A mild, catalytic and efficient Nazarov cyclization mediated by phosphomolybdic acid

Article abstract of DOI:10.1039/b918137g

A mild, selective and efficient Nazarov cyclization of divinyl ketones catalyzed by phosphomolybdic acid (PMA) is described. The process demonstrates a broad substrate scope with functional group tolerance under short reaction times. PMA supported on silica gel is more efficient than the bulk catalyst and is recycled up to three times without significant activity loss.

Full text of DOI:10.1039/b918137g

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A mild, catalytic and efficient Nazarov cyclization mediated by
phosphomolybdic acidw
Kaliyappan Murugan, Sankareswaran Srimurugan and Chinpiao Chen*
Received (in Cambridge, UK) 4th September 2009, Accepted 4th December 2009
First published as an Advance Article on the web 24th December 2009
DOI: 10.1039/b918137g
A mild, selective and efficient Nazarov cyclization of divinyl
ketones catalyzed by phosphomolybdic acid (PMA) is described.
Table 1 Optimization of HPA catalyst for Nazarov cyclization
The process demonstrates
a broad substrate scope with
functional group tolerance under short reaction times. PMA
supported on silica gel is more efficient than the bulk catalyst
and is recycled up to three times without significant activity loss.
Entry HPA
x (mol%) Solvent T/1C Time/h Yield (%)a
The Nazarov cyclization1 of divinyl ketones is a frequently
encountered protocol for constructing five-membered carbo-
cycles in pharmaceutically important target molecules and
natural product synthesis.2 The reaction proceeds either
photochemically or in the presence of Lewis3 or Brønsted4
acids as catalysts. The synthetic versatility of this method was
recently improved by interception of the cationic intermediate
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PMA
PMA
PMA
PMA
PMA
PMA
PMA
PMA
PMA
PMA
PMA
0.5
1.0
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
CH3CN RT
CH3CN RT
CH3CN RT
12.0
3.0
0.5
2.0
96
92
94
95
50
NR
80
CH3CN
Toluene
DMF
CH2Cl2
CHCl3
EtOH
THF
Water
CH3CN
CH3CN
CH3CN
40
40
40
40
40
40
40
40
40
40
40
20.0
20.0
20.0
6.0
20.0
20.0
20.0
25.0
25.0
25.0
85
Traces
60
with
a variety of nucleophiles affording functionalized
32b
52
30
32
cyclopentenones.5 A number of Brønsted acid catalysts have
been adopted for Nazarov cyclization of different classes of
divinyl ketone substrates; however, in a few cases, Brønsted
acids are less preferred because of their low yield, long reaction
time, high reaction temperature and high catalyst loading.
Although Lewis acid catalysts, on the other hand, are equally
efficient for transformation, some Lewis acids4 are limited
only to polarized Nazarov substrates and require stringent
anhydrous reaction conditions. Solid acids such as zeolites6
showed promising cyclization results, with high yields for less
reactive Nazarov substrates. Interestingly, the synthetic utility
of other solid acids has never been explored. Heteropoly
acids (HPAs) are promising solid acids; they are redox and
bifunctional catalysts in homogeneous as well as in hetero-
geneous conditions.7 These acids exhibit marked catalytic
activities and unique selectivities, allowing cleaner processing
compared with conventional liquid catalysts. Hence, HPAs are
regarded as green catalysts, even though Nazarov cyclization
under green (e.g., on silica gel) and solvent-free conditions
using a microwave has been reported.8 Replacing conventional
acids with HPAs for different transformations has significantly
reduced reaction times and catalyst loading and generated
milder reaction conditions. To the best of our knowledge, no
examples of Nazarov cyclization catalyzed by HPAs exist.
This study describes the efficient and mild electrocyclization
of different divinyl ketones in the presence of phosphomolybdic
acid as a catalyst. This catalyst system features high yields,
PWAc 0.5
SWAd 0.5
SMAe 0.5
a
b
Isolated yields. Water-trapped product. PWA—phosphotungstic
d
acid. SWA—silicotungstic acid. SMA—silicomolybdic acid.
c
e
short reaction times, functional group tolerance and efficient
recyclability in the bulk as well as in the supported form.
Initial attempts at Nazarov cyclization of compound 5 were
performed in acetonitrile with 0.5 mol% PMA as the catalyst
at ambient temperature and produced cyclopentenone 5a in
excellent yield after a long reaction time (Table 1, entry 1).
Optimization of the catalyst loading (Table 1, entries 1–3)
improved reaction efficiency and markedly reduced reaction
time. An elevated temperature (Table 1, entries 1, 4) considerably
enhanced reaction. Solvents other than acetonitrile (Table 1,
entries 5–10) did not improve yield or shorten reaction time.
Interestingly, the reaction in an aqueous medium9 afforded the
expected Nazarov product, though in a low yield (Table 1,
entry 11). The water-trapped Nazarov product was the major
product obtained. Attempts to improve the yield of the normal
Nazarov product via high catalyst loading, high temperature,
a phase-transfer catalyst, and aqueous acetonitrile as a solvent
were unsuccessful. Adding diisopropylamine to the aqueous
reaction, as in the literature,9 neutralized acidic sites on PMA
and no reaction was observed. When other heteropoly acids
were used in the place of PMA the reactions were sluggish
under identical conditions (Table 1, entries 12–14).
The optimized reaction conditions (0.5% PMA at 40 1C in
CH3CN) were exploited for structurally diverse divinyl
ketones. Polarized substrates with a carboethoxy group at
the a-position of the dienone were synthesized by adding the
sodium enolate of ethyl acetate to a,b-unsaturated esters.
Department of Chemistry, National Dong Hwa University, Shoufeng,
Hualien 974, Taiwan, Republic of China.
E-mail: chinpiao@mail.ndhu.edu.tw; Fax: +886-3-8630475;
Tel: +886-3-8633597
w Electronic supplementary information (ESI) available: Experimental
details and NMR and IR spectra. See DOI: 10.1039/b918137g
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Table 2 Nazarov cyclization of different divinyl ketones in the
presence of phosphomolybdic acid
Entry Substrate
Time/ha
Product
Yield (%)a,b
1
4
5
0.5 (0.08)
4a 99 (99)
Scheme 1 Synthetic route to Nazarov substrates.
2
2.0
5a 95
Knoevenagel condensation10 of the resulting b-keto ester 2
with various aldehydes afforded the corresponding dienones 3
in good overall yields compared to the generally adopted acid
chloride method3c (Scheme 1). The synthetic routes to other
substrates employed in this study are described in the ESI.w
All divinyl ketones 4–14 underwent smooth cyclization
under the conditions employed, forming the corresponding
cyclopentenones 4a–14a in excellent yields (Table 2). Reaction
times and the amount of catalyst required were strongly
dependent on the substituent pattern of the divinyl ketones.
2-Alkoxy dienones with an unsubstituted vinyl group required
a longer reaction time than when using similar substrates
carrying substituents either at the a-, or b-position (Table 2,
3
4
5
6
7
8
48.0c (2.0)
0.25
6a 62 (90)
7a 90
0.33
8a 90
6
7
9
24
9a 50e
10a 99
10 2.0
entries 1–5). The 2-ethoxypentadienone
9 reacted at a
considerably slower rate than its dihydropyranyl counterpart
(Table 2, entry 6) with subsequent loss of the ethoxy group in
the 9a product. Introducing the electron withdrawing carboxy-
ethyl group at the a-position of 4 had no significant effect on
reactivity, and dienone 10 required a longer reaction time than
that of 4 (Table 2, entry 7). Similarly, for compound 12, with a
methylene group in place of the alkoxy group of the dihydro-
pyranyl ring, the double bond in the product is localized less
selectively and reaction generated regioisomers 12a and 12b in
a 3.5 : 1 ratio. A ten-fold increase in catalyst loading was
desirable for complete conversion for cases of poorly polarized
divinyl ketones (Table 2, entries 10 and 11). The yield, reaction
time and broad substrate scope with this catalyst system are
superior to those of any catalyst system used for similar
transformations. The homo-Nazarov11 variant using vinyl-
cyclopropyl ketone 15 had a reactivity similar to that of its
dihydropyranyl counterpart, and produced bicyclic cyclo-
hexenone 15a in a higher yield and shorter reaction time
(Table 2, entry 12) compared with those of the reported
protocol.11 Reactions performed with 10% PMA by weight
supported on silica-gel at 0.5 mol% catalyst loading were more
efficient than those with the bulk catalyst, resulting in a sharp
reduction in reaction time (Table 2, entries 1, 3 and 12).
Divinyl ketones 16–19 with acid-labile functionalities were
subjected to Nazarov cyclization to investigate the chemo-
selectivity of the present catalyst system (Table 3). A high yield
of Nazarov product with no detectable deprotection or
rearrangement was encountered in the case of substrates
with a TBS ether (16) or an azide group (18). In other cases,
a slight modification of the reaction conditions, such as
lowering catalyst loading (in the case of MOM ether
dienone 17) or using an alternative solvent (CH2Cl2 in the
case of THP ether 19) that decelerates the electrocyclization
reaction, afforded high yields of cyclopentenone with intact
functionalities.
8
9
11 0.16
12 0.16
11a 98
12a
90 (3.5 : 1)
12b
10
11
13 0.75
14 0.50
13a 90d
14a 88d
12
15 1.5 (0.5)
15a 80 (82)
a
The values in parentheses refer to reactions performed with
b
0.5 mol% PMA/SiO2. Isolated yields. Reaction was not complete
c
d
e
after 48 h. Performed with 5 mol% catalyst. Ethyl group was
hydrolyzed.
The most reactive supported catalyst was further exploited
for catalyst reuse. The supported catalyst was effectively
recycled up to three times without appreciable change
in catalytic activity, as evidenced by the consistently high
TOF (turnover frequency) for all the cycles (Table 3,
entry 5). In each case, the catalyst used was washed repeatedly
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Table 3 Functional group tolerance and recyclability studies
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Yield
(%)
Entry Substrate
Time/h Product
1
16 0.08
16a 94
2
3
17 0.25
18 0.17
17a 80a
18a 85
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4
5
19 3.0b,c
19a 75c
4
4a
PMA/SiO2 (1st)
0.08
0.08
0.33
1.0
237 600d
237 600d
58 200d
19 000d
99
99
97
95
PMA/SiO2 (2nd)
PMA/SiO2 (3rd)
PMA/SiO2 (4th)
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a
b
0.1 mol% PMA was employed at room temperature. Reaction
c
performed in CH2Cl2. THP deprotected compound was formed in
20% yield. TOF (hÀ1).
d
with CH2Cl2 and dried under high vacuum pressure prior to
the next cycle.
In conclusion, PMA (in bulk and supported form) efficiently
catalyzes electrocyclization of divinyl ketones under short
reaction times in high yields. The supported catalyst system
was more effective than the bulk catalyst system and permits
recyclability of the used catalyst for up to three cycles with
similar catalytic activity levels. This catalyst system is chemo-
selective and acid-labile functionalities remain intact during
the cyclization process. The present method is therefore a
promising and useful addition to existing catalyst systems for
the construction of five-membered carbocycles in natural
product synthesis.
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We thank the National Science Council of the Republic of
China (NSC 97-2113-M-259-002-MY3) for generous support.
Notes and references
1 I. N. Nazarov and I. I. Zaretskaya, Izv. Akad. Nauk SSSR,
Ser. Khim., 1941, 211.
2 Recent reviews on the Nazarov reaction: (a) K. L. Habermas and
S. E. Denmark, Organic Reactions, John Wiley & Sons, New York,
1994, ch. 1, vol. 45; (b) C. Santelli-Rouvier and M. Santelli,
11 F. De Simone, J. Andres, R. Torosantucci and J. Waser, Org. Lett.,
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Chem. Commun., 2010, 46, 1127–1129 | 1129