Me3SiI-promoted reaction of salicylic aldehydes with ketones: A facile way to construct benzopyranic [2,3-b]ketals and spiroketals

Article abstract of DOI:10.1039/c2cc32545d

Me₃SiI-promoted reaction of salicylic aldehydes with ketones via arylmethylation at the α-site of the carbonyl group and cyclodehydration of keto-diol provided a facile way to construct heteroannular ketals, furnishing benzopyranic [2,3-b]ketals and spiroketals in moderate to good yields. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc32545d

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Me3SiI-promoted reaction of salicylic aldehydes with ketones: a facile
way to construct benzopyranic [2,3-b]ketals and spiroketalsw
Feijun Wang,*a Mingliang Qu,a Xi Lu,a Feng Chen,a Feng Chena and Min Shi*ab
Received 10th April 2012, Accepted 1st May 2012
DOI: 10.1039/c2cc32545d
Me3SiI-promoted reaction of salicylic aldehydes with ketones
via arylmethylation at the a-site of the carbonyl group and
cyclodehydration of keto-diol provided a facile way to construct
heteroannular ketals, furnishing benzopyranic [2,3-b]ketals and
spiroketals in moderate to good yields.
kinetic spirocyclization,6 oxidative cyclization,7 metal-catalyzed
spiroketalization of dihydroxy alkynes,8 and reductive cyclization
reaction9 have been developed. In spite of all these achievements,
the cyclodehydration of a keto-diol represents the most classical
route to the synthesis of heteroannular ketals.10 However, this
strategy involved a large number of steps such as carbonyl redox
and protecting-group manipulations to synthesize these precursors.
Therefore, general and flexible synthetic strategies leading to
functionalized heteroannular ketals involving cyclodehydration of
a keto-diol are still in high demand and remain challenging.
With well-established Me3SiI-promoted synthetic chemistry in
place,11 arylmethylation of the a-site of the carbonyl group directly
using aromatic aldehyde as an arylmethylation reagent12 and the
cyclodehydration of a keto-diol to furnish heteroannular ketals13
have been achieved by Me3SiI-promoted reactions. Therefore, we
reasoned that [2,3-b]ketals and 6,60-spiroketals were, respectively,
assembled by Me3SiI-promoted arylmethylation and cyclodehydra-
tion (Scheme 1). Herein we wish to report a highly convergent and
concise entry to construct complex [2,3-b]ketals and spiroketals by
the Me3SiI-promoted reaction of salicylic aldehydes with ketones.
Initially, the reaction of salicylic aldehyde 2a with acetone
1a was investigated as a model system to identify and optimize
the critical reaction parameters (Table 1) in the presence of
Me3SiI generated in situ from Me3SiCl and NaI in CH3CN. As
expected, 42% yield of [2,3-b]ketal 3aa and traces of 4aa were
obtained, respectively, at room temperature in the presence of
0.5 equiv. of acetone and 5.0 equiv. of Me3SiCl and NaI
(Table 1, entry1). The structure of product 3aa was further
confirmed by single-crystal X-ray diffraction.14 During the
optimization of reaction conditions, it was found that using
5.0 equiv. of acetone 1a in the presence of 10.0 equiv. of
Me3SiCl and NaI, product 3aa was obtained in up to 77%
yield (Table 1, entry 8).
The construction of various types of heteroannular ketals is a
fundamental and important subject in medicinal chemistry,
natural product chemistry and synthetic chemistry.1 As it is well
known, heteroannular ketals such as [2,3-b]ketals and spiroketals
(selected examples bearing a 4H-benzopyran scaffold shown in
Fig. 1) are widespread elements in natural products and showed
widespread and diverse biological activities such as antimalarial
activity, phytotoxic properties, erythropoietin gene expression,
and acetylcholine esterase inhibition.
Fig. 1 Selected examples of natural benzopyranic ketals.
Given their high importance, there is ongoing interest in the
development of convenient and general protocols for the synthesis
of these natural and natural ketal-like derivatives. Hence, in
recent years, novel approaches to the synthesis of ketals such as
hetero Diels–Alder reaction,2 Mannich–Ketalization reaction,3
Lewis acid catalyzed intermolecular cycloaddition,4 acid
catalyzed intramolecular cycloaddition,5 Ti(Oi-Pr)4-mediated
To probe the scope of this Me3SiI-promoted reaction, we
tested a series of salicylic aldehydes 2 under the optimized
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 MeiLong Road, Shanghai 200237, P. R. China.
E-mail: feijunwang@ecust.edu.cn
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of new compounds. CCDC 856081
and 856082. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc32545d
Scheme 1 Convergent assembly of [2,3-b]ketal and spiroketal.
Chem. Commun., 2012, 48, 6259–6261 6259
c
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Table 1 Optimization of the conditions for the Me3SiI promoted
reactiona
Entry
x
y (equiv.)
T/1C
Yield of 3aab (%)
Scheme 2 Me3SiI-promoted reaction of salicylic aldehydes with ketones
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
3.0
5.0
6.0
5.0
1.0
3.0
8.0
8.0
8.0
10.0
10.0
10.0
rt
rt
rt
rt
0
60
rt
rt
rt
42
1i and 1j.
Trace
28
43
35
29
75
77
76
3da in 90%, while only 25% yield of product 3ca was obtained for
ortho-substituted ketone 1c. The influence of the electronic property
of substituent on the aromatic ring of aryl methyl ketones was also
investigated. 4-OMe substituted acetophenone 1f gave a slightly
higher yield of the corresponding product 3 than that of 4-Cl
substituted acetophenone 1e (Table 2, entries 9 and 10). Using
1-(naphthalen-2-yl)ethanone 1g could also give the corre-
sponding [2,3-b]ketal 3ga in 41% yield (Table 2, entry 11).
a
Reaction conditions: 2a (1.0 mmol), 1a (x equiv.), NaI and Me3SiCl
b
(y equiv.), CH3CN, 24 h. Isolated yield.
Table 2 Me3SiI-promoted reaction of salicylic aldehyde and ketonea
However, when aryl ethyl ketone 1h was used, 4H-benzopyran
3ha instead of the desired [2,3-b]ketal was obtained in 37% yield
(Table 2, entry 12). The reason is probably due to the high steric
hindrance of the second arylmethylation at the same a-site of the
carbonyl group. This result suggested that the second arylmethyla-
tion at the other a-site of the carbonyl group to furnish spiroketal
could be achieved if the steric ketone has two sides of the
a-substituted group. Therefore, more sterically bulky C2-symmetric
ketones, 1i and 1j, were further tested in this Me3SiI-promoted
reaction (Scheme 2). In the presence of 15.0 equiv. of Me3SiCl and
NaI, spiroketal 4ia15 was exclusively obtained in 76% yield from
the reaction of 3-pentanone 1i with 2a, whereas the corresponding
[2,3-b]ketal 3 could not be isolated. The structure of product 4ia was
further confirmed by single-crystal X-ray diffraction.16 Spiroketals
4ie and 4if were also produced in 54% and 45% yields, respectively.
Moreover, using cyclopentanone 1j as a ketone, up to 87% yield of
spiroketal 4ja was obtained.
Entry Salicylic aldehyde Ketone
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
2b: R1 = 3-OMe 1a
2c: R1 = 4-Net2 1a
1a
3ab
3ac
3ad
3ae
3af
3ba
3ca
3da
3ea
65
37
52
50
50
64
25
90
56
65
2d: R1 = 5-F
2e: R1 = 5-Cl
1a
1a
2f: R1 = 5-Br
2a
2a
2a
2a
2a
1b: Ar = Ph
1c: Ar = 2-ClPh
1d: Ar = 3-ClPh
1e: Ar = 4-ClPh
1f: Ar = 4-OMePh 3fa
11
2a
2a
3ga
41
37
Keto-ols instead of ketones were further examined in this
Me3SiI-promoted reaction. For example, keto-ol 5a was used
to react with salicylic aldehyde 2a in the presence of 10.0 equiv.
of Me3SiCl and NaI, giving [2,3-b]ketal 3aa in 83% yield
(Scheme 3, eqn (1)). Interestingly, keto-ol 5b could also give
the same product 3aa in 47% yield (Scheme 3, eqn (2)).
Moreover, using salicylic aldehyde 2e, the asymmetric ketal
3aa0 was also successfully synthesized from keto-ol 5a or 5b.
Similarly, keto-ol 5c was reacted with salicylic aldehyde 2a,
affording spiroketal 4ia in 56% yield (Scheme 3, eqn (3)).
With the successful establishment to construct heteroannular
ketals, we became interested in studying the class of natural
heteroannular ketals and in developing a methodology that would
12
a
Reaction conditions: 2 (1.0 mmol), 1 (3.0 equiv.), NaI and Me3SiCl
b
(10.0 equiv.), CH3CN, 24 h. Isolated yield.
conditions (10.0 equiv. of Me3SiCl and NaI, 3.0 equiv. of 1a,
CH3CN, rt). Most reactions of salicylic aldehydes 2 with 1a
proceeded smoothly to give the corresponding products 3 in
moderate to good yields. Salicylic aldehyde 2b with a 3-MeO
group afforded product 3ab in 65% yield (Table 2, entry 1).
Salicylic aldehyde 2c with a 4-NEt2 group afforded product
3ac in 37% yield (Table 2, entry 2). Salicylic aldehydes 2 with
5-F, 5-Cl and 5-Br groups gave their corresponding products
in about 50% yield (Table 2, entries 3–5).
In order to avoid the formation of spiroketal 4 in this Me3SiI-
promoted reaction, aryl methyl ketones 1b–g with only one side of
a-CH atoms instead of acetone 1a were investigated. As expected,
[2,3-b]ketals 3 were exclusively obtained (Table 2, entries 6–11).
Different phenyl-substitution patterns in aryl methyl ketones
showed the significant influence on the reaction outcome
(Table 2, entries 7–9). For example, ketone 1d with a meta-
substituted group gave higher yield of the corresponding product
Scheme 3 Me3SiI-promoted reaction of salicylic aldehyde and keto-ol.
c
6260 Chem. Commun., 2012, 48, 6259–6261
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Ellis Horwood, Chichester, 1991; (d) D. O’Hagan, Nat. Prod.
Rep., 1995, 12, 1; (e) R. D. Norcross and I. Paterson, Chem.
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2 Selected examples, see: (a) L. Diao, C. Yang and P. Wan, J. Am.
Chem. Soc., 1995, 117, 5369; (b) J. S. Yadav, B. V. Subba Reddy,
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Jones, C. Selenski and T. R. R. Pettus, J. Org. Chem., 2002,
67, 6911.
Scheme 4 The application of Me3SiI-promoted reaction.
3 Selected examples, see: (a) M. Anniyappan, D. Muralidharan and
P. T. Perumal, Tetrahedron, 2002, 58, 10301; (b) M. Rueping and
M.-Y. Lin, Chem.–Eur. J., 2010, 16, 4169.
4 Selected examples, see: (a) J. Matsuo, S. Sasaki, H. Tanaka and
H. Ishibashi, J. Am. Chem. Soc., 2008, 130, 11600; (b) I. Coric and
´
B. List, Nature, 2012, 483, 315.
5 Selected examples, see: (a) X. Gao, Y. Matsuo and B. B. Snider,
Org. Lett., 2006, 8, 2123; (b) T. Miyazaki, S. Yokoshima,
S. Simizu, H. Osada, H. Tokuyama and T. Fukuyama, Org. Lett.,
2007, 9, 4737; (c) M. M. Abd Rabo Moustafa, A. C. Stevens,
B. P. Machin and B. L. Pagenkopf, Org. Lett., 2010, 12, 4736.
6 S. B. Moilanen, J. S. Potuzak and D. S. Tan, J. Am. Chem. Soc.,
2006, 128, 1792.
Scheme 5 Proposed mechanism for the Me3SiI-promoted reaction.
7 Selected examples, see: (a) J. T. Lowe, I. E. Wrona and J. S. Panek,
Org. Lett., 2007, 9, 327; (b) Y.-C. Liu, J. Sperry, D. C. K. Rathwell
and M. A. Brimble, Synlett, 2009, 793.
8 Selected examples, see: (a) B. M. Trost, D. B. Horne and
M. J. Woltering, Angew. Chem., Int. Ed., 2003, 42, 5987;
(b) B. D. Sherry, L. Maus, B. N. Laforteza and D. F. Toste,
J. Am. Chem. Soc., 2006, 128, 8132; (c) S. Benson, M.-P. Collin,
allow a ready access to the core structure of natural ketals. 6,60-
Spiroketal 6, a substructure of Cynantetrone which showed a high
scavenging activity to 2,2-diphenyl-1-picrylhydrazyl (DPPH) free
radicals,17 was easily prepared from the Me3SiI-promoted reaction
of keto-ol 5 with salicylic aldehyde 2a (Scheme 4).
A possible mechanism for the Me3SiI-promoted reaction of
salicylic aldehyde 2a with acetone 1a is proposed in Scheme 5.
The nucleophilic substitution of intermediate A18 to intermediate
A. Arlt, B. Gabor, R. Goddard and A. Furstner, Angew. Chem.,
Int. Ed., 2011, 50, 8739.
9 Selected examples, see: (a) D. Vellucci and S. D. Rychnovsky, Org.
Lett., 2007, 9, 711; (b) J. Marjanovic and S. A. Kozmin, Angew.
Chem.,Int. Ed., 2007, 46, 8854.
¨
B
19 with the elimination of silicone ether affords intermediate C,
which can be reduced by HI to give ketone 5a and I2. Further
arylmethylation takes place at the two sides of the carbonyl
group of intermediate 5a to give intermediates E and G. The
subsequent intramolecular condensation of intermediates E and
G in the presence of Me3SiI affords the desired [2,3-b]ketal 3aa
and 6,60-spiroketal 4aa, respectively.
10 Selected examples, see: (a) Y. Zhao, N. E. Pratt, M. J. Heeg and
K. F. Albizati, J. Org. Chem., 1993, 58, 1300; (b) M. T. Crimmins
and A. C. DeBaillie, J. Am. Chem. Soc., 2006, 128, 4936;
(c) A. Furstner, M. D. B. Fenster, B. Fasching, C. Godbout and
¨
K. Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5506;
(d) I. Paterson, A. D. Findlay and E. A. Anderson, Angew. Chem.,
Int. Ed., 2007, 46, 6699; (e) J. L.-Y. Chen and M. A. Brimble, Chem.
Commun., 2010, 46, 3967; (f) S. A. Rizvi, S. Liu, Z. Chen, C. Skau,
M. Pytynia, D. R. Kovar, S. J. Chmura and S. A. Kozmin, J. Am.
Chem. Soc., 2010, 132, 7288; (g) D. P. Canterbury and
G. C. Micalizio, J. Am. Chem. Soc., 2010, 132, 7602.
11 (a) G. A. Olah and S. C. Narang, Tetrahedron, 1982, 38, 2225;
(b) G. A. Olah, G. K. S. Prakach and R. Krishnamurtiy,
Adv. Silicon Chem., ed. G. L. Larson, Jai Press, Inc., Greenwich,
CT, 1991, vol. 1.
In conclusion, we have developed a highly versatile and uniquely
enabling methodology to construct benzopyranic heteroannular
ketals in one-pot from the Me3SiI-promoted reaction of salicylic
aldehydes with simple ketones as well as keto-ols. Based on this
synthetic strategy, the synthesis of these natural or natural-like
ketals (such as examples in Fig. 1) could be envisaged by retro-
synthetic analysis. Further exploration of this synthetic strategy in
the total synthesis of natural ketals is underway.
12 (a) T. Sakai, K. Miyata, S. Tsuboi and M. Utaka, Bull. Chem. Soc.
Jpn., 1989, 62, 4072; (b) F. Wang, M. Qu, F. Chen, L. Li and
M. Shi, Chem. Commun., 2012, 48, 437.
Financial support from the National Natural Science Founda-
tion of China (21072206, 20902019, 20472096, 20872162, 20672127,
20821002 and 20732008), the National Basic Research Program of
China (973)-2010CB833302, and the Fundamental Research Funds
for the Central Universities (WJ1014034 and WK1013004) is
gratefully acknowledged.
13 M. A. Brimble, C. L. Flowers, M. Trzoss and K. Y. Tsang,
Tetrahedron, 2006, 62, 5883.
14 CCDC 856081 3aa.
15 X. Wang, Z. Han, Z. Wang and K. Ding, Angew. Chem., Int. Ed.,
2012, 51, 936.
16 CCDC 856082 4ia.
17 P.-L. Huang and S.-J. Won, Helv. Chim. Acta, 1999, 82, 1716.
18 (a) T. Pei and R. A. Widenhoefer, Chem. Commun., 2002, 650;
(b) H.-X. Wei, S. H. Kim and G. Li, Org. Lett., 2002, 4, 3691;
(c) C. Timmons, A. Kattuboina, L. McPherson, J. Mills and G. Li,
Tetrahedron, 2005, 61, 11837.
Notes and references
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6259–6261 6261