Substituent-controlled electrocyclization of 2,4-dienones: Synthesis of 2,3,6-trisubstituted 2H-pyran-5-carboxylates and their transformations

Article abstract of DOI:10.1002/ejoc.201100780

A facile access to 2,3,6-trisubstituted 2H-pyran-5-carboxylates is developed by employing 2-alkyl-2-enals as reactants with acetoacetates. The reaction involves Knoevenagel condensation followed by a 6π- electrocyclization, in which the presence of the C2 alkyl substituent in the enals favors the formation of (E)-Knoevenagel adducts for the ensuing electrocyclization. The resulting 2H-pyrans are hydrogenated to form 3,4-dihydro-2H-pyrans and converted into the endoperoxides by singlet-oxygen cycloaddition.

Full text of DOI:10.1002/ejoc.201100780

FULL PAPER
DOI: 10.1002/ejoc.201100780
Substituent-Controlled Electrocyclization of 2,4-Dienones: Synthesis of
2,3,6-Trisubstituted 2H-Pyran-5-carboxylates and Their Transformations
Wei Peng,[a] Toshiaki Hirabaru,[a] Hiroyuki Kawafuchi,[b] and Tsutomu Inokuchi*[a]
Keywords: Oxygen heterocycles / Electrocyclic reactions / Substituent effects / Knoevenagel condensation / Endoperoxides
A facile access to 2,3,6-trisubstituted 2H-pyran-5-carboxyl- formation of (E)-Knoevenagel adducts for the ensuing elec-
ates is developed by employing 2-alkyl-2-enals as reactants
with acetoacetates. The reaction involves Knoevenagel con-
densation followed by a 6π-electrocyclization, in which the
presence of the C2 alkyl substituent in the enals favors the
trocyclization. The resulting 2H-pyrans are hydrogenated to
form 3,4-dihydro-2H-pyrans and converted into the endo-
peroxides by singlet-oxygen cycloaddition.
tives.[10] Alternative method for the synthesis of Knoevena-
gel adducts from 2-enals has been developed by Paquette et
al. using the indium-catalyzed addition of 4-bromo-3-meth-
oxycrotonate.[11]
Introduction
The pyran moiety is common to a wide range of natural
products, and therefore, development of an efficient access
to this class of substructures is a continuous challenge in
relation to the syntheses of biologically relevant com-
pounds.[1] In particular, the 1,2-addition of 1,3-dicarbonyl
compounds to 2-alkenylimminiums followed by electro-
cyclization of the resulting 2,4-dienone system is one of the
most versatile approaches to 2H-pyrans.[2] However, this
iminium-based strategy for the synthesis of 2H-pyrans has
only been successful when using 1,3-dicarbonyls with a
highly enolizable structure, such as cyclohexane-1,3-di-
ones,[3] 4-hydroxycoumarin,[4] and 4-hydroxypyrones,[5] as
the reactants. In addition to iminium activation, Lewis[6]
and Brønsted acid[7] catalyzed protocols were recently de-
veloped to dictate the synthesis of the same 2H-pyran struc-
ture. 2H-Pyrans have been synthesized by AgI-catalyzed
isomerization of propargyl vinyl ethers.[8]
In our approach to poly-substituted 2H-pyrans 3, we em-
ployed an iminium activation strategy[12] for the tandem re-
action of acetoacetates 2 and 2-alkenals 1. Thus, we now
describe that enals 1 with a C2 alkyl substituent undergo
1,2-addition with 2 and subsequent 6π-electrocyclization[13]
of the resulting 2,4-dienones to efficiently form poly-substi-
tuted 2H-pyran-5-carboxylates (Scheme 1). Furthermore,
we examined transformations of the resulting oxygen het-
erocycles to form 3,4-dihydro-2H-pyran derivatives by hy-
drogenation and 3,6-peroxy-3,6-dihydro-2H-pyrans by cy-
cloaddition of singlet oxygen.
On the other hand, acyclic acetoacetates and their ana-
logues as nucleophiles have suffered from poor yields[9a] or
low product selectivity due to the competitive formation of Scheme 1. Formation of poly-substituted 2H-pyran-5-carboxylates.
Knoevenagel adducts under less equilibrating conditions
with a carboxylate[9b] or hydroxide[9c] base. Furthermore,
the 1,4-addition rather than the 1,2-addition of acetoacet-
Results and Discussion
ates to the iminium of 2-alkenals is favored when the steri-
cally congested pyrrolidine catalyst is employed as demon-
strated by Jørgensen et al. for their performance during the
high enantioselective synthesis of cyclohexane deriva-
We employed 2-ethyl-2-hexenal (1a) and methyl aceto-
acetate (2a) as the reactants to test the reaction. As shown
in Table 1, the desired reaction is realized with secondary
amines such as piperidine (Table 1, entries 1–10)[14] and N-
methylhomopiperazine (Table 1, entry 14), affording the de-
sired 2H-pyran-5-carboxylate 3a. Consequently, the reac-
tion was optimized by varying the amount of piperidine
(0.2–2.0 equiv.), by changing the kind of acid catalysts, and
by performing the reaction without acid catalyst in THF
for 24 h. As shown in Table 1, entry 4, the best result was
obtained by using two equiv. of piperidine and acetic acid
[a] Department of Medicinal and Bioengineering Science,
Graduate School of Natural Science and Technology,
Okayama University,
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Fax: +81-86-251-8021
E-mail: inokuchi@cc.okayama-u.ac.jp
[b] Toyama National College of Technology,
Hongo-machi, Toyama, 939-8630, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100780.
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W. Peng, T. Hirabaru, H. Kawafuchi, T. Inokuchi
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(ca. 20 mol-%). Increasing the amount of piperidine in- curred when using electron-releasing acyl substituents
creased the yield significantly (Table 1, entries 1–3) and (Table 2, entries 6 and 7). Methyl (2a) and allyl esters (2c)
AcOH was favorable as an acid catalyst (Table 1, entries 5– showed good performances with respect to the yield
7). In contrast, five-membered amines such as pyrrolidine (Table 2, entries 1 and 3).
(Table 1, entry 11) and proline (Table 1, entry 12) were of
no use.
Table 2. Effect of acyl substituent L of 2 on the condensation and
electrocyclization reaction.[a]
Table 1. Optimization of reaction conditions by varying amines and
acid catalysts.[a]
[a] Reactions were carried out using 1a (1.0 mmol) and
2
(1.5 mmol) in the presence of piperidine (2.0 mmol) and AcOH
(0.2 mmol) in THP (2 mL) at room temperature for 24 h. [b] Yields
are based on the isolated products.
These results can be explained by taking the enolizability
of the acetoacetic derivatives and the existence of hydrogen
bonding in the enol form into account. Thus, acetoacetic
derivatives with electron-donating substituents are less
likely to form an enol form, whereas those with an electron-
withdrawing acyl substituent can invoke the enol form, al-
though slightly stabilized by internal hydrogen-bonding,
which is favorable for ensuing Knoevenagel condensation.
On the other hand, increased reactivity was found with cy-
clic keto esters (see below), since the enol form is a major
tautomer and lacks internal hydrogen bonding (Fig-
ure 1).[16]
[a] Reactions were carried out using 1a (1.0 mmol) and 2a
(1.5 mmol) in the presence of amine and acid catalyst in solvent
(2 mL) at room temperature for 24 h. PPTS = pyridinium p-tolu-
enesulfonate, pTsOH = p-toluenesulfonic acid, THP = tetra-
hydropyran, TMG = 1,1,3,3-tetramethylguanidine, DBU = 1,5-di-
azabicyclo[5.4.0]undec-5-ene. [b] Yields are based on the isolated
products.
As a result of screening the solvent effect, we found that
the yield of 3a was improved to 71% by use of THP for
24 h, compared with other solvents such as THF (61%),
Figure 1. Acyclic and cyclic acetoacetic derivatives.
In contrast to the smooth formation of 3a from 1a, the
CH2Cl2 (60%), and toluene (59%) (Table 1, entries 4, 8– reaction of 2-hexenal (4), which lacks an alkyl substituent
10). at the C2 position, with tert-butyl acetoacetate (2b) using
Subsequently, we examined the effect of acyl substituents a piperidine catalyst led to the three-component coupling
L of 2 by varying the substituents from common alkoxy product 5 as the major product (40%) (Scheme 2). The for-
groups to either electron-withdrawing ones, namely, tri- mation of 5 can be explained by Michael addition of an-
fluoroethoxy and 2,2,6,6-tetramethylpiperidine-N-oxyl other molecule of acetoacetate 2b adding to the δ position
(TEMPO),[15] or electron-donating ones, namely, R1R2N of the initially formed Knoevenagel adducts A followed by
(Table 2). As shown in Table 2, entries 1–4, moderate yields cyclization of the enol of B to form 5. Thus, the presence
were obtained with common alkoxy groups or the electron- of an alkyl substituent at the C2 position is indispensable
withdrawing nature of CF3CH2O, whereas no reactions oc- for the smooth formation of the 2H-pyran structure.
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Substituent-Controlled Electrocyclization of 2,4-Dienones
Table 3. Scope of condensation and electrocyclization reactions of
enals and keto esters.
Scheme 2. Reaction conditions: (i) 2b (1.5 equiv.), piperidine
(2.0 equiv.), AcOH (20 mol-%), THP, room temperature, 24 h,
40%.
Since condensation and cyclization invoked the instal-
lation of a substituent on the C2 of the 2-enals 1, the reac-
tion mechanism for 3 can be proposed as that described in
Scheme 3. Thus, the Knoevenagel condensation of iminium
C and 2 would lead to dienones D. Among them, dienone
(E)-D, which has the requisite configuration for the ensuing
electrocyclization, would be favored for steric reasons
through the amine-catalyzed equilibration of (Z)-D and
(E)-D. Eventually, the s-cis conformer of (E)-D undergoes
spontaneous 6π-electrocyclization to form the 2H-pyran
3.[2]
Scheme 3. Proposed mechanism for the 1,2-addition through
iminium activation followed by 6π-electrocyclization.
[a] Carried out by the reaction of enal (1, 1.0 mmol) and keto esters
(1.5 mmol) with piperidine (2.0 mmol) and AcOH (0.2 mmol) in
THP (2 mL) for 24–48 h. [b] Yield of isolated and fully charac-
terized products.
In the next stage, different kinds of acyl groups, R3, of
the β-keto ester counterpart were employed to gain insight
into the steric effect of R3 on the s-cis or s-trans conformers
The present method was applied to other enals, the re-
of (E)-D in the proposed mechanism (Scheme 3). As shown sults of which are shown in Table 3. Thus, acyclic 1b and 1c
in Table 3, the cyclohexanoyl- and phenylthioacetylacetates (Table 3, entries 5 and 6), cyclic 1d and 1e (Table 3, entries 7
6 and 8 produced the corresponding 2H-pyrans 7 and 9 in and 8), and aryl-substituted derivatives 1f and 1h[17]
66–70% yield (Table 3, entries 1 and 2), whereas benzo- (Table 3, entries 9 and 11) were successfully combined with
ylacetate (10) resulted in the desired 2H-pyrans 11 in a acetoacetate 2a, giving the corresponding 2H-pyrans 14–18
lower yield (39%; Table 3, entry 3). The condensation of 1a and 20 in moderate to good yields. In contrast to 1f, the
with the cyclic keto ester 12 proceeded promptly to give the reaction of 3-(2-furyl)-2-methyl-2-propenal (1g) and 2a ter-
bicyclic 2H-pyrans 13 in 69% yield (Table 3, entry 4).
minated at the Knoevenagel condensation stage of the pro-
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W. Peng, T. Hirabaru, H. Kawafuchi, T. Inokuchi
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cess, forming the corresponding (Z) adduct 19, presumably
due to the difficulty of amine-catalyzed equilibration be-
tween (E) and (Z) adducts (Table 3, entry 10). The result in
Table 3, entry 11, shows that an aryl group can be used as
a steric executing factor to produce the 3-phenyl-2H-pyran
20, although in a slightly decreased yield (42%; Table 3, en-
try 11).
Due to the instability of the resulting 2H-pyran-5-carb-
oxylates on standing, selected compounds 3a, 18, and 20
were hydrogenated to form the corresponding 3,4-dihydro-
2H-pyran-5-carboxylates 21a, 22, and 23, the structures of
which and the ratio of 2,3-cis or 2,3-trans stereoisomers
were determined on the basis of 1H NMR spectroscopic
analyses (Scheme 4). In general, the hydrogenation occurred
selectively on a double bond at the C3,4 positions[8] and the
cis isomers were predominant in the C2 alkyl derivatives,
namely, 21a and 23, whereas the C2 phenyl derivative 18
produced a mixture of cis/trans isomers 22.[18]
Scheme 5. Photooxidation of 2H-pyran-5-carboxylates: (i) O2, rose
bengal, hν, MeOH, –78 °C.
b
larger NOE between Hc and CH3 than that of the cis ad-
duct 26a (major isomer), indicating a cis relationship be-
c
b
tween CH3 and CH3 of 26a. Furthermore, the chemical
shift of the Ha of the cis adduct 26a appeared more down-
field presumably due to the deshielding effect of the adja-
cent peroxy group, compared with that of the trans adduct
26b; these results supported the assigned structure.
Scheme 4. Hydrogenation of 2H-pyran-5-carboxylates: (i) H2,
Pd/C, THF.
Stimulated by recent interest in endoperoxides as valu-
able organic intermediates, radical initiators, and oxi-
dants,[19] we attempted the preparation of the bridged 1,2,4-
trioxane structures by cycloaddition of singlet oxygen on
the obtained 2H-pyran-5-carboxylates (Scheme 5).[20] Thus,
irradiation of 14 with a 250 W halogen lamp in the presence
of rose bengal under oxygen bubbling afforded the desired
endoperoxide 26 in 82% yield as an inseparable mixture of
stereoisomers in a ratio of 4:1. Similarly, photooxidation of
compounds 3a, 11, 16, 18, and 20 under the same condi-
tions as those described above afforded the corresponding
endoperoxides 24, 25, 27, 28, and 29 in moderate to good
yields. In general, 2,3-cis isomers formed predominantly,
that is, 24, 25, 28, and 29, whereas the formation of mix-
tures of cis/trans isomers with reversed isomer ratios were
found with the conversions of 14 into 26 and 16 into 27.
Figure 2. Characteristic 1H NMR spectroscopic data and observed
NOE of 26.
Subsequently, we examined further transformation of en-
doperoxide 26 into versatile intermediates. Thus, acid treat-
The cis/trans stereochemistry of endoperoxide 26 was de- ment of 26 with pTsOH in the presence of Ph3P afforded
termined on the basis of NOE experiments (Figure 2). furan 30 in 65% yield, the formation of which could be
Namely, the trans adduct 26b (minor isomer) showed a ascribed to the rearrangement of endoperoxide 26 into 1,2-
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Substituent-Controlled Electrocyclization of 2,4-Dienones
AcOH (12 mg, 0.2 mmol) were consecutively added at room tem-
perature to a solution of 1a (126 mg, 1.0 mmol) and 2a (175 mg,
1.5 mmol) in THP (2 mL). The resulting mixture was stirred and
the reaction was continued until the aldehyde was no longer detect-
able by TLC monitoring, which took about 24 h. The reaction was
quenched with the addition of an aqueous solution of NH4Cl and
was extracted with AcOEt. The crude product was purified by col-
umn chromatography (SiO2, hexane/AcOEt 30:1 v/v) to give 3a as
a colorless oil (160 mg, 71%). Rf = 0.70 (hexane/AcOEt 7:1 v/v).
dioxide E, subsequent ring cleavage of E, the formation of
F, followed by continuous intramolecular aldol reaction of
F, and elimination of acetic acid from G (Scheme 6).[21]
IR (neat): ν = 2960, 2939, 2874, 1710, 1658, 1597, 1462, 1437, 1381,
˜
1365, 1329, 1274, 1263, 1240, 1228, 1190, 1172, 1149, 1080, 1057,
1030, 958, 779 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.93 (t, J =
7.3 Hz, 3 H), 1.09 (t, J = 7.3 Hz, 3 H), 1.38 (m, 2 H), 1.52 (m, 1
H), 1.73 (m, 1 H), 1.96 (m, 1 H), 2.05 (m, 1 H), 2.27 (s, 3 H), 3.73
(s, 3 H), 4.59 (dd, J = 9.5, 2.9 Hz, 1 H), 6.07 (s, 1 H) ppm. 13C
NMR (150.8 MHz, CDCl3): δ = 11.7, 13.9, 18.2, 19.5, 25.3, 34.3,
51.1, 78.8, 104.2, 113.7, 130.6, 163.3, 167.1 ppm. This product was
too unstable for successful element analysis or HRMS.
Scheme 6. Acid treatment of endoperoxide 26: (i) pTsOH, Ph3P,
CH2Cl2, 65%.
Methyl
3-Ethyl-6-methyl-2-propyl-3,4-dihydro-2H-pyran-5-carb-
On the other hand, treatment of 26 with a Lewis acid
such as Cu(OTf)2 (OTf = triflate) afforded the acetal 31 in
27% yield. Formation of 31 can be explained by an in-
terconversion reaction of 1,2-dioxide E and the α-oxyketone
group of F, producing diol H and acetaldehyde as a result
of intermolecular reduction and oxidation, which was fol-
lowed by acetalization, leading to 31 (Scheme 7).
oxylate (21a): 10% Pd/C (15 mg) at room temperature was added
to a solution of 3a (112 mg, 0.5 mmol) in THF (3 mL) . The mix-
ture was stirred overnight in a flask equipped with a balloon of
H2. The solvent was removed under reduced pressure and the crude
product was purified by column chromatography (SiO2, hexane/
AcOEt 30:1 v/v) to give 21a as a colorless oil (92 mg, 81%). Rf =
0.74 (hexane/AcOEt 7:1 v/v). IR (neat): ν = 2961, 2872, 1711, 1624,
˜
1460, 1433, 1379, 1265, 1244, 1231, 1188, 1107, 1071, 1020, 951,
939, 767 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.93 (m, 6 H),
1.13–1.40 (m, 3 H), 1.51–1.71 (m, 4 H), 1.90–2.03 (m, 1 H), 2.21
(m, 3 H), 2.33–2.43 (m, 1 H), 3.68 (s, 3 H), 4.01 (m, 1 H) ppm. 13
C
NMR (150.8 MHz, CDCl3): δ = 11.0 + 12.0, 14.0 + 14.1, 18.2 +
19.2, 20.1 + 20.2, 22.0 + 24.3, 25.3 + 25.7, 30.7 + 34.3, 36.1 + 36.2,
50.90 + 50.91, 78.7 + 79.6, 99.76 + 99.78, 164.0 + 164.3, 169.2 +
169.3 ppm. C13H22O3 (226.32): calcd. C 68.99, H 9.80; found C
68.95, H 9.98.
Photooxidation of 3a, Preparation of the cis-Methyl 1-Ethyl-
4-methyl-6-propyl-2,3,5-trioxabicyclo[2.2.2]oct-7-ene-8-carboxylate
(24): Compound 3a (224 mg, 1.0 mmol) and rose bengal (15 mg)
were dissolved in MeOH (10 mL) and cooled to –78 °C in a 50 mL
round-bottomed flask before being irradiated with a 250 W halo-
gen lamp under bubbling with oxygen for 4 h. The solution was
warmed to room temperature and the solvent was removed in
vacuo to afford a pink residue, which was purified by column
chromatography (SiO2, hexane/AcOEt 10:1 v/v) to give 24 as a
white solid (231 mg, 90%). Rf = 0.50 (hexane/AcOEt 5:1 v/v). IR
Scheme 7. Lewis acid treatment of endoperoxide 26: (i) Cu(OTf)2,
CH2Cl2, 27%.
Conclusions
(KBr): ν = 2961, 2878, 1728, 1626, 1460, 1433, 1381, 1333, 1275,
˜
1206, 1140, 1123, 1101, 1071, 1049, 964, 926, 854, 818, 745,
We developed a new access to poly-substituted 2H-pyr-
an-5-carboxylates from simple 2-alkyl-2-enals and 3-keto
esters, performed only by treatment with piperidine/acetic
acid. The reaction was improved by examining the effect of
the acyl substituent, the amine base, the C2 substituent of
the enals, and the alkanoyl group of the keto esters. The
success of the reaction is dependent on the presence of a
C2 substituent on the enals. 2H-Pyran-5-carboxylates were
photooxidized to give endoperoxides, which showed inter-
esting reactivities upon acid treatments.
1
679 cm–1. H NMR (600 MHz, CDCl3): δ = 0.89 (t, J = 7.2 Hz, 3
H), 1.03 (m, 1 H), 1.04 (t, J = 7.2 Hz, 3 H), 1.30 (m, 2 H), 1.45
(m, 1 H), 1.76 (s, 3 H), 1.79 (m, 1 H), 1.92 (m, 1 H), 3.81 (s, 3 H),
4.20 (dd, J = 10.2, 2.4 Hz, 1 H), 7.17 (s, 1 H) ppm. 13C NMR
(150.8 MHz, CDCl3): δ = 6.8, 13.9, 18.0, 19.6, 24.8, 33.3, 51.9, 76.8,
78.7, 97.0, 136.4, 138.9, 162.5 ppm. C13H20O5 (256.30): calcd. C
60.92, H 7.87; found C 61.22, H 7.69.
Methyl 2,5-Dimethylfuran-3-carboxylate (30): pTsOH (7 mg,
0.2 equiv.) and Ph3P (68 mg, 0.26 mmol) were added to a solution
of 26 (43 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) . The mixture was
stirred at room temperature overnight. The solvent was removed in
vacuo and the residue was purified by column chromatography
(SiO2, hexane/AcOEt 40:1 v/v) to give 30 as a colorless oil (20 mg,
65%). Rf = 0.82 (hexane/AcOEt 5:1 v/v). 1H NMR (600 MHz,
CDCl3): δ = 2.25 (s, 3 H), 2.53 (s, 3 H), 3.81 (s, 3 H), 6.21 (s, 1 H)
Experimental Section
Preparation of Methyl 3-Ethyl-6-methyl-2-propyl-2H-pyran-5-carb-
oxylate (3a). Typical Procedure: Piperidine (170 mg, 2.0 mmol) and
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W. Peng, T. Hirabaru, H. Kawafuchi, T. Inokuchi
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ppm. 13C NMR (150.8 MHz, CDCl3): δ = 13.2, 13.6, 51.2, 106.1,
113.7, 149.9, 157.7, 164.8 ppm.
[9] a) Z. A. Krasnaya, V. S. Bogdanov, S. A. Burova, Y. V. Smir-
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Methyl 2,3a,4,6-Tetramethyl-4,7a-dihydro-3aH-[1,3]dioxolo[4,5-c]-
pyran-7-carboxylate (31): Cu(OTf)2 (15 mg, 0.2 equiv.) was added
to a solution of 26 (43 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) . The
mixture was stirred at room temperature overnight. The solvent
was removed and the residue was purified by column chromatog-
raphy (SiO2, hexane/AcOEt 40:1 v/v) to give 31 as a white solid
(13 mg, 27%). Rf = 0.54 (hexane/AcOEt 5:1 v/v). 1H NMR
(600 MHz, CDCl3): δ = 0.98 (s, 3 H), 1.30 (d, J = 4.8 Hz, 3 H),
1.36 (d, J = 6.6 Hz, 3 H), 2.26 (s, 3 H), 3.75 (s, 3 H), 4.40 (s, 1 H),
4.98 (q, J = 6.6 Hz, 1 H), 5.48 (q, J = 5.4 Hz, 1 H) ppm. 13C NMR
(150.8 MHz, CDCl3): δ = 12.7, 14.1, 17.9, 20.3, 51.4, 70.9, 72.0,
76.5, 101.3, 101.5, 167.4, 168.8 ppm.
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Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and product characteriza-
tion.
Acknowledgments
We are grateful to Okayama University for support and to the Ad-
vanced Science Research Center for the NMR experiments and EA.
We thank the Ministry of Education, Culture, Sports, Science and
Technology (MEXT) for a scholarship to W.P. and Shiono Koryo
Kaisha Ltd. for a generous gift of 1-perillaldehyde.
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Published Online: August 12, 2011
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