Synthesis of dihydrobenzofurans with quaternary carbon center under mild and neutral conditions

Article abstract of DOI:10.1021/ol401897u

A new method has been developed for the construction of dihydrobenzofurans from O-aryloxime ethers bearing an α-cyano group using a sequential regioselective isomerization/[3,3]-sigmatropic rearrangement/cyclization reaction in MeOH without any catalysts under neutral conditions at ambient temperature. The current transformation provides environmentally benign and atom-economical access to a variety of dihydrobenzofurans containing a quaternary carbon from readily available cyclic and acyclic oxime ethers.

Full text of DOI:10.1021/ol401897u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Dihydrobenzofurans
with Quaternary Carbon Center
under Mild and Neutral Conditions
Norihiko Takeda,† Masafumi Ueda,† Syunsuke Kagehira,† Hiroyuki Komei,†
Norimitsu Tohnai,‡ Mikiji Miyata,‡ Takeaki Naito,† and Okiko Miyata*,†
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558,
Japan, and Graduate School of Engineering, Osaka University, Yamadaoka,
Suita, Osaka 565-0871, Japan
miyata@kobepharma-u.ac.jp
Received July 8, 2013
ABSTRACT
A new method has beendeveloped for the construction of dihydrobenzofurans from O-aryloxime ethers bearing an r-cyano groupusing a sequential
regioselective isomerization/[3,3]-sigmatropic rearrangement/cyclization reaction in MeOH without any catalysts under neutral conditions atambient
temperature. The current transformation provides environmentally benign and atom-economical access to a variety of dihydrobenzofurans
containing a quaternary carbon from readily available cyclic and acyclic oxime ethers.
Dihydrobenzofuran derivatives are an important mem-
ber of the benzofuran family,1 and cis-dihydrobenzofurans
bearing an all-carbon quaternary center, in particular, can
be found in a variety of biologically important compounds,
including galantamine-,2 morphine-,3 and lunarine-based4
alkaloids, as well as marine natural products such as
diazonamides.5 In light of their interesting biological activ-
ities, a number of different synthetic strategies have been
developed for the construction of dihydrobenzofurans, in-
cluding strategies based on the phenolic oxidative coupling,6
intramolecular Heck reaction,7 Claisen rearrangement,8
BirchꢀCope sequence,9 and intramolecular cyclization
reaction.10 Furthermore, the synthesis of dihydrobenzofurans
bearing a quaternary carbon via the [3,3]-sigmatropic
rearrangement of enehydroxylamines derived from oxime
ethers is arguably one of the most straightforward
† Kobe Pharmaceutical University.
‡ Osaka University.
(1) (a) Sheppard, T. D. J. Chem. Res. 2011, 35, 337. (b) Ward, R. S.
Nat. Prod. Rep. 1995, 183.
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New York, 1987; Vol. 30, pp 251ꢀ376. (b) Hoshino, O. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, pp 323ꢀ424.
(c) Marco-Contelles, J.; Carreiras, M. D. C.; Rodriguez, C.; Villarroya,
M.; Garcia, A. G. Chem. Rev. 2006, 106, 116.
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R.; Tohma, H.; Takeda, T. J. Org. Chem. 1998, 63, 6625. (b) Kodama, S.;
Hamashima, Y.; Nishida, K.; Node, M. Angew. Chem., Int. Ed. 2004, 43,
2659. (c) Node, M.; Kodama, S.; Hamashima, Y.; Kato, T.; Nishida, K.;
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R. G. A., Eds.; Academic Press: New York, 1979; Vol. 17, pp 385ꢀ519. (b)
Taber, D. F.; Neubert, T. D.; Schlecht, M. F. The Enantioselective
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5, 353. (c) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449.
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r
10.1021/ol401897u
XXXX American Chemical Society

synthetic methods currently available for the construction
of these compounds.11 Unfortunately, however, the appli-
cation of this protocol has been severely limited because
of its requirement for strongly acidic and high tempera-
ture conditions, which can lead to the decomposition of
the substrates as well as other undesired side reactions.12
Furthermore, it can be difficult to control the regio-
chemical outcome of the enamine formation under these
conditions, with mixtures of the different regioisomers
invariably being formed. When R-monosubstituted oxime
ether was employed in this transformation, the isomeriza-
tion of the imine led predominately to the least substituted
enamine which underwent sequential [3,3]-sigmatropic
rearrangement, cyclization, and elimination reactions to
give the undesired benzofuran.13,14 The synthesis of dihy-
drobenzofurans bearing a quaternary carbon center via
a sequential regioselective isomerization and [3,3]-sigma-
tropic rearrangement pathway under neutral conditions
therefore represents a highly desirable and challenging
transformation in organic synthesis. With this in mind, it
was envisaged that the regioselective formation of a more
stable enamine through H-bonding would lead to the desired
dihydrobenzofurans.
state of the Claisen rearrangement of an allyl vinyl ether that
effectively accelerated the rate of the reaction (Figure 1).
Similar H-bond promoted Claisen rearrangement reac-
tions18,19 encouraged us to investigate the possibility of
developing an acid- and waste-free strategy for the synthesis
of dihydrobenzofurans, with the key step being the regio-
selective isomerization of an oxime ether followed by a
[3,3]-sigmatropic rearrangement sequence. It was envisaged
that an oxime ether bearing an electron-withdrawing
group(EWG), suchasanesterora nitrile, atthe R-position
of the imine moiety would give rise to the thermody-
namically stable enamine and subsequently accelerate the
[3,3]-sigmatropic rearrangement through H-bonding with
water (Figure 1, IfIIfIII).
Hydrogen bonding has recently emerged as an important
factor in the advancement of organic synthesis. Powerful
organocatalysts and environmentally benign protic solvents,
in particular, have been used to good effect as H-bond
donors for the development of effective CꢀC bond forming
reactions.15 For example, Jorgensen16 and Hillier17 reported
the occurrence of two H-bonds with water in the transition
Figure 1. Proposed acceleration of the regioselective isomeriza-
tion and subsequent [3,3]-sigmatropic rearrangement through
H-bonding.
Oxime ethers of this particular type would then not only
trigger the regioselective isomerization but also accelerate the
subsequent sigmatropic rearrangement through H-bonding
with a protic solvent. Herein, we present the first
reported example of the regioselective isomerizationꢀ
rearrangementꢀcyclization reaction sequence of oxime
ethers promoted by a H-bonding effect. To the best of our
knowledge, there have been no other reports in the literature
concerning the efficient synthesis of valuable dihydroben-
zofurans under mild and acid-free conditions.20
(11) For the synthesis of benzofurans and selected examples, see:
(a) Sheradsky, T. Tetrahedron Lett. 1966, 5225. (b) Maimone, T. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 9990. (c) Contiero, F.;
Jones, K. M.; Matts, E. A.; Porzello, A.; Tomkinson, N. C. O. Synlett
2009, 3003.
(12) Benzofuran synthesis by the Au-catalyzed tandem condensa-
tion/rearrangement/cyclization reaction of O-arylhydroxylamine with
1,3-dicarbonyl compounds has been reported: Liu, Y.; Qian, J.; Lou, S.;
Xu, Z. J. Org. Chem. 2010, 75, 6300.
(13) Kaminsky, D.; Shavel, J., Jr.; Meltzer, R. I. Tetrahedron Lett.
1967, 8, 859.
(14) Symmetrically R,R0-disubstituted oxime ether is known to give
the dihydrobenzofuran with quarternary carbon under acidic and
thermal conditions; see: Laronze, J.-Y.; Boukili, R. E.; Patigny, D.;
Oxime ether 1a was selected as a model substrate for our
initial evaluation of the regioselective isomerization and
subsequent rearrangement, because it contained a cyano
group which is both electron-withdrawing and provides
minimal steric hindrance. The reaction of 1a was initially
screened against a range of different solvents that could
perform as H-bond donors or acceptors (Table 1). When a
suspension of 1a was stirred in H2O at ambient tempera-
ture for 72 h, none of the desired product was formed
and only the starting material was recovered. The lack of
reactivity in this case, however, was attributed to the poor
solubility of 1a in water (Table 1, entry 1).
ꢀ
Dridi, S.; Cartier, D.; Levy, J. Tetrahedron 1991, 47, 10003.
(15) For reviews, see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299. (b) Bernardi, L.; Fochi, M.; Franchini, M. C.; Ricci, A. Org.
Biomol. Chem. 2012, 10, 2911. (c) Pirrung, M. C. Chem.;Eur. J. 2006,
12, 1312. (d) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (e)
€
Lindstrom, U. F. Chem. Rev. 2002, 102, 2751.
(16) (a) Severance, D. L.; Jorgensen, W. L. J. Am. Chem. Soc. 1992,
114, 10966. (b) Jorgensen, W. L.; Blake, J. F.; Lim, D.; Severance, D. L.
J. Chem. Soc., Faraday Trans. 1994, 90, 1727.
(17) Davidson, M. M.; Hillier, I. H. J. Phys. Chem. 1995, 99, 6748.
(18) For examples of accelerated Claisen rearrangement in the protic
solvent, see: (a) Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936.
(b) Mark, M. D.; Ian, H. H. J. Phys. Chem. 1995, 99, 6748. (c) Gajewski,
J. J. J. Org. Chem. 1992, 57, 5500. (d) Gajewski, J. J. Acc. Chem. Res.
1997, 30, 219. (e) “Structure and Reactivity in Aqueous Solution”:
Gajewski, J. J.; Brichford, N. L. ACS Symp. Ser. 1994, 568, 229. (f)
Severance, D. L.; Jorgensen, W. L. J. Am. Chem. Soc. 1992, 114, 10966.
(19) Acceleration of Claisen rearrangement utilizing organocatalysts
as a hydrogen bond donor have been developed; see: (a) Curran, D. P.;
Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647. (b) Kirsten, M.; Rehbein,
J.; Hiersemann, M.; Strassner, T. J. Org. Chem. 2007, 72, 4001. (c)
Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228. (d)
Annamalai, V. R.; Linton, E. C.; Kozlowski, M. C. Org. Lett. 2009,
11, 621.
Pleasingly, when the reaction was conducted in MeOH,
the desired cis-dihydrobenzofuran 2a was formed as the
(20) (a) Takeda, N.; Miyata, O.; Naito, T. Eur. J. Org. Chem. 2007,
1491. (b) Takeda, N.; Miyata, O.; Kitamura, M.; Kagehira, S.; Naito, T.
Synlett 2006, 3415. (c) Miyata, O.; Takeda, N.; Naito, T. Heterocycles
2009, 78, 843.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Solvent and Substituent Effects
Figure 2. Different conformations of the enamines generated from 3.
entry substrate
solvent
H2O
t (h) product yield (%)a,b
proceeded to investigate the application of the isomeri-
zation/rearrangement/cyclization reaction sequence to a
variety of different oxime ethers 1bꢀh (Table 2). The
reactions of 1b and 1c with cycloheptane and cyclooctane
rings, respectively, in MeOH proceeded smoothly to pro-
vide the corresponding dihydrobenzofurans 2b and 2c
in high yields (Table 2, entries 1 and 2), although longer
reaction times were required than that of 1a. The reaction
of 1d bearing a macrocyclic ring in a mixture of MeOH and
CH2Cl2 afforded the desired product 2d in 84% yield
(Table 2, entry 3).23 We were also pleased to find that the
reaction system could be successfully applied to the acyclic
R-cyano oxime ethers. For example, the reactions of 1eꢀh
proceeded smoothly under the optimal conditions to
give the corresponding dihydrobenzofurans 2eꢀh in high
yields as mixtures of diastereomers (Table 2, entries 4ꢀ7).
Interestingly, the reaction of oxime ether 1i bearing no
alkyl group at the R-position gave the uncyclized product 9
in quantitative yield through the isomerization of the
R-cyanoimine E to the stable β-enaminonitrile 9 following
the [3,3]-sigmatropic rearrangement (Table 2, entry 8).
Wethenproceededtoexaminetheeffect ofdifferentsub-
stituents on the benzene ring using a series of oxime ethers
(Table 3). All of the oxime ethers studied were smoothly
converted to the corresponding dihydrobenzofurans
2jꢀm in good to high yields under the optimal conditions.
Pleasingly, substrates 1l and 1m bearing a methyl or a
trifluoromethyl group at the o-positions of their benzene
ring, respectively, also worked well (Table 3, entries 3 and 4).
The oxime ether 1n bearing a m-methyl group on its benzene
ring afforded the dihydrobenzofurans 2n and 2n0 as a
mixture of regioisomers in 73% yield (Table 3, entry 5).
To elucidate the mechanism of the transformation,
the reaction was studied by 1H NMR analysis. 1H NMR
spectra of a solution of 1a in CD3OD collected during the
course of the reaction only revealed the consumption of
1a and the generation of dihydrobenzofuran 2a. After 24 h
at ambient temperature, only 2a could be detected by 1H
NMR as the sole product of the reaction. These results
suggested that the [3,3]-sigmatropic rearrangement reac-
tion of the O-aryl-N-vinylhydroxylamine and subsequent
cyclization reaction must have occurred immediately after
the isomerization of 1a in the first step to form 2a.
1
1a
1a
1a
1a
1a
1a
1a
1a
3
72
2a
2a
2a
2a
2a
2a
2a
2a
4
ꢀ (84)
94
2
MeOH
EtOH
24
3
72
81
4
i-PrOH
CF3CH2OH
Et2O
120
72
74
5
47 (12)
ꢀ (99)
ꢀ (97)
ꢀ (99)
ꢀ (99)
ꢀ (99)
ꢀ (99)
6
72
7
CH2Cl2
none
120
120
48
8
9
MeOH
MeOH
MeOH
10
11
5
48
6
7
48
8
a Isolated yields. b Yields in parentheses are for the recovered starting
materials.
sole product in high yield (Table 1, entry 2).21 The applica-
tion of other alcohols such as EtOH and i-PrOH led to
lower yields of 2a with longer reaction times also being
required (Table 1, entries 3 and 4). Furthermore, the use
of CF3CH2OH led to a significant reduction in the yield
of 2a (Table 1, entry 5). When the reaction was conducted
in Et2O or CH2Cl2 or under neat conditions, none of the
desired product was formed, which indicated that protic
solvents and hydrogen donors were critical to the success
of the reaction (Table 1, entries 6ꢀ8).
To gain insight into the effect of the cyano group on
this reaction, several other oxime ethers bearing a variety
of other substituents were also subjected to the optimal
reaction conditions. Interestingly, the MeOH-mediated
reaction of 3 bearing the ethoxycarbonyl group did not
take place. Given that the electron-withdrawing properties
of the cyano group are similar to those of the ethoxycar-
bonyl group,22 the corresponding enamine should have
beenformed(Figure 2). The transition state B0 for the [3.3]-
sigmatropic rearrangement, however, would have been
conformationally disfavored because of steric repulsion,
and the oxime ether 3 was subsequently recovered via the
isomerization of the enamine (i.e., Af3). The acidity of the
R-proton of the imine was also determined to be important
to the success of this transformation, because the applica-
tionof the optimalreaction conditions tothe unsubstituted
oxime ether 5 and the alkyne-substituted oxime ether 7 did
not provide any of the desired products.
Having established the importance of the electron-with-
drawing R-cyano group and the methanol solvent, we
Based on the experimental observation from the current
study, we have proposed a possible reaction pathway
for the construction of dihydrobenzofuran 2 (Scheme 1).
(21) The stereostructure of 2a was firmly established by the single-
crystal X-ray analysis of the trifluoroacetamide 10 which was prepared
by trifluoroacetylation of 2a with TFAA (see Supporting Information).
(22) A value of the cyano and ethoxycarbonyl groups are 1.0 and
5.5 kJ molꢀ1 respectively.
(23) CH2Cl2 was used as a cosolvent.
3
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C

Table 2. Reaction of Various Oxime Ethers
Table 3. Substituent Effects on the Benzene Ring
a Reaction conditions: Oxime ether 1 in MeOH at ambient tempera-
ture. b Isolated yields.
a Reaction conditions: Oxime ether 1 in MeOH at ambient tempera-
ture. b Isolated yields. c Reaction in a 5:2 (v/v) mixture of MeOH and
CH2Cl2. d dr = 1:1. e dr = 4.5:1 f E/Z = 1:1.
Scheme 1. Possible Reaction Pathway
Thus, the regioselective isomerization of oxime ether 1
activated by H-bonding would lead to the formation
of the O-aryl-N-vinylhydroxylamine D. The subsequent
sequential [3,3]-sigmatropic rearrangement and cycliza-
tion reaction would give rise to dihydrobenzofuran 2.
In the case of the unsubstituted oxime 1i (R1 = H, R2 =
Ph), the β-enaminonitrile 9 was presumably formed as
a consequence of the rearomatization of E. The MeOH
solvent was important for two reasons, including (i)
promoting a shift in the imine-enamine equilibrium of 1
and (ii) accelerating the [3,3]-sigmatropic rearrangement
of D.24
In summary, we established a highly efficient and general
synthetic method for the construction of dihydrobenzofurans
via the application of an isomerization/rearrangement/
cyclization reaction sequence to R-cyano oxime ethers in
MeOH. The MeOH-mediated reaction described herein
presents several advantages over the existing methods,
including the fact that the reaction proceeds under neutral
conditions and does not require an extensive workup
procedure. This new method therefore represents a much
more operationally simple and practicable procedure.
Acknowledgment. This work was supported by Grants-
in Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (MEXT), and the
MEXT-Supported Program for the Strategic Research
Foundation at Private Universities.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) The possibility that MeOH is accerlating only the imineꢀ
enamine equibrium of 1a cannot be excluded.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX