A domino pericyclic route to polysubstituted salicylic acid derivatives: Four sequential processes from enynones and ketene silyl acetals

Article abstract of DOI:10.1039/c1cc11758k

Alkenyl alkynyl ketones and ketene silyl acetals (KSAs) undergo regioselective [2+2]-cycloaddition under thermal conditions, triggering domino pericyclic reactions en route to various poly-substituted salicylic acid derivatives.

Full text of DOI:10.1039/c1cc11758k

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A domino pericyclic route to polysubstituted salicylic acid derivatives:
four sequential processes from enynones and ketene silyl acetalsw
Toshiyuki Hamura,z Shin Iwata and Keisuke Suzuki*
Received 28th March 2011, Accepted 4th May 2011
DOI: 10.1039/c1cc11758k
Alkenyl alkynyl ketones and ketene silyl acetals (KSAs) undergo
regioselective [2+2]-cycloaddition under thermal conditions,
triggering domino pericyclic reactions en route to various
poly-substituted salicylic acid derivatives.
Domino reactions, i.e., sequential one-pot chemical transfor-
Scheme 2 Clue no. 1: potential reactivity in 3.
mations without isolating intermediates, provide unique
opportunities in organic synthesis.1 Among attractive features,
reaction (steps 2 and 3, Scheme 1), giving 1,3-diene 4 as a side
worth mentioning are rapid increase in the molecular complexity
and reduction of the operational/material loads.
product (Scheme 2).
The second clue was that ene–yne substrate 5 was found to
react at its yne moiety to give dienone 6, convincing us to test
the domino process (Scheme 3).
We report herein a domino pericyclic process en route to
poly-substituted salicylic acid derivatives (Scheme 1). The
[2+2] cycloaddition of enynone I to ketene silyl acetal
(KSA) II (step 1)2 is a prelude to a three-step domino process,
electrocyclic ring opening (step 2),3 1,5-silatropy (step 3),4 and
6p-electrocyclization (step 4),5 allowing access to salicylate VI.
Scheme 3 Clue no. 2.
As a test case, dienone 6 was exposed to thermal conditions
(Table 1). Upon heating in xylene (140 1C), dienone 6 was quickly
consumed (5 min), giving diester 7 in 82% yield (entry 1).
Note that diester 7 is representing the formation of hexatriene
70, as the hydrolysis (70 - 7) is quite facile in silica-gel chromato-
graphy. As entry 2 shows, on heating for a longer time, the
initially formed hexatriene 70 (judged by the amount of 7 by a
TLC-assay) was gradually consumed, giving cyclohexadiene 8
(19% yield), the aromatized product 9 by thermal elimination of
MeOH (49% yield) and some remaining diester 7.8,9 When
the reaction was performed at a higher temperature (165 1C),
the domino reaction including the final aromatization was driven
to completion, giving salicylate 9 in 78% yield (entry 3). Addition
of 2,6-lutidine, though not essential, realized a slightly faster
reaction, giving 9 in 80% yield (entry 4).
Scheme 1 Domino pericyclic reaction.
Two clues were drawn from our previous study.2 Firstly, the
[2+2] cycloaddition of alkynone 1 to KSA 2a proceeded with
rigorous regioselectivity, giving cycloadduct 36,7 with the
siloxy group near the carbonyl group. This regioselectivity
provides cyclobutene 3 with a unique reactivity: the thermal
electrocyclic opening is accompanied by a 1,5-silatropic
We then attempted to perform all the steps in one pot,
starting from the [2+2] cycloaddition of enynone 5 to KSA
2a (Scheme 4). A mixture of enynone 5 and KSA 2a was
heated at 60 1C under solvent-free conditions, and the TLC
assay confirmed the completion of the [2+2]-cycloaddition
after 1 h. After the reaction mixture was diluted with mesitylene
(0.1 M), heating was continued at 165 1C for 14 h, thereby
affording salicylate 9 in 75% yield (listed as entry 1 in Table 2).
Importantly, the dilution was essential at the stage of the
Department of Chemistry, Tokyo Institute of Technology,
and SORST, JST Agency, 2-12-1 O-okayama, Meguro-ku,
Tokyo 152-8551, Japan. E-mail: ksuzuki@chem.titech.ac.jp;
Fax: +81 3-5734-2788
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/c1cc11758k
z Present address: Department of Chemistry, School of Science and
Technology, Kwansei Gakuin University, and PRESTO, JST Agency,
2-1 Gakuen, Sanda, Hyogo 669-1337, Japan.
c
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Table 1 Model experiments
Table 2 One-pot domino pericyclic reaction of enynone and KSA
Entry Substrate KSA
Conditions Productc
Yield (%)
75
1a
60 1C, 1 h
165 1C, 14 h
Yield of Yield of Yield of
7 (%) 8 (%) 9 (%)
60 1C, 5 h
2a
71
66
165 1C, 12 h
Entry Conditions
1
2
3
4
Xylene, 140 1C, 5 min
Xylene, 140 1C, 12 h
Mesitylene, 165 1C, 14 h
82
24
—
—
19
—
—
—
49
78
80
60 1C, 8 h
165 1C, 12 h
3a
Mesitylene, 2,6-lutidine, 165 1C, 10 h —
60 1C, 1 h
4b
5b
6b
86d
62
140 1C, 3 h
140 1C, 3 h
Scheme 4 Domino pericyclic reaction to give salicylate 9.
60 1C, 7 h
140 1C, 2 h
6p-electrocyclization, avoiding the competing polymerization
of the hexatriene intermediate.
56e
Table 2 summarizes the application of this one-pot protocol
to various substrate combinations. Upon heating enynone 10
with KSA 2a, the domino process occurred smoothly to give
penta-substituted benzene 13 in 71% yield (entry 2). Similarly,
the reaction of 11 with a cyclohexenyl group gave tetra-
hydronaphthalene 14 in good yield (entry 3).
80 1C, 5 h
7b
50e,f
140 1C, 8 h
8b
60
60 1C, 10 h
140 1C, 5 h
When KSA 2b was used as the substrate (entry 4), the
initially formed [2+2] cycloadduct was reactive, proceeding
readily to the following steps at lower temperature.10 Interest-
ingly, however, the aromatization stage was relatively slow in
this case, giving cyclohexadiene 15 as the product (86% yield),
with the cis isomer predominating.
a
e
b
c
d
In mesitylene. In xylene. SiR3 = Sit-BuMe2. cis/trans = 6 : 1.
f
Single isomer. Stereochemistry was not determined.
Less oxygenated KSA 2c reacted also smoothly with
enynone 5 (entry 5). In this case, better results were obtained
by omitting the pre-heating at 60 1C at the stage of the [2+2]
cycloaddition. By just applying higher reaction temperatures
from the outset (140 1C, xylene), cyclohexadiene 16 was
obtained in 62% yield.
Comparison of the reactivities of KSA 2a–c (entries 1, 4,
and 5) suggested that the domino pericyclic processes are more
facile for less substituted cases (2a o 2b o 2c). The tendency is
consistent with the reactivity order of the ring opening of the
cyclobutene A11 as well as the electrocyclic closure of the
corresponding hexatriene B (Fig. 1).12,13
Fig. 1 Reactivity of substituted cyclobutenes and hexatrienes.
It is notable that the final 6p electrocyclization proceeded for
a sterically congested hexatriene (not shown).
For exploring further scope of the domino process, we
addressed the applicability to more substituted enynones. As
the initial [2+2]-cycloaddition required the Me3Al-promoted
conditions for the b-substituted alkynes such as 20
(Scheme 5),2 advanced substrates, dienones 22 and 24,14 were
prepared from the [2+2]-cycloadduct 21 and subjected to the
thermal conditions.
Similarly, the reactions worked well with ketones 10 and 11
by treatment with KSA 2b, affording the poly-functionalized
products 17 and 18 as single stereoisomers, respectively (entries
6 and 7). Furthermore, the pericyclic domino process proved
applicable to substrate 12 with a b,b-substituted olefinic moiety
(entry 8), and heating with KSA 2b gave cyclohexadiene 19.
c
6892 Chem. Commun., 2011, 47, 6891–6893
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1996, 96, 115; (f) H. Pellissier, Tetrahedron, 2006, 62, 1619;
(g) H. Pellissier, Tetrahedron, 2006, 62, 2143; (h) T.-L. Ho, Tandem
Organic Reactions, Wiley, New York, 1992, p. 502; (i) R. A. Bunce,
Tetrahedron, 1995, 51, 13103.
2 S. Iwata, T. Hamura and K. Suzuki, Chem. Commun., 2010, 46,
2211.
3 (a) M. L. Graziano, M. R. Iesce and F. Cermola, Synthesis, 1994,
149; (b) E. V. Dehmlow and A. L. Veretenov, Synthesis, 1992, 939.
4 J. Choi, E. Imai, M. Mihara, Y. Oderatoshi, S. Minakata and
M. Komatsu, J. Org. Chem., 2003, 68, 6164.
Scheme 5 [2+2] Cycloaddition of phenyl-substituted ynoate 20.
5 (a) L. M. Bishop, R. E. Roberson, R. G. Bergman and D. Trauner,
Synthesis, 2010, 2233; (b) H. W. Sunnemann, M. G. Banwell and
¨
A. de Meijere, Eur. J. Org. Chem., 2007, 3879; (c) R. von Essen,
D. Frank, H. W. Sunnemann, D. Vidovic, J. Magull and A. de
¨
Meijere, Chem.–Eur. J., 2005, 11, 6583; (d) N. A. Magomedov,
P. L. Ruggiero and Y. Tang, J. Am. Chem. Soc., 2004, 126, 1624.
6 For reviews of cyclobutene derivatives, see: J. L. Segura and
N. Martin, Chem. Rev., 1999, 99, 3199.
7 For our contributions, see: (a) T. Matsumoto, T. Hamura,
M. Miyamoto and K. Suzuki, Tetrahedron Lett., 1998, 39, 4853;
(b) T. Hamura, M. Miyamoto, T. Matsumoto and K. Suzuki, Org.
Lett., 2002, 4, 229; (c) T. Hamura, M. Miyamoto, K. Imura,
T. Matsumoto and K. Suzuki, Org. Lett., 2002, 4, 1675;
(d) T. Hamura, T. Suzuki, T. Matsumoto and K. Suzuki, Angew.
Chem., Int. Ed., 2006, 45, 6294.
Scheme
6 Domino pericyclic reaction of fully substituted
cyclobutenes.
8 Initially formed triene as IV by the ring opening of 6 was not
detected.
We were pleased to find that, upon heating, cyclobutene 22
having a 2-methylbut-2-enoyl group and a phenyl group on the
four-membered ring underwent the domino reaction smoothly,
giving hexa-substituted benzene 23 in 77% yield (Scheme 6).
Similarly, the related substrate 24 with a cyclohexenylcarbonyl
group was cleanly converted to poly-substituted dihydro-
phenanthrene 25.
9 All new compounds were fully characterized by spectroscopic
means and combustion analysis. For details, see ESIw.
10 Due to its high reactivity, the [2+2] cycloadduct easily isomerized
to the corresponding ring opened product during purification.
11 For the conrotatory ring opening of substituted cyclobutenes,
outward rotation becomes more preferred, as the donor character
of the substituent increases. In the case of fully oxygenated
cyclobutene Aa (X=Y=OMe), one of the two methoxy groups
has to rotate inward, which is energetically unpreferable. For
theoretical studies on torquoselectivity, see: (a) N. G. Rondan
and K. N. Houk, J. Am. Chem. Soc., 1985, 107, 2099;
(b) K. N. Houk, D. C. Spellmeyer, C. W. Jefford,
C. G. Rimbault, Y. Wang and R. D. Miller, J. Org. Chem.,
1988, 53, 2125.
In summary, we described domino pericyclic reactions to
poly-substituted 6-membered compounds by reaction of the
alkenyl alkynyl ketone with KSA. Further studies are currently
in progress.
12 Calculation showed that steric effects pose a larger influence on the
preference for inward/outward rotation of the substituent in the
substituted 1,3,5-hexatrienes, see: J. D. Evanseck, B. E. Thomas
IV, D. C. Spellmeyer and K. N. Houk, J. Org. Chem., 1995, 60,
7134.
13 Stereochemistry of the cyclobutene and hexatriene intermediates in
the reaction of KSA 2b was not determined.
14 For preparation, see ESI.w See also ref. 2.
Notes and references
1 (a) A. Steve and B. Louis, Chem. Commun., 2007, 2211;
(b) K. C. Nicolaou, D. J. Demonds and P. G. Bulger, Angew.
Chem., Int. Ed., 2006, 45, 7134; (c) L. F. Tietze, G. Brasche and
K. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH,
Weinheim, 2006, p. 672; (d) L. F. Tietze and U. Beifuss, Angew.
Chem., Int. Ed. Engl., 1993, 32, 131; (e) L. F. Tietze, Chem. Rev.,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6891–6893 6893