Mild synthesis of furans with a quaternary carbon substituent at the 2-position

Article abstract of DOI:10.1246/cl.2012.1586

The reaction of cis-4-oxopent-2-enal with β-carbonyl compounds in the presence of weak acids such as hexafluoroisopropyl alcohol was found to give furans with a quaternary carbon substituent at the 2-positon at room temperature or below. Reactivity was dependent on the identity of the substrates.

Full text of DOI:10.1246/cl.2012.1586

doi:10.1246/cl.2012.1586
1586
Published on the web November 24, 2012
Mild Synthesis of Furans with a Quaternary Carbon Substituent at the 2-Position
Akihisa Iwamoto,1 Aki Katori,1 Yoshiaki Sashihara,1 and Satoshi Kojima*1,2
1Department of Chemistry, Graduate School of Science, Hiroshima University,
1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526
2Center for Quantum Life Sciences, Hiroshima University,
1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526
(Received August 20, 2012; CL-120864; E-mail: skojima@sci.hiroshima-u.ac.jp)
The reaction of cis-4-oxopent-2-enal with ¢-carbonyl
£-oxo-¡-enal.6 This reported reaction, however, requires the use
of stoichiometric amounts of ZnCl2 and heating for the reaction
to proceed, the latter of which would be unfavorable in
asymmetric investigations. An examination of our reaction
revealed that it is general, it proceeds under mild conditions, and
it is accelerated in the presence of weak acids. Herein we present
our results.
compounds in the presence of weak acids such as hexafluoro-
isopropyl alcohol was found to give furans with a quaternary
carbon substituent at the 2-positon at room temperature or
below. Reactivity was dependent on the identity of the
substrates.
To determine suitable reaction conditions, 1-Z was exam-
ined as the acceptor, which is easily prepared by the oxidation of
2-methylfuran.7 Benzyl 2-oxocyclopentanecarboxylate (2a) was
selected as the donor and was subjected to several conditions as
shown in Table 1. In a preliminary reaction using off-the-shelf
CH2Cl2 (Entry 1), it was found that the reaction is over in
30 min. However, only 50% conversion was achieved in 24 h
when distilled solvent was used. This implied that either a
proton source or a trace amount of acid was accelerating the
reaction. Thus, MeOH and THF-H2O were examined as
solvents. However, the reactions were somewhat sluggish, and
we concluded that it must have been the trace amount of acid
that was beneficial for the reaction. Thus, acids were next
examined, and it was found that weak acids such as hexafluoro-
isopropyl alcohol (HFIP) and benzoic acid were effective,
whereas strong acids such as (PhO)2P(O)OH and camphorsul-
fonic acid (CSA) turned out to be detrimental, leading to
decomposition. It was also revealed that trans-4-oxopent-2-enal
Owing to the versatility of furans as synthetic intermediates
in organic synthesis,1 extensive studies on preparation have been
documented.2 Among the many known methods, the Paal-Knorr
method3 based upon the intramolecular cyclization reaction of
1,4-dicarbonyl compounds has long been recognized as a highly
versatile method. On the other hand, £-hydroxy-¡-enones and
enals are at the same oxidation level as 1,4-dicarbonyl
compounds and thus may also be regarded as candidates for
the intramolecular cyclization reaction. In fact, the utility of such
substrates for furan synthesis has been demonstrated.4 The
hydroxy moiety of such compounds can be obtained by the 1,2-
addition of nucleophiles to £-oxo-¡-enals, enabling a tandem
process for the formation of furans. The advantage of such a
process is the potential for an asymmetric variant of the reaction
by the use of prochiral nucleophiles. A candidate nucleophile for
such purpose would be the enolate of unsymmetric ¢-carbonyl
compounds, products of which would be useful for further
chemical transformations. However, it is known that carbonyl
adducts of the enolate of ¢-carbonyl compounds are generally
unstable as intermediates and they must either undergo sub-
sequent reaction such as dehydration as in the Knoevenagel
reaction or else they will revert back to the more stable reactants.
Probably due to this potential difficulty, synthetic methodology
based upon the use of £-oxo-¡-enals has not been exploited in
furan chemistry.
Table 1. Examination of reaction conditionsa
O
O
O
H
CO2Bn
O
solvent, additive
rt
O
O
OBn
1-Z
2a
4a
Entry Solvent
Additive Reaction time
Yield/%
1
CH2Cl2
CH2Cl2
MeOH
THF-H2Oc
None
None
None
12 h
24 h
2 h
91
50
86
86
2b
3
O
1,4 addition
ð1Þ
BnO2C
with base
O
O
4
None
12 h
O
H
MeOC
CHO
O
3
HFIP
OBn
5
CH2Cl2
<30 min
<30 min
1 h
89
90
71
(10 equiv)
PhCO2H
(1 equiv)
PhCO2H
(1 equiv)
HFIP
CO2Bn
O
1,2 addition
without base
1-Z
2a
O
ð2Þ
6
CH2Cl2
4a
THF-H2Oc
CH2Cl2
During our investigation of the Michael reaction using
amines as catalysts,5 we incidentally found in the reaction of
cis-4-oxopent-2-enal (1-Z) that while the Michael adduct is
exclusively formed when an amine catalysts is used, only the
furan derivative is formed in the absence of the amine (eqs 1 and
2). A similar furan forming reaction has been observed in the
reaction of commercially available dihydrodimethoxyfuran,
which can be regarded as a synthon of fumaraldehyde, a typical
7
8d
24 h
No reaction
(10 equiv)
aOff-the-shelf solvents were used unless stated otherwise.
c
d
bFreshly distilled solvent was used. THF-H2O = 9:1. trans-
4-Oxopent-2-enal was used. This was recovered intact after the
reaction time.
Chem. Lett. 2012, 41, 1586-1587
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1587
Table 2. Furan synthesis in HFIP-CH2Cl2 (1:1) at rta
(Entry 8) does not give either the furan or the Michael adduct
under conditions similar to those in Entry 5.
R1
O
O
H
2a-g
O
O
O
O
H
O
nucleophiles
O
R2
HFIP-CH2Cl2, rt
H
ð3Þ
3
1-Z
4a-g R
O
1-Z
1-E
Entry
1
Time
Product, Yieldb/%
Although the trans substrate could be envisioned to give
furans with an extra geometric isomerization process, efficient
furan formation could not be effected even in the presence
of nucleophiles that could induce isomerization or by irradiation
of the reaction mixture. The instability of the 1,2-adduct is
supported by the fact that NMR monitoring of the reaction
shows only the presence of the reactants and products, and no
intermediates. Neither have analogous 1,2-adducts of stabilized
C-nucleophiles been reported in the literature except for highly
activated aldehydes.8 The reason for the lack of reactivity in the
presence of base therefore seems to be due to the isomerization
of the cis-acceptor to the trans-isomer induced by the nucleo-
philic base. In fact, NMR monitoring at rt of mixtures of the
acceptor with some nucleophile showed facile isomerization to
the trans-isomer to occur. With 1,4-diazabicyclo[2.2.2]octane
(0.1 equiv) isomerization was complete in about an hour and
with pyrrolidine (0.1 equiv) within 15 min (eq 3). Bases are also
unfavorable from the point that they scavenge acids.
As for the scope of the reaction, several substrates were
examined as shown in Table 2.9 The reaction was found to be
generally fast except for 2b, 2c, and 2g. NMR measurements of
the dicarbonyl reactants showed that for substrates with high
reactivity, the keto form is exclusive besides 2d whereas a high
content of the enol form is observed for those of slow reactions.
This may imply that when reversion of the initial 1,2-adduct to
reactants is facile, the overall reaction is generally slow. For
selected substrates, reactions in MeOH were also carried out, but
resulted in slower reactions.
O
O
CO2Bn
O
2a 30 min
O
4a 89
(86)c
OBn
OEt
(2 h)c
O
O
CO2Et
O
2d
2b
2c
9 h
7 h
4b 60
O
O
O
COMe
COMe
3
O
O
4c 61
4d 70
4e 62
O
O
COMe
O
4
O
2d 30 min
O
O
O
O
O
O
O
5
2e 30 min
O
O
O
O
O
(1 d)c
(87)c
O
O
Bn
O
O
O
O
O
6
2f
1 h
2 d
4f 73
Bn
O
O
MeO2C
O
CO2Me
O
MeO2C
CO2Me
7
2g
4g 78
(6:4)e
In summary, we have established a mild synthesis of furans
bearing a quaternary carbon at the 2-position. The mild
conditions are expected to be favorable for application to
asymmetric reactions. Since, in addition to the oxidation of
furans, (Z)-£-oxo-¡-enals can be prepared either by the partial
hydrogenation of £-oxo-¡-ynals or by Z-selective Horner-
Wadsworth-Emmons reactions, wide-spread application of the
furan formation reaction is expected. Furthermore, substrates
that are labile to strongly acidic conditions might also be
applicable under the mild reaction conditions. Examination of
an asymmetric version of the present reaction is currently
underway.
aReactions were carried out in 0.5 M solutions with 1.5 equiv
c
of 1-Z. bIsolated yields. Reactions were carried out in 1 M
MeOH solutions. dReaction was carried out in a 1 M HFIP
e
solution. Yield based upon recovered 2b is 79%. Diastereo-
meric ratio. Stereochemistry was not assigned.
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Lett. 1996, 37, 6065.
Results of the amine-catalyzed reaction will be reported in due
course.
3
4
References and Notes
1
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5
6
7
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Journal Web site, http://www.csj.jp/journals/chem-lett/index.
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2
For representative reviews on the synthesis of furans see: a)
H. N. C. Wong, Pure Appl. Chem. 1996, 68, 335. b) X. L. Hou,
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8
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Chem. Lett. 2012, 41, 1586-1587
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/