Auto-tandem catalysis: Facile synthesis of substituted alkylidenecyclohexanones by domino (4+2) cycloaddition-elimination reaction

Article abstract of DOI:10.1039/c0cc03336g

A catalytic domino reaction producing substituted 2-alkylidenecyclohexanone from 3-oxymethyl-2-siloxy-1,3-butadienes, which can be prepared from Baylis-Hillman adducts, and α,β-unsaturated ketones is described. The process involves two mechanistically dis

Full text of DOI:10.1039/c0cc03336g

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Auto-tandem catalysis: facile synthesis of substituted
alkylidenecyclohexanones by domino (4+2) cycloaddition–elimination
reactionw
Kiyosei Takasu,* Toru Tanaka, Takumi Azuma and Yoshiji Takemoto*
Received 18th August 2010, Accepted 14th September 2010
DOI: 10.1039/c0cc03336g
A catalytic domino reaction producing substituted 2-alkylidene-
cyclohexanone from 3-oxymethyl-2-siloxy-1,3-butadienes, which
can be prepared from Baylis–Hillman adducts, and a,b-unsaturated
ketones is described. The process involves two mechanistically
distinct reactions, (4+2) cycloaddition and elimination. Both of
these reactions are catalyzed by Tf2NH.
3-position with enones, followed by elimination of the generated
2-oxymethyl-1-siloxycyclohexenes, afforded 2-alkylidenecyclo-
hexanones, exo-enones (Scheme 1). exo-Enones are versatile
synthetic substrates in organic synthesis, such as dienophiles in
Diels–Alder reaction, Michael acceptors and oxa-dienes in
hetero Diels–Alder reaction.6 Moreover, compounds possessing
exo-enone moiety have attracted attention as potential drug
candidates to show various biological activities, such as
antitumor and antiviral effects.7 We wish to report herein a
new auto-tandem catalysis producing substituted exo-2-
alkylidenecyclohexanones.
Domino (cascade) reactions, where multiple chemical
transformations proceed in one sequence without isolation
of intermediates, represent efficient, economic and ecological
processes in organic synthesis.1 The catalytic variants have
also been receiving a great deal of attention as powerful and
useful methods for several reasons, including atom economy,
energy-efficiency and reaction diversity controlled by the
catalyst. As a related chemistry, auto-tandem catalysis has
received a great interest in synthetic efficiency.2 The term
‘auto-tandem catalysis’ is defined as one catalyst which
promotes two or more mechanistically distinct reactions in a
domino process. Recently, we have reported auto-tandem
catalysis of acid catalysts in domino (4+2)–(2+2) cycloaddition
producing bicyclo[4.2.0]octanes.3,4 In the domino process,
both of the (4+2) and (2+2) cycloadditions are activated by
the same catalyst, such as EtAlCl2 and triflic imide (Tf2NH).5
During the course of our continuous study to develop new
transformation reactions, we have found a novel auto-tandem
catalysis in which Tf2NH independently catalyzes both (4+2)
cycloaddition and elimination reactions. Thus, the cycloaddition
of 2-siloxydienes bearing a hydroxymethyl substituent at
3-Oxymethyl-2-siloxybutadienes 3 were prepared easily
from methyl vinyl ketone (MVK, 1) utilizing the Morita–
Baylis–Hillman reaction (Scheme 2).8 Namely, the reaction
of 1 and aldehydes in the presence of diazabicyclooctane
(DABCO) followed by protection of the generated hydroxyl
group, afforded enones 2. Treatment of 2 with silyl chloride
or triflate in the presence of triethylamine furnished
2-siloxydienes 3. 3-Methoxymethyl-2-siloxybutadienes 3f and
3j were prepared from benzaldehyde dimethyl acetal according
to the reported procedure by Kim et al.9
With the substrates in hand, the Tf2NH-catalyzed reaction
of 3 with enone 4 was explored first (Scheme 3). When 2 mol%
Scheme 1 Domino (4+2) cycloaddition–elimination reaction.
Scheme 2 Synthesis of 3-oxymethyl-2-siloxydienes.
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto, 606-8571, Japan.
E-mail: kay-t@pharm.kyoto-u.ac.jp; Fax: +81 75 753 4610;
Tel: +81 75 753 4610
w Electronic supplementary information (ESI) available: Experimental
procedure and characterization data for new compounds. See DOI:
10.1039/c0cc03336g
Scheme 3 Catalytic domino reaction of 3 and 4.
c
8246 Chem. Commun., 2010, 46, 8246–8248
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Table 1 Effects of silyl group and reaction temperaturea
% Yield
would be caused by the weakness of its silyl–oxygen bond. The
chemical yield of 5a was improved, as expected, when the
reaction performed with 3b and 3c bearing more bulky silyl
groups, TES and TBS, respectively (entries 2 and 3). Reaction
at 0 1C afforded 5a in moderate yield (entry 5). On the
contrary, no cycloaddition proceeded at ꢀ60 1C (entry 4).
These results indicate that promotion of cycloaddition
requires more than ca ꢀ40 1C, but decomposition of 3
increases at higher temperatures.10 No silyl enol ether 6a was
detected on TLC and NMR in the reaction of 3a–c.
5ab
2ab
Entry
3 (Si, R, R0)
Temperature/1C
1
2
3
4
5
3a (TMS, H, TBS)
3b (TES, H, TBS)
3c (TBS, H, TBS)
3c
3c
–40
–40
–40
–60
0
31
53
66
0
14
9
8
Trace
20
47
a
Conditions: 3 (1.2 equiv.), 4a (1.0 equiv.), Tf2NH (2 mol%), toluene,
b
10 min. Yields of 5 and 2 were calculated based on 3.
Next, the effects of the leaving group of 3 (R0O) were
examined (Table 2). Siloxy and methoxy substituents show
good leaving ability in the domino reaction (entries 1–3).
Reaction of substrate 3g having methoxymethyl (MOM)
group with 4a furnished the desired 5g in 13% yield along
with silyl enol ether 6g in 28% yield (entry 4). The reaction
cascade was completed within 10 min by using 10 mol% of
Tf2NH (entry 5). We have considered that the domino reaction
involves an auto-tandem catalysis in which Tf2NH activates
both (4+2) cycloaddition and elimination. It was also
made clear that the desilylative elimination of 6g (R = Ph,
R0 = MOM, Si = TES) was promoted by the assistance of the
catalyst. In the absence of Tf2NH, no formation of enone 5g
from 6g was observed at ꢀ40 1C. On the other hand, 5g was
quantitatively obtained within 1 h when 6g was treated with
10 mol% of Tf2NH at the same temperature. Decomposition
of siloxydiene 3 was detected in all of the reactions tested. No
cycloaddition of benzoate 3h with 4a occurred under the same
conditions (entry 6). Finally, the chemical yield of 5 could be
improved to 78% when an excess amount (2.0 equiv.) of
substrate 3d was employed in the presence of 10 mol% of
Tf2NH (entry 7).11 It is noteworthy that the chemical yield
would be not too dependent on the R substituent of the
substrate.
Table 2 Effects of leaving groupa
% Yield
5bb
6b
Entry
3 (Si, R, R0)
Solvent
1
2
3
3d (TES, Ph, TES)
3e (TES, Ph, TMS)
3f (TES, Ph, Me)
3g (TES, Ph, MOM)
3g
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
66
58
66
13
48
0
0
0
0
28
0
0
4c
5e
6d
7e
3h (TES, Ph, Bz)
3d
78
0
a
Conditions: 3 (1.2 equiv.), 4a (1.0 equiv.), Tf2NH (2 mol%), toluene,
c
b
ꢀ40 1C, 10 min. Yields of 5 and 6 were calculated based on 3. 18%
d
of 3g was recovered. 92% of 3h was recovered. 3d (2.0 equiv.) and
e
Tf2NH (10 mol%) were used.
of Tf2NH was treated with a mixture of 3a (Si = TMS) and
5,5-dimethylcyclopenten-2-one (4a) in toluene at ꢀ40 1C, 3a
was completely consumed within 10 min to give 2-methylene-
cyclohexanone 5a in 31% yield along with 2a (Table 1, entry 1).
We considered that decomposition of 3a into 2a by desilylation
Table 3 Synthesis of substituted alkylidenecyclohexanones by domino (4+2) cycloaddition–elimination reactiona
Entry
Enone
Siloxydiene
Product
% Yield of 5
1
2
76
68
3b
3f
50 (single diastereomer)
4
4a
51
5
6
4a
4a
46 (single diastereomer)
49 (single diastereomer)
a
b
Conditions: 3 (2.0 equiv.), 1 or 4 (1.0 equiv.), Tf2NH (10 mol%), toluene, ꢀ40 1C, 10 min. 3f (1.5 equiv.) was used.
c
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Optimal conditions in hand, synthesis of several alkylide-
necyclohexanones by the domino reaction was explored
(Table 3). Substituted exo-enones 5c–5g were obtained in
moderate to good yields. trans-b-Substituted enone 4b
afforded cycloadduct 5e as a single diastereomer, whose
stereochemistry at the C(4) and C(5) substituents was assigned
to be anti (entry 3). It is noteworthy that both geometrical
isomers of 2-siloxybutadiene 3k bearing a methyl substituent
at the C(1) position afforded 5g as a single diastereomer
(entries 5 and 6). The observation suggests that the cyclization
occurs via a stepwise double Michael pathway rather than a
concerted Diels–Alder reaction.12,13 Stereochemistry of all the
products was determined by 1H NMR (J values) and NOESY
experiments.
catalyzes a stepwise (4+2) cycloaddition and elimination
reactions.
This work was supported by a Grant-in Aid for Science
Research and Target Proteins Research Program from the
Ministry of Education, Culture, Sports and Technology
(MEXT), Japan, the Shorai Foundation for Science and
Takeda Science Foundation.
Notes and references
1 L. F. Tietze, G. Brasche and K. M. Gericke, Domino Reactions in
Organic Chemistry, Wiley-VCH, Weinheim, 2007; S. Suga,
D. Yamada and J. Yoshida, Chem. Lett., 2010, 404.
2 For recent reviews, see: D. E. Fogg and E. N. dos Santos, Coord.
Chem. Rev., 2004, 248, 2365; J.-C. Wasilke, S. J. Obrey, R. T. Baler
and G. C. Bazan, Chem. Rev., 2005, 105, 1001; N. Shindoh,
Y. Takemoto and K. Takasu, Chem.–Eur. J., 2009, 15, 12168.
3 K. Inanaga, K. Takasu and M. Ihara, J. Am. Chem. Soc., 2004,
126, 1352; K. Takasu, K. Inanaga and M. Ihara, Tetrahedron Lett.,
2007, 49, 4220.
4 Reviews, see: K. Takasu, J. Synth. Org. Chem. Jpn., 2008, 66, 554;
K. Takasu, Synlett, 2009, 1905.
5 B. Mathieu and L. Ghosez, Tetrahedron Lett., 1997, 38, 5497;
B. Mathieu and L. Ghosez, Tetrahedron, 2002, 58, 8219;
O. Mendoza, G. Rossey and L. Ghosez, Tetrahedron Lett., 2010,
51, 2571.
6 D. Batty and D. Crich, J. Chem. Soc., Perkin Trans. 1, 1992, 3205;
Y. Du and X. Lu, J. Org. Chem., 2003, 68, 6462; D. J. Wallace,
R. L. Sidda and R. L. Reamer, J. Org. Chem., 2007, 48, 4749.
7 E. A. Oho-Amaize, E. J. Nchekwube, H. B. Cottam, R. Bai,
P. Verdier-Pinard, V. N. Kakkanaiah, J. I. Okogun,
A. A. Adesomoju, O. A. Oyemade and E. Hamel, Cancer Res.,
2002, 62, 4007; R. Sancho, M. Medarde, S. S. Palomino,
B. M. Madrigal, J. Alcami, E. Munoz and A. S. Feliciano, Bioorg.
Med. Chem. Lett., 2004, 14, 4483.
Next, we assessed an oxa Diels–Alder reaction of exo-enone
5 to develop a new auto-tandem catalysis in domino reaction.
No cycloadduct was obtained when 5a was treated with ethyl
vinyl ether (7) in the presence of Tf2NH. In contrast, when
ZnBr2 was employed as a catalyst, tricyclic dihydropyran 8
was obtained from 5a as a single diastereomer. When a
solution of ZnBr2 (30 mol%) was added to an equimolar
mixture of 3c and 4a at ambient temperature, followed by
treatment with excess amounts of 7, tricyclic compound 8 was
obtained in 25% yield as a single diastereomer (its stereo-
chemistry was not determined). Albeit a low conversion, it was
clear that in the domino process the catalyst activates three
different reactions: (4+2) cycloaddition, elimination and the
hetero Diels–Alder reaction (Scheme 4).
8 Z. He, X. Tang, Y. Cheng and Z. He, Adv. Synth. Catal., 2006, 348,
4173.
9 S. Kim, Y. G. Kim and J. H. Park, Tetrahedron Lett., 1991, 32,
2043.
10 Effects of solvent and catalyst were examined. CH2Cl2 and toluene
were optimal solvents. In contrast, chemical yields of 5 decreased
in polar solvents such as CH3CN. Several Lewis acids such as
BF3–OEt2, ZnBr2, ZnI2 and EtAlCl2 promoted the domino
reaction, although 20–100 mol% of the catalyst was required to
complete the reaction (see ESIw).
11 Representative procedure: to a solution of 3d (0.40 mmol) and 4a
(0.20 mmol) in toluene (1.5 mL) was added a solution of Tf2NH
(20 mmol) in toluene at ꢀ40 1C. After stirring for 10 min, the mixture
was quenched with NEt3 (approximately 0.1 mmol) at the same
temperature. Concentration of the resulting mixture, followed by
column chromatography on silica gel (AcOEt : hexane = 10 : 90),
furnished 5b (42 mg, 78% yield) as colorless solids. Spectral data
Scheme 4 One-pot synthesis of tricyclic acetal of 8 by a domino
for 5b; mp 78–79 1C, IR (neat): 3058, 2961, 1742, 1687 cmꢀ1 1H
,
NMR (CDCl3, 400 MHz) d: 7.61 (1H, s), 7.41–7.33 (5H, m),
3.11–2.75 (5H, m), 2.46 (1H, dd, J = 14.6, 6.1 Hz), 2.14 (1H,
dd, J = 13.2, 7.3 Hz), 1.42 (1H, dd, J = 13.2, 9.8 Hz), 1.08 (3H, s),
1.05 (3H, s), 13C NMR (CDCl3, 125 MHz) d: 222.1, 200.4, 136.3,
134.8, 133.1, 129.8, 128.8, 128.5, 45.9, 44.2, 43.3, 42.8, 28.5, 24.9,
(4+2)-cycloaddition–elimination–oxa Diels–Alder reaction.
In summary, we have developed a new catalytic domino
reaction producing substituted 2-alkylidenecyclohexanones
from 3-oxymethyl-2-siloxydienes and a,b-unsaturated
ketones. We consider that our developed reaction giving
exo-cyclohexenones from 3-oxymethyl-2-siloxydienes would
be complementary to the reaction of Danishefsky’s diene
(1-methoxy-3-siloxydiene) to afford endo-cyclohexenones.14
It is noted that the catalytic domino reaction includes an
auto-tandem catalysis in which Tf2NH independently
24.7, 22.9, HRMS (FAB+) calcd for C18H19O2 (M ꢀ H)+
:
267.1380, found: 267.1380.
12 M. E. Jung and D. G. Ho, Org. Lett., 2007, 9, 375.
13 The stepwise mechanism is also supported by the following
observation: reaction of 3d with 4a in the presence of Tf2NH
(Table 2, entry 1), Mukaiyama–Michael adduct was obtained in
12% yield (see ESIw).
14 S. Danishefsky and T. Kitahara, J. Am. Chem. Soc., 1974, 96,
7807.
c
8248 Chem. Commun., 2010, 46, 8246–8248
This journal is The Royal Society of Chemistry 2010