Highly enantioselective synthesis of 2-furanyl-hydroxyacetates from furans via the Friedel-Crafts reaction

Article abstract of DOI:10.1021/ol800927w

(Chemical Equation Presented) The Friedel-Crafts reaction of alkyl glyoxylates with variously substituted furans was found to be efficiently catalyzed under simple, undemanding conditions by a 6,6′-dibromo-BINOL/ Ti(IV) complex with high enantioselectivity. The reaction afforded chiral substituted 2-furanyl-hydroxyacetic acid esters, compounds of high synthetic interest, in good yield and enantiomeric excess, in most examples in the range of 90-97%.

Full text of DOI:10.1021/ol800927w

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2955-2958
Highly Enantioselective Synthesis of
2-Furanyl-hydroxyacetates from Furans
via the Friedel-Crafts Reaction
Jakub Majer,† Piotr Kwiatkowski,† and Janusz Jurczak*,†,‡
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland,
and Department of Chemistry, UniVersity of Warsaw, 02-093 Warsaw, Poland
jurczak@icho.edu.pl
Received April 22, 2008
ABSTRACT
The Friedel-Crafts reaction of alkyl glyoxylates with variously substituted furans was found to be efficiently catalyzed under simple, undemanding
conditions by a 6,6′-dibromo-BINOL/Ti(IV) complex with high enantioselectivity. The reaction afforded chiral substituted 2-furanyl-hydroxyacetic
acid esters, compounds of high synthetic interest, in good yield and enantiomeric excess, in most examples in the range of 90-97%.
One of the most attractive approaches to the synthesis of
chiral aromatic or heteroaromatic compounds having a
stereogenic center in the benzylic position is the Friedel-Crafts
(F-C) reaction with carbonyl compounds, imines, or some
electron-deficient alkenes.1 Of particular interest are enan-
tioselective catalytic processes of this type leading to products
having high optical purity. This chemistry has been inten-
sively explored since about 2000, and interest in this field is
still increasing. Most of the described enantioselective
reactions concerning the F-C reactions utilize electron-rich
aromatic and heteroaromatic compounds, in most cases
aniline and indole derivatives,2 catalyzed by chiral Lewis
acids, usually with bisoxazoline or BINOL ligands, as well
as various organocatalysts, e.g., based on BINOL-derived
monophosphoric acids,3 Cinchona alkaloids,4 and MacMill-
an’s imidazolidinones.5
We focused our attention on the asymmetric F-C reactions
of furans with active aldehydes, namely, glyoxylates, includ-
ing diastereoselective6 and enantioselective approaches.7 The
products of this reaction, 2-furanyl-hydroxyacetic acid esters
(I) (Scheme 1), are very interesting building blocks for the
synthesis,8 and after reduction to diols II, these synthons
can be transformed under oxidizing conditions to linear (III)
as well as cyclic products, e.g., dihydropyranones (IV) or
dihydropyridones (V). Such an approach was utilized for the
(3) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004,
126, 11804. (b) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007,
129, 1484. (c) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129,
292.
(4) (a) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.;
Mhadgut, S. C.; Yan, P.; Prakesh, G. K. S. Angew. Chem., Int. Ed. 2005,
44, 3086. (b) Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063. (c)
Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006,
128, 8156.
† Polish Academy of Sciences.
(5) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370. (b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 7894.
‡ University of Warsaw.
(1) (a) Olah, G. A.; Krishnamurti, R.; Prakashi, G. K. S. In Compre-
hansiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 3, p 293. (b) Meima, G. R.; Lee, G. S.; Garces, J. M.
In Friedel-Crafts Alkylation; Sheldon, R. A., Bekkum, H., Eds.; Wiley-
VCH: New York, 2001; p 151.
(2) For reviews on enantioselective F-C reactions, see:(a) Poulsen, T. B.;
Jørgensen, K. A. Chem. ReV. 2008, ASAP. (b) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550. (c) Jørgensen,
K. A. Synthesis 2003, 1117.
(6) (a) Jurczak, J.; Belniak, S.; Kozluk, T. Bull. Pol. Acad. Sci. 1991,
39, 271. (b) Kwiatkowski, P.; Majer, J.; Chaładaj, W.; Jurczak, J. Org.
Lett. 2006, 8, 5045.
(7) (a) Kwiatkowski, P.; Wojaczyn˜ska, E.; Jurczak, J. Tetrahedron:
Asymmetry 2003, 14, 3643. (b) Kwiatkowski, P.; Wojaczyn˜ska, E.; Jurczak,
J. J. Mol. Catal. A: Chem. 2006, 257, 124.
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10.1021/ol800927w CCC: $40.75
Published on Web 06/24/2008
2008 American Chemical Society

ate enantioselectivity (up to 76% ee).7 The catalytic enan-
tioselective version of this reaction with bisoxazoline-copper
complexes was also investigated by Jørgensen and co-
workers,19 although, in the case of reaction of 2-methylfuran
(silvan) and ethyl glyoxylate, the enantioselectivity was low
(45% ee),20 in contrast to high ee values in the case of
anilines (usually >80% ee). However, in the case of the F-C
reactions of furans, other electrophiles, e.g., imines3a,21 and
R,ꢀ-unsaturated carbonyl compounds,22 gave better results.
It was of interest for us to find an efficient and readily
accessible catalytic system for the reaction of furans with
glyoxylates. Jørgensen’s19 and our7 studies in this field
showed that bisoxazoline and salen metal complexes were
not efficient enough in this case. We focused our attention
on chiral BINOL-type ligands23 and found that their com-
plexes with Ti(IV), generated from BINOL and Ti(OPri)4,
were efficient catalysts for this reaction. The BINOL/Ti(IV)
complexes were successfully introduced to asymmetric
synthesis by Mikami24 and Keck,25 e.g., to ene, hetero-
Diels-Alder, allylation,26 and Mukaiyama aldol reactions.
Mikami27 also reported the first enantioselective F-C
reactions of protected phenols with trifluoroacetaldehyde,
catalyzed by the BINOL/Ti(IV) complexes. These complexes
were also successfully applied in the reaction of glyoxylates
with anilines by Ding et al.28 and recently with indoles,29
whereas the BINOL/Zr(IV) complexes were used in the
reactions of R,ꢀ-unsaturated carbonyl compounds with
indoles.30
Scheme 1
.
Application of Furanyl R-Hydroxyacetates in the
Synthesis
synthesis of multifunctional chain compounds,9 higher-
carbon sugars,10 aza sugars,11 and, e.g., in the synthesis of
papulacandin D.12
The literature reports a few methods for the synthesis of
optically pure 2-furanyl-hydroxyacetates or their derivatives
by applying enzymatic resolution of racemic mixtures using
lipases,13 kinetic resolution using the Sharpless reagent,14
reduction of furanyl-substituted 1,2-dicarbonyl compounds,15
or addition of cyanides to furfurals.16 The appropriate 1,2-
diols of type II can be obtained via Sharpless asymmetric
dihydroxylation of 5-substituted vinylfurans12 or reduction
of corresponding furanyl hydroxymethyl ketones,17 and the
simplest one (R ) H) from the sugar derivatives (e.g.,
d-glucal).18
Compared to the above-mentioned methods, the synthesis
of optically pure furanyl derivatives of type I or II via the
F-C reaction directly from easily accessible furans and
glyoxylates seems to be a very attractive and competitive
approach. Until now, there is no effective, catalytic enanti-
oselective method for the synthesis of 2-furanyl-hydroxy-
acetates directly from furans. Recently, we published a highly
diastereoselective reaction of furans with chiral (1R,2S,5R)-
8-phenylmenthyl glyoxylate promoted by magnesium
bromide.6b Our previous attempts with chiral catalysts, e.g.,
salen-cobalt complexes, led to the F-C products of moder-
Now we describe the first highly enantioselective Friedel-
Crafts reaction of variously substituted furans 1a-m with
n-butyl glyoxylate (2). At the beginning, the reaction of 2
with 2-methylfuran (1a) was investigated (Scheme 2).
Catalysts were generated in situ from either (R)-BINOL (L1)
or (R)-6,6′-dibromo-BINOL (L2) and Ti(OPri)4 in toluene
at ambient temperature. In our study, the titanium complex
of 6,6′-dibromo-BINOL (2 mol %) gave higher enantiose-
(19) (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009.
(20) Higher enantioselectivity in the F-C reaction of furans was
observed for pyruvates instead of ethyl glyoxylate.
(21) Saaby, S.; Bayo´n, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem.
2002, 67, 4352
.
(22) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Evans, D. A.; Fandrick, K. R.;
Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (c) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
(23) (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV. 2003, 103, 3155.
(b) Brunel, J. M. Chem. ReV. 2005, 105, 857.
(9) Pikul, S.; Raczko, J.; Ankner, K.; Jurczak, J. J. Am. Chem. Soc.
1987, 109, 3981.
(10) (a) Achmatowicz, O., Jr.; Burzyn˜ska, M. H. Carbohydr. Res. 1985,
141, 67. (b) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982.
(24) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989,
111, 1940. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990,
112, 3949. (c) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc.
1994, 116, 2812. (d) Mikami, K.; Motoyama, Y.; Terada, M. Inorg. Chim.
Acta 1994, 222, 71. (e) Terada, M.; Motoyama, Y.; Mikami, K. Tetrahedron
Lett. 1994, 35, 6693.
(11) (a) Liao, L.-X.; Wang, Z.-M.; Zhang, H-X.; Zhou, W.-S. Tetra-
hedron: Asymmetry 1999, 10, 3649. (b) Haukaas, M. H.; O’Doherty, G. A.
Org. Lett. 2001, 3, 401.
(12) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863.
(13) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732.
(14) Kobayashi, Y.; Kusakabe, M.; Kitano, Y.; Sato, F. J. Org. Chem.
1988, 53, 1586.
(25) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467. (b) Keck, G. E.; Li, X.; Krishnamurthy, D. J. Org. Chem.
1995, 60, 5998. (c) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc.
1995, 117, 2363.
ˇ
(15) (a) Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron Lett. 2004,
(26) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001.
45, 535. (b) Yang, J. W.; List, B. Org. Lett. 2006, 8, 5653.
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Soc. 2005, 127, 10776.
(27) (a) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013. (b)
Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65, 1597.
(28) Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004, 69,
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Synth. Catal. 2007, 349, 1597.
2956
Org. Lett., Vol. 10, No. 14, 2008

At the next stage of our studies, we decided to use the
6,6′-dibromo-BINOL/Ti catalyst of 2:1 stoichiometry. Among
the tested solvents (toluene, CH2Cl2, Et2O), toluene gave the
best results, even without drying. As shown in Table 2,
loading of the catalyst (0.5-5 mol %, entries 1-3), tem-
perature (in the range of -20 to +20 °C, entries 1, 4, and
5), and reagent concentrations (0.5 and 0.25 mol/L, entries
1 and 6) had rather negligible effect on the ee of this model
reaction. The yield was lower only in the case when furan
was used in excess (entry 7, yield calculated with respect to
glyoxylate). We also investigated other alkyl glyoxylates in
this reaction. For t-butyl and iso-propyl glyoxylates, the
yields and enantioselectivity were lower compared to n-butyl,
and commercially available ethyl glyoxylate gave slightly
lower enantioselectivity.31 What is important is that this
reaction needs not to use freshly distilled n-butyl glyoxylate
and dry toluene to obtain satisfactory ee.
Scheme 2. Model Friedel-Crafts Reaction and Ligands Used
Having established the optimized conditions for asym-
metric reactions of 2-methylfuran (1a) with 2, we investi-
gated the F-C reaction with other furan derivatives. As
lectivity compared to the complex of nonsubstituted BINOL
ligand (96% vs 90% ee, respectively, Table 1). In all the
Table 2. Optimization of the Model Reaction of 1a with 2a
Table 1. Screening of the BINOL/Ti Complexes in the Reaction
of 1a with 2a
mol % of the cat.
(L2)2/Ti(OPri)4
entry
temp (°C)
yield (%)b
ee (%)c
entry
catalyst
yield (%)b
ee (%)c
1
2
0
0
94
96
89
81
95
90
71
96
1
L1/Ti(OPri)4
1: 1
2: 1
1: 1
2: 1
93
94
92
94
89
90
95
96
2
5
96.5
96
2
L1/Ti(OPri)4
L2/Ti(OPri)4
L2/Ti(OPri)4
3
0.5
2
0
3
4
-20
20
0
97
4d
5
2
93
a The reactions were carried out using of 2 mol % of catalyst, 1.5 mmol
of n-butyl glyoxylate (2) in 2 mL of toluene, and 1.0 mmol of silvan (1a),
at 0 °C (2 h). b Isolated yield. c Enantiomeric excess determined by GC
and HPLC using chiral columns. d For reaction carried out in Et2O and
CH2Cl2, yields and enantioselectivities were 98% and 92% ee and 94%
and 93% ee, respectively.
6d
2
97
7e
2
0
96
a The reactions were carried out with 1 mmol of silvan (1a) and 1.5
mmol of n-butyl glyoxylate (2) in 2 mL of toluene. b Isolated yield. c ee
determined by GC and HPLC. d Reaction in 4 mL of toluene. e Excess of
silvan was used (1.5 equiv), yield with respect to glyoxylate.
shown in Table 3, this reaction works well for a broad range
of substituted furans usually affording very good yield and
enantioselectivity (usually >90% ee). 2-Alkyl-substituted
furans gave very good yield and enantioselectivity with 2
mol % of the catalyst (L2)2/Ti(OPri)4 at 0 °C in 2-3 h (Table
3, entries 1 and 3-6, conditions A). Only in the case of 2-t-
butylfuran, the results were slightly worse (entry 4). Use of
the less reactive nonsubstituted furan (1b, entry 2, conditions
B) resulted in a significant drop in yield, although the
enantioselectivity was still high.
cases, we observed a very good yield (>90%) of the model
reaction. The molar ratio of BINOL/Ti(IV) (1:1 or 2:1) was
of no significance for this reaction, but the complexes L2/Ti
revealed a slightly better ee, were more active,25 and also
had a positive nonlinear effect (Figure 1).
We have also studied the reaction of 2 with benzyl furfuryl
ether (1g, entry 7), that was originally used by Achmatowicz
in the total synthesis of racemic uloses.10a This reaction, due
to lower reactivity of furan 1g compared to 2-alkylfurans,
requires 5 mol % of the catalyst, higher temperature, and
longer reaction time (conditions B). Under the modified
conditions, we obtained the product 3g in 85% yield and
95% ee (Table 3, entry 7).
(30) Blay, G.; Ferna´ndez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9,
2601.
(31) Finally, we decided to use n-butyl glyoxylate because of difficulties
with reproducibility of results experienced for ethyl glyoxylate, as well as
difficulties with purification of ethyl esters by chromatography on silica,
because of similarity of their Rf values to that of 6,6′-Br2-BINOL.
Figure 1. Effect of optical purity of L2 on the reaction ee.
Org. Lett., Vol. 10, No. 14, 2008
2957

(entry 11, conditions B) gave a slightly lower enantioselec-
tivity of about 90%. At least we demonstrated that this
reaction can be successfully carried out using also the
disubstituted, e.g., 2,3- and 2,4-dimethylfurans, to give 96%
ee (entries 12 and 13, respectively).
Table 3. Scope of Furans in the Friedel-Crafts Reaction with 2
a
Catalyzed by ((R)-6,6′-Br2-BINOL)2/Ti(OPri)4
We also demonstrated that this methodology worked
effectively for the reactions on a multigram scale with low
loading of the catalyst (L2)2/Ti (0.1-0.5 mol %) and higher
concentration of reagents, affording a very good yield and
enantioselectivity over 91% with 2-methylfuran (Scheme 3).
Scheme 3. Scaled-Up Synthesis of 2-Furanyl-hydroxyacetates
A high yield and good ee was obtained also for furan 1f (10
mmol scale, 0.5 mol % of the catalyst) and even for less
reactive 2-benzyloxymethylfuran (1g).
Out of thirteen products, 3a-m, three compounds (3a, 3b,
3l) have been subjected to determination of the absolute
configuration by chemical correlations.6b,7b,18 In all these
cases, the products having (R) configuration were obtained
from the (R)-6,6′-Br2-BINOL/Ti complex. Such a direction
of induction is in accordance with the literature data
concerning the other F-C reactions28,29 as well as the
additions and cycloadditions to glyoxylates catalyzed by
BINOL-Ti complexes.24,25,32
In summary, we have developed an efficient and easy method
for the enantioselective synthesis of the very interesting building
blocks chiral variously 5-substituted 2-furanyl-hydroxyacetates in
good yield and high optical purity (ee usually >90%, up to 97%).
The reaction is clearly and reproducibly catalyzed by the (6,6′-
Br2-BINOL)2/Ti(IV) complex readily prepared from the com-
mercially available reagents with no need of using dry toluene and
inert atmosphere. According to our knowledge, this is the first
example of efficient and highly enantioselective reaction of furans
with glyoxylates.
a The reactions were carried out using 2 mol % or 5 mol % of the
catalyst (L2)2/Ti(OPri)4, 1.5 mmol of n-butyl glyoxylate (2) in 2.0 or 4.0
mL of toluene, and 1.0 mmol of furan 1a, 1c-1m (1b was used in excess).
b Conditions A: 2 mol % of the catalyst, 4.0 mL of toluene, 0 °C, 2-3 h;
B: 5 mol % of the catalyst, 2.0 mL of toluene, 0 to 20 °C, 20 h; C: 5 mol
% of the catalyst, 2.0 mL of toluene, 0 °C, 4 h. c Isolated yield.
d Enantiomeric excess determined by GC and HPLC using chiral columns.
Acknowledgment. Financial support from the Ministry
of Science and Higher Education (Grant PBZ-KBN-126/T09/
06) and from the Foundation for Polish Science (individually
for P.K.) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for all the F-C products (3a-m)
with reprints of NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
This reaction is not limited to 2-alkyl-substituted furans
only. It works well also with vinyl, aryl, and silicon
2-substituted furans (entries 8-11). A very high yield and
enantioselectivity was obtained with 2-styrylfuran (1h, entry
8, conditions C). Reactions with 2-arylfurans 1j and 1k
(entries 9 and 10, conditions C) and 2-(trimethylsilyl)furan
OL800927W
(32) Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N.
Tetrahedron Lett. 1997, 38, 6513
.
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Org. Lett., Vol. 10, No. 14, 2008