A new one-pot synthesis of 2-quaternary 1,3-diketones

Article abstract of DOI:10.1055/s-2001-18707

A facile one-pot synthesis of 1,3-diketones with stereogenic quaternary center at C-2 has been developed on the basis of an oxidative-rearrangement of a series of tertiary α-hydroxy epoxides on treatment with pyridinium chlorochromate (PCC). A possible mechanism is also discussed.

Full text of DOI:10.1055/s-2001-18707

2384
PAPER
A New One-Pot Synthesis of 2-Quaternary 1,3-Diketones
O
ne-Pot Synth
h
esis of 2-Q
u
i
a
ternar
-
y 1, 3-D
i
K
s
uo Ren,a Fei Wang,a Hua-Ni Dou,a Chun-An Fan,a Lan He,b Zhen-Lei Song,a Wu-Jiong Xia,a De-Run Li,a Yan-
Xing Jia,a Xin Li,a Yong-Qiang Tu*a
a
Department of Chemistry & National Laboratory of Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
Fax +86(931)8912582; E-mail: tuyq@lzu.edu.cn
b
Department of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
Received 2 July 2001
merically pure 2-quaternary 1,3-diketone; and 5) the dias-
tereo-differentiation between two C-1 epimers in some
examples. Herein, we present our experimental results, a
few of which have been mentioned in our previous re-
port.7
Abstract: A facile one-pot synthesis of 1,3-diketones with stereo-
genic quaternary center at C-2 has been developed on the basis of
an oxidative-rearrangement of a series of tertiary -hydroxy ep-
oxides on treatment with pyridinium chlorochromate (PCC). A pos-
sible mechanism is also discussed.
Key words: 1,3-diketones, quaternary carbon, pyridinium chloro-
chromate, tertiary -hydroxy epoxides, oxidative rearrangement
In consideration of their wide presence in organic com-
pounds, we selected here mainly the -hydroxy epoxide
substrates with the cyclohexyl and cyclopentyl units for
investigation, which were prepared from the correspond-
ing racemic -hydroxy alkenes by epoxidation with m-
CPBA or t-BuOOH/VO(acac)2.8 The rearrangement-oxi-
dation was carried out in a typical procedure (see experi-
mental section) with 1.5 equivalents of PCC in CH2Cl2
solution at room temperature, as shown in Scheme 1. The
obtained results are listed in Table 1, from which we can
see that all examples afforded the 2-quaternary 1,3-dike-
tones in moderate to excellent yields.
1,3-Diketones with quaternary C-2 are strongly required
building blocks in organic synthesis due to the fact that
many important organic compounds incorporate this kind
of key structural units, or similar “2-quaternary 3-hydroxy
ketone”1 or “2-quaternary 1,3-diol”2 units such as the bio-
logically active taxol3 and epothilone,4 and various chiral
ligands used for preparing asymmetric catalysts.5 Al-
though several synthetic procedures for 2-quaternary 1,3-
diketones have been developed,6 they generally involve
two or more reaction steps. In connection with our recent
investigation on the diastereo-recognizable reaction of
tertiary -hydroxy epoxides with Cr(VI) reagents,7 we
found interestingly that a few -hydroxy epoxides bearing
aromatic groups at C-1 could undergo a carbon-to-carbon
1,2-migration and the successive oxidation of the hydroxy
group with pyridinium chlorochromate (PCC) in a one-
pot reaction. This observation reminded us to expand this
reaction and develop a new one-pot procedure for the
preparation of 2-quaternary 1,3-diketones. The major dis-
tinct features of this method involve: 1) the easy construc-
tion of a stereogenic quaternary carbon center that is
generally difficult to access in organic synthesis; 2) the
convenient experimental procedure; 3) the mild reaction
condition and the inexpensive reagent; 4) the more impor-
tant synthetic value is that two C-1 epimers of the tertiary
-hydroxy epoxides could afford a single diastereoiso-
Interestingly, entries 1–3, in which the sterically hinder-
ing methyl group is situated at the six-membered ring of
the substrate pairs, showed the diastereo-recognizable ac-
tivity. Thus, the PCC reagent reacted selectively with the
isomers 1b,2b and 3a to form the 2-quaternary 1,3-dike-
tones 1c,2c and 3c, respectively, while the isomers 1a,2a
and 3b were recovered in yields of 42%, 40% and 25%
and with de values of 75%, 66% and 96%, respectively. In
contrast, entries 4 and 6–9, in which all the substrates pos-
sess a pair of C-1 epimers, gave only products 4c and 6c–
9c, respectively. We were not able to isolate other isomer-
ic products, or recover any enriched C-1 epimers of the
substrates in these examples. This fact is of great use in or-
ganic synthesis.7
By further inspection of the results in Table 1, we can see
that the product yields were dependent, to some extent,
upon the property of migratory group or the substrate
Scheme 1
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2384,2388,ftx,en;F05501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
One-Pot Synthesis of 2-Quaternary 1,3-Diketones
2385
structures. For example in entries 4–7, all substrates incor- of relationship between the product yields and the migra-
porated similarly the ‘cyclohexene oxide’ units and gave tory aptitude of groups or the substrate structures.
high yields (91–99%) of the 2-quaternary 1,3-diketones
4c–7c. Whereas entry 8, which involved the migration of
2 -thiophenyl group, afforded only 67% of 8c. In entries 9
and 10, the substrates possess similarly the ‘cyclopentene
oxide’ units and gave only moderate yields of 9c and 10c.
At this stage, however, we were not clear about the details
Generally, the oxidation with Cr(VI) reagents involves
complex processes, some of which are proposed only on
the basis of deduction.9 For this rearrangement-oxidation
reaction here reported, we presume that, in entries 4–10,
this reaction may involve two steps: 1) the tertiary -hy-
droxy epoxide a/b rearranged to form the intramolecular
rearrangement product ( -hydroxy ketone) via migration
Table 1 Preparation of 2-Quternary 1,3-Diketonesa,b
Entry
1
Substrate
syn/anti Ratio
Reaction Time
10 h
Product
Yield (%)
84
63:37
1a/1b
2a/2b
1c
2c
2
3
56:44
69:31
25 h
25 h
71
98
3c
4c
5c
6c
7c
3a/3b
4a/4b
5a
4
5
6
7
8
70:30
–
18 h
24 h
4 h
94
99
91
93
67
79:21
99:1
80:20
6a/6b
24 h
25 h
7a/7b
8a/8b
9a/9b
8c
9
80:20
–
5 d
61
77
9c
10
48 h
10c
10a
a Structures of all products were determined by 1H and 13C NMR and MS. Isomer ratios were measured with 1H NMR and/or GC, and the
stereochemistry was determined using 2D NMR techniques.
b The yields of entries 1–3 refer to single starting isomers 1b,2b and 3a
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S.-K. Ren et al.
PAPER
of aryl group; and 2) after transfer of the hydride and elec-
tron between Cr(VI) reagent and rearrangement product,
a final product c (2-quaternary 1,3-diketone) was formed
in a one-pot reaction. To assign a possible reaction mech-
anism, we conducted supporting experiments. It is well
known that PCC has a slightly acidic character,10 so in the
present reaction we used PCC in combination with
NaOAc, which acted as a buffer to avoid the effect of the
acidic character of PCC on this reaction. As a result, we
found that the reaction worked very slowly. For example,
in entry 4, treatment of 4a/4b with PCC/NaOAc (1:1) for
24 hours afforded only a small amount of product 4c, and
most of the substrates 4a/4b did not react. This fact shows Figure Favorable and unfavorable chair conformations of 1a–3a
and 1b–3b for oxidation with PCC
that sufficiently acidic character is essential for accelera-
tion of this reaction and there seems to be a possibility that
the rearrangement reaction may be prompted by acid.
Consequently, we treated 4a/4b (50 mg) in CH2Cl2 (5 mL) For entries 1 and 2, the controlling step of the reaction
with concentratedd HCl (0.02 mL) at room temperature would be, first the coordination of Cr(VI) of PCC with C-
and found that in less than 30 minutes 4a/4b disappeared 1 OH, hence the isomers 1b and 2b, in which the C-5 Me
completely to give the rearrangement product ( -hydroxy (1b) or C-6 Me (2b) and C-1 located at different sides of
ketone). After that, we added PCC (1.5 equiv) to the reac- the cyclohexane plane are more reactive than 1a and 2a,
tion mixture above, which was stirred for further 12 hours in which the C-5 Me (1a) or C-6 Me (2a) and C-1 are lo-
to afford the 2-quaternary 1,3-diketone 4c in high yield. cated at the same side of the cyclohexane plane (see Fig-
But 4a/4b did not react at all with the basic PDC (pyridin- ure). While in entry 3, the two big phenyl groups attached
ium dichromate).11 These facts indicate that this one-pot to C-1 prevent Cr(VI) of PCC from approaching to C-1
reaction may first undergo rearrangement prompted by OH. So the controlling step in entry 3 would be, first the
acid and PCC simply oxidized the rearrangement products coordination of Cr(VI) of PCC with epoxy oxygen, and
to afford 2-quaternary 1,3-diketones.
thus the isomer 3a is more reactive than 3b for the same
reason as above.
In addition, from entries 1–3 we selected 1a/1b for further
investigations. We treated 1a/1b (50 mg) in CH2Cl2 (5 In conclusion, we have successfully developed a new syn-
mL) with concentrated HCl (0.02 mL) at room tempera- thetic method for 2-quaternary 1,3-diketones and further
ture, and in less than 1 hour 1a/1b disappeared completely examination of its scope and applications are in progress.
to afford the rearrangement product ( -hydroxy ketone).
However, it did not show diastereo-recognizable activity
at all and we were not able to recover any enriched C-1
epimer 1a or 1b. These experimental results indicated that
the reaction mechanism for entries 1–3 may be different
from that for entries 4–10. So we presumed that it first in-
volves the coordination of Cr(VI) of PCC with C-1 OH
and epoxy oxygen, which promoted the ring opening of
the epoxide, as shown in Scheme 2. Concomitantly, an
anti 1,2-migration of R3 led to the formation of stereogen-
ic C-2 quaternary carbon center and C-1 carbonyl. Then
the 2-quternary 1,3-diketone was formed through oxida-
tion of the hydroxy group by Cr(VI) of PCC. As for the di-
astereo-recognization of this reaction in entries 1 3, we
thought it would be effected by the sterically hindering
methyl situated at the six-membered ring in substrates 1a/
b–3a/b, as shown in the chair conformations in the Figure.
Reaction of Tertiary -Hydroxy Epoxides 1–10 with PCC;
General Procedure
To a stirred solution of tertiary -hydroxy epoxide a/b (0.47 mmol)
in CH2Cl2 (15 mL) was added PCC (0.71 mmol). The reaction mix-
ture was stirred at r.t. until the reactants disappeared completely
(TLC monitoring), then diluted with Et2O (15 mL) and stirred for
further 5 min. The black reaction mixture was passed through a neu-
tral Al2O3 column, eluting with Et2O (20 mL). The obtained overall
fractions were concentrated under reduced pressure and the crude
product was chromatographed on silica gel eluting with petroleum
ether (bp 60 90 °C)/EtOAc (10:0 10:3) to afford pure 1,3-dike-
tones c. The 1H, 13C NMR and mass spectral data of all products are
listed in Table 2.
Scheme 2
Synthesis 2001, No. 16, 2384–2388 ISSN 0039-7881 © Thieme Stuttgart · New York

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One-Pot Synthesis of 2-Quaternary 1,3-Diketones
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Table 2 Spectral Data of 2-Quaternary 1,3-Diketonesa,b
Product
1H NMR , J (Hz)
13C NMR
MS m/z (%)
1c
0.83 (d, J = 6.4, 3 H), 1.15 (m, 1 H),
21.8, 28.5, 29.4, 31.8, 35.7, 48.7, 70.6, 230 (M+, <1), 188 (100), 146 (22), 117 (20),
1.66 (m, 1 H), 1.90 (s, 3 H), 2.31 (m, 4 127.8 (3 C), 129.2 (2 C), 137.0, 206.6, 115 (15), 103 (18), 97 (13), 91 (43), 84 (18),
H), 2.56 (m, 1 H), 7.13–7.35 (m, 5 H) 210.5
77 (17) (HRMS: [M+] calcd for C15H18O2,
230.1307; found, 230.1314)
2c
3c
4c
0.93 (d, J = 6.4, 3 H), 1.36–2.66 (m, 10 21.2, 27.1, 28.7, 35.9, 40.0, 41.1, 70.8, 230 (M+, <1), 188 (100), 173 (15), 146 (43),
H), 7.14–7.41 (m, 5 H)
127.7–129.3 (5 C), 137.6, 206.5, 211.4 118 (27), 115 (13), 103 (16), 97 (3), 91 (21),
77 (15), 43 (16) (HRMS: [M+] calcd for
C15H18O2, 230.1307; found, 230.1320)
1.05 (d, J = 6.3, 3 H), 1.64–2.80 (m, 7 21.3, 27.2, 34.9, 40.3, 43.4, 70.6,
292 (M+, 6), 129 (1), 128 (1), 115 (2), 105
(100), 103 (3), 91 (5), 89 (2), 77(21) (HRMS:
[M+] calcd for C20H20O2, 292.1463; found,
292.1466)
H), 7.23–7.51 (m, 10 H)
127.2–131.1 (10 C), 137.4, 137.8,
200.7, 210.8
1.63 (m, 2 H), 1.78 (m, 2 H), 1.92 (s, 3 21.4, 27.6, 33.6 (2 C), 40.9, 71.7,
216 (M+, <1), 197 (0.2), 174 (100), 156 (6),
H), 2.43 (m, 3 H), 2.56 (m, 1 H), 7.11– 127.8, 127.9 (2 C), 129.0 (2 C), 136.7, 146 (19), 115 (20), 91 (60), 77 (17), 43 (32)
7.34 (m, 5 H)
206.7, 209.7
(HRMS: [M+] calcd for C14H16O2 + Na,
239.1043; found, 239.1039)
5c
6c
1.67 (m, 3 H), 1.96 (m, 1 H), 2.15 (m, 22.3, 27.6, 37.9, 42.0, 71.1, 127.5–
278 (M+, 6), 165 (1), 149 (2), 105 (100), 77
(19), 51 (3) (HRMS: [M+] calcd for C19H18O2
+ H, 279.1380; found, 279.1378)
1 H), 2.47 (m, 2 H), 2.83 (m, 1 H),
7.16–7.48 (m, 10 H)
132.4 (10 C), 136.4, 138.0, 200.1,
207.9
0.68 (t, J = 7.3, 3 H), 1.02–1.07 (m, 1 14.0, 21.5, 22.0, 26.1, 27.7, 33.7, 39.5, 258 (M+, 0.2), 211 (0.1), 176 (1), 174 (100),
H), 1.34 (m, 1 H), 1.62–1.66 (m, 3 H), 41.1, 71.8, 127.7, 128.0 (2 C), 128.9 (2 146 (5), 91 (7), 77 (2), 63 (0.6) (HRMS: [M+]
1.76–1.80 (m, 3 H), 2.08–2.11 (m, 1
H), 2.26–2.58 (m, 5 H), 7.11–7.33 (m,
5 H)
C), 136.9, 209.0, 209.9
calcd for C17H22O2 + H, 259.1693; found,
259.1696)
7c
0.63, 0.65 (2 d, J = 6.7, 2 3 H), 1.12 21.5, 22.1, 22.3, 27.3, 27.7, 32.9, 33.7, 272 (M+, 2), 257 (0.2), 211 (0.2), 174 (100),
(m, 1 H), 1.27 (m, 1 H), 1.62 (m, 3 H), 37.8, 41.0, 71.6, 127.7, 128.0 (2 C),
1.79 (m, 2 H), 2.08 (m, 1 H), 2.30 (m, 128.9 (2 C), 136.8, 209.2, 210.0
1 H), 2.44 (m, 3 H), 2.56 (m, 1 H),
156 (3), 115 (8), 91 (16), 84 (20), 77 (5), 55
(3), 43 (8) (HRMS: calcd for C18H24O2 + Na,
295.1669; found, 295.1667)
7.12–7.34 (m, 5 H)
8c
9c
1.85 (m, 4 H), 2.06 (s, 3 H), 2.24 (m, 1 21.8, 26.8, 27.0, 36.3, 40.7, 68.9,
H), 2.46 (m, 1 H), 2.67 (m, 1 H), 2.76 126.1,127.0 (2 C), 140.5, 204.6, 207.3 123 (25), 97 (19), 65 (3), 43 (13) (HRMS:
(m, 1 H), 6.69 (m, 1 H), 7.03 (m, 1 H),
7.35 (m, 1 H)
222 (M+, <1), 180 (100), 151 (17), 134 (1),
[M+] calcd for C12H14O2S + Na: 245.0607,
found, 245.0611)
1.81–1.96 (m, 2 H), 1.97 (s, 3 H), 2.29 19.6, 26.7, 34.6, 39.2, 73.1, 127.9 (2
(m, 1 H), 2.39 (m, 2 H), 2.88 (m, 1 H), C), 128.3, 129.7 (2 C), 139.1, 204.1,
160 (M+–42, 100), 159 (26), 131 (5), 117 (15),
91 (12), 77 (13), 63 (4), 43 (16) (HRMS: [M+]
calcd for (C13H14O2 + Na, 225.0886, found,
225.0882)
7.26–7.40 (m, 5 H)
214.0
10c
1.87–1.94 (m,1 H), 2.03–2.07 (m, 1
19.8, 35.4, 38.3, 71.2, 128.1–133.4 (10 264 (M+, 4), 219 (0.3), 181 (2), 165 (2), 128
H), 2.35–2.45 (m, 2 H), 2.75–2.81 (m, C), 135.6, 139.0, 198.3, 212.4
1 H), 2.85–2.90 (m, 1 H), 7.26–7.69
(m, 10 H)
(2), 105 (100), 77 (25), 51 (5) (HRMS: [M+]
calcd for C18H16O2 + Na, 287.1043, found,
287.1047)
a The NMR spectra were measured on Bruker AM-400 MHz spectrometer using CDCl3 as solvent and TMS as standard.
b The mass spectral data for all products were measured as GC-MS (EI: 70eV). The HRMS for 1c–3c were recorded on VG ZAB-HS spec-
trometer using FAB mode, and those for 4c–10c on Bruker Daltonics APEX II spectrometer using ESI positive mode.
Acknowledgement
References
We are grateful for the financial support from NSFC (No.
29972019, 29925205 and QT program), FUKTME of China, the
Young Teachers’ Fund of Ministry of Education and the Fund of
Ministry of Education (No. 99209).
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