Efficient oxidation-Wittig olefination-Diels-Alder multicomponent reactions of α-hydroxyketones

Article abstract of DOI:10.1016/j.tetlet.2010.10.121

α-Hydroxyketones undergo efficient tandem oxidation-Wittig olefination reactions in the presence of an oxidant to produce high yields of γ-ketocrotonate products. On carrying out the oxidation-Wittig olefination reaction in the presence of 2,3-dimethyl-1,3-butadiene, a novel multicomponent reaction sequence provides access to cycloadducts in high yield.

Full text of DOI:10.1016/j.tetlet.2010.10.121

Tetrahedron Letters 51 (2010) 6890–6892
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient oxidation-Wittig olefination-Diels–Alder multicomponent reactions
of a-hydroxyketones
⇑
Geraint H. Harris, Andrew E. Graham
Sustainable Environment Research Centre (SERC), Department of Science and Sport, University of Glamorgan, Glyntaff, Pontypridd CF37 4AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Hydroxyketones undergo efficient tandem oxidation-Wittig olefination reactions in the presence of an
Received 2 September 2010
Revised 8 October 2010
Accepted 22 October 2010
Available online 30 October 2010
oxidant to produce high yields of -ketocrotonate products. On carrying out the oxidation-Wittig olefin-
ation reaction in the presence of 2,3-dimethyl-1,3-butadiene, a novel multicomponent reaction sequence
provides access to cycloadducts in high yield.
c
Ó 2010 Elsevier Ltd. All rights reserved.
There has been considerable interest in reaction processes that
efficiently create complex structures from simple reactants
through one-pot operations, which has led to significant advances
in the areas of multicomponent processes (MCRs), domino reac-
tions, combinatorial chemistry and sequential/tandem transforma-
ficult to isolate due to their instability, toxicity or volatility. Singly
activated dienophiles, such as ethyl cinnamate, are easily con-
structed using this approach, but cycloaddition employing these
materials typically require prolonged reaction times at very high
temperatures or high pressures in order to achieve acceptable
1
7
tions. This interest has primarily been stimulated by the
yields. Indeed, in our hands, this dienophile produced no cycload-
requirement to generate diverse libraries of heterocyclic com-
pounds for drug discovery applications, and a number of innova-
tive approaches have been described.2 The incorporation of
cycloaddition reactions into MCR strategies is a highly attractive
proposition for the rapid generation of molecular complexity, as
multiple bonds are formed in a single step, and indeed, a number
of MCR strategies incorporating intramolecular Diels–Alder reac-
duct products under a variety of reaction conditions when gener-
ated from benzyl alcohol in the presence of manganese dioxide,
ylide 1a and 2,3-dimethyl-1,3-butadiene. We, therefore, consid-
ered alternative dienophile candidates, such as
c-ketocrotonates,
which being doubly activated, are more reactive in Diels–Alder
cycloadditions and so require milder reaction conditions. The
inclusion of additional functionality into the dienophile compo-
nent has the additional benefit that it provides cycloadducts which
are highly attractive advanced intermediates for subsequent elab-
oration into a range of natural products including anthraquinones
3
tions have been described, particularly for heterocycle formation.
It is surprising that the inclusion of intermolecular Diels–Alder
4
reactions into MCR sequences has attracted less interest, espe-
7
a,8
cially given the opportunities for introducing high levels of skeletal
and stereochemical complexity. As part of an ongoing programme
concerned with the development of efficient routes to heterocyclic
and hydrindane targets.
The synthesis of c-ketocrotonates from
the corresponding -ketoaldehydes, has been reported to be prob-
a
lematic due the high reactivity of the aldehyde carbonyl group
5
natural products, we envisioned that the exploitation of such
which leads to facile hydration, aerial oxidation or polymerisation
9
methodology would provide a potentially rapid and highly flexible
route for the construction of a variety of highly functionalised cyc-
lic structures. With this in mind, we explored a MCR strategy in
which construction of the dienophile component was achieved
employing a tandem oxidation-Wittig olefination strategy, which
subsequently underwent Diels–Alder cycloaddition in the presence
of a diene (Scheme 1).
reactions. Their synthesis, however, has been described from
a-
hydroxyketones, such as hydroxyacetophenone 2 and hydroxyace-
tone 3, employing a tandem oxidation-Wittig approach.10
In order to establish conditions for our proposed MCR, we ini-
tially concentrated our efforts on the critical cycloaddition compo-
nent in order to ensure compatibility with the oxidation-Wittig
sequence. Thus, c-ketocrotonate 4a, produced from hydroxyaceto-
A number of groups have reported the successful development
of tandem protocols for the direct transformation of alcohols into
olefins employing stabilised ylides in the presence of an oxidant.
These protocols not only lead to increases in efficiency, but are
especially useful when applied to carbonyl compounds that are dif-
6
1
1
O
R
CO
H
R 1a R = Et
1b R2 = Me
2
R2
R2
(
Ph) P
3
OR1
R
OH
R2
Oxidant,
⇑
Corresponding author.
E-mail addresses: AEGraham@glamorgan.ac.uk, GrahamAE@Cardiff.ac.uk
R2
(
A.E. Graham).
Scheme 1.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.121

G. H. Harris, A. E. Graham / Tetrahedron Letters 51 (2010) 6890–6892
6891
O
O
OEt acetone, rt, 24 h 27%
chloroform, Δ, 6 h 72%
toluene, Δ, 4 h 91%
OEt
Ph
Solvent
Ph
O
4a
5a
O
Scheme 2.
phenone 2,10 was reacted with 2,3-dimethyl-1,3-butadiene under a
variety of reaction conditions (Scheme 2), of which, toluene at re-
flux proved to be most efficient giving an excellent yield of the cyc-
loadduct 5a.
With conditions for the cycloaddition in place, we next studied
the MCR of 2 with ylides 1a and 1b in the presence of activated
1a in the presence of 2,3-dimethyl-1,3-butadiene under these reac-
tion conditions (entry 3).
1H NMR analysis of the crude reaction mixtures indicated that
these low isolated yields of cycloadduct were explained by poor
conversion of 3 under these reaction conditions leading us to con-
sider alternative oxidising agents. We have previously reported
MnO
2
and an excess of 2,3-dimethyl-1,3-butadiene, and were de-
that employing less activate grades of MnO
cial in MnO -mediated tandem oxidation-Wittig sequences pro-
ducing improved yields, especially where the starting material or
2
can be highly benefi-
lighted to observe that these substrates underwent an efficient oxi-
dation-Wittig olefination-Diels–Alder sequence to produce
cycloadducts 5a and 5b in high isolated yield (Table 1, entries 1
and 2). The reaction was also achieved in a sequential, one-pot ap-
proach, in which the diene component was added to the reaction
mixture on completion of the oxidation-Wittig olefination se-
quence. Disappointingly, however, only poor yields of cycloadduct
2
1
1
product is prone to decomposition. Replacing the activated grade
oxidant with MnO of particle sizes <10 m, however, gave no sig-
2
l
nificant improvement in the formation of 6a (Table 2, entry 1). We
next considered the use of silica-supported pyridinium chlorochro-
mate (PCC), a reagent that has been successfully employed in
sequential and tandem oxidation-Wittig sequences.5
b,6h
In light
7
a were isolated from the reaction of hydroxyacetone 3 and ylide
of the fact that there have been no previous examples of its use
in tandem processes employing -hydroxyketones, we first under-
a
took a short study to assess the suitability of this reagent with
these substrates (Table 2). We were delighted to observe that, in
the presence of excess silica-supported PCC, sodium acetate and
ylide 1a, excellent yields of 6a were achieved under a range of
reaction conditions (Table 2, entries 2–4). Importantly, the tandem
oxidation-Wittig olefination sequence proceeded readily when car-
ried out at the elevated temperatures required for efficient cyclo-
addition reaction (Table 2, entry 4). Application of these modified
reaction conditions to the oxidation-Wittig olefination reaction of
Table 1
Multicomponent oxidation-Wittig olefination-Diels–Alder reactions of
hydroxyketones
a-
O
1
CO R
2
O
Oxidant,
(Ph) P
3
OR1
H
OH
R
R
toluene, 6 h, Δ
2
3
R = Ph
R = Me
O
5a, b
7a, b
2
also proved to be successful, giving 4a in high isolated yield
Producta
Yieldb (%)
12
Entry
Alcohol
Ylide
Oxidant
(Table 2, entry 5).
Finally, we investigated the multicomponent reactions of
a-
O
hydroxyketones 2 and 3 under our modified PCC-mediated condi-
tions and were satisfied to observe that both alcohols underwent
highly efficient oxidation-Wittig olefination-Diels–Alder sequences
OEt
Ph
76
80
13
1
2
1a
MnO
MnO
2
2
2
c
to give cycloadducts 5a and 5b (Table 1, entries 4 and 5) and 7a and
O
O
5a
1
4
7
b (entries 6 and 7) in high isolated yields. This novel sequence
allows for the efficient formation of multiple carbon–carbon bonds
in a simple, three-component, one-pot operation.
OMe
Ph
2
2
1b
70
11
In conclusion, we have demonstrated that
a-hydroxyketones
undergo efficient tandem oxidation-Wittig olefination reactions
in the presence of silica-supported PCC to produce high yields of
O
O
5b
OEt
3
4
3
2
1a
1a
MnO
PCC
Table 2
PCC-mediated oxidation of
7a
a
-hydroxyketones 2 and 3
O
5a
82
O
Oxidant
O
c
85
OH
R
OEt
O
4a or 6a
5
6
2
3
1b
1a
PCC
PCC
5b
7a
77
82
CO Et
R
2
(Ph) P
3
c
2 or 3
H
71
O
O
Yielda (%)
Entry
Reaction conditions
3/MnO (<10 m)/toluene/
3/PCC-NaOAc/CH Cl/ 4 h
3/PCC-NaOAc/toluene/rt/24 h
OMe
1
2
3
4
5
2
l
D
Traceb
75
78
7
3
1b
PCC
67
3
D
7b
3/PCC-NaOAc/toluene/
D
D
3 h
3 h
86
81
c
2/PCC-NaOAc/toluene/
a
All products gave satisfactory spectroscopic data.
b
c
a
b
c
Yields refer to isolated purified yields of isomer shown.
Diene component added on completion of the oxidation-Wittig-olefination
Reactions produced ꢀ5% Z-isomer.
Determined from 1H NMR analysis of the crude reaction mixture.
reaction.
Product is 4a.

6
892
G. H. Harris, A. E. Graham / Tetrahedron Letters 51 (2010) 6890–6892
Niizuma, S.; Matsuda, A. J. J. Org. Chem. 1998, 63, 4489–4493; (d) Barrett, A. G.
c
-ketocrotonate products. On carrying out this oxidation-Wittig
M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem. 1997, 62, 9376–9378; (e)
Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 6339–6344; (f)
MacCoss, R. N.; Balskus, E. P.; Ley, S. V. Tetrahedron Lett. 2003, 44, 7779–
7781; (g) Bagley, M. C.; Hughes, D. D.; Sabo, H. M.; Taylor, P. H.; Xiong, X. Synlett
olefination sequence in the presence of 2,3-dimethyl-1,3-butadi-
ene, a novel multicomponent reaction protocol can be achieved
in which the
Diels–Alder reaction giving cycloadducts in high yield. The simplic-
ity and convenience of this MCR protocol, and its efficiency in cre-
ating skeletal and stereochemical complexity in a single operation,
provides ready access to functionalised cyclic building blocks that
can be elaborated into complex structural motifs found in a range
of natural products.
c-ketocrotonates, once formed, undergo efficient
2003, 1443–1446; (h) Shet, J.; Desai, V.; Tilve, S. Synthesis 2004, 1859–1863.
7
.
.
(a) Fieser, L. F.; Fieser, M. J. Am. Chem. Soc. 1935, 57, 1679–1681; (b) Holmes, H.
L.; Husband, R. M.; Lee, C. C.; Kawulka, P. J. Am. Chem. Soc. 1948, 70, 141–142;
(c) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517–3520.
(a) Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron 1998, 54, 12071–12150; (b)
Lee, J. H.; Kim, W. H.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 5482–5484;
8
(
c) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4428.
9. Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198–2200.
10. Runcie, K. A.; Taylor, R. J. K. Chem. Commun. 2002, 974–975.
11. (a) Phillips, D. J.; Pillinger, K. S.; Li, W.; Taylor, A. E.; Graham, A. E. Chem.
Commun. 2006, 2280–2282; (b) Phillips, D. J.; Graham, A. E. Synlett 2008, 649–
Acknowledgements
652; (c) Smith, B. M.; Graham, A. E. Tetrahedron Lett. 2006, 47, 9317–9319; (d)
Smith, B. M.; Graham, A. E. Tetrahedron Lett. 2007, 48, 4891–4894; (e) Bagley,
M. C.; Lin, V.; Phillips, D. J.; Graham, A. E. Tetrahedron Lett. 2009, 50, 6823–
The authors thank EPSRC National Mass Spectrometry Service,
Swansea University and the Nuffield Foundation for funding.
6825; (f) Phillips, D. J.; Graham, A. E. Synlett 2010, 769–773.
1
2. Typical procedure for the tandem oxidation/Wittig reaction of hydroxyacetone 3
using silica-supported PCC/NaOAc: Hydroxyacetone (143 mg, 1.93 mmol) was
added to a solution of silica-supported PCC (830 mg, 3.85 mmol, ground with
References and notes
2
wt equiv of silica), NaOAc (316 mg, 3.85 mmol) and (carbethoxymethylene)-
triphenylphosphorane 1a (1.68 g, 4.8 mmol) in CHCl (15 mL) and stirred at
reflux for 4 h. The reaction mixture was then cooled to room temperature and
filtered through Celite pad which was washed with additional CHCl
2 Â 10 mL). The combined solvents were then removed to give a yellow oil
which was purified by column chromatography (hexane?5% EtOAc/hexane) to
1
.
(a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b)Multicomponent Reactions; Zhu,
J., Bienaymé, H., Eds.; Wiley: Weinheim, 2005; (c) Taylor, R. J. K.; Reid, M.; Foot,
J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851–869; (d) Tietze, L. F. Chem. Rev. 1996,
3
a
3
9
6, 115–136; (e) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–
634; (f) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137–165; (g)
Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001–
020.
(
1
15
give (E)-ethyl 4-oxo-2-pentenoate 6a as a yellow oil (206 mg, 75%);
m
max (film)/
1
cm , 2985, 1721, 1701, 1290, 1182, 978, 869, 587; 1H NMR (400 MHz; CDCl
À1
3
)
2
.
.
(a) Isambert, N.; Lavilla, R. Chem. Eur. J. 2008, 14, 8444–8454; (b) Zhu, J. Eur. J.
Org. Chem. 2003, 1133–1144; (c) Hume, C.; Gore, V. Curr. Med. Chem. 2003, 10,
d = 6.95 (1H, d, J = 16 Hz), 6.55 (1H, d, J = 16 Hz), 4.22 (2H, q, J = 7 Hz), 2.30 (3H, s),
1
6
.25 (3H, t, J = 7 Hz). 13C NMR (100 MHz, CDCl
) d = 198.0, 165.9, 140.3, 132.0,
7 11 3
) calcd for C H O
3
5
1–80; (d) D’Souza, D. M.; Müller, T. J. J. Chem. Soc. Rev 2007, 36, 1095–1108;
e) Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486.
(a) Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115–118; (b) Fayol, A.; Zhu, J. Tetrahedron
005, 61, 11511–11519; (c) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem., Int.
Ed. 2007, 119, 2537–2540; (d) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000,
, 709–712; (e) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6,
231–4233.
(a) Zhu, W.; Mena, M.; Jnoff, E.; Na, S.; Pasau, P.; Ghosez, L. Angew. Chem., Int. Ed.
+
1.8, 28.5, 14.5; MS (ES, NH
3
) m/z 143 (M+H) , HRMS (ES, NH
3
(
+
+
+
(
M+H) , 143.0703 (M+H) , found (M+H) 143.0704.
3. The possibility that the Diels–Alder cycloaddition is catalysed by the presence
of silica or a metal species derived from PCC or MnO cannot at this time be
3
1
2
2
ruled out. Studies to clarify this point and to assess the potential of Lewis acid
catalysis of the cycloaddition step are ongoing. For studies on the beneficial
role of silica on Diels–Alder reactions, see: (a) Cunningham, I. D.; Crawley, V. J.
Mol. Catal. A 2009, 301, 47–51; (b) Okamura, H.; Iiji, H.; Hamada, T.; Iwagawa,
T.; Furuno, H. Tetrahedron 2009, 65, 10709–10714; (c) Veselovsky, V. V.; Gybin,
A. S.; Lozanova, A. V.; Molseenkov, A. M.; Smit, W. A. Tetrahedron Lett. 1998, 29,
2
4
4
.
2009, 48, 5880–5883; (b) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc.
2004, 126, 1352–1353; (c) Gaddam, V.; Nagarajan, R. Tetrahedron Lett. 2009, 50,
1243–1248; (d) Yamaguchi, R.; Hamasaki, T.; Sasaki, T.; Ohta, T.; Utimoto, K.;
1
75–178; For Cr(III) and Mn(II) catalysed Diels–Alder cycloadditions see: (d)
Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
043–6046; (e) Phomkeon, K.; Takemoto, T.; Ishima, Y.; Shibatomi, K.; Iwasa,
Kozima, S.; Takaya, H. J. Org. Chem. 1993, 58, 1136–1143; (e) Ramachary, D. B.;
Chowdari, N. S.; Barbas, C. F. Angew. Chem., Int. Ed. 2003, 42, 4233–4237; (f) van
Berkom, L. W. A.; Kuster, G. J. T.; Kalmoua, F.; de Gelder, R.; Scheeren, H. W.
Tetrahedron Lett. 2003, 44, 5091–5093; For the application of intermolecular
hetero Diels–Alder reactions in MCR sequences, see: (g) Powell, D. A.; Batey, R.
A. Org. Lett. 2002, 4, 2913–2916; (h) Lallemand, J.-Y.; Six, Y.; Ricard, L. Eur. J. Org.
Chem. 2002, 503–513; (i) Touré, B. B.; Hall, D. G. Angew. Chem., Int. Ed. 2004, 43,
6
W.; Nishiyama, H. Tetrahedron 2008, 64, 1813–1822.
1
4. Typical procedure for the MCR of 3 in the presence of silica-supported PCC/NaOAc:
Hydroxyacetone (210 mg, 2.8 mmol) was added to a solution of 2,3-dimethyl-
1,3-butadiene (700 mg, 8.2 mmol), silica-supported PCC (1.22 g, 5.7 mmol,
ground with 2 wt equiv of silica), NaOAc (465 mg, 5.68 mmol) and
2
001–2004; (j) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629.
(a) Smith, B. M.; Skellam, E. J.; Oxley, S. J.; Graham, A. E. Org. Biomol. Chem.
007, 5, 1979–1982; (b) Phillips, D. J.; Pillinger, K. S.; Li, W.; Taylor, A. E.;
(
(
carbethoxymethylene)triphenylphosphorane 1a (2.47 g, 7.1 mmol) in toluene
15 mL) and stirred at reflux for 6 h. The reaction mixture was then cooled to
5
.
2
room temperature and filtered through a Celite pad which was washed with
additional toluene (2 Â 10 mL). The combined solvents were removed to give a
yellow oil which was purified by column chromatography (hexane?5% EtOAc/
Graham, A. E. Tetrahedron 2007, 63, 10528–10533; (c) Cott, D.; Owens, V.;
Zeigler, K. J.; Glennon, J. D.; Graham, A. E.; Holmes, J. D. Green Chem. 2005, 7,
1
05–110; (d) Robinson, M. W. C.; Davies, A. M.; Buckle, R.; Mabbett, I.; Taylor, S.
*
*
hexane) to give (1R ,2R )-ethyl 2-acetyl-4,5-dimethylcyclohex-4-enecarboxy-
H.; Graham, A. E. Org. Biomol. Chem. 2009, 7, 2559–2564; (e) Smith, B. M.; Kean,
S. D.; Wyatt, M. F.; Graham, A. E. Synlett 2009, 1953–1956; (f) Robinson, M. W.
C.; Graham, A. E. Tetrahedron Lett. 2007, 48, 4727–4731; (g) Robinson, M. W. C.;
Davies, A. M.; Mabbett, I.; Apperley, D. C.; Taylor, S. H.; Graham, A. E. J. Mol.
Catal. A 2009, 314, 10–14; (h) Robinson, M. W. C.; Davies, A. M.; Mabbett, I.;
Davies, T. E.; Apperley, D. C.; Taylor, S. H.; Graham, A. E. J. Mol. Catal. A 2010,
16
À1
late 7a as a yellow oil (514 mg, 82%);
179, 1155, 1032, 616; 1H NMR (400 MHz; CDCl
1H, dt, J = 11and 5 Hz), 2.70(1H, dt, J = 11and5 Hz), 2.25–1.80(4H, m), 2.15(3H,
m
max (film)/cm ; 2913, 1727, 1712, 1231,
1
(
3
) d = 4.10 (2H, q, J = 7 Hz), 2.90
1
3
s), 1.55 (6H, s), 1.15 (3H, t, J = 7 Hz); C NMR (100 MHz, CDCl
3
) d = 211.0, 175.2,
) m/z+
225.1485 (M+H) , found (M+H)
1
2
2
24.3, 123.6, 60.5, 49.0, 41.8, 34.3, 33.8, 29.0, 18.7, 18.6, 14.2; MS (CI, NH
3
+
+
25 (M+H) , HRMS (ES, NH
3
) calcd for C13
H
21
O
3
329, 57–63; (i) Robinson, M. W. C.; Pillinger, K. S.; Mabbett, I.; Timms, D. A.;
25.1484.
Graham, A. E. Tetrahedron 2010, 66, 8377–8382.
(a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815–3818; (b) Blackburn,
L.; Wei, X.; Taylor, R. J. K. Chem. Commun. 1999, 1337–1338; (c) Shuto, S.;
1
1
5. Bonete, P.; Nájera, C. Tetrahedron 1995, 51, 2763–2776.
6. Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998, 63, 4336–4373.
6
.