A one-pot oxidation/allylation/oxidation sequence for the preparation of β,γ-unsaturated ketones directly from primary alcohols

Article abstract of DOI:10.1016/j.tetlet.2011.03.033

A one-pot oxidation/allylation/oxidation procedure has been developed for the conversion of primary alcohols into β,γ-unsaturated ketones. The methodology has been applied to a range of alcohols, and in some cases, isomerisation to produce the corresponding α,β-unsaturated ketones has been carried out.

Full text of DOI:10.1016/j.tetlet.2011.03.033

Tetrahedron Letters 52 (2011) 2511–2514
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A one-pot oxidation/allylation/oxidation sequence for the preparation
of b,c
-unsaturated ketones directly from primary alcohols
⇑
Catherine L. Moody, David S. Pugh, Richard J. K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot oxidation/allylation/oxidation procedure has been developed for the conversion of primary
Received 4 January 2011
Revised 28 February 2011
Accepted 4 March 2011
Available online 11 March 2011
alcohols into b,
in some cases, isomerisation to produce the corresponding
c-unsaturated ketones. The methodology has been applied to a range of alcohols, and
a
,b-unsaturated ketones has been carried out.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Allylation
b,c-Unsaturated ketones
a,b-Unsaturated ketones
a
,b- and b,
in organic synthesis.1 As part of a natural product project, we
required a straightforward method of preparing b, -unsaturated
c
-Unsaturated ketones are important building blocks
oxidation of allylic alcohol 4 to produce the target b,c-unsaturated
ketones 5 in a one-pot process. In addition, we anticipated that it
would be straightforward to extend this sequence to produce
c
ketones 5 (R = aryl, hetaryl, alkyl, etc.). Most of the available
procedures, such as the Barbier-type allylation of nitriles2 and
the Hosomi–Sakurai reaction of allyl silanes with acid chlorides,3
proceed from carboxylic acid derivatives,4 whereas we wished to
use alcohols 1 as simple starting materials.5,6 Given our interest
in tandem oxidation processes,7 the approach outlined in Scheme
1 appeared to present an attractive option. The idea was to oxidise
alcohols 1 to aldehydes 2 in the presence of an allylating reagent 3;
by using the oxidant in excess we hoped to achieve the in situ
a,b-unsaturated ketones 6 given the numerous methods reported
for effecting this type of isomerisation.8
Preliminary studies were carried out to assess the viability of a
one-pot approach to b,c-unsaturated ketones using p-chlorobenzyl
alcohol (7), p-chlorobenzaldehyde (8) and secondary alcohol 9 as
test substrates (Scheme 2). The initial oxidation of p-chlorobenzyl
alcohol 7 was straightforward, as expected, with MnO2 and
Dess–Martin periodinane (DMP) giving the most reliable results.9
Many methods are available for the allylation of aldehydes and
M
Ox.
OH
OH
O
Ox.
O
3
R
R
R
R
2
5
1
4
O
R
6
Scheme 1.
⇑
Corresponding author. Tel.: +44 0 1904 322606; fax: +44 0 1904 324523.
E-mail addresses: richard.taylor@york.ac.uk, tet@york.ac.uk (R.J.K. Taylor).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.033

2512
C. L. Moody et al. / Tetrahedron Letters 52 (2011) 2511–2514
ketones,10 but in our hands with p-chlorobenzaldehyde (8), the use
of allyl stannane (3a) with catalytic Yb(OTf)3,11 or allyl trifluorob-
orate (3b) with boron trifluoride etherate12,13 or Montmorillonite
K10 (MK10)13 proved the most straightforward giving the allyl
alcohol 9 via a practically simple process at room temperature.
The final step, the oxidation of the secondary benzylic alcohol 9,
proved more troublesome. No oxidation was observed using
MnO2 or TPAP/NMO, with DMP being most reliable for the forma-
tion of b,
-unsaturated ketone 10.14
c
Having studied the individual steps, we went on to examine
one-pot processes for the three-step sequence (Scheme 3). As can
be seen, with MnO2 as oxidant, it was possible to carry out a
tandem oxidation/allylation giving allylic alcohol 9 in low yield,
but further oxidation did not occur (as was expected after the
OH
(i) MnO2, CH2Cl2 or MeCN
rt, 4 h, >86%
O
Ox.
or
(ii) DMP, CH 2Cl2 , rt, 1 h
quant.
Cl
Cl
Cl
7
8
(i) M = SnBu3 (3a);
10 mol% Yb(OTf)3
MeCN, rt, 24 h, 84%
or
O
OH
M
(ii) M = BF3K (3b);
MK10
Cl
9
8
aq. CH2Cl2 , rt, 45 min, 88%
O
OH
(i) MnO2, CH2Cl2 or MeCN, rt, 3 d
Ox.
0%
or
Cl
Cl
(ii) DMP, CH 2Cl2 , rt, 3 h
quant.
9
10
Scheme 2.
MnO2 (5 eq)
OH
OH
SnBu3 3a
10 mol% Yb(OTf)3
MeCN, rt, 24 h
Cl
Cl
9 (12%) + 7 + 8
7
MnO2 (5 eq)
OH
OH
BF3K 3b
BF3.OEt2
CH2Cl2, rt, 24 h
Cl
Cl
9 (36%) + 7
7
DMP (2.5 eq)
OH
OH
O
BF3K 3b
BF3.OEt2
CH2Cl2, rt, 24 h
Cl
Cl
Cl
Cl
7
7
8 (only observable product)
O
i. DMP, CH2Cl2, rt, 1 h
BF3K 3b
ii.
MK10, rt, 1 h
iii. DMP, rt, 1 h
10 (71%)
Scheme 3.

C. L. Moody et al. / Tetrahedron Letters 52 (2011) 2511–2514
2513
D
-galactopyranose, entry viii). In all cases the yields were good to
excellent and the b, -unsaturated ketones were usually stable for
a day or so, although isomerisation to give the corresponding
preliminary studies shown in Scheme 2). Concentrating on the use
of DMP as oxidant, the tandem process gave mainly aldehyde 8
with trace amounts of allylated adducts 9 and 10, at best. We,
therefore, developed a sequential process in which DMP oxidation
was followed by the addition of allyl trifluoroborate (3b) and
MK10, and finally additional DMP was added to ensure complete
c
a
,b-unsaturated ketones was observed on prolonged storage.
As mentioned earlier, if conjugated ketones are required, these
are easily obtained from the corresponding b,
ketones. In our hands, DBU in diethyl ether16 gave the cleanest
isomerisation, with ,b-unsaturated ketones 25–27 being isolated
in almost quantitative yields, exclusively or predominantly as the
E-isomers (Scheme 4).
In summary, we have developed a one-pot oxidation/allylation/
oxidation procedure for the conversion of primary alcohols into
b,c-unsaturated ketones which involves DMP oxidation followed
by the addition of allyl trifluoroborate (3b) and Montmorillonite
K10 and finally additional DMP. The methodology has been applied
to a range of benzylic alcohols, as well as to an allylic and an
c-unsaturated
oxidation. In this manner, the required
10 was obtained in a 71% yield by a one-pot procedure.
Having established a reliable one-pot procedure for the oxida-
tion/allylation/oxidation route to b,c-unsaturated ketone 10, we
went on to explore its scope (Table 1). As can be seen, the sequence
was successful with a range of electron-rich and electron-poor ben-
zylic alcohols (entries i–iv), with 2-naphthyl-methanol (entry v)
and with thiophene-2-methanol (entry vi). In addition to benzylic
and related systems, an allylic example proved successful (entry
vii), as did an unactivated alcohol (1,2:3,4-di-O-isopropylidene-
a,b-unsaturated ketone
a
Table 1
One-pot oxidation/allylation/oxidation sequencea
Entry
Substrate
Product
Isolated Yieldb (%)
OH
O
i
714a
Cl
Cl
7
10
OH
O
ii
924b
854a,c
964a
MeO
MeO
11
12
O
OH
iii
iv
v
Br
Br
13
14
OH
O
O2N
O2N
15
16
OH
O
754d
17
18
OH
O
vi
764e
S
S
20
19
OH
O
vii
674f
Ph
Ph
21
22
OH
O
O
O
O
O
O
O
Me
Me
Me
Me
viii
7515
O
O
O
O
Me
Me
Me
Me
23
24
a
On a 0.25 mmol scale; (i) DMP (1.5–2.0 equiv), CH2Cl2, rt, 1 h; (ii) MK10, 3 (1.5–2.0 equiv), rt, 1 h; (iii) DMP (2.0–2.5 equiv), rt, 1 h.
Quenched with sat. aq. NaHCO3 and sat. aq. Na2S2O3; purified by flash column chromatography.
b

2514
C. L. Moody et al. / Tetrahedron Letters 52 (2011) 2511–2514
2846; (c) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186; (d) Tada, M.;
O
O
DBU, Et O
2
Hiratsuka, M.; Goto, H. J. Org. Chem. 1990, 55, 4364; (e) Felpin, F.-X.; Bertrand,
M.-J.; Lebreton, J. Tetrahedron 2002, 58, 7381; (f) Jiang, D.; Peng, J.; Chen, Y. Org.
Lett. 2008, 10, 1695.
24 h, 96%
E- only
5. For an elegant ruthenium-catalysed procedure for converting alcohols into b,c-
MeO
MeO
unsaturated ketones, see: (a) Omura, S.; Fukuyama, T.; Horiguchi, J.; Murakami,
Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094; (b) Shibahara, F.; Bower, J. F.;
Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14120.
12
25
6. For other recent methods for the conversion of alcohols into homologated
allylic alcohols and b,c-unsaturated ketones, see: (a) Zhang, L.; Zha, Z.; Zhang,
Z.; Li, Y.; Wang, Z. Chem. Commun. 2010, 46, 7196; (b) Nomura, K.; Matsubara, S.
Synlett 2008, 1412.
O
O
DBU, Et O
2
24 h, 87%
7. Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851. and
references cited therein.
8. Foster, C. E.; Mackie, P. R. Chapter 3.05 in Ref. 1.
E- only
S
S
9. All known compounds were characterised spectroscopically (comparison to
literature data) and by mp. comparison when available; novel compounds were
fully characterised.
26
20
10. For excellent reviews, see: (a) Denmark, S. E.; Almstead, N. G. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000. Chapter 10; (b)
Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000. Chapter 11; (c) Yamamoto, Y.; Asao, N. Chem. Rev. 1993,
93, 2207.
11. Aspinall, H. C.; Browning, A. F.; Greeves, N.; Ravenscroft, P. Tetrahedron Lett.
1994, 35, 4639.
12. Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett. 1999, 40, 4289.
13. Nowrouzi, F.; Thadani, A. N.; Batey, R. A. Org. Lett. 2009, 11, 2631.
14. Pyridinium chlorochromate was also successful in this oxidation reaction.
15. Representative experimental procedure: Galactopyranose derivative 24: To
O
O
O
O
DBU, Et O
2
O
O
24 h, 70%
O
O
O
O
Me
Me
Me
Me
E:Z > 20:1
O
O
Me
Me
Me
Me
27
24
Scheme 4.
1,2:3,4-di-O-isopropylidene-D-galactopyranose (23) (64 mg, 0.25 mmol) in
unactivated carbohydrate example. In three examples, base-medi-
ated isomerisation to produce the corresponding ,b-unsaturated
ketones has been carried out. We are currently applying this
sequence to more complex systems as part of a natural product
programme.
dry CH2Cl2 (5 mL) at rt under argon was added DMP (209 mg, 0.49 mmol)
and the mixture stirred for 1 h. Montmorillonite K10 (50 mg) was then added
followed by potassium allyl trifluoroborate (73 mg, 0.49 mmol) and the
mixture stirred for 1 h before adding a further portion of DMP (261 mg,
0.62 mmol). After stirring for a further 1 h, the reaction was quenched with sat.
aq NaHCO3 (5 mL) and sat. aq Na2S2O3 (5 mL) and allowed to stir for 1 h before
diluting with brine (10 mL) and CH2Cl2 (10 mL). The mixture was filtered and
then the layers separated. The aqueous portion was further extracted with
CH2Cl2 (2 Â 5 mL) and the combined organic extracts dried (Na2SO4) and
concentrated in vacuo. The residue was purified by silica gel chromatography
(0–5% acetone in CH2Cl2) to give the compound 24 (55 mg, 75%) as a colourless
micro-crystalline solid, mp 47–49 °C; Rf (CH2Cl2) = 0.15; vmax/cmÀ1 (thin film)
a
Acknowledgements
The authors thank the EPSRC for Ph.D. project studentship fund-
ing (D.S.P., EP/03456X/1), and the University of York and Elsevier
for additional studentship funding (C.L.M.).
2988, 2936, 1723 (C@O), 1383; [a]D À144 (c 0.4, CH2Cl2); dH (400 MHz, CDCl3)
5.97 (1H, ddt, J = 17.0, 10.5, 7.0, H-8), 5.64 (1H, d, J = 5.0, H-1), 5.20–5.08 (2H,
m, H-9), 4.63 (1H, dd, J = 8.0, 2.5, H-3), 4.56 (1H, dd, J = 8.0, 2.0, H-4), 4.35 (1H,
dd, J = 5.0, 2.5, H-2), 4.22 (1H, d, J = 2.0, H-5), 3.50 (1H, ddt, J = 18.5, 7.0, 1.5, H-
7a), 3.33 (1H, ddt, J = 18.5, 7.0, 1.5, H-7b), 1.49 (3H, s), 1.44 (3H, s), 1.33 (3H, s),
1.30 (3H, s); dC (100 MHz, CDCl3) 207.2 (C-6), 130.0 (C-8), 118.7 (C-9), 109.6,
109.0, 96.4 (C-1), 73.5 (C-5), 72.3 (C-4), 70.6 (C-3), 70.4 (C-2), 44.6 (C-7), 25.9,
25.8, 24.8, 24.2; m/z (ESI) 321 [M+Na]+; [HRMS (ESI): Calcd for C15H22NaO6,
321.1309. Found: [M+Na]+, 321.1317 (À2.7 ppm error)]; [C15H22O6 requires C,
60.39; H, 7.43. Found C, 60.35; H, 7.35].
References and notes
1. Comprehensive Organic Functional Group Transformations II; Katritzky, A. R.,
Taylor, R. J. K., Eds.; Elsevier, 2005.
2. Lee, A. S.-Y.; Lin, L.-S. Tetrahedron Lett. 2000, 41, 8803.
3. Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Parimala, G. Synthesis 2003, 2390.
4. For other procedures, see: (a) Gohain, M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S.
New J. Chem. 2003, 27, 1038; (b) Larock, R. C.; Lu, Y.-D. J. Org. Chem. 1993, 58,
16. Chiu, P.; Wong, S. T. Synth. Commun. 1998, 28, 4513.