DABCO-catalyzed reaction of 2,6-disubstituted 6-hydroxy-2H-pyran-3(6H)-ones to 1,2,5-triketones

Article abstract of DOI:10.1055/s-0030-1258285

The DABCO-catalyzed isomerization/redox rearrangement readily converts 2,6-dialkyl-6-hydroxy-2H-pyran-3(6H)-ones into 1,2,5-triketones. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258285

SHORT PAPER
3977
DABCO-Catalyzed Reaction of 2,6-Disubstituted 6-Hydroxy-2H-pyran-
3(6H)-ones to 1,2,5-Triketones
D
ABCO-Catalyzed Rea
ction lliam H. Miles,* Peter G. Gildner, Zain Ahmed, Evan M. Cohen
Department of Chemistry, Lafayette College, Easton, PA 18042, USA
Fax +1(610)3305714; E-mail: milesw@lafayette.edu
Received 2 July 2010; revised 26 August 2010
Table 1 DABCO-Catalyzed Reaction of 2,6-Disubstituted 6-Hy-
droxy-2H-pyran-3(6H)-ones 2
Abstract: The DABCO-catalyzed isomerization/redox rearrange-
ment readily converts 2,6-dialkyl-6-hydroxy-2H-pyran-3(6H)-ones
into 1,2,5-triketones.
R1 OH
O
O
DABCO
O
Key words: furans, ketones, oxidation, isomerization, catalysis
R1
R2
MeCN
R2
O
O
Furans exhibit multifaceted reactivity that can be exploit-
ed for the synthesis of diverse natural products.1 The oxi-
dative rearrangement of a-hydroxyalkylfurans 1, the
Achmatowicz reaction,2 has been one of the most heavily
utilized reactions (Scheme 1). The resulting pyranones 2
have been further manipulated into various polyfunctional
intermediates for the total synthesis of biologically impor-
tant compounds such as the seco-acids of erythromycin A
and B,3 englerin A,4 and anthrax tetrasaccharide.5
2
3
Starting material R1
R2
Yield (%) of 3
2a
2b
2c
2d
2e
2f
Me
c-C6H11
Me
86
33
79
78
83
55a
81
55
62
75
Me
Me
Me
Me
Me
Me
Et
n-Bu
Me(CH2)9
i-Pr
R1 OH
OH
R2
R1
[O]
allyl
O
O
polyfunctional
compounds
R2
2g
2h
2i
4-MeC6H4
Me
O
1
2
Scheme 1
Et
Et
2j
(CH2)3CH=CH2 i-Pr
Although the manipulation of pyranones 2 into 1,2,5-
triketones 3 is conceptually possible through a suitable se-
ries of oxidation and reduction steps, there are no reports
of the synthesis of 3 based on 2. The 1,2,5-triketone moi-
ety has appeared in some natural products,6,7 and has
served as an intermediate for the synthesis of spiroacetals
of marine natural products.8 Given the general availability
of pyranones 2 and the importance of triketones 3, we
report the direct synthesis of 3 from 2 by the DABCO-
catalyzed isomerization/redox rearrangement reactions
(Table 1).
a Product was (E)-MeCOCH2CH2COCOCH=CHMe.
good yields of 3, although comparable to the optimized
procedure. With a lower catalyst load (10 mol% DABCO)
and longer reaction times, slightly diminished yields were
obtained (e.g., 78% for 2a). In the case of allylic pyranone
2f, further isomerization to the unsaturated ketone was ob-
served (Table 1).
The potential to prepare aldehydes by this method was
briefly investigated with pyranones 2k and 2l (Figure 1).
Pyranone 2k was unreactive under the standard reaction
conditions; forcing the reaction by increasing the catalyst
loading and longer reaction times gave unidentified com-
pounds with a very low yield of the desired aldehyde, as
evidenced by the crude 1H NMR spectrum. In the case of
pyranone 2l, the conversion of starting material was rapid,
but the yields of the desired aldehyde product again were
very low.
The preferred catalyst for the conversion of 2 into 3 is
DABCO (40 mol%), with more basic amines such as
Hünig’s base, triethylamine, DBU, and DBN giving lower
yields due to unidentified side reactions. Acetonitrile was
the optimal solvent, although reactions conducted in chlo-
roform and dichloromethane gave comparable yields, but
at a slower rate of reaction. Higher catalyst loadings, low-
er reaction temperature, and longer reaction times gave
When the DABCO-catalyzed reaction of 2 was monitored
by 1H NMR spectroscopy, an intermediate was observed,
which was identified as the diketone (E)-4 (Scheme 2). In
the case of the DABCO-catalyzed rearrangement of 2a to
SYNTHESIS 2010, No. 23, pp 3977–3979
Advanced online publication: 05.10.2010
DOI: 10.1055/s-0030-1258285; Art ID: M04710SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3978
W. H. Miles et al.
SHORT PAPER
ever-growing list of useful synthetic transformations us-
ing furan intermediates.
H
OH
O
OH
O
All reactions were carried out under argon. IR spectra were obtained
1
on a Mattson Satellite FT-IR spectrophotometer. The H and 13C
H
O
NMR spectra were recorded at 400 MHz and 100 MHz, respective-
ly, on a JEOL Eclipse+400 spectrometer; all chemical shifts are re-
ported in ppm relative to TMS (d = 0.00 ppm) or CHCl3 (d = 7.26
ppm) in the 1H NMR and relative to CDCl3 (d = 77.16 ppm) in the
13C NMR. HRMS were obtained on a GCT Premier mass spectrom-
eter at the MSU Mass Spectrometry Facility. Flash chromatography
O
2k
2l
Figure 1 Pyranones 2k and 2l
3a, the formation of substantial amount of (E)-4a was ob- was performed on Merck silica gel 60 (230–400 mesh). Pyranones
2 were prepared according to literature procedures.10
served [40% yield of (E)-4a at 70% conversion of 2a].
With smaller R2 groups (such as 2c), a much lower con-
1-Cyclohexylhexane-1,2,5-trione (3a); Typical Procedure
centration of the intermediate diketone (E)-4 was
To a reaction flask charged with 2-cyclohexyl-6-hydroxy-6-methyl-
observed. Based on this limited information and the pre-
viously described amine-catalyzed conversion of chaeto-
globosin B [possessing the (E)-4 substructure] to chaeto-
globosin G (a 1,2,5-triketone),6 the conversion of 2 into 3
is proposed to proceed by the pathway shown in
Scheme 2. Tautomerism of 2 to the unobserved open-
chain tautomer (Z)-4 is followed by the attack by DABCO
and subsequent isomerization to (E)-4. DABCO-cata-
lyzed keto-enol tautomerism of (E)-4 gives enol 5, which
gives 6 and then triketone 3. The larger R2 groups would
impede tautomerism of (E)-4 to 5 due to steric effects, but
would have limited effect on the isomerization of (Z)-4 to
(E)-4, hence the build-up of (E)-4a in our NMR studies.
2H-pyran-3(6H)-one10 (0.423 g, 2.01 mmol) and MeCN (15 mL)
was added a solution of DABCO (0.0899 g, 0.801 mmol) in MeCN
(5 mL) under argon while stirring. The flask was kept in an oil bath
and the solution was heated to reflux for 2 h. The contents of the re-
action flask were transferred to a separatory funnel with EtOAc (75
mL). The organic phase was washed with H2O (50 mL), aq 0.1 M
HCl (25 mL), H2O (25 mL), and brine (50 mL). The organic phase
was dried (Na2SO4) and evaporated on the rotary evaporator to give
the crude 1,2,5-triketone 3a. Kugelrohr distillation (75 °C/0.1
mmHg) gave pure 3a; yield: 0.365 g (86%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 3.11 (m, 1 H), 2.92 (m, 2 H), 2.80
(m, 2 H), 2.19 (s, 3 H), 1.87–1.64 (m, 5 H), 1.40–1.14 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 206.5, 202.2, 199.1, 43.3, 37.1,
30.7, 29.7, 27.8, 25.9, 25.5.
HRMS: m/z calcd for C12H18O3: 210.1256; found: 210.1252.
R1
N
O
Heptane-2,3,6-trione (3b)11
Yield: 33%; yellow oil (60 °C/0.1 mmHg).
1H NMR (400 MHz, CDCl3): d = 2.92 (m, 2 H), 2.82 (m, 2 H), 2.34
(s, 3 H), 2.19 (s, 3 H).
R1 OH
O
N
O
R1
OH
OH
H
R2
R2
R2
O
O
O
Decane-2,5,6-trione (3c)
Yield: 79%; yellow solid (60 °C/0.1 mmHg); mp 29–31 °C.
2
(Z)-4
(E)-4
1H NMR (400 MHz, CDCl3): d = 2.93 (m, 2 H), 2.81 (m, 2 H), 2.74
(t, J = 7.4 Hz, 2 H), 2.19 (s, 3 H), 1.57 (pent, J = 7.5 Hz, 2 H), 1.34
(sext, J = 7.4 Hz, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.7, 199.8, 198.6, 37.5, 35.8,
30.1, 29.7, 25.1, 22.4, 13.9.
O
O
R1
O
R1
OH
3
HRMS: m/z calcd for C10H16O3: 184.1099; found: 184.1095.
R2
R2
OH
OH
Hexadecane-2,5,6-trione (3d)
Yield: 78%; yellow solid (140 °C/0.1 mmHg); mp 62–64 °C.
6
5
1H NMR (400 MHz, CDCl3): d = 2.94 (m, 2 H), 2.82 (m, 2 H), 2.74
(t, J = 7.3 Hz, 2 H), 2.20 (s, 3 H), 1.59 (m, 4 H), 1.27 (m, 12 H), 0.88
(t, J = 7.0 Hz, 3 H).
Scheme 2
13C NMR (100 MHz, CDCl3): d = 206.7, 199.8, 198.6, 37.4, 36.2,
The one-pot DABCO-catalyzed reaction of 2 to 3 is a
practical method for the synthesis of 1,2,5-triketones.
Since the disconnection for a given 1,2,5-triketone syn-
thetic target would be different from the disconnection
based on alkyne intermediates,8 this method compliments
existing methodology. The conversion of 2 into 3 by this
methodology is inherently ‘greener’ with greater atom
economy9 than a series of oxidation and reduction steps.
Finally, the conversion of 2 into 3 adds to the long and
32.0, 30.1, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 23.1, 22.8, 14.2.
HRMS: m/z calcd for C16H28O2 (M – H2O): 250.1933; found:
250.1935.
7-Methyloctane-2,5,6-trione (3e)
Yield: 83%; yellow oil (60 °C/0.1 mmHg).
1H NMR (400 MHz, CDCl3): d = 3.34 (sept, J = 6.9 Hz, 1 H), 2.94
(m, 2 H), 2.80 (m, 2 H), 2.19 (s, 3 H), 1.10 (d, J = 7.0 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 206.6, 202.9, 199.0, 37.1, 33.9,
30.8, 29.7, 17.5.
Synthesis 2010, No. 23, 3977–3979 © Thieme Stuttgart · New York

SHORT PAPER
DABCO-Catalyzed Reaction
3979
HRMS: m/z calcd for C9H14O3: 170.0943; found: 170.0944.
HRMS: m/z calcd for C13H18O2 (M – H2O): 206.1307; found:
206.1309.
(7E)-Non-7-ene-2,5,6-trione (3f)
Yield: 55%; yellow oil (60 °C/0.1 mmHg). Decomposed on stand-
ing at r.t.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 7.17 (dq, J = 16.1, 6.9 Hz, 1 H),
6.64 (dm, J = 15.8 Hz, 1 H), 2.99 (t, J = 6.0 Hz, 2 H), 2.81 (t, J = 6.0
Hz, 2 H), 2.20 (s, 3 H), 1.98 (dd, J = 7.0, 1.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.7, 200.2, 187.9, 149.9, 124.9,
37.1, 30.9, 29.8, 19.2.
We thank the Petroleum Research Foundation, administered by the
American Chemical Society and Lafayette College’s Academic Re-
search Committee for financial support. We gratefully acknowledge
a grant from the Kresge Foundation for the purchase a 400 MHz
NMR spectrometer. We thank the MSU Mass Spectrometry Facility
for performing the HRMS.
HRMS: m/z calcd for C9H12O3: 168.0786; found: 168.0790.
1-(4-Methylphenyl)hexane-1,2,5-trione (3g)
Yield: 81%; yellow oil (110 °C/0.1 mmHg).
References
(1) Merino, P.; Tejero, T.; Delso, J. I.; Matute, R. Curr. Org.
Chem. 2007, 11, 1076.
(2) Achmatowicz, O. Jr.; Bukowski, P.; Szechner, B.;
Zwierzchowska, Z.; Zamjoski, A. J. Tetrahedron 1971, 27,
1973.
(3) Martin, S. F.; Lee, W.; Pacofsky, G. J.; Gist, R. P.; Mulhern,
T. A. J. Am. Chem. Soc. 1994, 116, 4674.
(4) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.; Chen, D. Y. J. Am.
Chem. Soc. 2010, 132, 8219.
1H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 8.0 Hz, 2 H), 7.28 (d,
J = 8.0 Hz, 2 H), 3.08 (m, 2 H), 2.90 (m, 2 H), 2.41 (s, 3 H), 2.23 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 206.7, 202.0, 192.0, 145.9, 130.6,
129.6, 129.4, 36.9, 32.5, 29.8, 22.0.
HRMS: m/z calcd for C13H12O2 (M – H2O): 200.0837; found:
200.0835.
(5) (a) Guo, H.; O’Doherty, G. A. J. Org. Chem. 2008, 73,
5211. (b) See also: Balachari, D.; O’Doherty, G. A. Org.
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(6) Sekita, S.; Yoshihira, K.; Natori, S.; Kuwano, H. Chem.
Pharm. Bull. 1982, 30, 1629.
(7) For the synthesis of 1,2-diketones, see: Kashiwabara, T.;
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(8) (a) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S.
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Kamikawa, A.; Murai, A. Chem. Commun. 2001, 1392.
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(d) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett.
1997, 38, 7379.
Octane-2,3,6-trione (3h)
Yield: 55%; yellow oil (60 °C/0.1 mmHg).
1H NMR (400 MHz, CDCl3): d = 2.92 (m, 2 H), 2.79 (m, 2 H), 2.48
(q, J = 7.4 Hz, 2 H), 2.34 (s, 3 H), 1.06 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 209.6, 198.3, 197.3, 36.3, 35.7,
29.7, 23.8, 7.8.
HRMS: m/z calcd for C8H12O3: 156.0786; found: 156.0784.
Nonane-3,4,7-trione (3i)12
Yield: 62%; yellow solid (80 °C/0.1 mmHg); mp 35–37 °C.
1H NMR (400 MHz, CDCl3): d = 2.95 (m, 2 H), 2.80 (m, 2 H), 2.79
(q, J = 7.4 Hz, 2 H), 2.49 (q, J = 7.3 Hz, 2 H), 1.10 (t, J = 7.0 Hz, 3
H), 1.07 (t, J = 7.3 Hz, 3 H).
(9) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970.
(10) For the synthesis of the starting pyranones, see: (a)Kuo, Y.;
Shih, K. Heterocycles 1990, 31, 1941. (b) Costa, J. S.;
Lima, E. L. S.; MPallatinos, M. A.; Correia, C. R. D. J. Braz.
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Ital. 1995, 125, 325.
2-Methyldodec-11-ene-3,4,7-trione (3j)
Yield: 75%; yellow oil (100 °C/0.1 mmHg).
1H NMR (400 MHz, CDCl3): d = 5.57 (ddt, J = 17.2, 10.3, 6.6 Hz,
1 H), 4.94–5.05 (m, 2 H), 3.34 (sept, J = 7.0 Hz, 1 H), 2.94 (m, 2 H),
2.77 (m, 2 H), 2.46 (t, J = 7.3 Hz, 2 H), 2.05 (br q, J = 7.1 Hz, 2 H),
1.68 (pent, J = 7.3 Hz, 2 H), 1.10 (d, J = 7.0 Hz, 6 H).
(11) Pitacco, G.; Pizzioli, A.; Valentin, E. Synthesis 1996, 242.
(12) Bestmann, H. J.; Groß, A. Tetrahedron Lett. 1997, 38, 4765.
13C NMR (100 MHz, CDCl3): d = 208.7, 202.9, 199.1, 138.0, 115.4,
41.8, 36.3, 33.9, 33.1, 30.8, 22.9, 17.5.
Synthesis 2010, No. 23, 3977–3979 © Thieme Stuttgart · New York