Highly enantioselective friedel-crafts reaction of thiophenes with glyoxylates: Formal synthesis of duloxetine

Article abstract of DOI:10.1021/ol901906r

An efficient Friedel-Crafts reaction of a series of 2-substituted thiophenes with alkyl glyoxylates has been developed using a catalytic amount of an easy accessible 6,6'-dlbromo-BINOL/TI(IV) complex. A variety of hydroxy(thiophene-2-yl)acetates can be synthesized In high enantioselectivites (92-98% ee) and good yields. This Is the first report on the efficient asymmetric F-C reaction of thiophenes with alkyl glyoxylates. Starting from simple thiophene and n-butyl glyoxylate, we demonstrated the formal synthesis of duloxetine.

Full text of DOI:10.1021/ol901906r

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4636-4639
Highly Enantioselective Friedel-Crafts
Reaction of Thiophenes with
Glyoxylates: Formal Synthesis of
Duloxetine
Jakub Majer,† Piotr Kwiatkowski,†,‡ and Janusz Jurczak*,†,‡
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland,
and Faculty of Chemistry, UniVersity of Warsaw, 02-093 Warsaw, Poland
jurczak@icho.edu.pl
Received August 17, 2009
ABSTRACT
An efficient Friedel-Crafts reaction of a series of 2-substituted thiophenes with alkyl glyoxylates has been developed using a catalytic amount
of an easy accessible 6,6′-dibromo-BINOL/Ti(IV) complex. A variety of hydroxy(thiophene-2-yl)acetates can be synthesized in high
enantioselectivites (92-98% ee) and good yields. This is the first report on the efficient asymmetric F-C reaction of thiophenes with alkyl
glyoxylates. Starting from simple thiophene and n-butyl glyoxylate, we demonstrated the formal synthesis of duloxetine.
The thiophene ring can be recognized in various biologically
active compounds with applications in medicine1 or agro-
chemistry,2 which often reveal higher activity compared to
analogous phenyl-type substituents.3 Structures containing
thiophenes are also useful in the synthesis of new materials4
and catalysts.5 Quite stabile S-metal bonds create the
possibility of using thiophene derivatives as ligands for
catalysis.5 Moreover, oligothiophenes are interesting materi-
als in organic electronics6 and in the preparation of fluores-
cent biosensors.7
We focused our attention on the enantioselective synthesis
of chiral derivatives of 2-thienylcarbinols directly from
simple thiophenes and reactive carbonyl compounds, e.g.,
glyoxylates. The Friedel-Crafts (F-C) hydroxyalkylation
reaction of this type seems to offer a very attractive, direct,
and atom-economic approach to the synthesis of hydroxy-
† Polish Academy of Sciences.
‡ University of Warsaw.
(4) (a) Yu, J.; Holdcroft, S. Chem. Mater. 2002, 14, 3705. (b)
Narasimhaswamy, T.; Somanathan, N.; Lee, D. K.; Ramamoorthy, A. Chem.
Mater. 2005, 17, 2013. (c) Querner, C.; Benedetto, A.; Demadrille, A.;
Rannou, P.; Reiss, P. Chem. Mater. 2006, 18, 4817.
(1) (a) Wu, C.; Decker, E. R.; Blok, N.; Bui, H.; You, T. J.; Wang, J.;
Bourgoyne, A. R.; Knowles, V.; Berens, K. L.; Holland, G. W.; Brock,
T. A.; Dixon, R. A. F. J. Med. Chem. 2004, 47, 1969. (b) Oberdorf, C.;
Schepmann, D.; Vela, J. M.; Diaz, J. L.; Holenz, J.; Wu¨nsch, B. J. Med.
Chem. 2008, 51, 6531. (c) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.;
Cara, C. L.; Cruz-Lopez, O.; Iaconinoto, M. A.; Preti, D.; Shryock, J. C.;
Moorman, A. R.; Vincenzi, F.; Varani, K.; Borea, P. A. J. Med. Chem.
2008, 51, 5875. (d) Wang, W. L.; Chai, S. C.; Huang, M.; He, H. Z.; Hurley,
T. D.; Ye, Q. Z. J. Med. Chem. 2008, 51, 6110.
(5) (a) Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801. (b)
Gao, M. Z.; Kong, D.; Clearfield, A.; Zingaro, R. A. Tetrahedron Lett.
2004, 45, 5649. (c) Bandini, M.; Benaglia, M.; Quinto, T.; Tommasi, S.;
Umani-Ronchi, A. AdV. Synth. Catal. 2006, 348, 1521. (d) Zhang, X. Q.;
Li, Y. Y.; Zhang, H.; Gao, J. X. Tetrahedron: Asymmetry 2007, 18, 2049.
(6) (a) Barbarella, G.; Melucci, M.; Sotgiu, G. AdV. Mater. 2005, 17,
1581. (b) Melucci, M.; Barbarella, G.; Gazzano, M.; Cavallini, M.; Biscarini,
F.; Bongini, A.; Piccinelli, F.; Monari, M.; Bandini, M.; Umani-Ronchi,
A.; Biscarini, P. Chem.sEur. J. 2006, 12, 7304.
(2) (a) Hwang, I. T.; Kim, H. R.; Jeon, D. J.; Hong, K. S.; Song, J. H.;
Cho, K. Y. J. Agric. Food Chem. 2005, 53, 8639. (b) Fokialakis, N.; Cantrell,
C. L.; Duke, S. O.; Skaltsounis, A. L.; Wedge, D. E. J. Agric. Food Chem.
2006, 54, 1651.
(7) Dore, K.; Dubus, S.; Ho, H.-A.; Levesque, I.; Brunette, M.; Corbeil,
G.; Boissinot, M.; Boivin, G.; Bergeron, M. G.; Boudreau, D.; Leclerc, M.
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(3) Lamberth, C.; Jeanguenat, A.; Cederbaum, F.; Mesmaeker, A.; Zeller,
M.; Kempf, H. J.; Zeun, R. Bioorg. Med. Chem. 2008, 16, 1531.
10.1021/ol901906r CCC: $40.75
Published on Web 09/18/2009
 2009 American Chemical Society

(thiophene-2-yl)acetates. However, to the best of our knowl-
edge, until now there has been no report on successful
catalytic enantioselective F-C reaction of thiophenes with
aldehydes and ketones.8 One of the difficulties could be the
reactivity of thiophene toward electrophiles, which is lower
than for pyrrole, indole, and furan.9 The literature describes
examples of efficient enantioselective reactions of reactive
carbonyl compounds (e.g., glyoxylates) with other activated
arenes and heteroarenes (e.g., anilines10 and indoles11).
Recently, we demonstrated a highly enantioselective syn-
thesis of furan-2-yl-hydroxyacetates from furans and gly-
oxylates.12
presence of well-known types of chiral Lewis acids, e.g.,
(R,R)-(Salen)CrBF4 (5), (R)-Ph-BOX/Cu(OTf)2 (6), and
BINOL/Ti(OPri)4 (7) (Figure 1). With salen-chromium and
Concerning applications of thiophenes in asymmetric
catalytic F-C reactions, Jørgensen and co-workers reported
an enantioselective reaction of trifluoropyruvate with 2-me-
thylthiophene catalyzed by t-Bu-BOX-Cu(II) complexes
with 79% ee and only 16% yield.13 Much better results were
obtained in the enantioselective reaction of activated thiophenes
with R-imino esters.14
The catalytic reaction of thiophenes and other arenes and
heteroarenes with glyoxylates in a racemic version was
investigated by Wang.15 Using Yb(OTf)3 as a catalyst in the
reaction of 2-methylthiophene (1a) and ethyl glyoxylate (2a),
instead of compound 3 they isolated product 4 containing
two thiophene rings in good yield (Scheme 1, the model
Figure 1. Chiral Lewis acid catalysts used.
bisoxazoline-copper complexes, we observed low ee of
product 3 and also formation of byproduct 4 (Table 1).
Table 1. Screening of Chiral Lewis Acids in the Reaction of 1a
with 2a
Scheme 1. Model Friedel-Crafts Reaction
entry catalyst yield of 3e (%) ee of 3f (%) yield of 4e (%)
1b
2b, c
3
4
5
5
6
54
44
68
83
89
90
90
26
28
81
82
84
84
90
12
14
g
g
g
7a
7b
8a
8b
8b
6
g
g
7d
reaction in our studies); however, with other arenes the
desired R-hydroxy ester was received. Results obtained with
2-methylthiophene suggest that control of chemoselectivity
in this reaction is not trivial.
Herein we describe the first highly enantioselective
Friedel-Crafts reaction of variously substituted thiophenes
1a-k with ethyl or n-butyl gloxylates (2a and 2b) yielding
hydroxy(thiophene-2-yl)acetates. Initially, the reaction be-
tween commercially available ethyl gloxylate (2a) and
2-methylthiophene (1a) (Scheme 1) was studied in the
a The reactions were carried out using 2 mol % of catalyst and 1.5
mmol of ethyl glyoxylate (2a) in 2 mL of toluene and 1.0 mmol of
2-methylthiophene (1a) at 0 °C (3 h). b 5 mol % of catalyst, from 0 to 20
°C (5 days). c 2 mL of dry THF. d Reaction with 1.5 mmol of n-butyl
glyoxylate (2b). e Isolated yield. f Enantiomeric excess determined by HPLC
using chiral columns. g Product was not observed on TLC.
BINOL-Ti complex, generated in situ from BINOL ligand
and Ti(OPri)4, proved sufficiently active to catalyze this
reaction with good yield and selectively to product 3 and
also higher and promising enantioselectivity (82% ee).
BINOL-titanium complexes were introduced to asymmetric
catalysis by Mikami16 and Keck17 and used in F-C type
reactions for the first time by Mikami.18 We also successfully
applied this catalyst for F-C reactions of furans with
glyoxylates.12
(8) For a recent review in asymmetric F-C reaction, see: Poulsen, T. B.;
Jørgensen, K. A. Chem. ReV. 2008, 108, 2903.
(9) Cyran˜ski, M. K.; Krygowski, T. M.; Katritzky, A. R.; Schleyer, P.
v. R. J. Org. Chem. 2002, 67, 1333.
(10) (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517. (b) Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org.
Chem. 2004, 69, 146.
(11) (a) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J.
AdV. Synth. Catal. 2007, 349, 1597. (b) Li, H.; Wang, Y.-Q.; Deng, L.
Org. Lett. 2006, 8, 4063.
To compare the relative reactivity of furans and thiophenes
in the investigated reaction we mixed 2-methylthiophene
(12) Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2008, 10, 2955.
(13) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2001, 66, 1009.
(16) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940.
(14) (a) Saaby, S.; Bayo´n, P.; Aburel, P. S.; Jørgensen, K. A. J. Org.
Chem. 2002, 67, 4352. (b) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am.
Chem. Soc. 2005, 127, 2858.
(17) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
(18) Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65,
(15) (a) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732.
1597.
Org. Lett., Vol. 11, No. 20, 2009
4637

(1a), 2-methylfuran, and ethyl glyoxylate in a ratio of 1:1:1
in the presence of BINOL-Ti catalyst. This competitive
experiment showed that thiophene is significantly less
reactive, and an almost exclusively furan-containing product
was formed (25:1 product ratio); however, in the absence of
furan we were able to obtain product 3 with good yield.
Table 3. Scope of Thiophenes in Friedel-Crafts Reaction with
2b Catalyzed by 8ba
Among the BINOL-titanium catalysts, the complex
containing 6,6′-Br2BINOL ligand (catalyst 8) gave slightly
better results in terms of yield and enantioselectivity
compared to nonsubstituted BINOL. The molar ratio of
BINOL/Ti (1:1 or 2:1) has practically no influence on this
reaction; however, the complexes 7b and 8b (2:1) are usually
slightly more active and enantioselective. At the next stage
of our research, we decided to use the 6,6′-dibromo-BINOL/
Ti catalyst of 2:1 stoichiometry. Replacing commercially
available ethyl glyoxylate (84% ee, Table 1, entry 6) with
n-butyl glyoxylate resulted in an increase of enantiomeric
excess to 90% (entry 7).19
Optimization studies with titanium complex 8b revealed
that toluene gave better results than CH2Cl2 and Et2O. As
shown in Table 2, loading of the catalyst (0.5-5 mol %,
Table 2. Optimization of the Model Reaction of 1a with 2ba
entrya 8b (mol %) T (°C) toluene (mL) yieldb (%) eec (%)
1
2
3
2
5
0.5
2
2
2
2
2
2
0
0
0
0
0
2
5
0.5
1
2
2
2
1
1
90
91
81
97
70
87
75
78
37
90
91
88
90
90
85
92
94
93
4
5d
6
20
-20
-50
-60
7
8e
9e
a The reactions were carried out with 1 mmol of 2-methylthiophene
(1a) and 1.5 mmol of n-butyl glyoxylate (2b) for 3 h. b Isolated yield. c ee
determined by HPLC. d An excess of 2-methylthiophene was used (1.5
equiv); yield with respect to glyoxylate. e The reactions was carried out for
7 h.
a The reactions were carried out using 2 mol % or 5 mol % of the
catalyst 8b and 1.5 mmol of n-butyl glyoxylate (2b) in 1.0 or 2.0 mL of
toluene and 1.0 mmol of thiophene (1a-1k). b Conditions: (A) 2 mol % of
the catalyst, 1.0 mL of toluene, -50 °C, 7 h; (B) 5 mol % of the catalyst,
2.0 mL of toluene, 0 °C, 4 h; (C) 5 mol % of the catalyst, 2.0 mL of toluene,
0-20 °C, 24 h. c Isolated yield. d Enantiomeric excess determined by HPLC
using chiral columns.
entries 1-3), temperature (in the range of -20 to +20 °C,
entries 1, 6, and 7), and reagent concentration (0.5-1 mol/
L, entries 1 and 4) had a rather negligible effect on the ee of
this model reaction. The yield was lower only in the case
when thiophene was used in excess (entry 5, yield calculated
with respect to glyoxylate) or when the reaction was carried
out at very low temperature (entry 9). In conclusion, 2 mol
% of catalyst at -50 °C seems to be the optimal condition
for the model reaction and provides the product with 94%
ee and good yield. Importantly, this reaction does not require
the use of dried toluene to obtain high ee.
for a broad range of 2-substituted thiophenes, usually
affording very good yield and enantioselectivity (92-98%
ee).
Optimized conditions for the model reaction (2 mol % of
catalyst 8b at -50 °C for 7 h; conditions A) work very well
with other thiophenes substituted with alkyl groups at
position 2 (e.g., Et, t-Bu, Bn, entries 2-4). Also, the reaction
of highly activated 2-methoxythiophene with 2b at -50 °C
gives product with very high ee and yield (entry 5).
Higher loading of catalyst (5 mol %) and temperature 0
°C was applied for thiophenes substituted with aryl and vinyl
groups (conditions B, entries 6 and 7). Reactions with less
reactive thiophenes having protected hydroxymethyl and
trimethylsilyl groups or nonsubstituted thiophene (entries
8-10) require higher temperature and prolonged reaction
time (conditions C, 20 °C, 24 h). However, use of nonsub-
Having optimized conditions for asymmetric reactions of
2-methylthiophene with 2b, we investigated the scope of
thiophenes. As shown in Table 3, this reaction works well
(19) Other alkyl glyoxylates were also investigated in this reaction; for
tert-butyl and isopropyl glyoxylates, the yields and enantioselectivity were
lower compared to n-butyl glyoxylate.
4638
Org. Lett., Vol. 11, No. 20, 2009

stituted thiophene resulted in a significant drop in yield,
although the enantioselectivity was still high (entry 10).
Reaction is also possible with disubstituted thiophenes. Very
high enantioselectivity and yield were obtained using 2,3-
dimethylthiophene (entry 11). In the case of 2,5-dimethyl-
tiophene, product substituted in position 3 was formed, albeit
with low enantioselectivity (35% ee). In conclusion, this
method works very well for 2-substituted thiophenes with
alkyl, vinyl, aryl, and other activating groups.
with 88% yield. The nitrile is known in the literature and
was applied in a four-step synthesis of duloxetine in 56%
yield.22b Using our methodology, we can easily synthesize
new analogues of duloxetine with a modified thienyl ring.
Absolute configuration was determined for 2 of 11
products: for 3 directly using X-ray crystallographic analysis
(Figure 2) and for 9j based on chemical correlation to (S)-
We also demonstrate that this methodology works ef-
fectively in multigram scale for thiophenes 1c, 1f, 1h and
low loading of catalyst 8b (1-2 mol %) affording products
with very good yield and enantioselectivity (Table 4).
Table 4. Scaled-Up Synthesis of Hydroxy(thiophene-2-yl)acetates
product
conditionsa
yield (%) ee (%)
9c
9f
1 mol % of 8b; -50 °C for 12 h
2 mol % of 8b; 0 °C for 24 h
2 mol % of 8b; 0 f 20 °C for 24 h 78; 2.61 g
73; 1.97 g
98; 3.10 g
97
93
93
Figure 2. X-ray crystal structure of compound (S)-3: assignment
of absolute configuration.
9h
a Catalyst 8b and 1.25 equiv of n-butyl glyoxylate (2b); a higher
concentration of reagents was used.
(-)-nitrile 12. Hydroxy(thiophene-2-yl)acetates having (S)
configuration were obtained from the (R)-6,6′-Br2-BINOL/
Ti complex. Such a direction of induction is in accordance
with the data in the literature concerning other F-C
reactions10b catalyzed by BINOL-Ti complexes.
We have also demonstrated application of the product 9j
in the formal synthesis of duloxetine (Scheme 2),20
a
In summary, we have developed an efficient method for
the enantioselective synthesis of chiral variously 5-substituted
thiophene-2-yl R-hydroxy esters from thiophenes and n-butyl
glyoxylate in good yield and high optical purity (92-98%
ee), utilizing readily available (6,6′-Br2-BINOL)2/Ti(IV)
complex as a catalyst. To our knowledge, this is the first
example of the highly enantioselective reaction of thiophenes
with aldehydes, namely glyoxylates. Moreover, the product
of the reaction between thiophene and n-butyl glyoxylate
was applied to the formal synthesis of duloxetine.
Scheme 2. Formal Synthesis of Duloxetine
Acknowledgment. Financial support from the Polish
Ministry of Science and Higher Education (Grant No. 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 F-C products (3, 9a-k)
with copies of NMR spectra and CIF file for product (S)-3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
serotonin-norepinephrine reuptake inhibitor of wide phar-
macology utility.21 Our approach is an alternative to the other
duloxetine synthesis described in the literature.22
We scaled up the reaction of simple thiophene with n-butyl
glyoxylate and 1 mol % of catalyst 8b. The reaction provides
product 9j with moderate yield (42%) and 92% enantiose-
lectivity. The F-C product was reduced to the diol 10, and
the primary hydroxy group was protected with tosyl group
(11) which was subsequently substituted with cyanide. The
nitrile 12 was obtained in three steps from F-C product 9j
OL901906R
(21) Kornstein, S. G.; Russell, J. M.; Spann, M. E.; Crits-Christoph, P.;
Ball, S. G. Expert ReV. Neurother. 2009, 9, 155.
(22) (a) Ratovelomanana-Vidal, V.; C. Girard, C.; R. Touati, R.; J. P.
Tranchier, J. P.; B. Ben, B.; Hassine, B. B.; J. P. Geneˆt, J. P. AdV. Synth.
Catal. 2003, 345, 261. (b) Kamal, A.; Khanna, G. B. R.; Ramu, R.;
Krishnaji, T. Tetrahedron Lett. 2003, 44, 4783. (c) Genov, D. G.; Ager,
D. J. Angew. Chem., Int. Ed. 2004, 43, 2816. (d) Kuo, F.; Gillespie, T. A.;
Kulanthaivel, P.; Lantz, R. J.; Ma, T. W.; Nelson, D. L.; Threlkeld, P. G.;
Wheeler, W. J.; Yi, P.; Zmijewski, M. Bioorg. Med. Chem. Lett. 2004, 14,
3481.
(20) Wong, D. T.; Robertson, D. W.; Bymaster, F. P.; Krushinski, J. H.;
Reid, L. R. Life Sci. 1988, 43, 2049.
Org. Lett., Vol. 11, No. 20, 2009
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