An improved asymmetric Reformatsky reaction mediated by (-)-N,N-dimethylaminoisoborneol

Article abstract of DOI:10.1021/ol0531381

(-)-N,N-Dimethylaminoisoborneol ((-)-DAIB) was found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to aromatic and aliphatic aldehydes. Enantioselectivities up to 93% ee were obtained with sulfur-containing aldehydes.

Full text of DOI:10.1021/ol0531381

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1125-1128
An Improved Asymmetric Reformatsky
Reaction Mediated by
(−)-N,N-Dimethylaminoisoborneol
Ralf J. Kloetzing, Tobias Thaler, and Paul Knochel*
Department of Chemistry and Biochemistry, Ludwig-Maximilians-UniVersity,
Butenandtstrasse 5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received December 27, 2005
ABSTRACT
(−)-N,N-Dimethylaminoisoborneol ((−)-DAIB) was found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to
aromatic and aliphatic aldehydes. Enantioselectivities up to 93% ee were obtained with sulfur-containing aldehydes.
Organozinc reagents are useful synthetic intermediates as a
result of their convenient synthesis and high tolerance toward
functional groups.1,2 The Reformatsky reaction allows the
synthesis of â-hydroxy esters by the direct insertion of zinc
in R-halogenated esters and subsequent addition of the
resulting organozinc enolate to aldehydes or ketones.3 An
enantioselective reaction allows an easy and direct access
to synthetically useful chiral â-hydroxy esters,4 which are
valuable precursors for the synthesis of natural products and
pharmaceutically active compounds. So far, several methods
have been reported using chiral auxiliaries5 or ligands.6
Recently, a highly efficient imino-Reformatsky reaction,
affording â-amino esters, has been disclosed.7 The methods
for the direct Reformatsky reaction using the insertion of
activated zinc into R-bromo acetates lack generality, and high
enantioselectivities could not be achieved.
To improve this reaction, we have tested various amino
alcohols that proved to give high asymmetric inductions as
chiral ligands for the addition of diethylzinc to aldehydes.2
Benzaldehyde was chosen as a test substrate for the enan-
tioselective addition of the Reformatsky reagent (1a,b),
which was prepared from bromoacetic esters via the direct
insertion of zinc (Scheme 1 and Table 1). All reactions were
(4) For other recent asymmetric syntheses of â-hydroxy carbonyl
compounds, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138-5175. (b) List, B. Tetrahedron 2002, 58, 5573-5590 and
references therein. (c) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005,
7, 1729-1732. (d) Trost, B. M.; Shin, S.; Sclafani, J. A. J. Am. Chem. Soc.
2005, 127, 8602-8603. (e) Denmark, S. E.; Beutner, G. L.; Wynn, T.;
Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774-3789. (f) Kesanli, B.;
Lin, W. Chem. Commun. 2004, 2284-2285. (g) Hu, A.; Ngo, H. L.; Lin,
W. Angew. Chem., Int. Ed. 2004, 43, 2501-2504. (h) Ruck, R. T.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 2882-2883.
(1) (a) Knochel, P. Sci. Synth. 2004, 3, 5-90. (b) Nakamura, E. In
Organometallics in Synthesis, a Manual; Schlosser, M., Ed; Wiley: New
York, 2002; p 579. (c) Fu¨rstner, A. In Organozinc Reagents; Knochel, P.,
Jones, P., Eds.; Oxford University Press: New York, 1999; p 287.
(2) For an overview on the enantioselective addition of organozinc
reagents to aldehydes, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994; p 255. (b) Soai, K.; Niwa, S. Chem.
ReV. 1992, 92, 833-856.
(3) (a) Reformatsky, S. Chem. Ber. 1887, 20, 1210-1211. For a review,
see: (b) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325-
9374. (c) Orsini, F.; Sello, G. Curr. Org. Chem. 2004, 1, 111-135. (d)
Fu¨rstner, A. Synthesis 1989, 571-590. (e) Suh, Y.; Rieke, R. D. Tetrahedron
Lett. 2004, 45, 1807-1809.
(5) (a) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J. Org.
Chem. 1999, 64, 8461-8464. For an imino variant with sulfinylimines,
see: (b) Sorochinsky, A.; Voloshin, N.; Markovsky, A.; Belik, M.; Yasuda,
N.; Uekusa, H.; Ono, T.; Berbasov, D. O.; Soloshonok, V. A. J. Org. Chem.
2003, 68, 7448-7454.
10.1021/ol0531381 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/21/2006

which is more readily available than (-)-DAIB (5), yielded
here a slightly lower enantioselectivity of 72% ee (entry 6).
Diethylzinc was used for the deprotonation of the amino
alcohol in order to avoid using an excess of the Reformatsky
reagent 1. With BuLi as base, product 7a was obtained in
racemic form, and with MeMgCl as deprotonating agent only
a low enantioselectivity of 20% ee was found.
Scheme 1. Preparation of Reformatsky Reagents 1a-c
The scope of the reaction using (-)-DAIB (5) as chiral
inductor was examined (Table 2). For o- and p-bromo-
benzaldehyde (entries 1 and 3) the resulting enantioselec-
tivities were lower than those for the reaction with benzal-
dehyde. The lowest enantioselectivity (78% ee) was found
with the ortho-isomer (entry 2). For 4-chlorobenzaldehyde
(entry 3) the enantioselectivity is comparable with those of
the bromo-benzaldehydes (80% ee). The electron-withdraw-
ing nitrile group (entry 4) led to an even lower enantiose-
lectivity (72% ee), but better results were obtained with
electron-rich aldehydes (entries 5 and 6). Although the
conversion is lower, better enantioselectivities are achieved
(88% and 93% ee). When thiophene aldehydes were used
(entries 7-9), the enantioselectivity was also high. The
sterically most hindered â-benzothiophene aldehyde reacted
slowly (62% conversion) but gave 90% ee. The 2- and
3-thiophene aldehydes yielded the best enantioselectivities
(92% and 93% ee). Product 7g is a key intermediate in a
synthesis of duloxetine, a potent inhibitor of the serotonine
and norepinephedrine uptake carriers.13 The best reported
enantioselective synthesis to date gave product 7g with 90%
ee.13 Furfural (entry 10) produces the â-hydroxy ester 7k
with a enantioselectivity (84% ee) similar to that of benzal-
dehyde (86% ee). These experiments show that a sulfur-
performed using 1.2 equiv of the chiral amino alcohol. 1,4-
Pyridazine derivative 28 (entry 1) gave high conversion but
only moderate enantiomeric excess. When quinine (3)6e,9 or
the indanol derivative 410 were used, the enantioselectivity
remained low (entries 2 and 3), whereas with (-)-N,N-
dimethylaminoisoborneol (5, (-)-DAIB)11 an enantioselec-
tivity of 86% ee and an isolated yield of 75% were achieved
(entry 4). The use of sterically hindered tert-butyl bromo-
acetate (entry 5, R ) t-Bu) for the preparation of the
Reformatsky reagent led to a decreased enantioselectivity
of 78% ee. Nugent’s morpholine derivative 612 ((-)-MIB),
Table 1. Reformatsky Reaction with Various Chiral Amino
Alcohols
(6) For the use of sparteine, see: (a) Sorger, K.; Petersen, H.; Stohrer,
J. Eur. Pat. Appl. EP 1394140, 2004. High enantioselectivity (91% ee) could
also be achieved with thiophene-2-carbaldehyde. (b) Guette´, M.; Guette´, J.
P.; Capillon, J. Tetrahedron Lett. 1971, 12, 2863-2863. (c) Guette´, M.;
Capillon, J.; Guette´, J. P. Tetrahedron 1973, 29, 3659-3667. For the use
of amino alcohols, see: (d) Fujiwara, Y.; Katagiri, T.; Uneyama, K.
Tetrahedron Lett. 2003, 44, 6161-6163. (e) Ojida, A.; Yamano, T.; Taya,
N.; Tasaka, A. Org. Lett. 2002, 4, 3051-3054. (f) Andre´s, J. M.; Pedrosa,
R.; Pe´rez-Encabo, A. Tetrahedron 2000, 56, 1217-1223. (g) Mi, A.; Wang,
Z.; Chen, Z.; Jiang, Y.; Chan, A. S. C.; Yang, T. Tetrahedron: Asymmetry
1995, 6, 2641-2642. (h) Pini, D.; Mastantuono, A.; Salvadori, P.
Tetrahedron: Asymmetry 1994, 5, 1875-1876. (i) Soai, K.; Oshio, A.; Saito,
T. J. Chem. Soc., Chem. Commun. 1993, 811-812. (j) Soai, K.; Kawase,
Y. Tetrahedron: Asymmetry 1991, 2, 781-784.
(7) (a) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600-
3603. (b) Ukaji, Y.; Takenaka, S.; Horita, Y.; Inomata, K. Chem. Lett. 2001,
3, 254-255. For a large scale Reformatsky reaction with imines, see: (c)
Awasthi, A. K.; Boys, M. L.; Cain-Janicki, K. J.; Colson, P.-J.; Double-
day: W. W.; Duran, J. E.; Farid, P. N. J. Org. Chem. 2005, 70, 5387-
5397. (d) Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-
J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable, C. M.; Lantz, M.
K.; Moore, C. M. V.; Murphy, J. B.; Rogers, T. E.; Ruminski, P. G.; Shah,
A. S.; Storer, N.; Wise, B. E. Org. Proc. Res. DeV. 2004, 8, 51-61.
(8) Ortiz, A.; Farfa´n, N.; Ho¨pfl, H.; Santillan, R.; Ochoa, M. E.; Gutie´rrez,
A. Tetrahedron: Asymmetry 1999, 10, 799-811.
(9) (a) Park, D. H.; Choi, H. J.; Lee, S.-G. J. Korean Chem. Soc. 2003,
47, 597-600. (b) Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52,
135-137. (c) Muchow, G.; Vannoorenberghe, Y.; Buono, G. Tetrahedron
Lett. 1987, 28, 6163-6166.
(10) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005,
44, 3881-3884.
entry
amino alcohol
R
yield (%)
eed (%)
1
2
3
4
5
6
2
3
4
5
5
6
Me
Me
Me
Me
tBu
Me
99b
99b
99b
75c
84b
93b
61
9
26
86
78
72
(11) (a) White, J. D.; Wardrop, D. J.; Sundermann, K. F. Org. Synth.
2003, 79, 125-138. (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 4832-4842. (c) Kitamura, M.; Suga, S.; Kawai,
K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6072-6074.
a All reactions were performed on a 0.5 mmol scale using amino alcohol
(1.2 equiv, 0.6 equiv in case of 2), Et2Zn (0.7 equiv), and Reformatsky
reagent (1.1 equiv). b Conversion determined by GC analysis with tetrade-
cane as internal standard. c Isolated yield. d Determined by GC analysis
(Chiraldex CB).
(12) Nugent, W. A. Chem. Commun. 1999, 1369-1370.
(13) Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J. P.;
Hassine, B. B.; Geneˆt, J. P. AdV. Synth. Catal. 2003, 345, 261-274.
1126
Org. Lett., Vol. 8, No. 6, 2006

Table 2. Reformatsky Reaction with (-)-DAIB and Various
Table 3. Reformatsky Reaction with the Difluoro Reagent 1c,
(-)-DAIB and Various Aldehydes
Aldehydesa
conv yieldb eec,d
conv
(%)
yieldb
(%)
eec,d
(%)
entry
R
product (%)
(%)
(%)
entry
R
product
1
2
3
4
5
6
7
8
9
4-bromophenyl
2-bromophenyl
4-chlorophenyl
4-cyanophenyl
4-isopropylphenyl
4-methylthiophenyle
3-benzothienyl
2-thienyl
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
79
71
85
89
63
57
62
86
88
99
77
64
61
79
48
87
91
65
88
90
93
94
85
87
86
83
88
85
87
92
81
78
80
72
88
93
90
92
93
84
92
78
74
66
71
1
2
3
4
5
6
phenyl
8a
8b
8c
8d
8e
8f
92
96
91
66
69
91
82
83
88
90
84
81
88
87
84
90
87
80
4-bromophenyl
4-cyanophenyl
2-thienyl
3-thienyl
neopentyl
a-cSee Table 2. d The absolute stereochemistry (R) was assigned by
comparison of the optical rotation with literature data.14a
3-thienyl
10 2-furyl
11 neopentyl
12 n-pentyl
13 2,2-dimethyl-2-methoxyethyl
14 benzyloxymethyl
15 2-phenylvinyl
was lower than for the Reformatsky reagent 1a, so that 87%
ee was obtained in the case of p-bromobenzaldehyde (entry
2) and 84% ee with p-cyanobenzaldehyde (entry 3). With
2- or 3-thiophene aldehyde (entries 4 and 5) high enantio-
selectivity could be accomplished (90% and 87% ee). The
advantageous influence of the sulfur heterocycle is less
marked than for the Reformatsky reagent 1a. With the
sterically hindered aliphatic aldehyde 3,3-dimethylbutanal
(entry 6) 80% ee was obtained.
a See Table 1. b Isolated yield based on conversion. c Determined by
chiral GC (Chiraldex CB) or chiral HPLC (Chiralcel OD-H). d The absolute
stereochemistry (S) was assigned by comparison of the optical rotation with
literature data.4e,13 e For a procedure, see ref 17.
containing heterocycle enhances the enantiomeric excesses
regardless of the sulfur’s position. For aliphatic aldehydes
(entries 11 and 12), a sterically hindered aldehyde must be
used in order to achieve high enantioselectivity. As an
example, 3,3-dimethylbutanal (entry 11) gave 92% ee,
whereas with hexanal (entry 12) only 78% ee was achieved.
The same phenomenon was observed when aliphatic alde-
hydes containing an ether moiety were used (entries 13 and
14). The sterically hindered 3-methoxy-3-methylbutanal
(entry 13) provided a higher enantioselectivity (74% ee),
whereas benzyloxy acetaldehyde gave only 66% ee. Cin-
namyl aldehyde (entry 15) led to 71% ee along with a low
conversion.
We have extended the scope of the reaction to the difluoro-
Reformatsky reagent 1c, which was prepared by direct
insertion of zinc into ethyl bromodifluoroacetate (Scheme 1
and Table 3).14 The 2,2-difluoro-3-hydroxycarboxylates are
versatile intermediates for the synthesis of fluorinated
peptides.15 As a result of its high electronegativity, the CF2
group is an isosteric and isopolar replacement site for
oxygen.16 With benzaldehyde (Table 3, entry 1), an enan-
tioselectivity of 88% ee was observed. The decrease of
enantioselectivity, when electron-poor aldehydes were used,
To gain an insight into the nature of the beneficial effect
of sulfur-containing heterocyclic substrates on the enantio-
(16) For other asymmetric syntheses of 2,2-difluoro-3-hydroxycarboxy-
lates, see: (a) Kuroki, Y.; Asada, D.; Iseki, K. Tetrahedron Lett. 2000, 41,
9853-9858. (b) Iseki, K.; Kuroki, Y.; Asada, D.; Kobayashi, Y. Tetrahedron
Lett. 1997, 38, 1447-1448. For diastereoselective syntheses, see: (c) Evans,
G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J.
Med. Chem. 2003, 46, 3412-3423. (d) Ding, Y.; Wang, J.; Abboud, K.
A.; Xu, Y.; Dolbier, W. R., Jr.; Richards, N. G. J. J. Org. Chem. 2001, 66,
6381-6388.
(17) Procedure for the Synthesis of Alcohol 7g. (Table 2, entry 6) In
a 25 mL three-necked flask equipped with an efficient reflux condenser, a
dropping funnel, a magnetic stirring bar and a thermometer, zinc (dust,
1.26 g, 19.3 mmol) was suspended in THF (8 mL) and stirred vigorously.
The temperature was raised to 40 °C, and trimethylsilyl chloride (0.30 mL,
0.26 g, 2.4 mmol) was added. The temperature was then raised to 55 °C
and kept for 15 min. The pressure in the flask was reduced to 330 mbar,
which ensures that the temperature is kept at 37 °C (refluxing THF). Methyl
bromoacetate (1.68 mL, 2.70 g, 17.7 mmol) was added during 10 min
(CAUTION: exothermic reaction) and stirred for 5 min. The flask was
then refilled with argon, and the remaining solid material was allowed to
settle. The supernatant liquid was decanted with a cannula. The concentration
was determined by titration with iodine in THF (2 mL) at 0 °C to be 1.7
M. (-)-DAIB (5, 140 mg, 0.728 mmol) was dissolved in THF (0.5 mL)
and diethylzinc (1.9 m in THF, 0.23 mL, 0.44 mmol) was added at 0 °C.
After the mixture had been stirred for 10 min, the temperature was lowered
to -20 °C, and the above prepared Reformatsky reagent (0.41 mL, 0.70
mmol) was added. Then the mixture was stirred for 20 min. The aldehyde
(94.2 mg, 0.619 mmol) was added as a solution in THF (0.5 mL) together
with tetradecane as internal standard. After 2 h, the temperature was allowed
to rise to 0 °C. Concentrated aqueous ammonia (3 mL) and a saturated
solution of NH4Cl (30 mL) were added after 12 h, and the mixture was
extracted with ethyl acetate. The organic phase was washed with brine and
dried over MgSO4. The solvent was evaporated, and the product was purified
by column chromatography (SiO2, pentane/diethyl ether 3:1 to 1:1). Alcohol
7g was obtained as white solid (74 mg, 0.33 mmol, 93% based on 57%
conv).
(14) (a) Andre´s, J. M.; Mart´ınez, M. M.; Pedrosa, R.; Pe´rez-Encabo, A.
Synthesis 1996, 1070-1072. (b) Braun, M.; Vonderhagen, A.; Waldmu¨ller,
D. Liebigs Ann. 1995, 1447-1450. (c) Sato, K.; Tarui, A.; Kita, T.; Ishida,
Y.; Tamura, H.; Omote, M.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2004,
45, 5735-5737.
(15) Kirk, K. L. In Fluorine-Containing Amino-Acids; Kukhar, V. P.,
Soloshonok, V. A., Eds.; Wiley: New York, 1995; p 343.
Org. Lett., Vol. 8, No. 6, 2006
1127

selectivity of the addition, the reaction of the Reformatsky
reagent 1a with benzaldehyde (Table 1) was performed, using
thiophene or tetrahydrothiophene as additives (Scheme 2).
suitable additives that increase the enantioselectivity of the
Reformatsky reaction. An attempt to use (-)-DAIB in
catalytic amounts (10 mol %) along with stoichiometric
amounts of thiophene (1.2 equiv) gave the product 7a only
with 19% ee.
In conclusion, we have shown that (-)-DAIB is an
excellent ligand for the enantioselective addition of the
Reformatsky reagent 1a to various aldehydes. High enantio-
selectivities were obtained for thiophene aldehydes (up to
93% ee) or sterically hindered aliphatic aldehydes (92% ee).
The addition of the difluoro zinc reagent 1c also proceeded
with high enantioselectivity (up to 90% ee). Extensions of
this enantioselective Reformatsky reaction are currently
underway in our laboratories.
Scheme 2. Reformatsky Reaction Using Sulfur Additives
Acknowledgment. R.J.K. thanks the Stiftung Stipen-
dien-Fonds des VCI (Frankfurt) and the Bundesministerium
fu¨r Bildung und Forschung for a scholarship. We thank
WACKER Chemie GmbH (Mu¨nchen) for the gift of chemi-
cals.
Supporting Information Available: Experimental de-
tails, chromatograms, and spectra for all compounds and
analytical data. This material is available free of charge via
the Internet at http://pubs.acs.org.
With thiophene as additive (1.2 equiv) 70% conversion
and 90% ee were obtained. With tetrahydrothiophene (1.2
equiv) 84% conversion and 88% ee were observed. Without
additive, the reaction led to 86% ee (Table 1, entry 4). This
shows that tetrahydrothiophene and especially thiophene are
OL0531381
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Org. Lett., Vol. 8, No. 6, 2006