[1,5]-H shift of aldehyde hydrogen in dienal compounds to produce ketenes

Article abstract of DOI:10.1021/ol2016302

In 3-ethoxycarbonyl-2,4-dienal compounds, a thermal [1,5]-H shift of aldehyde hydrogen easily proceeded to produce the corresponding vinyl ketenes due to the remarkable substituent effect caused by the C3 ester group. The produced ketenes were captured by

Full text of DOI:10.1021/ol2016302

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4292–4295
[1,5]-H Shift of Aldehyde Hydrogen in
Dienal Compounds to Produce Ketenes
Taku Sakaguchi, Yudai Okuno, Yohei Tsutsumi, Hiroshi Tsuchikawa,† and
Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda,
Hyogo 669-1337, Japan
katsumura@kwansei.ac.jp
Received June 17, 2011
ABSTRACT
In 3-ethoxycarbonyl-2,4-dienal compounds, a thermal [1,5]-H shift of aldehyde hydrogen easily proceeded to produce the corresponding vinyl
ketenes due to the remarkable substituent effect caused by the C3 ester group. The produced ketenes were captured by an alcohol and olefins to
afford the corresponding esters and four-membered ring compounds, respectively.
The thermal [1,5] sigmatropic rearrangement is one of
the typical pericyclic reactions, and usually called [1,5]-H
shift because the moving atom in most cases is hydrogen.1
As representative examples of such a thermal sigmatropic
rearrangement, the [1,5]-H shifts in 2-deutero-6-methyl-
2,4-octadiene and cyclopentadiene derivatives have been
described.2 In the case of methylcyclopentadiene, the
smooth rearrangement proceeds at room temperature to
produce three regioisomers.2b Recently, the [1,5]-H migra-
tion was applied in some cascade reactions to construct the
designed ring systems.3,4 Although many examples of the
[1,5]-H shift have been reported, most of the rearranging
hydrogens are the reactive benzylic or allylic ones attached
to an sp3 carbon.1a Meanwhile, the rearrangement of the
hydrogen attached to an sp2 carbon, such as vinyl5 and
aldehyde, is quite rare. In particular, the migration of an
aldehyde hydrogen appears unfavorable because the re-
sulting product is rather thermodynamically unfavorable
ketene. To the best of our knowledge, the thermal [1,5]-H
shift of an aldehyde hydrogen could only be found in
three papers. The first example was postulated in the flash
pyrolysisof3,4-epoxycyclopentene(Scheme1A). The flash
pyrolysis of this epoxide (410 °C, 1 Torr, 0.1 s.) would
produce 2,4-pentadienal, which would rearrange into the
corresponding ketene via the thermal [1,5]-H shift and then
trapped with methanol to give the corresponding methyl
ester.6a The second example was described for the thermal
isomerization of β-ionylideneacetoaldehyde (Scheme 1B).7
It was reported that simple distillation in vacuo of this
dienal produced the tricyclic cyclobutanone derivatives
through an initial E to Z- isomerization of the double
† Present address: Department of Chemistry, Graduate School of Science,
Osaka University, 1ꢀ1 Machikaneyama, Toyonaka, Osaka 560ꢀ0043,
Japan.
(1) (a) Spangler, C. W. Chem. Rev. 1976, 76, 187–217. (b) Houk,
K. H.; Li, Y; Evanseck, J. D. Angew. Chem., Int. Ed. Engl. 1992, 31,
682–708.
(2) (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, 1970. (b) Fleming, I. Pericyclic
Reactions; Oxford Science Publications: New York, 1999.
(3) (a) Faza, O. N.; Lopez, C. S.; de Lera, A. R. J. Org. Chem. 2007, 72,
2617–2624. (b) Palenzuela, J. A.; Elnagar, H. Y.; Okamura, W. H. J. Am.
Chem. Soc. 1989, 111, 1770–1773. (c) Shu, X.-Z.; Ji, K.-G.; Zhao, S.-C.;
Zheng, Z.-J.; Chen, J.; Lu, L.; Liu, X.-Y.; Liang, Y.-M. Chem.;Eur.
J. 2008, 14, 10556–10559.
(4) (a) Alajarin, M.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.
J. Org. Chem. 2006, 71, 8126–8139. (b) Alajarin, M.; Bonillo, B.; Ortin,
M.-M.; Sanchez-Andrada, P.; Vidal, A. Org. Lett. 2006, 8, 5645–5648.
(c) Alajarin, M.; Bonillo, B.; Sanchez-Andrada, P.; Vidal, A. J. Org.
Chem. 2010, 75, 3737–3750. (d) Rao, V. V. R.; Fulloon, B. E.; Bernhardt,
P. V.; Koch, R.; Wentrup, C. J. Org. Chem. 1998, 63, 5779–5786.
(5) Crowley, K. J. J. Org. Chem. 1968, 3679–3686.
(6) (a) Schiess, P.; Radimerski, P. Angew. Chem. 1972, 84, 345–346.
Photoreactions: (b) Schiess, P.; Suter, C. Helv. Chim. Acta 1971, 54,
2636–2645. (c) Schiess, P.; Wisson, M. Helv. Chim. Acta 1974, 57,
1692–1703.
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r
10.1021/ol2016302
Published on Web 07/14/2011
2011 American Chemical Society

Over the past 10 years, we have developed efficient
synthetic methods for multisubstituted pyridines and chir-
al piperidine compounds based on the rapid 6π-azaelec-
trocyclization from 1-azatrienes due to the remarkable
accelerating effect of its substituents that we had originally
discovered (Scheme 3A).9 For instance, the one-pot syn-
thetic protocol from three easily available components in
the presence of Pd(0) catalyst enabled us to obtain the
2-arylpyridine derivatives in high yield.9k In this reaction,
the key azaelectrocyclization step is dramatically acceler-
ated by the C-4 ester substituent in the azatriene 10 due to
the enhancement of the HOMOꢀLUMO interaction in
the 6π-electron system.
Scheme 1. Examples of [1,5]-H Shift of Aldehyde Hydrogens
Scheme 3. Development of One-pot 6π-Azaelectrocyclization
and Discovery of Mild [1,5]-H Shift
bond adjacent to the carbonyl group, followed by the [1,5]-
H shift of the aldehyde hydrogen and the intramolecular
[2 þ 2] cycloaddition of the resulting ketene with the cyclo-
hexene double bond. The last one was recently reported by
the group of Houk and Vanderwal (Scheme 1C).8 The
thermal reaction of (5-(dialkylamino)-2,4-pentadienals
(Zincke aldehydes, 1) (>160 °C, microwave irradiation)
afforded Z-R,β,γ,δ-unsaturated amides 5 through several
cascade rearrangements, in which an initial double bond
isomerization followed by the thermal [1,5]-H shift of the
aldehyde hydrogen produced the intermediary ketene that
was subsequently trapped by the intramolecular amino
group and then underwent ring-opening, was postulated
based on the detailed mechanistic study using quantum
mechanical methods. As shown in these examples, it is not
easy to utilize the ketene formation via the thermal [1,5]-H
shift of an aldehyde hydrogen as a synthetic method
because of the requirement of unusual conditions for it
and the thermodynamic instability of the resulting ketene.
To investigate the role of a palladium catalyst for the
imine formation step in the one-pot pyridine synthesis, the
phenyl dienal 13, which was the precusor of the azatriene
10 and was easily prepared in situ by coupling between
vinyl iodide 11 and vinyl stannane 12, was heated at 80 °C
in DMF without a Pd catalyst. Surprisingly, we obtained
the unexpected carboxylic acid 15 as the major product
(Scheme 3B). Furthermore, the ester derivative 16 was
produced by heating in the presence of benzyl alcohol. We
postulated that the reaction must be through ketene 14 as
an intermediate, which would be an unprecedented mild
condition for its formation from aldehyde. We then in-
vestigated this ketene forming reaction including the re-
activity and the generality.
Scheme 2. [1,5]-H Shift
First, we optimized the reaction conditions (Table 1).
Using p-methoxybenzylalcohol (PMBOH) as a trapping
We now describe the thermal [1,5]-H shift of aldehyde
hydrogens based on the substituent-driven acceleration
effect to produce the corresponding ketenes 7 under a
milder condition than previous reports, which are success-
fully captured by appropriate alcohols and olefins to
produce esters 8 with various C5-substituents and four-
member ring compounds such as β-lactam 9, respectively
(Scheme 2).
(9) Synthesis of chiral piperidine and natural alkaloid synthesis: (a)
Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660–9661. (b)
Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004,
69, 5906–5925. (c) Kobayashi, T.; Tanaka, K.; Miwa, J.; Katsumura, S.
Tetrahedron Asymmetry 2004, 15, 185–188. (d) Kobayashi, T.; Nakashima,
M.; Hakogi, T.; Tanaka, K.; Katsumura, S. Org. Lett. 2006, 8, 3809–3812.
(e) Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura, S. Org. Lett.
2006, 8, 3813–3816. (f) Kobayashi, T.; Takeuchi, K.; Miwa, J.; Tsuchikawa,
H.; Katsumura, S. Chem. Commun. 2009, 3363–3365. (g) Li, Y.; Kobayashi,
T.; Katsumura, S. Tetrahedron Lett. 2009, 50, 4482–4484. (h) Sakaguchi, T.;
Kobayashi, S.; Katsumura, S. Org. Biomol. Chem. 2011, 9, 257–264.
Pyridine synthesis: (i) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373–
375. (j) Kobayashi, T.; Hatano, S.; Tsuchikawa, H.; Katsumura, S.
Tetrahedron Lett. 2008, 49, 4349–4351. (k) Sakaguchi, T.; Kobayashi, T.;
Hatano, S.; Tsuchikawa, H.; Fukase, K.; Tanaka, K.; Katsumura, S. Chem.
ꢀAsian J. 2009, 4, 1573–1577.
(8) (a) Paton, R. S.; Steinhardt, S. E.; Vanderwal, C. D.; Houk, K. N.
J. Am. Chem. Soc. 2011, 133, 3895–3905. (b) Steinhardt, S. E.; Vanderwal,
C. D. J. Am. Chem. Soc. 2009, 131, 7546–7547. (c) Steinhardt, S. E.;
Silverston, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130,
7560–7561.
Org. Lett., Vol. 13, No. 16, 2011
4293

Table 1. Investigation of the Reaction Condition
Table 2. Generality at C5 and C2 Positions
reagent of the ketene, we searched for the best solvent and
temperature. In a polar solvent such as DMF, 1,4-dioxane
and acetonitrile at 100 °C, the corresponding ester pro-
ducts were obtained in 24, 47 and 27% yields, respectively
(Entries 1, 2 and 3). We found that toluene under reflux
condition gave the best results (Entry 4). We next investi-
gated the alcohol to trap the generated ketene. Though the
benzyl alcohol derivatives gave similar results (Entries 5
and 6), 2-methoxyethanol gavethe best result in 78% yield,
which has a sufficiently high boiling point (124 °C) (Entry 7).
Thus, we established the reaction conditions.
a The substrate exists as a ring-closed form, 25d. b Methyl ester
derivative at C4 was used.
We next tested the generality of this thermal ester form-
ing reaction from dienal 13 by changing the substituent at
the C5 position. The results are shown in Table 2. The
rearrangement of the dienal derivatives substituted at the
C5 position with 3-thiophene, 3-pyridine and 3-quinoline
smoothly proceeded to produce the corresponding esters
22p, 23p and 24p in 83, 73 and 44% yields, respectively
(Entries 2, 3 and 4). Siloxyethyl derivative 25, which exists
as dihydropyrane 25d resulting from the oxoelectrocycli-
zation of dienal 25, also afforded the expected product
(Entry 5). The 3-indole derivative also produced the desired
product 26p in 56% yield along with a byproduct 26c,
which would be produced by E- to Z-isomerization of the
4,5-double bond followed by 6π-electrocyclization in 18%
yield (Entry 6). In the case of alkenyl substrate 27, the
similar 6π-electrocyclization product 27c was obtained in
35% yield as the major product. Meanwhile, compound 28
having a bulky alkenyl group gave the rearranged product
28p via the [1,5]-H shift (Entry 8). Moreover, the tetra-
substituted compound with an ethyl group at C2 also
produced the corresponding rearranged product 29p in
good yield, thoughthe reaction ratewasslower thanthatof
the trisubstituted compounds (Entry 9). The obtained
results strongly suggested that the aldehyde hydrogen of
dienalwithvariousC5substituentssuccessfully rearranged
to the C5 position to produce the intermediary ketene,
which was captured by the alcohol to produce the corre-
sponding esters efficiently. Insome cases, this novel [1,5]-H
shift of the aldehyde hydrogen could prevail over the
isomerization-electrocyclization.
To broaden the utility of this facile ketene forming
reaction, we then tried the Staudinger ketene cycloaddi-
tion, namely, the [2 þ 2] cycloaddition (Scheme 4). Thus,
heating phenyl dienal 13 with butylvinylether under the
established reaction conditions afforded the expected cy-
clobutanone 30 via a [2 þ 2] cycloaddition between the
double bond of ketene and the vinylether. In the case of
phenylimine reactants such as N-phenyl-, N-methyl- and
N-benzylimines, the corresponding β-lactam products 31,
32 and 33 were obtained in 76, 71 and 81% yields,
respectively. The stereochemistry of these products were
determined by the detailed NMR analysis. Furthermore,
heating with azo-compounds (DEAD and DIAD) yielded
the corresponding 1,2-diazetidin-3-one 34 and 35 in 56 and
4294
Org. Lett., Vol. 13, No. 16, 2011

47% yield, respectively. These results obviously demon-
strated the ketene formation via the [1,5] sigmatropic
rearrangement of the aldehyde hydrogen and that this
rearrangement could be useful as the novel one-pot pre-
paration method of various substituted cyclobutanones
and azacyclobutanones.
the starting material of 51% (1:1 of E/Z isomers at C2). In
the case of cis-β-ionylideneacetoaldehyde (37), though
simple distillation in vacuo of this dienal was reported to
give a [2 þ 2] cycloaddition product via the [1,5]-H shift of
the aldehyde hydrogen (Scheme 1B),7 37 was completely
recovered under the established condition (compared to
Entry 8 in Table 2). These results clearly indicated that the
ester group at the C3 position remarkably accelarated the
rearrangement.
Scheme 4. [2 þ 2] Cycloaddition of Intermediary Ketene 14
Scheme 5. Substituent Effect at C3 Position
Quite recently, Houk and Vanderwal reported the trans-
formation of Zincke aldehyde 1 to Z-R,β,γ,δ-unsaturated
amide 5 by microwave irradiation (Scheme 1C).8a They
tried to elucidate the reaction pathway by calculating the
transition state energies of the possibly generated inter-
mediates of this rearrangement, and concluded the inter-
mediary formation of the corresponding ketene resulting
from the [1,5]-H shift of the aldehyde. However, they did
not succeed in the intermolecular capture of the intermedi-
ate 3 with some alcohols, presumably because their com-
pounds would further proceed the intramolecular cascade
reactions under the microwave irradiation conditions at
high temperature (>160 °C). Meanwhile, our compound,
such as 13 possessing an ester group at the C3 position,
would be favorable for the pericyclic reaction as already
reported,9 and that led to the formation of the versatile
ketene, which could react with various alcohols and
olefins.
We then further examined the substituent effect at the
C3 position (Scheme 5). Under the established condition,
dienal with 3-t-butyldiphenylsiloxymethyl instead of 3-etho-
xycarbonyl derivative 36 gave trace of the rearranged
product 36p, and 74% of the starting materials 36 and
360 (2.7:1 of E/Z isomers at C2) were recovered after 3 h
(compared to Entry 1 in Table 2). After 24 h, the rear-
ranged product 36p was obtained in 25% yield along with
In conclusion, we have clearly demonstrated that the
thermal [1,5]-H shift of the aldehyde hydrogen in linear
dienal compounds is a feasible reaction to produce the
corresponding ketene under a relatively mild condition,
which was followed by capturing the intermediary-pro-
duced ketene with both an alcohol and olefins yielding the
corresponding ester and [2 þ 2] cycloadducts. Applications
of this novel ketene formation to the synthesis of biologi-
cally active natural products as well as its mechanistic
study are currently underway in our laboratory.
Acknowledgment. This work was supported by a
Grant-in-Aid for Science Research on Innovative Areas
“Organic Synthesis Based on Reaction Integration”
(No. 215) and a Matching Fund Subsidy for a Private
University.
Supporting Information Available. The experimental
details of reactions and 1H and 13C NMR spectra of the
substrates and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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