5-substituted-2-furaldehydes: A synthetic protocol utilizing an organozinc route

Article abstract of DOI:10.1021/jo301836x

Facile synthetic routes for the preparation of a wide range of 5-substituted 2-furaldehydes have been revealed. They were accomplished through either Pd-catalyzed cross-coupling reaction of various aryl- and heteroarylzinc halides with 5-bromo-2-furaldehyde or utilization of a new organozinc reagent, 5-(1,3-dioxolan-2-yl)-2-furanylzinc bromide, which was easily prepared by the direct insertion of highly active zinc to 2-(5-bromofuran-2-yl-1,3-dioxolane. Of special note is the uniqueness of using a new organozinc reagent, representing a first example of the direct synthesis of the corresponding organozinc halide. The subsequent coupling reactions in various types of reaction conditions led to the formation of somewhat different furan derivatives. It is also of significance that all of the cross-coupling reactions were carried out under mild conditions.

Full text of DOI:10.1021/jo301836x

Article
pubs.acs.org/joc
5‑Substituted-2-furaldehydes: A Synthetic Protocol Utilizing an
Organozinc Route
Seung-Hoi Kim† and Reuben D. Rieke*,‡
†Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Korea
‡Rieke Metals, Inc., 1001 Kingbird Rd., Lincoln, Nebraska 68521, United States
S
* Supporting Information
ABSTRACT: Facile synthetic routes for the preparation of a
wide range of 5-substituted 2-furaldehydes have been revealed.
They were accomplished through either Pd-catalyzed cross-
coupling reaction of various aryl- and heteroarylzinc halides
with 5-bromo-2-furaldehyde or utilization of a new organozinc
reagent, 5-(1,3-dioxolan-2-yl)-2-furanylzinc bromide, which
was easily prepared by the direct insertion of highly active
zinc to 2-(5-bromofuran-2-yl-1,3-dioxolane. Of special note is
the uniqueness of using a new organozinc reagent, representing a first example of the direct synthesis of the corresponding
organozinc halide. The subsequent coupling reactions in various types of reaction conditions led to the formation of somewhat
different furan derivatives. It is also of significance that all of the cross-coupling reactions were carried out under mild conditions.
by transmetalation. Generally, cryogenic conditions are
required for the lithiation of organic compounds. McClure et
al. has reported a one-pot synthesis of 5-aryl-2-furaldehydes via
the Suzuki coupling reaction prepared using protected furan
moiety route B, Scheme 1) and also the regioselective
palladium-catalyzed direct arylation of 2-furaldehyde (route
C, Scheme 1).6 More recently, simple 2-substituted furan
derivatives were prepared by iron- and palladium-catalyzed
coupling reaction using the Grignard and Suzuki coupling
reagents.7 Knochel has also reported the regio- and chemo-
selective synthesis of highly substituted furans using Grignard
reagents.8
Despite the present methodologies, there is still a need to
introduce a convenient route for the preparation of a variety of
5-substituted furaldehydes. Thus, we herein would like to
report an alternative synthetic route providing a unique way of
preparing highly functionalized 2-furaldehydes under mild
conditions.
To explore the variety of ways of the preparation of furan
derivatives, our attention was focused on the utilization of
organozinc reagents that were readily accessible. It is well-
known that the use of organozinc reagents is advantageous over
the other organometallics such as the Grignard, Suzuki, and
Stille coupling reactions mainly because of the functional group
tolerance of the organozincs. The arylzinc reagents used in the
coupling reactions with 5-bromo-2-furaldehyde9 in this study
(Tables 1, 2, and 3) were easily prepared by the direct insertion
of highly active zinc (Rieke zinc) to the corresponding aryl
INTRODUCTION
■
Widespread applications of furan-containing derivatives can be
found in a wide range of chemical industries such as
pharmaceuticals, textiles, dyes, fossil fuels, photo sensitizers,
cosmetics, and even in agrochemicals.1 This rich variety of
applicability is attributed to the preparation of numerous furan
derivatives. In general, the preparation methods for these
derivatives consist of two approaches, ring construction and
derivatization of preformed furan rings. Among these, the latter
case is a more readily accessible route since many of these
derivatives are commercially available.
It is significant that the furan moiety is an interesting
structural unit playing a prominent role especially in natural
products that show a wide range of biological activity.2 Of
special interest are aryl-substituted furan intermediates, which
have been intensively used in the preparation of furan-
containing pharmaceuticals.2a Due to the particular interest in
this area, considerable time and effort has been spent in the
development of a versatile synthetic methodology for the
preparation of 2,5-disubstituted furan derivatives.
Among the better-known procedures as depicted in Scheme
1, transition-metal-catalyzed cross-coupling reactions of the
corresponding organometallic reagents are one of the
predominant approaches.3 Of these organometallics, unfortu-
nately, little work has been performed using arylmetallic
reagents. O’Doherty described the preparation of 5-aryl-2-
furaldehydes using palladium-catalyzed cross-coupling reaction
of protected furylstannes and/or furylzincs (routes A and B,
Scheme 1).4 Recently, a similar approach using a one-pot, four-
step sequence palladium-catalyzed cross-coupling reaction of
triorganozincates was reported by Gauthier et al. (route B,
Scheme 1).5 The organometallic reagents used in these studies
were prepared by the lithiation of the protected furans followed
Special Issue: Howard Zimmerman Memorial Issue
Received: September 18, 2012
Published: October 17, 2012
© 2012 American Chemical Society
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Scheme 1. Representative Synthetic Routes for 5-Substituted 2-Furaldehydes
halides.10 It was also of interest that all of the subsequent cross-
Table 1. Coupling Reactions with Arylzinc Halides
coupling reactions of the resulting organozincs were efficiently
carried out in the presence of a catalytic amount of Pd(0)-
catalyst under very mild conditions affording the cross-coupling
products in good to excellent yield. A wide range of 5-
substituted 2-furaldehydes were provided through this method-
ology, and the results are summarized in Tables 1, 2, and 3.
RESULTS AND DISCUSSION
■
Our first attempt was conducted with arylzinc halides bearing
various functionalities. As described in Table 1, many
functionalized arylzinc halides underwent the coupling reaction
with 5-bromo-2-furaldehyde under the mild conditions (1 mol
% Pd[P(Ph)3]4, room temperature) and successfully gave 5-
aryl-substituted 2-furaldehydes. In the case of electron-with-
drawing groups (Table 1, entries 1−4), excellent yields (82−
93%) were achieved with the exception of 3-cyanophenylzinc
iodide (42%, 1d, entry 4, Table 1). For most of the cases, the
reactions were completed in 1 h at room temperature.
However, when 4-methylphenylzinc bromide bearing an
electron-donating group was treated with 5-bromo-2-furalde-
hyde under the same conditions (room temperature, 1 h) used
above (Table 1, entry 7), the corresponding cross-coupling
product (1g, Table 1) was obtained in slightly reduced yields
(55%). GC−MS analysis showed that the major impurity was
the unreacted 5-bromo-2-furaldehyde. Thus, in the following
coupling reaction containing another electron-donating group,
4-methoxyphenylzinc bromide, a longer reaction time was
employed to lead the coupling reaction to completion yielding
1h (Table 1, entry 8). With this coupling product (1h), a more
interesting result was observed. The color of the isolated
product was immediately changed from light yellow to greenish
black upon storage at atmosphere. Presumably, we assumed
that this was caused by air-oxidation, but no further study of
this observation was executed.
In addition to the results above, the Pd(0)-catalyzed coupling
reaction is also applicable to the synthesis of several different
types of 5-heteroaryl-2-furaldehydes. Again, the aforementioned
mild reaction conditions worked well for the following coupling
reactions. The results are summarized in Table 2. Expansion of
this strategy was first conducted by the coupling reaction of
thienylzinc bromides containing a halogen atom, 1,3-dioxane,
and ester functionalities. As described in entries 1−3 in Table 2,
the corresponding products (2a, 2b, and 2c, respectively) were
obtained in good to excellent isolated yields. Significantly, these
functionalities derived from the corresponding organozinc
reagents could be used for the further modification along
with the aldehyde at the 2-position of the furan ring.
Unfortunately, product 2b appears to be an unstable
compound, which leads to the formation of self-deprotected
mixture upon storage at room temperature. It is of interest that
a
b
Isolated yield (based on furaldehyde). Conversion by GC, no
isolated product.
an unsymmetrical furan−furan linkage (2d, Table 2) has been
constructed in 83% isolated yield by treatment with 5-
ethoxycarbonyl-2-furylzinc bromide (Table 2, entry 4). We
also examined the use of heteroarylzinc bromides possessing
two hetero atoms in a ring compound such as 2-thiazoylzinc
and 5-pyrimidylzinc bromides. As noted in entries 5 and 6 in
Table 2, yields (43% and 33%) were somewhat lower than
other heteroarylzincs. 3-Quinolinylzinc bromide appeared to be
a good coupling partner for 5-bromo-2-furaldehyde resulting in
the formation of 2g in moderate yield (Table 2, entry 7).
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Table 2. Coupling Reactions with Heteroarylzinc Halides
Table 3. Pd-Catalyzed Coupling Reactions with Pyridylzincs
a
Isolated yield (based on furaldehyde).
To magnify the scope of our methodology, special
heteroarylzinc reagents, pyridylzinc halides was chosen and
employed in the coupling reaction with 5-bromo-2-furaldehyde
since 5-pyridyl-2-furaldehydes have been frequently used for
synthetic intermediates in pharmaceuticals.5 The pyridylzinc
halides used in this study were also easily prepared by the direct
oxidative addition of active zinc to the corresponding halides.11
As summarized in Table 3, the coupling reactions were carried
out under the same reaction conditions as used in the previous
study (a catalytic amount of Pd[P(Ph3)]4 at room temperature
in THF). An excellent yield was obtained from the reaction of
simple 2-pyridylzinc bromide in 1 h (Table 3, entry 1).
Sterically hindered organozinc, 3-methyl-2-pyridylzinc bromide,
required a prolonged reaction time affording 3b in lower yield
(Table 3, entry 2). The coupling reaction of 5-methyl-2-
pyridylzinc bromide, however, was completed in 6 h at room
temperature to produce 3C in good yield (Table 3, entry 3). An
extended time (24 h) was required for the methoxy-substituted
pyridylzinc bromide at room temperature in THF (Table 3,
entry 4). 2-Pyridylzinc bromide containing a fluorine atom was
successfully employed in the coupling reaction with 5-bromo-2-
furaldehyde to give the coupled product 3e in 60% yield (Table
3, entry 5). Along with the 2-pyridylzinc reagents, 3-pyridylzinc
bromides (Table 3, entries 6−8) were also easily reacted with
5-bromo-2-furaldehyde at room temperature in THF to afford
the corresponding products (3f, 3g, and 3h, Table 3) in good
to excellent yields. Moreover, in the reaction with 2-chloro-4-
pyridylzinc bromide, the coupling reaction proceeded smoothly
to give 3i in 66% yield (Table 3, entry 9).
a
Isolated yield (based on furaldehyde).
Even though those approaches used above provided a variety
of furan derivatives, we developed a somewhat different
approache for the preparation of 5-substituted 2-furalhehydes
containing a unique functionality on 5-position. One of the
reasons is that some of the organozinc reagents bearing
especially hydroxy- and amino- functionalities are not readily
available using the direct insertion method. More interestingly,
introducing a carbonyl group on 5-position is not obtainable
from the methodology used in previous approaches. In contrast
to this fact, it is successfully accomplished by the direct
preparation of furylzinc reagent and its subsequent application
for the coupling reaction in our study (route B in Scheme 1).
As shown in Scheme 2, 5-(1,3-dioxolan-2-yl)-2-furanylzinc
bromide 1 was easily prepared as expected by the direct
insertion of active zinc to 2-(5-bromofuran-2-yl)-1,3-dioxolane
under mild conditions. To confirm the formation of the
corresponding organozinc reagent, an aliquot of the reaction
mixture was quenched with iodine and analyzed by GC and
GC−MS. Both analyses clearly showed the formation of 2-(5-
iodofuran-2-yl)-1,3-dioxolane. From this result, it could be
inferred that the corresponding organozinc reagent (1) was
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Scheme 2. Preparation of 5-(1,3-Dioxolan-2-yl)-2-furanylzinc Bromide (1)
successfully formed. To find out the usefulness of the resulting
organozinc reagent, subsequent coupling reactions were
performed with a variety of different types of electrophiles
such as aromatic halides, haloamines, haloalcohols, and
carboxylic acid chlorides.
Prior to the general applications of 5-(1,3-dioxolan-2-yl)-2-
furanylzinc bromide 1, a typical Pd-catalyzed C−C bond-
forming reaction with 1-bromo-4-iodobenzene was carried out.
As described in Scheme 3, two derivatives were achieved
depending upon the workup procedure.
tert-butylphenyl, and acenaphthyl bromides leading to the
corresponding products, 4d, 4e, and 4f in excellent yields
(entries 4−6, Table 4), respectively. This condition was also
very effective with an electron-rich N,N-dimethylaminophenyl
bromide (entry 7, Table 4).
We then attempted the coupling reaction with haloaromatic
compounds containing a hydroxyl or an amino functional group
that would be more challenging. Even though there are very
limited examples of coupling reactions of organozinc
compounds with haloaromatic alcohols and amines,11 to our
best knowledge no report revealed the coupling reaction with
furanylzinc bromide. In our study, the coupling reaction was
easily accomplished using 2 mol % Pd(OAc)2 and 4 mol %
SPhos in THF at room temperature. As described in Table 5, it
was found that some of the coupling products were not stable
enough to be obtained as an isolated product in the
atmosphere. It was of interest that the stability of the coupling
product is dependent upon the position of the functional group
of the aromatic ring. For instance, 4-iodophenol was coupled
well with 1 under mild conditions affording the corresponding
product, 5a, in 92% isolated yield (entry 1, Table 5). In
contrast, even though the formation of the expected coupling
products (5b and 5c) was confirmed by GS−MS analysis of the
reaction aliquot from the reaction using 3-iodophenol and 2-
iodophenol, respectively, the isolated products (5b and 5c)
immediately decomposed upon solvent removal after column
chromatography (entries 2 and 3, Table 5). In the case of
employing aniline, a similar result was also observed. Again, we
were not able to isolate the coupling product 5d using 4-
iodoaniline (entry 5, Table 5). Meanwhile, 3-iodoaniline was
coupled with 1 giving rise to a stable coupling product 5e in
80% isolated yield as an orange oily product (entry 6, Table 5).
Regarding the stability of the products described above, again
no further investigations were performed.
Subsequent investigation of this chemistry was focused on
introducing a carbonyl group in the 5-position of furan. To this
end, copper-catalyzed coupling reactions with an acid chloride
were applied since this methodology has been one of the most
widely used strategies in Negishi coupling. The first attempt
was carried out with benzoyl chloride in a standard fashion (10
mol % CuI and 20 mol % LiCl). The coupling product 6a was
achieved in excellent isolated yield (93%, entry 1, Table 6).
Alkyl acid chlorides (entries 3 and 4, Table 6) were also
coupled with 1 to generate ketones 6c and 6d in good yields. It
should be mentioned that the heterocyclic acid chlorides were
also successfully employed in the coupling reaction with 1,
providing unsymmetrical heterocyclic ketones 6e and 6f in
moderate to good yields (entries 5 and 6, Table 6), respectively.
An interesting result was that trifluoroacetic anhydride was also
a good coupling partner, and the coupling reaction with 1 gave
ketone 6g in moderate yield (entry 7, Table 6). Finally, a SN2′-
type reaction was performed with allyl bromide resulting in the
formation of 2-(5-allylfuran-2-yl)-1,3-dioxolane 6h in 70% yield
(entry 8, Table 6).
Scheme 3. Preparation of 5-Aryl-substituted Furans
The coupling reaction was completed in 1 h at room
temperature in THF in the presence of 1 mol % Pd[P(Ph3)]4.
As is typical, an acidic workup procedure gave rise to the 5-(4-
bromophenyl)-2-furaldehyde (b) in 89% isolated yield. Mean-
while, a protected furaldehyde (a) was obtained from the
workup procedure using ammonium chloride in excellent yield.
As described in the aforementioned report,5 these types of
molecules are easily accessible via the cross-coupling reaction of
2-bromo-5-furaldehyde with the corresponding organozinc
regents. In order to produce more complex molecules, we
have tried several new reaction conditions. Table 4 shows the
results observed from Pd-catalyzed cross-coupling reactions
with a variety of aryl bromides. In an effort to evaluate the
overall feasibility of the organozinc 1, coupling reactions with 2-
bromo-5-furaldehyde were carried out first to obtain a
pseudosymmetrical bifuraldehyde under the conditions de-
picted in Table 4.
The reaction proceeded smoothly at room temperature and
was completed in 30 min. Even though the formation of the
cross-coupling product was confirmed by GC and GC−MS,
unfortunately, the separation of coupling product failed due to
the instability of the product in the atmosphere (entry 1, Table
4). However, the similar compound 4b that has an ester
functionality was successfully produced in 63% isolated yield
(entry 2, Table 4). The next attempt was to couple some
aromatic bromides for which the corresponding organozinc
reagents were not readily available from the direct insertion
method using active zinc route.12 Use of the Pd(OAc)2/SPhos
catalytic system successfully afforded the coupling product 4c in
73% isolated yield (entry 3, Table 4). In the following several
reactions (entries 4−7 in Table 4), it should be emphasized
that no extra ligand was necessary for the coupling reaction in
the presence of Pd[P(Ph3)]2Cl2. It worked effectively in the
coupling reaction at room temperature with tetramethylphenyl,
In conclusion, facile synthetic routes for the preparation of a
wide range of 5-substituted 2-furaldehydes have been revealed.
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Table 4. Pd-Catalyzed Synthesis of 2-(5-Aryfuran-2-yl)-1,3-dioxolanes
a
b
Isolated yield (based on aryl halide), otherwise mentioned. Conversion by GC, no isolated product.
(Hz). High-resolution mass spectra (HRMS-TOF) are measured with
electron impact (EI). All melting points are uncorrected.
They were accomplished through either Pd-catalyzed cross-
coupling reaction of various aryl- and heteroarylzinc halides
with 5-bromo-2-furaldehyde (route A) or utilization of a new
organozinc reagent, 5-(1,3-dioxolan-2-yl)-2-furanylzinc bro-
mide 1, which was easily prepared by the direct insertion of
highly active zinc to 2-(5-bromofuran-2-yl-1,3-dioxolane (route
B). Of special note is the uniqueness of the route B,
representing a first example of the direct synthesis of the
corresponding organozinc halide. The subsequent coupling
reactions of 1 in various types of reaction conditions led to the
formation of somewhat different furan derivatives, such as a
furan possessing a hydroxy or aminophenyl substituent and a
furan bearing a carbonyl group directly attached at the 5-
position. It is also of significance that all of the cross-coupling
reactions were carried out under mild conditions.
General Procedure for Pd-Catalyzed Cross-Coupling Reac-
tions. 5-(4-Chlorophenyl)furan-2-carbaldehyde 1a. A 50 mL round-
bottomed flask equipped with a stirring bar, a thermometer, and a
septum was charged with 0. 1g of Pd[P(Ph)3]4, and then 20 mL of a
0.5 M solution of 4-chlorophenylzinc bromide (10 mmol) in THF was
added into the flask via a syringe. Next, 1.40 g (8 mmol) of 5-
bromofuran-2-carbaldehyde was cannulated while being stirred at
room temperature. After 1.0 h of stirring at room temperature, the
reaction mixture was quenched with saturated 3 M HCl solution and
then extracted with ether, which was washed with saturated Na2S2O3
and brine and then dried over MgSO4. The mixture was purified by a
flash column chromatography on a silica gel column (10% EtOAc/
90% heptane) to afford 0.77 g of 1a as a white solid in 93% isolated
yield: mp 127−128 °C; 1H NMR (CDCl3, 500 MHz) δ 9.68 (s, 1 H),
7.77 (d, J = 10.0 Hz, 2 H), 7.44 (d, J = 10.0 Hz, 2 H), 7.33 (d, J = 5.0
Hz, 1 H), 6.85 (d, J = 5.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
177.2, 158.2, 152.1, 135.7, 129.3, 127.5, 126.5, 116.8, 108.0; HRMS
(EI) for [C11H7O2Cl] calcd 206.0135, found 206.0142; GC−MS (EI,
70 eV) m/z (%) 206 (100) [M+], 178 (10), 151 (20), 149 (59), 115
(22).
EXPERIMENTAL SECTION
■
All reactions were carried out under positive argon pressure. Active
zinc was prepared by a literature method.10 Other commercially
available reagents including the solvent (THF, from Sigma-Aldrich)
were used without further purification. Flash chromatography was
performed on Kieselgel 60 (230−400 mesh). NMR spectra were
recorded at 300 or 500 MHz using CDCl3 (TMS) as a solvent.
Chemical shifts (δ) are reported in part per million (ppm) for 1H and
13C NMR spectra. The coupling constants (J) are reported in hertz
5-(4-Ethoxycarbonylphenyl)furan-2-carbaldehyde 1b. Following
the general procedure, 0.80 g of 1b was obtained as a salmon solid in
1
82% isolated yield: mp 122−123 °C; H NMR (CDCl3, 500 MHz) δ
9.70 (s, 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.35
(d, J = 3.5 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H),
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5-(4-Methylphenyl)furan-2-carbaldehyde 1g. Following the gen-
eral procedure, 0.41g of 1g was obtained as a yellow solid in 55%
isolated yield: mp 57−58 °C; 1H NMR (CDCl3, 500 MHz) δ 9.65 (s,
1H), 7.74 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.27 (d, J = 8.5
Hz, 2H), 6.81 (d, J = 3.5 Hz, 1H), 2.42 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 177.1, 159.8, 151.8, 140.1, 129.7, 126.3, 125.3, 123.9,
107.1, 21.5; GC−MS (EI, 70 eV) m/z (%) 186 (100) [M+], 158 (10),
129 (63), 115 (9), 77 (8).
Table 5. Coupling with Haloamines and Alcohols
5-(4-Methoxyphenyl)furan-2-carbaldehyde 1h. Following the
general procedure, 0.56 g of 1h was obtained as pale yellow oil.
However, the product was immediately oxidized to an unidentified
product upon the expose to the air after column chromatography. The
structure was confirmed by GC−MS (EI, 70 eV) m/z (%) 202 (100)
[M+], 187 (50), 174 (10), 159 (25), 145 (38).
5-(5-Bromothiophen-2-yl)furan-2-carbaldehyde 2a. A 50 mL
round-bottomed flask equipped with a stirring bar, a thermometer,
and a septum was charged with 0.1 g of Pd[P(Ph)3]4, and then 20 mL
of 0.5 M solution of 5-bromo-2-thienylzinc bromide (10 mmol) in
THF was added into the flask via a syringe. Next, 1.40 g (8 mmol) of
5-bromofuran-2-carbaldehyde was cannulated while being stirred at
room temperature. After 1.0 h of stirring at room temperature, the
reaction mixture was quenched with saturated 3 M HCl solution and
then extracted with ether, which was washed with saturated Na2S2O3
and brine and then dried over MgSO4. The mixture was purified by a
flash column chromatography on a silica gel column (10% EtOAc/
90% heptane) to afford 1.54 g of 2a as a pale yellow solid in 75%
isolated yield: mp 91−92 °C; 1H NMR (CDCl3, 500 MHz) δ 9.64 (s,
1H), 7.29 (d, J = 3.5 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 4.0
Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
176.9, 153.5, 151.6, 133.1, 131.1, 126.3, 115.0, 107.7; HRMS (EI) for
[C9H5O2BrS] calcd 257.9173, found 257.9178.
5-(5-(1,3-Dioxolan-2-yl)thiophen-2-yl)furan-2-carbaldehyde 2b.
Following the general procedure, 0.95 g of 2b was obtained as a
yellow oil in 95% isolated yield: H NMR (CDCl3, 500 MHz) δ 9.63
(s, 1H), 7.42 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.16 (d, J =
5.0 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 6.13 (s, 1H), 4.14−4.09 (m,
2H), 4.05−4.02 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 177.4,
154.5, 152.5, 144.3, 132.2, 126.7, 125.8, 107.8, 99.9, 65.3; GC−MS
(EI, 70 eV) m/z (%) 250 (57) [M+], 221 (13), 205 (40), 191 (41),
178 (100), 150 (13), 121 (32).
a
b
1
Isolated (based on halide), otherwise mentioned. Conversion by
GC, no isolated product.
1.42 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.5, 165.9,
157.9, 152.5, 132.7, 131.1, 130.2, 125.0, 109.4, 61.3, 14.3.
4-(5-Formylfuran-2-yl)benzonitrile 1c. Following the general
procedure, 0.72 g of 1c was obtained as a pale orange solid in 91%
isolated yield: mp 163 °C; H NMR (CDCl3, 500 MHz) δ 9.74 (s,
Ethyl 5-(5-Formylfuran-2-yl)thiophene-2-carboxylate 2c. Follow-
ing the general procedure, 0.92 g of 2c was obtained as a salmon solid
1
1H), 7.94 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 3.5
Hz, 1H), 7.01 (d, J = 3.5 Hz, 1H) ; 13C NMR (CDCl3, 125 MHz) δ
177.5, 156.7, 152.8, 132.8, 125.6, 122.9, 118.4, 112.8, 110.1; GC−MS
(EI, 70 eV) m/z (%) 197 (100) [M+], 169 (8), 140 (60), 113 (16).
3-(5-Formylfuran-2-yl)benzonitrile 1d. Following the general
procedure, 0.33g of 1d was obtained as a beige solid in 42% isolated
yield: mp 195−196 °C (dec.); 1H NMR (CDCl3, 500 MHz) δ 9.73 (s,
1H), 8.11 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H),
7.60 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H), 6.96 (d, J = 3.5 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 177.5, 156.44, 152.6, 132.6,
130.3, 130.0, 129.1, 128.6, 123.0, 118.1, 113.5, 109.1.
3-(5-Formylfuran-2-yl)phenyl Acetate 1e. Following the general
procedure, 0.0.76 g of 1e was obtained as a yellow oil in 83% isolated
yield: 1H NMR (CDCl3, 500 MHz) δ 9.66 (s, 1H), 7.67 (d, J = 5.0 Hz,
1H), 7.58 (s, 1H), 7.46 (t, J = 5.0 Hz, 1H), 7.31 (d, J = 5.0 Hz, 1H),
7.15−7.13 (m, 1H), 6.86−6.85 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 177.4, 169.4, 158.2, 152.1, 151.2, 130.1, 129.9, 122.9, 122.7,
120.3, 117.0, 108.4, 65.9, 21.1; HRMS (EI) for [C13H10O4] calcd
230.0579, found 230.0578; GC−MS (EI, 70 eV) m/z (%) 230 (26)
[M+], 188 (100), 160 (15), 131 (30), 102 (11), 77 (18).
1
in 92% isolated yield: mp 84−85 °C; H NMR (CDCl3, 500 MHz) δ
9.69 (s, 1H), 7.77 (d, J = 4.0 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.32
(d, J = 3.5 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H),
1.41 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.2, 161.7,
153.4, 152.1, 137.3, 134.9, 133.9, 126.0, 109.3, 61.6, 14.3
Ethyl 5-(5-Formylfuran-2-yl)furan-2-carboxylate 2d. Following
the general procedure, 0.78 g of 2d was obtained as a yellow solid in
1
83% isolated yield: mp 81−82 °C; H NMR (CDCl3, 500 MHz) δ
9.66 (s, 1H), 7.32 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H), 6.96
(d, J = 3.5 Hz, 1H), 6.94 (d, J = 3.5 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H),
1.38 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.3, 158.3,
152.3, 149.7, 147.6, 145.3, 122.9, 119.4, 110.5, 109.9, 61.3, 14.3;
HRMS (EI) for [C12H10O5] calcd 234.0528, found 234.0532.
5-(Thiazol-2-yl)furan-2-carbaldehyde 2e. Following the general
procedure, 0.31g of 2e was obtained as a pale yellow solid in 43%
isolated yield: mp 70−71 °C; 1H NMR (CDCl3, 500 MHz) δ 9.74 (s,
1H), 7.94 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 3.5
Hz, 1H), 7.18 (d, J = 3.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
177.6, 156.4, 153.2, 152.2, 144.5, 128.5, 122.4, 120.7, 110.5; HRMS
(EI) for [C8H5NO2S] calcd 179.0041, found 179.0047.
5-(3-Chloro-4-fluorophenyl)furan-2-carbaldehyde 1f. Following
5-(Pyrimidin-5-yl)furan-2-carbaldehyde 2f. Following the general
procedure, 0.23 g of 2f was obtained as an off-white solid in 33%
the general procedure, 0.81g of 1f was obtained as a beige solid in 90%
isolated yield: mp 106−107 °C; H NMR (CDCl3, 300 MHz) δ 9.66
(s, 1H), 7.88 (d, J = 3.0 Hz, 1H), 7.86 (d, J = 3.0 Hz, 1H), 7.71−7.66
(m, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 6.81 (d, J =
6.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 177.4, 160.6, 157.2, 152.5,
127.8, 126.5, 125.4, 123.5, 122.4, 117.6, 108.3; HRMS (EI) for
[C11H6O2ClF] calcd 224.0040, found 224.0042.
1
1
isolated yield: mp 164−165 °C; H NMR (CDCl3, 500 MHz) δ 9.77
(s, 1H), 9.25 (s, 1H), 9.18 (s, 2H), 7.39 (d, J = 3.5 Hz, 1H), 7.05 (d, J
= 3.5 Hz, 1H) ; 13C NMR (CDCl3, 125 MHz) δ 177.5, 158.7, 153.2,
153.1, 153.0, 123.7, 110.0; HRMS (EI) for [C9H6N2O2] calcd
174.0429, found 174.0434.
1989
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Table 6. Cu-Catalyzed Coupling Reaction
a
Isolated yield (based on electrophile).
5-(Quinolin-3-yl)furan-2-carbaldehyde 2g. Following the general
procedure, 0.37 g of 2g was obtained as a beige solid in 41% isolated
yield: mp 150 °C; H NMR (CDCl3, 500 MHz) δ 9.74 (s, 1H), 9.30
110.7; HRMS (EI) for [C10H7NO2] calcd 173.0477, found 173.0477;
GC−MS (EI, 70 eV) m/z (%) 173 (100) [M+], 144 (25), 116 (36), 89
(32), 63 (20).
1
(s, 1H), 8.64 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz,
1H), 7.78 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 3.5
Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
177.3, 156.7, 152.6, 148.1, 147.1, 131.9, 130.6, 129.5, 128.4, 127.7,
127.5, 123.6, 122.3, 108.9, 103.8.
5-(3-Methylpyridin-2-yl)furan-2-carbaldehyde 3b. Following the
general procedure, 0.85 g of 3b was obtained as a creamy solid in 56%
isolated yield: mp 113−114 °C; H NMR (CDCl3, 500 MHz) δ 9.74
(s, 1H), 8.53 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.38−7.37 (m, 1H),
7.2−7.20 (m, 2H), 2.67 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
177.8, 159.5, 152.6, 147.3, 146.4, 139.8, 131.7, 123.6, 121.9, 112.9,
20.5.
1
5-(Pyridin-2-yl)furan-2-carbaldehyde 3a. Into a 50 mL round-
bottomed flask equipped with a stirring bar, a thermometer, and a
septum were added Pd(PPh3)4 (0.10 g, 1 mol %) and 5-bromo-2-
furaldehyde (1.40g, 8.0 mmol) under an argon atmosphere. Next, 20
mL of 2-pyridylzinc bromide (0.5 M in THF, 10.0 mmol) was added
via a syringe. The resulting mixture was stirred at room temperature
for 1.0 h, quenched with saturated NH4Cl solution, and then extracted
with ethyl acetate (10 mL × 3), which was washed with saturated
Na2S2O3 solution and brine and then dried over anhydrous MgSO4.
Purification by column chromatography on silica gel (20% ethyl
acetate/80% heptane) afforded 5-(2-pyridyl)-2-furaldehyde (3a, 1.28
5-(5-Methylpyridin-2-yl)furan-2-carbaldehyde 3c. Following the
general procedure, 0.60 g of 3c was obtained as a beige solid in 80%
1
isolated yield: mp 100 °C; H NMR (CDCl3, 500 MHz) δ 9.67 (s,
1H), 8.45 (s, 1H), 7.58−7.56 (m, 1H), 7.33 (d, J = 3.5 Hz, 1H), 7.17
(d, J = 3.5 Hz, 1H), 2.54 (s, 3H) ; 13C NMR (CDCl3, 125 MHz) δ
177.6, 158.7, 152.3, 150.5, 145.3, 137.3, 133.9, 123.3, 119.8, 110.0,
18.5; GC−MS (EI, 70 eV) m/z (%) 187 (100) [M+], 158 (34), 130
(42), 103 (12), 77 (24).
1
5-(6-Methoxypyridin-2-yl)furan-2-carbaldehyde 3d. Following
the general procedure, 0.41 g of 3d was obtained as a pale brown
g) as a white solid in 92% isolated yield: mp 87−88 °C; H NMR
(CDCl3, 500 MHz) δ 9.70 (s, 1 H), 8.63 (d, J = 5.0 Hz, 1 H), 7.90 (d,
J = 5.0 Hz, 1 H), 7.77, (dt, J = 5.0 Hz, 1 H), 7.34 (d, J = 5.0 Hz, 1 H),
7.28 (m, 1 H), 7.26 (d, J = 5.0 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 177.7, 158.3, 152.6, 150.0, 147.8, 137.0, 136.9, 124.0, 120.1,
1
solid in 50% isolated yield: mp 93−94 °C; H NMR (CDCl3, 500
MHz) δ 9.70 (s, 1H), 7.69−7.65 (m, 1H), 7.55−7.53 (m, 1H), 7.35
(d, J = 3.5 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H), 6.77 (d, J = 1.0 Hz, H),
1990
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4.00 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.6, 163.9, 158.6,
152.4, 145.1, 139.2, 123.2, 113.0, 111.8, 110.6, 53.4.
eV) m/z (%) 234 (767) [M+], 205 (23), 189 (25), 175 (68), 162
(100), 133 (31), 105 (22).
2-(5-(3,4,5-Trimethoxyphenyl)furan-2-yl)-1,3-dioxolane 4c. Fol-
5-(5-Fluoropyridin-2-yl)furan-2-carbaldehyde 3e. Following the
general procedure, 0.46 g of 3e was obtained as an off-white solid in
lowing the general procedure, 0.67 g of 4c was obtained as a yellow
1
1
solid in 73% isolated yield: mp 104−105 °C; H NMR (CDCl3, 300
60% isolated yield: mp 107−108 °C; H NMR (CDCl3, 500 MHz) δ
MHz) δ 6.89 (s, 2H), 6.53 (q, J = 3.0 Hz, 2H), 6.00 (s, 1H), 4.15 (m,
2H), 4.05 (m, 2H), 3.91 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
154.6, 153.7, 150.7, 138.2, 126.4, 110.7, 105.3, 101.7, 98.1, 65.3, 61.1,
56.4; HRMS (EI) for [C16H18O6] calcd 306.1103, found 306.1108.
2-(5-(2,3,5,6-Tetramethylphenyl)furan-2-yl)-1,3-dioxolane 4d.
Following the general procedure, 0.52 g of 4d was obtained as a
white solid in 64% isolated yield: mp 117−118 °C; 1H NMR (CDCl3,
300 MHz) δ 7.01 (s, 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.19 (d, J = 3.0 Hz,
1H), 5.96 (s, 1H), 4.16−4.12 (m, 2H), 4.02−3.98 (m, 2H), 2.23 (s,
6H), 2.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 154.2, 150.4, 134.9,
133.8, 132.4, 131.2, 109.8, 109.5, 98.2, 65.3, 20.2, 17.1; HRMS (EI) for
[C17H20O3] calcd 272.1412, found 272.1410.
2-(5-(4-tert-Butylphenyl)furan-2-yl)-1,3-dioxolane 4e. Following
the general procedure, 0.67 g of 4e was obtained as a light orange oil in
82% isolated yield: 1H NMR (CDCl3, 500 MHz) δ 7.60 (d, J = 10 Hz,
2H), 7.39 (d, J = 10 Hz, 2H), 6.55 (d, J = 5.0 Hz, 1H), 6.50 (d, J = 5.0
Hz, 1H), 5.99 (s, 1H), 4.17−4.13 (m, 2H), 4.0−4.01 (m, 2H), 1.34 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 154.9, 150.9, 150.5, 128.0,
125.7, 124.0, 110.6, 105.0, 98.1, 65.3, 34.8, 31.4; GC−MS (EI, 70 eV)
m/z (%) 272 (100) [M+], 257 (100), 227 (16), 213 (55), 185 (63),
157 (16), 115 (17), 73 (22).
9.72 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 7.97−7.95 (m, 1H), 7.5−7.51
(m, 1H), 7.36 (d, J = 3.5 Hz, 1H), 7.20 (d, J = 3.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 177.6, 160.3, 158.2, 157.5, 152.5, 144.2, 138.5,
123.6, 123.3, 121.3, 110.5; HRMS (EI) for [C10H6NO2F] calcd
191.0383, found 191.0389.
5-(Pyridin-3-yl)furan-2-carbaldehyde 3f. Following the general
procedure, 1.18 g of 3f was obtained as an off-white solid in 85%
1
isolated yield: mp 100−101 °C; H NMR (CDCl3, 500 MHz) δ 9.72
(s, 1H), 9.06 (s, 1H), 8.64−8.63 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H),
7.42−7.40 (m, 1H), 7.36 (d, J = 3.5 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 177.4, 156.3, 152.6, 150.3, 146.7,
132.2, 125.2, 123.8, 123.1, 108.8; GC−MS (EI, 70 eV) m/z (%) 173
(100) [M+], 145 (7), 116 (51), 89 (26), 63 (32).
5-(6-Chloropyridin-3-yl)furan-2-carbaldehyde 3g. Following the
general procedure, 0.79 g of 3g was obtained as a beige solid in 95%
1
isolated yield: mp 169−170 °C; H NMR (CDCl3, 500 MHz) δ 9.72
(s, 1H), 8.84 (s, 1H), 8.10 (dd, J = 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz,
1H), 7.36 (d, J = 3.5 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H) ; 13C NMR
(CDCl3, 125 MHz) δ 177.4, 155.1, 152.8, 152.1, 146.4, 134.9, 124.7,
124.3, 123.0, 109.2; GC−MS (EI, 70 eV) m/z (%) 207 (100) [M+],
179 (9), 150 (47), 115 (15), 63 (18).
2-(5-(1,2-Dihydroacenaphthylen-6-yl)furan-2-yl)-1,3-dioxolane
5-(2-Chloropyridin-3-yl)furan-2-carbaldehyde 3h. Following the
general procedure, 0.61 g of 3h was obtained as a white solid in 72%
4f. Following the general procedure, 0.82 g of 4f was obtained as a
1
light brown oil in 93% isolated yield: H NMR (CDCl3, 500 MHz) δ
1
isolated yield: mp 103−104 °C; H NMR (CDCl3, 500 MHz) δ 9.74
8.11 (d, J = 10 Hz, 1H), 7.75 (d, J = 10 Hz, 1H), 7.50−7.47 (m, 1H),
7.30−7.27 (m, 2H), 6.68 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 5.0 Hz, 1H),
6.05 (s, 1H), 4.20−4.15 (m, 2H), 4.05−4.00 (m, 2H), 3.39−3.35 (m,
4H); 13C NMR (CDCl3, 125 MHz) δ 154.6, 150.6, 146.9, 146.5,
139.8, 128.8, 128.4, 127.3, 123.8, 121.0, 119.8, 119.2, 110.5, 108.3,
98.2, 65.4, 30.6, 30.3; GC−MS (EI, 70 eV) m/z (%) 292 (100) [M+],
248 (15), 233 (70), 220 (45), 189 (25), 152 (16).
3-(5-(1,3-Dioxolan-2-yl)furan-2-yl)-N,N-dimethylbenzenamine
4g. Following the general procedure, 0.71 g of 4g was obtained as a
yellow oil in 92% isolated yield: 1H NMR (CDCl3, 500 MHz) δ 7.24−
7.06(m, 3H), 6.69(br s, 1H), 6.59(d, J = 5.0 Hz, 1H), 6.50 (d, J = 5.0
Hz, 1H),6.01 (s, 1H), 4.18−4.14 (m, 2H), 4.06−4.03 (m, 2H), 3.02
(s,6H); GC−MS (EI, 70 eV) m/z (%) 259 (100) [M+], 228 (5), 214
(19), 200 (54), 187 (30).
(s, 1H), 8.45−8.43 (m, 1H), 8.39 (dd, J = 2.0 Hz, 1H), 7.47 (d, J = 4.0
Hz, 1H), 7.43−7.41 (m, 1H), 7.40 (d, J = 4.0 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 177.5, 153.1, 152.3, 149.3, 147.7, 137.3, 124.9,
122.8, 114.2.
5-(2-Chloropyridin-4-yl)furan-2-carbaldehyde 3i. Following the
general procedure, 0.55 g of 3i was obtained as an off-white solid in
1
66% isolated yield: mp 115−116 °C; H NMR (CDCl3, 500 MHz) δ
9.77 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J = 5.5
Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H), 7.10 (d, J = 3.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 177.7, 154.5, 153.1, 152.7, 150.5, 138.6, 122.2,
119.4, 117.6, 111.5; GC−MS (EI, 70 eV) m/z (%) 207 (100) [M+],
179 (5), 150 (31), 115 (10), 89 (17), 63 (19).
Preparation of 5-(1,3-Dioxolan-2-yl)-2-furanylzinc Bromide. In an
oven-dried 50 mL round-bottomed flask equipped with a stir bar was
added 0.93 g of active zinc (Zn*, 14.25 mmol). 2-(5-Bromofuran-2-
yl)-1,3-dioxolane (2.08 g, 9.5 mmol) was then cannulated neat into the
flask at room temperature. The resulting mixture was stirred at room
temperature for 3 h. The whole mixture was allowed to settle, and then
the supernatant was used for the subsequent coupling reactions.
Ethyl 5-(5-(1,3-Dioxolan-2-yl)furan-2-yl)furan-2-carboxylate 4b.
In a 25 mL round-bottomed flask was added Pd[P(Ph3)]4 (0.06 g, 1
mol %) under an argon atmosphere, and then 10 mL of 5-(1,3-
dioxolan-2-yl)-2-furanylzinc bromide (0.5 M in THF, 5.0 mmol) was
added via a syringe. Next, ethyl 5-bromofuran-2-carboxylate (0.88 g,
4.0 mmol) was added into the flask. The resulting mixture was stirred
at room temperature overnight, quenched with saturated NH4Cl
solution, and then extracted with ethyl ether (10 mL × 3). Washed
with saturated Na2S2O3 solution and brine, then dried over anhydrous
MgSO4. Purification by column chromatography on silica gel (10%
ethyl acetate/90% heptane) afforded ethyl 5-(5-(1,3-dioxolan-2-
yl)furan-2-yl)furan-2-carboxylate (4b, 0.70 g) in 63% isolated yield
as a light yellow viscous oil; 1H NMR (CDCl3, 500 MHz) δ 7.21 (d, J
= 5.0 Hz, 1 H), 6.77 (d, J = 5.0 Hz, 1 H), 6.67 (d, J = 5.0 Hz, 1 H),
6.53 (d, J = 5.0 Hz, 1 H), 5.97 (s, 1 H), 4.37 (q, J = 5.0 Hz, 2 H), 4.13
(m, 2 H), 4.04 (m, 2 H), 1.38 (t, J = 5.0 Hz, 3 H); 13C NMR (CDCl3,
125 MHz) δ 158.8, 152.0, 149.4, 145.9, 143.9, 119.7, 110.7, 108.6,
107.4, 97.7, 65.4, 61.1, 14.5; GC−MS (EI, 70 eV) m/z (%) 259 (100)
[M+], 214 (20), 200 (53), 187 (30).
4-(5-(1,3-Dioxolan-2-yl)furan-2-yl)phenol 5a. In a 25 mL round-
bottomed flask, Pd(OAc)2 (0.02 g, 2.0 mol %), SPhos (0.08 g, 4.0 mol
%) and THF (5 mL) were placed. Next, 5-(1,3-dioxolan-2-yl)-2-
furanylzinc bromide (0.5 M in THF, 10 mL) was added slowly. After
being stirred for 1 h at room temperature, quenched with saturated
NH4Cl solution, then extracted with ethyl acetate (10 mL × 3), which
was washed with saturated Na2S2O3 solution and brine and then dried
over anhydrous MgSO4. Purification by column chromatography on
silica gel (20% ethyl acetate/80% heptane) afforded 4-(5-(1,3-
Dioxolan-2-yl)furan-2-yl)phenol (5a, 0.85 g) as a beige solid in 92%
1
isolated yield; mp 150−152 °C; H NMR (CDCl3, 500 MHz) δ 7.54
(d, J = 10.0 Hz, 2 H), 6.83 (d, J = 10.0 Hz, 2 H), 6.50 (d, J = 5.0 Hz, 1
H), 6.45 (d, J = 5.0 Hz, 1 H), 5.99 (s, 1 H), 5.20 (br s, 1 H), 4.18 (t, J
= 5.0 Hz, 2 H), 4.05 (t, J = 5.0 Hz, 2 H); 13C NMR (CDCl3, 125
MHz) δ 155.5, 154.9, 149.9, 125.9, 115.77, 110.9, 104.0, 98.1, 65.6;
GC−MS (EI, 70 eV) m/z (%) 232 (100) [M+], 187 (22), 173 (100),
160 (58), 131 (42), 73 (41).
3-(5-(1,3-Dioxolan-2-yl)furan-2-yl)phenol 5b. Following the gen-
eral procedure; the formation of the desired product was confirmed by
GC−MS (EI, 70 eV) m/z (%) 232 (100) [M+], 187 (43), 173 (99),
160 (86), 131 (57), 73 (80).
2-(5-(1,3-Dioxolan-2-yl)furan-2-yl)phenol 5c. The conversion to
the corresponding product was confirmed by GC.
4-(5-(1,3-Dioxolan-2-yl)furan-2-yl)benzenamine 5d. The forma-
tion of the desired product was confirmed by GC−MS (EI, 70 eV) m/
z (%) 231 (100) [M+], 200 (6), 187 (14), 172 (95), 159 (34), 130
(33).
5-(5-(1,3-Dioxolan-2-yl)furan-2-yl)furan-2-carbaldehyde 4a. The
formation of the desired product was confirmed by GC−MS (EI, 70
1991
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3-(5-(1,3-Dioxolan-2-yl)furan-2-yl)benzenamine 5e. Following
the general procedure, 0.74 g of 5e was obtained as light brown oil
in 80% isolated yield: H NMR (CDCl3, 500 MHz) δ 7.15 (t, J = 5.0
Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 7.01 (br s, 1H), 6.60−6.58 (m, 1H),
6.55 (d, J = 5.0 Hz, 1H), 6.49 (d, J = 5.0 Hz, 1H), 6.00 (s, 1H), 4.19−
4.16 (m, 2H), 4.06−4.04 (m, 2H), 3.48 (br s, 2H); 13C NMR (CDCl3,
125 MHz) δ 154.9, 150.6, 146.8, 131.6, 129.7, 114.8, 114.7, 110.7,
105.6, 98.1, 65.4; GC−MS (EI, 70 eV) m/z (%) 231 (100) [M+], 186
(29), 172 (79), 159 (93), 130 (40).
124.6, 121.2, 111.0, 97.4, 65.6; HRMS (EI) for [C13H10ClNO4] calcd
279.0298, found 279.0299.
1-(5-(1,3-Dioxolan-2-yl)furan-2-yl)-2,2,2-trifluoroethanone 6g.
1
Following the general procedure, 0.77 g of 6g was obtained as a
1
pale yellow oil in 65% isolated yield: H NMR (CDCl3, 500 MHz) δ
7.47 (d, J = 5.0 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 6.02 (s, 1H), 4.10−
4.12 (m, 2H), 4.08−3.74 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
168.6(q), 160.1, 146.8, 124.7, 116.1 (q), 111.2, 97.1, 65.7; GC−MS
(EI, 70 eV) m/z (%) 235 (15) [M-1], 191 (33), 177 (17), 139 (100),
123 (16), 95 (44), 79 (54).
5-(1,3-Dioxolan-2-yl)furan-2-yl-(phenyl)methanone 6a. Follow-
ing the general procedure, 0.91 g of 6a was obtained as a colorless oil
2-(5-Allylfuran-2-yl)-1,3-dioxolane 6h. Following the general
1
procedure, 0.63 g of 6h was obtained as a pale yellow oil in 70%
in 93% isolated yield: H NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H),
1
isolated yield: H NMR (CDCl3, 500 MHz) δ 6.35 (d, J = 5.0 Hz,
7.95 (d, J = 5.0 Hz, 1H), 7.58 (t, J = 10 Hz, 1H), 7.49 (t, J = 10 Hz,
2H), 7.19(d, J = 5.0 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 6.04 (s, 1H),
4.16−4.13 (m, 2H), 4.09−4.04 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 182.6, 156.4, 152.4, 137.3, 132.8, 129.5, 128.6, 120.9, 110.4,
97.6, 65.5.
1H), 5.98 (d, J = 5.0 Hz, 1H), 5.95−5.88 (m, 1H), 5.86 (s, 1H), 5.16−
5.10 (m, 2H), 4.13−4.09 (m, 2H), 4.02−3.95 (m, 2H), 3.39 (d, J = 5.0
Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 155.1, 149.6, 133.6, 117.3,
109.9, 106.3, 98.0, 65.2, 32.8; GC−MS (EI, 70 eV) m/z (%) 180 (34)
[M+], 139 (100), 121 (46), 95 (24), 79 (73).
5-(1,3-Dioxolan-2-yl)furan-2-yl-(3-bromophenyl)methanone 6b.
Following the general procedure, 1.07 g of 6b was obtained as a
viscous yellow oil in 83% isolated yield: 1H NMR (CDCl3, 500 MHz)
δ 8.12 (s, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.38
(t, J = 5.0 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.63 (d, J = 5.0 Hz, 1H),
6.03 (s, 1H), 4.19−4.13 (m, 2H), 4.10−3.74 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 180.8, 156.9, 152.0, 138.9, 135.7, 132.5, 130.2,
128.1, 122.8, 121.3, 110.1, 97.5, 65.6; GC−MS (EI, 70 eV) m/z (%)
323 (12) [M+], 279 (10), 183 (15), 155 (12), 139 (100), 95 (24).
5-(1,3-Dioxolan-2-yl)furan-2-yl-(cyclohexyl)methanone 6c. In a
25 mL round-bottomed flask, CuI (0.10 g, 10 mol %) and LiCl (0.04
g, 20 mol %) and HF (5 mL) were placed and then the flask was
cooled down to 0 °C using an ice-bath. 5-(1,3-Dioxolan-2-yl)-2-
furanylzinc bromide (0.5 M in THF, 10 mL) was added. Cyclo-
hexanecarbonyl chloride (0.59 g, 4.0 mmol) was slowly added while
being stirred at 0 °C. After being stirred for 1 h, quenched with
saturated NH4Cl solution, then extracted with ethyl acetate (10 mL ×
3). Washed with saturated Na2S2O3 solution and brine, then dried over
anhydrous MgSO4. Purification by column chromatography on silica
gel (20% ethyl acetate/80% heptane) afforded 5-(1,3-dioxolan-2-
yl)furan-2-yl-(cyclohexyl)methanone (6c, 0.90 g) as a white solid in
2-(5-(4-Bromophenyl)furan-2-yl)-1,3-dioxolane a. Following the
general procedure, 1.08 g of a was obtained as a yellow oil in 92%
1
isolated yield: H NMR (CDCl3, 500 MHz) δ 7.49 (dd, J = 10.0 Hz,
4H), 6.59 (d, J = 5.0 Hz, 1 Hz, 6.50 (d, J = 5.0 Hz, 1H), 5.96 (s, 1H),
4.15−4.13 (m, 2H), 4.03−4.00 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 153.6, 151.2, 131.9, 129.5, 125.6, 121.6, 110.8, 106.1, 97.9,
65.3.
5-(4-Bromophenyl)furan-2-carbaldehyde b. Following the general
procedure, 0.89 g of b was obtained as a pale yellow solid in 89%
1
isolated yield: mp 151−152 °C; H NMR (CDCl3, 500 MHz) δ 9.65
(s, 1H), 7.68 (d, J = 10.0 Hz, 2H), 7.57 (d, J = 10.0 Hz, 2H), 7.31 (d, J
= 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ 177.4, 158.4, 152.3, 132.4, 128.1, 126.9, 124.1, 108.3; HRMS (EI) for
[C11H7O2Br] calcd 251.9609, found 251.9608.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR and 13C NMR. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
90% isolated yield: mp 73−74 °C; H NMR (CDCl3, 500 MHz) δ
AUTHOR INFORMATION
Corresponding Author
*E-mail: sales@riekemetals.com.
■
7.13 (d, J = 5.0 Hz, 1H), 6.54 (d, J = 5.0 Hz, 1H), 5.99 (s, 1H), 4.15−
4.12 (m, 2H), 4.08−4.03 (m, 2H), 3.07−3.04 (m, 1H), 1.83 (t, J = 15
Hz, 4H), 1.72 (d, J = 15 Hz, 1H), 1.51 (q, J = 15 Hz, 2H), 1.34 (q, J =
15 Hz, 2H), 1.27 (t, J = 15 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
193.2, 155.4, 152.5, 117.4, 110.4, 97.6, 65.5, 46.5, 29.1, 26.0, 25.9;
HRMS (EI) for [C14H18O4] calcd 250.1205, found 250.1208.
Notes
The authors declare no competing financial interest.
1-(5-(1,3-Dioxolan-2-yl)furan-2-yl)-2,2-dimethylpropan-1-one
REFERENCES
6d. Following the general procedure, 0.80 g of 6d was obtained as a
■
1
pale yellow oil in 89% isolated yield: H NMR (CDCl3, 500 MHz) δ
(1) (a) Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic
Chemistry II; Bird, C. W., Ed.; Elsevier: New York, 1996; Vol. 2,
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7.14 (d, J = 5 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 5.98 (s, 1H), 4.13 (q,
J = 5.0 Hz, 2H0, 4.05 (q, J = 5.0 Hz, 2H), 1.35 (s, 9H); 13C NMR
(CDCl3, 125 MHz) δ 195.0, 154.3, 152.6, 118.4, 109.9, 97.5, 65.5,
43.2, 26.9; GC−MS (EI, 70 eV) m/z (%) 224 (25) [M+], 209 (4), 167
(100), 139 (86), 95 (87), 73 (53), 57 (100).
5-(1,3-Dioxolan-2-yl)furan-2-yl-(thiophen-3-yl)methanone 6e.
Following the general procedure, 0.75 g of 6e was obtained as a
1
pale yellow oil in 75% isolated yield: H NMR (CDCl3, 500 MHz) δ
8.41 (s, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.36 (d, J = 5.0 Hz, 1H), 7.30
(d, J = 5.0 Hz, 1H), 6.62 (d, J = 5.0 Hz, 1H), 6.04 (s, 1H), 4.16−4.12
(m, 2H), 4.10−4.05 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 175.4,
155.6, 153.2, 140.1, 133.9, 128.5, 126.0, 119.4, 110.6, 97.6, 65.5; GC−
MS (EI, 70 eV) m/z (%) 250 (22) [M+], 205 (17), 191 (13), 139
(100), 111 (60), 95 (26).
5-(1,3-Dioxolan-2-yl)furan-2-yl-(6-chloropyridin-3-yl)methanone
6f. Following the general procedure, 0.92 g of 6f was obtained as an
off-white solid in 83% isolated yield: mp 78−79 °C; 1H NMR (CDCl3,
500 MHz) δ 9.06 (d, J = 5.0 Hz, 1H), 8.27 (d, J = 5.0 Hz, 1H), 7.49
(dd, J = 5.0 Hz, 1H), 7.32 (d, J = 5.0 Hz, 1H), 6.67 (d, J = 5.0 Hz,
1H), 6.02 (s, 1H), 4.16−4.12 (m, 2), 4.10−4.05 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 179.1, 157.0, 155.3, 152.1, 150.9, 139.7, 131.5,
(2) (a) Dunlop, A. P.; Peters, F. N. The Furans; Reinhold Publishing
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The Journal of Organic Chemistry
Article
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(b) McClure, M. S.; Roschanger, F.; Hodson, S. J.; Millar, A.;
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(12) An attempt for the preparation of 3,4,5-trimethoxyphenylzinc
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corresponding organic halide was unsuccessful. Instead, an unidenti-
fied mixture was obtained (unpublished result from our lab).
1993
dx.doi.org/10.1021/jo301836x | J. Org. Chem. 2013, 78, 1984−1993