, 4H), 4.53 (s, 2H), 3.67 (s, 1H), 2.67 (s, 1H); 13C NMR (125
MHz, CDCl3): δ 211.4, 141.3, 128.6, 128.5, 127.5, 84.6, 66.2; IR
(KBr): 3422, 3060, 3030, 2924, 2858, 1719, 1600, 1448, 1061, 745,
700 cm−1; HRMS (EI) m/z for C15H14O3Na (M + Na)+: calcd,
265.0841; found, 265.0843.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra of compounds 2a−2q, 5, 6, 7c, 8c, 8e, and 8n.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00740.
AUTHOR INFORMATION
■
Corresponding Authors
*(D.-L.M.) E-mail: moeastlight@mailbox.gxnu.edu.cn.
*(G.-F.S.) E-mail: gfysglgx@163.com.
Notes
The authors declare no competing financial interest.
E
DOI: 10.1021/acs.joc.5b00740
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(l) Richardson, R. D.; Desaize, M.; Wirth, T. Chem.Eur. J. 2007, 13,
6745. (m) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006,
45, 4402. (n) Yusubov, M. S.; Wirth, T. Org. Lett. 2005, 7, 519.
(o) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893.
(12) Ochiai, M.; Kunishima, M.; Fuji, K.; Nagao, Y. J. Org. Chem.
1989, 54, 4038.
(13) (a) Serna, S.; Tellitu, I.; Dominguez, E.; Moreno, I.; SanMartin,
R. Org. Lett. 2005, 7, 3073. (b) Tellitu, I.; Serna, S.; Herrero, M. T.;
Moreno, I.; Dominguez, E.; SanMartin, R. J. Org. Chem. 2007, 72,
1526.
ACKNOWLEDGMENTS
■
Financial support from the Basic Rearch Program of Guangxi
Normal University (grant no. 2014ZD005), the Natural Science
Foundation of Guangxi (2011GXNSFA018042), the Ministry
of Education of China (IRT1225), and the Guilin Science and
Technology Development Fund (20110331) is greatly
appreciated.
DEDICATION
■
(14) For some other examples of the oxidation of alkynes by
This work is dedicated to Prof. Xue-Long Hou, Shanghai
Institute of Organic Chemistry, on the occasion of his 60th
birthday.
PhI(OAc)2, see (a) Jiang, Q.; Zhao, A.; Guo, C. J. Org. Chem. 2014, 79,
́
2709. (b) Souto, J. A.; Becker, P.; Lglesias, A.; Muniz, K. J. Am. Chem.
̃
Soc. 2012, 134, 15505. (c) Mo, D. L.; Ding, C. H.; Dai, L. X.; Hou, X.
L. Chem.Asian J. 2011, 6, 3200. (d) Saito, A.; Matsumoto, A.;
Hanzawa, Y. J. Tetrahedron Lett. 2010, 51, 2247. (e) Mo, D. L.; Dai, L.
X.; Hou, X. L. Tetrahedron Lett. 2009, 50, 5578. (f) Chen, J. M.;
Huang, X. Synthesis 2004, 15, 2459.
REFERENCES
■
(1) For some examples of the synthesis of acetoxy α-ketols, see
(a) Renata, H.; Zhou, Q. H.; Dunstl, G.; Felding, J.; Merchant, R. R.;
̈
(15) Xu, C. F.; Xu, M.; Yang, L. Q.; Li, C. Y. J. Org. Chem. 2012, 77,
4645.
(16) Zong, H.; Huang, H. Y.; Liu, J. F.; Bian, G. L.; Song, L. J. Org.
Chem. 2012, 77, 3010.
(17) Saito, T.; Kumobayashi, H.; Murahashi, S. Patent EP 482834,
1992.
Yeh, C. H.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 1330.
(b) Murahashi, S. I.; Saito, T.; Hanaoka, H.; Murakami, Y.; Naota, T.;
Kumobayashi, H.; Akutagawa, S. J. Org. Chem. 1993, 58, 2929.
(c) Arcamone, F. Top. Antibiot. Chem. 1978, 2, 102.
(2) For some examples of the synthesis of 1,3-dihydroxyketone
compounds, see (a) Chung, K.; Banik, S. M.; De Crisci, A. G.; Pearson,
D. M.; Blake, T. R.; Olsson, J. V.; Ingram, A. J.; Zare, R. N.;
Waymouth, R. M. J. Am. Chem. Soc. 2013, 135, 7593. (b) Smith, M. E.
B.; Smithies, K.; Senussi, T.; Dalby, P. A.; Hailes, H. C. Eur. J. Org.
Chem. 2006, 1121. (c) Galman, J. L.; Steadman, D.; Haigh, L.; Hailes,
H. C. Org. Biomol. Chem. 2012, 10, 2621.
(18) Nazarov, I. N.; Burmistrov, M. S.; Akhrem, A. A. Zh. Obshch.
Khim. 1959, 29, 735.
(3) For some examples of the synthesis of glycerol derivatives, see
(a) Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.;
Yang, J. J. Org. Chem. 2004, 69, 2454. (b) Bongini, A.; Cardillo, G.;
Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1982, 47, 4626.
(c) Gulea, M.; Lopez-Romero, J. M.; Fensterbank, L.; Malacria, M.
Org. Lett. 2000, 2, 2591.
(4) Pozzo, G.; Prandini, B. D. Acta Derm.-Venereol. 1971, 52, 40.
(5) (a) Yu, W. X.; Tang, L. N.; Ling, F.; Yao, Y.; Shen, Z. Med. Oncol.
2015, 32, 307. (b) Temma, K.; Akera, T.; Chugun, A.; Kondo, H.;
Hagane, K.; Hirano, S. I. Eur. J. Pharmacol. 1993, 234, 173.
(6) See the following review: Redpath, J.; Zeelen, F. J. Chem. Soc. Rev.
1983, 12, 75.
(7) Mandhapati, A. R.; Rajender, S.; Shaw, J.; Crich, D. Angew. Chem.,
Int. Ed. 2015, 54, 1275.
(8) For some examples, see (a) Papa, D.; Ginsberg, H. F.; Villani, F.
J. J. Am. Chem. Soc. 1954, 76, 4441. (b) Suzuki, M.; Kimura, Y.;
Terashima, S. Chem. Lett. 1984, 1543. (c) Fetizon, M.; Goulaouic, P.;
Hanna, I. Tetrahedron Lett. 1985, 26, 4925.
(9) Boar, R. B.; McGhie, J. F.; Robinson, M.; Barton, D. H. R. J.
Chem. Soc., Perkin Trans. 1 1975, 1242.
(10) For some reviews of hypervalent iodine reagents, see (a) Dohi,
T.; Kita, Y. Chem. Commun. 2009, 2073. (b) Zhdankin, V. V.; Stang, P.
J. Chem. Rev. 2008, 108, 5299. (c) Wirth, T. Angew. Chem., Int. Ed.
2005, 44, 3656. (d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523.
(11) For some examples of hypervalent iodine reagents in organic
synthesis, see (a) Sun, J. Y.; Zhang-Negrerie, D.; Du, Y. F.; Zhao, K. J.
Org. Chem. 2015, 80, 1200. (b) Kiyokawa, K.; Yahata, S.; Kokima, T.;
Minakata, S. Org. Lett. 2014, 16, 4646. (c) Chen, H.; Kaga, A.; Chiba,
S. Org. Lett. 2014, 16, 6136. (d) Frei, R.; Wodrich, M. D.; Hari, D. P.;
Borin, P. A.; Chauvier, C.; Waser, J. J. Am. Chem. Soc. 2014, 136,
16563. (e) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du, Y. F.; Zhao, K. Org.
Lett. 2014, 16, 5772. (f) Purkait, N.; Okumura, S.; Souto, J. A.; Muniz,
K. Org. Lett. 2014, 16, 4750. (g) Mendelsohn, B. A.; Lee, S.; Kim, S.;
Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett. 2009, 11, 1539.
(h) Fan, R. H.; Li, W. X.; Pu, D. M.; Zhang, L. Org. Lett. 2009, 11,
1425. (i) Jiang, M.; Shi, M. Tetrahedron 2009, 65, 798. (j) Fan, R. H.;
Ye, Y.; Li, W. X.; Wang, L. F. Adv. Synth. Catal. 2008, 350, 2488.
(k) Yusubov, M. S.; Funk, T. V.; Chi, K. W.; Cha, E. H.; Kim, G. H.;
Kirschning, A.; Zhdankin, V. V. J. Org. Chem. 2008, 73, 295.
F
DOI: 10.1021/acs.joc.5b00740
J. Org. Chem. XXXX, XXX, XXX−XXX