5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide; Direct preparation, and its application for the synthesis of 5-substituted furan derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.01.006

5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide was easily prepared by the direct insertion of active zinc to 2-bromo-5-(1,3-dioxolane)furan under mild conditions. Of interest, the resulting organozinc was successfully coupled with aryl halides and acid chlorides affording the corresponding coupling products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.01.006

Tetrahedron Letters 52 (2011) 1128–1131
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide; direct preparation, and its
application for the synthesis of 5-substituted furan derivatives
Reuben D. Rieke a, Seung-Hoi Kim b,
⇑
a Rieke Metals, Inc., 1001 Kingbird Rd. Lincoln, NE 68521, USA
b Department of Chemistry, Dankook University, 29 Anseo Cheonan 330-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide was easily prepared by the direct insertion of active zinc to
2-bromo-5-(1,3-dioxolane)furan under mild conditions. Of interest, the resulting organozinc was suc-
cessfully coupled with aryl halides and acid chlorides affording the corresponding coupling products in
good to excellent yields.
Received 15 November 2010
Revised 20 December 2010
Accepted 5 January 2011
Available online 12 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organozincs
Coupling reaction
1,3-Dioxolan-2-yl-furan
Due to the particular interest in the furan moiety in natural
products,1 numerous studies have focused on the development of
a versatile synthetic methodology for the preparation of furan
derivatives, especially for the 2,5-disubstituted furan compounds.
Among the well-known procedures, palladium-catalyzed cross-
coupling reactions of metalated furans are one of the predominant
approaches.2 O’Doherty described the preparation of 5-aryl-2-fur-
aldehydes using palladium-catalyzed cross-coupling reaction of
protected furylstannes and/or furylzincs.3 A similar approach using
a cross-coupling reaction of triorganozincates was also reported by
Gauthier.4 The organometallic reagents used in these studies were
prepared by the lithiation of the protected furans followed by
transmetallation with zinc halide. Generally, cryogenic conditions
are required for the lithiation of organic compounds. McClure also
reported the regioselective palladium-catalyzed direct arylation of
2-furaldehyde.5 More recently, a convenient synthetic route for 5-
arylsubstituted 2-furaldehydes utilizing the coupling reaction of
various organozinc reagents with 5-bromo-2-furaldehyde was re-
ported.6 Even though this route could provide a variety of 5-substi-
tuted furaldehydes, a drawback to this procedure is that some of
organozinc reagents are not readily available. Therefore, in spite
of the present methodologies, there is still a need to explore a ver-
satile synthetic methodology for the preparation of 5-substituted
furan derivatives.
that this methodology provides a unique way of preparing highly
functionalized 2-furaldehydes.
As shown in Scheme 1 and 5-(1,3-dioxolan-2-yl)-2-furanylzinc
bromide 1 was easily prepared by the direct insertion of active zinc
to 2-(5-bromofuran-2-yl)-1,3-dioxolane under mild conditions.7
To confirm the formation of the corresponding organozinc reagent,
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 in-
ferred that the corresponding organozinc reagent (1) was success-
fully obtained. To find out the usefullness of the resulting
organozinc reagent, subsequent coupling reactions have been per-
formed with a variety of different types of electrophiles such as
aromatic halides, haloamines, halophenols, 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 de-
scribed in Scheme 2, two derivatives were achieved depending
upon the work-up procedure.
The coupling reaction was completed in 1 h at room tempera-
ture in THF in the presence of 1 mol % Pd(PPh3)4. As is typical, an
acidic work-up procedure gave rise to the 5-(4-bromophenyl)-
2-furaldehyde B in 89% isolated yield. Meanwhile, a protected
furaldehyde A was obtained from the work-up procedure using
ammonium chloride in excellent yield.
We herein would like to report a convenient synthetic route for
the preparation of 5-substituted furan derivatives. It is of interest
As described in aforementioned report,6 these types of mole-
cules are easily accessible via the cross-coupling reaction of 2-bro-
mo-5-furaldehyde with the corresponding organozinc regents.
Therefore, we have tried somewhat different types of coupling
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.006

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 1128–1131
1129
1.5 eq Zn*
THF/rt/3h
I2
O
O
O
I
Br
ZnBr
O
O
O
O
O
O
1
> 98 % by GC
Scheme 1. Preparation of 5-(1,3-dioxolan-2-yl)-2-furanylzinc bromide.
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 prod-
uct failed due to the instability of the product in the atmosphere
(Table 1, entry 1). However, a similar compound 1b which has an
ester functionality was successfully obtained in 63% isolated yield
(Table 1, entry 2). The next attempt was to couple some aromatic
bromides that the corresponding organozinc reagents were not
readily available from the direct insertion method using active zinc
route. Use of Pd(OAc)2/SPhos catalytic system successfully afforded
the coupling product 1c in 73% isolated yield (Table 1, entry 3). It is
of importance that no extra ligand was necessary for the coupling
reaction in the presence of Pd(PPh3)2Cl2. It worked effectively in
the coupling reaction at room temperature with tetramethylphe-
nyl, tert-butylphenyl, and acenaphthyl bromides leading to the cor-
responding products, 1d, 1e, and 1f in excellent yields (Table 1,
entries 4–6), respectively. This condition was also very effective
with an electron-rich phenyl bromide (Table 1, entry 7).
O
O
A
92%
I
Br
O
NH4Cl
HCl
Br
Br
O
0.8 eq
ZnBr
O
1 % Pd(PPh3)4
THF/rt/1h
O
1.0 eq
H
O
O
B
89%
Scheme 2. Preparation of 5-aryl-substituted furans.
reactions to achieve complex molecules. Table 1 shows the results
observed from Pd-catalyzed cross-coupling reactions with a vari-
ety of aryl bromides.
In an effort to evaluate the overall feasibility of the organozinc
1, coupling reaction with 2-bromo-5-furaldehyde was carried first
under the conditions depicted in Table 1. The reaction proceeded
Table 1
Pd-catalyzed coupling reaction
conditions
product
O
+
ArBr
ZnBr
O
1.0 eq
THF
O
1a 1g
-
0.6 eq
Entry
1
Halide
Conditions
Product
Yielda (%)
98b
O
O
O
O
O
CHO
Br
CHO
1% Pd(PPh3)4 rt/30 min
1% Pd(PPh3)4 rt/24 h
1a
O
O
O
O
O
O
O
CO2Et
1b
CO2Et
Br
2
3
63
73
O
OCH3
OCH3
OCH3
OCH3
1c
1d
2% Pd(OAC)2 4% SPhos rt/overnight
Br
OCH3
OCH3
CH3
CH3
CH3
O
H3C
Br
CH3
O
4
5
5% Pd(PPh3)2Cl2 rt/24 h
5% Pd(PPh3)2Cl2 rt/2 h
64
82
O
CH3
H3C
CH3
O
O
1e
1f
O
O
Br
Br
O
6
7
5% Pd(PPh3)2Cl2 rt/2 h
5% Pd(PPh3)2Cl2 rt/5 h
93
92
O
O
O
N(CH3)2
1g
Br
N(CH3)2
O
a
Isolated yield (based on aryl halide) otherwise mentioned.
Conversion by GC, no isolated product.
b

1130
R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 1128–1131
Table 2
Coupling reaction with alcohols and amines
O
2 % Pd(OAc)2
O
O
Halo-Alcohol
or
ZnBr
OH(NH2)
+
O
O
4 % SPhos
THF
O
Halo-Amine
2a 2e
~
1.0 eq
Entry
1
Halide
Conditions
rt/30 min
Product
Yielda (%)
92
I
O
O
O
O
2a
2b
OH
OH
OH
OH
0.4 eq
I
O
O
2
3
rt/30 min
rt/30 min
72
0.4 eq
OH
OH
O
O
O
O
I
I
(>98%)b
2c
O
O
2d
2e
4
5
rt/30 min
rt/30 min
(>98%)b
NH2
NH2
NH2
NH2
0.8 eq
0.8 eq
I
O
O
O
80
a
Isolated (based on halide), otherwise mentioned.
Conversion by GC, no isolated product.
b
Table 3
Copper-catalyze coupling reaction
O
10 % CuI
O
ZnBr
Electrophile
+
E
O
O
20 % LiCl
THF
O
O
3a 3h
~
1.0 eq
0.8 eq
Entry
1
Electrophile
COCl
Conditions
Product
Yielda (%)
93
O
O
3a
0 °C to rt/1 h
O
O
Br
COCl
O
O
3b
2
0 °C to rt/1 h
83
Br
O
O
COCl
O
O
3c
3
4
0 °C to rt/1 h
0 °C/1 h
90
89
O
O
O
O
COCl
O
O
3d
COCl
S
O
O
3e
5
6
0 °C to rt/1 h
75
83
S
O
O
O
O
COCl
Cl
N
O
O
3f
rt/1 h
Cl
N

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 1128–1131
1131
Table 3 (continued)
Entry
Electrophile
Conditions
Product
Yielda (%)
(CF3CO)2O
O
O
O
O
CF3
3g
3h
7
0 °C/1 h
65
70
O
O
O
Br
8
rt/1 h
a
Isolated yield (based on electrophile).
We then attempted the coupling reaction with haloaromatic
compounds containing an alcohol or an amine functional group
which would be more challenging. Even though there are very lim-
ited examples of coupling reactions of organozinc compounds with
haloaromatic alcohols and amines,8 to our knowledge, no report
revealed the coupling reaction with furanylzinc bromide.
chlorides has been revealed. Of special note is the very mild reac-
tion conditions used in this study.9 Further applications of this
methodology are under investigation.
A. Supplementary data
en our study, the coupling reaction was easily accomplished
using 2 mol % Pd(OAc)2 and 4 mol % SPhos in THF at room temper-
ature. As described in Table 2, it was found that some of the
coupling products were not stable enough to be isolated as a
coupling product in the atmosphere. Interestingly, the stability of
the coupling product is depending upon the position of functional
group. For instance, 4-iodophenol and 3-iodophenol were coupled
well with 1 under mild conditions affording the corresponding
products, 2a and 2b, in 92% and 72% isolated yields, respectively
(Table 2, entries 1 and 2). However, no isolated product was ob-
tained from the reaction using 2-iodophenol even though the cou-
pling reaction proceeded smoothly under the same conditions
(Table 2, entry 3). In the case of employing aniline, a similar result
was also observed. Again, we were not able to isolate the coupling
product 2d using 4-iodoaniline (Table 2, entry 5). Meanwhile,
3-iodoaniline was coupled with 1 giving rise to the coupling
product 2e in 80% isolated yield (Table 2, entry 6). In our study,
no further investigations on the stability of the unstable com-
pounds were executed.
Subsequent investigation of this chemistry was focused on
introducing a carbonyl group on 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 acylation. The first attempt was carried
out with benzoyl chloride in a standard fashion (10 mol % CuI
and 20 mol % LiCl). The coupling product 3a was achieved in excel-
lent isolated yield (93%, Table 3, entry 1). Alkyl acid chlorides (Ta-
ble 3, entries 3 and 4) were also coupled with 1 to generate ketones
3c and 3d in good yields. Interestingly, heterocyclic acid chlorides
were also successfully employed in the coupling reaction with 1
providing unsymmetrical heterocyclic ketones 3e and 3f in moder-
ate to good yields (Table 3, entries 5 and 6), respectively. It was ob-
served that trifluoroacetic anhydride was also a good coupling
partner and the coupling reaction with 1 gave ketone 3g in moder-
ate yield (Table 3, entry 7). Finally, a SN20-type reaction was
performed with allyl bromide resulting in the formation of 2-(5-
allylfuran-2-yl)-1,3-dioxolane 3h in 70% yield (Table 3, entry 8).
In conclusion, an efficient synthetic procedure for the synthesis
of a wide range of 5-substituted furaldehydes via either Pd- or
copper-catalyzed cross-coupling reactions of 5-(1,3-dioxolan-2-
yl)-2-furanylzinc bromide with readily available halides and acid
Experimental procedures and copies of 1H, 13C NMR data.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.006.
References and notes
1. (a) Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry II; Bird, C.
W., Ed.; Elsevier: New York, 1996; Vol. 2, pp 395–436. Chapter 2.08; (b)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795; (c) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.;
Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955; For
review of furan, see: (d) Konig, B. In Science of Synthesis; Maas, G., Regitz, M.,
Eds.; Houben-Weyl Methods of Molecular Transformations, Catalory 2; Georg
Thiem Verlag: New York, 2001; Vol. 9, pp 183–286.
2. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry, 2nd ed. In A Guide for
the Synthetic Chemist; Elsevier, 2007.
3. (a) Balachari, D.; Quinn, L.; O’Doherty, G. A. Tetrahedron Lett. 1999, 40, 4769; (b)
Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863; (c) Balachari, D.; O’Doherty,
G. A. Org. Lett. 2000, 2, 4033.
4. Gauthier, D. R., Jr.; Szumigala, R. H., Jr.; Dormer, P. G.; Armstrong, J. D., III;
Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 375.
5. (a) McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.;
Roschangar, F. Org. Lett. 2001, 3, 1677; Other example of direct coupling: (b)
Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74,
1826.
6. Kim, S. H.; Rieke, R. D. Tetrahedron Lett. 2010, 51, 2657.
7. For recent examples of the direct preparation of organozinc reagents: (a) Kim, S.
H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 6985; (b) Kim, S. H.; Rieke, R. D.
Tetrahedron 2010, 66, 3135; For a general procedure for the preparation of
organozincs, see: (c) Rieke, R. D.; Hanson, M. V. Tetrahedron 1997, 53, 1925.
8. (a) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org.
Lett. 2008, 10, 2765; (b) Charifson, P. S.; Grillot, A.-L.; Grossman, T. H.; Parsons, J.
D.; Badia, M.; Bellon, S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.; LeTiran, A.;
Liao, Y.; Mani, N.; Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L.
L.; Tang, Q.; Tessier, P. R.; Tian, S.-K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.;
Stamos, D. J. Med. Chem. 2008, 51, 5243.
9. (a) Preparation of 5-(1,3-dioxolan-2-yl)-2-furanylzinc bromide (1); 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 neatly into the flask at room temperature. The
resulting mixture was stirred for 3 h. The whole mixture was settled down and
then the supernatant was used for the subsequent coupling reactions. (b)
Representative coupling reaction procedure; Into a 50 mL round-bottomed flask
were added Pd(PPh3)2Cl2 (0.17 g, 5 mol %) and 3-bromo-N,N-dimethylaniline
(0.60 g, 3 mmol) under an argon atmosphere. Next, 10 mL of 5-(1,3-dioxolan-2-
yl)-2-furanylzinc bromide (0.5 M in THF, 5 mmol) was added via a syringe. The
resulting mixture was stirred at rt for 3.0 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
3-(5-(1,3-dioxolan-2-yl)furan-2-yl)-N,N-dimethylaniline (1g, 0.71 g) in 92%
isolated yield.