Catalytic enantioselective reformatsky reaction with ortho-substituted diarylketones

Article abstract of DOI:10.1021/ol801574m

(Chemical Equation Presented) The catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones with good enantioselectivities and moderate to good yields is reported. A readily available BINOL derivative is used as a chiral catalyst, and the reactions are performed with ethyl iodoacetate as a nucleophile and Me₂Zn as the zinc source. The presence of air was found to be crucial to achieve an effective C-C bond formation pointing to a radical mechanism.

Full text of DOI:10.1021/ol801574m

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4041-4044
Catalytic Enantioselective Reformatsky
Reaction with ortho-Substituted
Diarylketones
´
M. Angeles Ferna´ndez-Iba´n˜ez, Beatriz Macia´,
Adriaan J. Minnaard, and Ben L. Feringa*
Stratingh Institute for Chemistry, UniVersity of Groningen, Nijenborgh 4,
9747 AG, Groningen, The Netherlands
b.l.feringa@rug.nl
Received July 11, 2008
ABSTRACT
The catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones with good enantioselectivities and moderate to good
yields is reported. A readily available BINOL derivative is used as a chiral catalyst, and the reactions are performed with ethyl iodoacetate as
a nucleophile and Me2Zn as the zinc source. The presence of air was found to be crucial to achieve an effective C-C bond formation pointing
to a radical mechanism.
Chiral tertiary alcohols are important structural units present
in many biologically active compounds and pharmaceutical
intermediates. An important strategy for the construction of
this moiety is the catalytic enantioselective addition of carbon
nucleophiles to ketones. A range of highly effective catalysts
have been developed for the enantioselective nucleophilic
addition to ketones.1 Furthermore, several approaches toward
catalytic enantioselective hydrogenation of diarylketones
have been described to provide the corresponding diaryl-
methanols.2 However, to the best of our knowledge, there
have been no reports of efficient asymmetric catalytic
nucleophilic addition to diarylketones. Such enantioselective
C-C bond formation via nucleophilic addition to diarylke-
tones is extremely difficult due to the similarity of the
substituents at the ketone functionality. Herein, we disclose
a catalytic asymmetric process providing chiral tertiary
alcohols with two aryl substituents.
The Reformatsky reaction3 consists of the zinc-induced
formation of ꢀ-hydroxy esters by the reaction of R-haloge-
nated esters with aldehydes or ketones.4 Recently, we
developed a new catalytic system for the Reformatsky
reaction with aldehydes based on the use of BINOL
(3) (a) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210–1211.
For reviews, see: (b) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004,
60, 9325. (c) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org. Chem.
2005, 70, 1048. (d) Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2.
(4) (a) Fu¨rstner, A. Synthesis 1989, 571. (b) Fu¨rstnerA. In Organozinc
Reagents; Knochel, P., Jones, P., Eds.; Oxford University Press: New York,
1999; p 287. (c) Marshall, J. A. Chemtracts 2000, 13, 705. (d) Podlech, J.;
Maier, T. C. Synthesis 2003, 633. (e) Nakamura, E. In Organometallics in
Synthesis: Manual A; Schlosser, M., Ed.; Wiley: New York, 2002; p 579.
(f) Orsini, F.; Sello, G. Curr. Org. Synth. 2004, 1, 111. (g) Suh, Y.; Rieke,
R. D. Tetrahedron Lett. 2004, 45, 1807. (h) Ku¨rti, L.; Czako´, B. Strategic
Applications of Named Reactions in Organic Synthesis; Elsevier Academic
Press: Boston, 2005; p 374. (i) Cozzi, P. C.; Benfatti, F.; Guiteras Capdevila,
M.; Mignogna, A. Chem. Commun. 2008, 22, 3317.
(1) (a) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.; Feng,
X.; Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654. (b) Zhang, D.; Yuan,
C. Tetrahedron 2008, 64, 2480. (c) Chen, C.-A.; Wu, K.-H.; Gau, H.-M.
Angew. Chem., Int. Ed. 2007, 46, 5373. (d) Miller, J. J.; Sigman, M. S.
J. Am. Chem. Soc. 2007, 129, 2752. (e) Riant, O.; Hannedouche, J. Org.
Biomol. Chem. 2007, 5, 873, and references therein.
(2) (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
ReV. 2006, 35, 454. (b) Kokura, A.; Tanaka, I.; Yamada, T. Org. Lett. 2006,
8, 3025. (c) Truppo, M. D.; Pollard, D.; Devine, P. Org. Lett. 2007, 9, 335.
(d) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999.
10.1021/ol801574m CCC: $40.75
Published on Web 08/21/2008
2008 American Chemical Society

derivative (S)-L1, Me2Zn, and ethyl iodoacetate as a nu-
cleophile in the presence of air.5 The presence of oxygen
Table 1. Reformatsky Reaction with Diarylketones
was found to be crucial to initiate a radical pathway.6,7
A
similar catalytic system was also developed for the reaction
with ketones.8 Preliminary experiments with phenyl o-tolyl
ketone (1a), using 20 mol % of (S)-L1, 2 equiv of ethyl
iodoacetate, 8 equiv of Me2Zn in two portions, and the slow
addition of the ketone over 30 min in the presence of air
provided the chiral alcohol 2a in 40% yield with 82% ee
(Scheme 1).8
Scheme 1. Reformatsky Reaction with Phenyl o-Tolyl Ketone
Inspired by this amazing result, we decided to study several
of the key parameters of this new transformation (Table 1).
Although, unfortunately, the para- and meta-substituted
diarylketones provided the racemic carbinol (Table 1, entries
1-3), the reaction with the ortho-substituted ketone 1e gave
the corresponding carbinol with high enantioselectivity, albeit
initially in low yield (entry 4). No byproducts were detected
in the reaction mixture, and the starting material could be
recovered. To improve the conversion, we tested several
Lewis acids and additives (TMSCl, BF3·OEt2, TiCl4, PPh3,
4-phenylpyridine N-oxide, LiCl, and CuTC), but none of
these induced any improvement.
a Isolated yield after column chromatography. b Determined by chiral
HLPC. c Conversion determined by GC-MS. d Direct addition of 1e. e Using
30 mol % of (S)-L1 and direct addition of 1e.
ketones8 to suppress the uncatalyzed reaction. This protocol,
however, generally gives lower conversions than that based
on direct addition of the electrophile. Direct addition of the
diarylketone 1e indeed provided better conversion (40%) and,
as expected, lower enantioselectivity (77% ee) (Table 1, entry
5). For this reason, we decided to perform direct addition of
the ketone and to increase the amount of ligand to 30 mol
%. Under these conditions we obtained higher enantioselec-
tivity (84% ee) and similar conversion (40%) (Table 1, entry
6). We also tested differing amounts of Me2Zn and ethyl
iodoacetate. The optimal reaction conditions were found to
be 30 mol % of (S)-L1, 6 equiv of ethyl iodoacetate, and 12
equiv of Me2Zn (in three portions) to provide the carbinol
2e in 52% yield and 84% ee (Table 2, entry 3).
While we were screening different diarylketones under the
optimal conditions, Cozzi et al. reported the use of triph-
enylphosphine oxide as an additive in the Reformatsky
reaction with aldehydes and ketones to improve yields.9 In
our catalytic system, the use of 20 mol % of Ph3PO afforded
similar yields but higher enantioselectivities (Table 2,
compare entries 1-2, 3-4, 5-6, 7-8, 9-10).10
The slow addition of the electrophile to the reaction
mixture was used in our previous work with aldehydes5 and
(5) Ferna´ndez-Iba´n˜ez, M. A.; Macia´, B.; Minnaard, A. J.; Feringa, B. L.
Angew. Chem., Int. Ed. 2008, 47, 1317.
´
(6) (a) Lew´ınski, J.; Sliwin´ski, W.; Dranka, M.; Justyniak, I.; Lipkowski,
J. Angew. Chem., Int. Ed. 2006, 45, 4826. (b) Lew´ınski, J.; Ochal, Z.;
Bojarski, E.; Tratkiewicz, E.; Justyniak, I.; Lipkowski, J. Angew. Chem.,
Int. Ed. 2003, 42, 4643. (c) For a review, see: Bertrand, M.; Feray, L.;
Gastaldi, S. C. R. Chim. 2002, 623
.
(7) For reactions promoted by the combination of oxygen and R2Zn,
see: (a) Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P.
Tetrahedron 2007, 63, 77. (b) Yamada, K.-i.; Yamamoto, Y.; Maekawa,
M.; Akindele, T.; Umeki, H.; Tomioka, K. Org. Lett. 2006, 8, 87. (c) Cozzi,
P. G. AdV. Synth. Catal. 2006, 348, 2075. (d) Akindele, T.; Yamamoto, Y.;
Maekawa, M.; Umeki, H.; Yamada, K.- I.; Tomioka, K. Org. Lett. 2006,
8, 5729. (e) Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.-i.;
Tomioka, K. Tetrahedron 2005, 61, 379. (f) Yamada, K.-i.; Yamamoto,
Y.; Maekawa, M.; Tomioka, K. J. Org. Chem. 2004, 69, 1531. (g)
Yamamoto, Y.; Yamada, K.-i.; Tomioka, K. Tetrahedron Lett. 2004, 45,
795. (h) Yamada, K.-i.; Yamamoto, Y.; Maekawa, M.; Chen, J.; Tomioka,
K. Tetrahedron Lett. 2004, 45, 6595. (i) Yamada, K.-i.; Yamamoto, Y.;
Tomioka, K. Org. Lett. 2003, 5, 1797. (j) Yamada, K.-i.; Fujihara, H. F.;
Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509.
(k) van der Deen, H.; Kellogg, R. M.; Feringa, B. L. Org. Lett. 2000, 2,
1593. (l) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
The reaction of the diarylketone 1a gave 68% yield and
85% ee (Table 2, entry 1). The use of 20 mol % of Ph3PO
(entry 2) slightly improved the yield (74%), whereas the
(9) Cozzi, P. G.; Mignogna, A.; Vicennati, P. AdV. Synth. Catal. 2008,
350, 975.
1999, 64, 9189
.
(8) Ferna´ndez-Iba´n˜ez, M. A.; Macia´, B.; Minnaard, A. J.; Feringa, B. L.
(10) The use of 10 or 30 mol % of Ph3PO provided 88% ee in both
cases for substrate 1a.
Chem. Commun. 2008, 22, 2571.
4042
Org. Lett., Vol. 10, No. 18, 2008

enantioselectivity was significantly enhanced (91% ee). The
Reformatsky reaction of the ortho-halogen-substituted dia-
rylketones 1e-1f (entries 3-6) gave the corresponding
carbinols with good yields and excellent enantioselectivities
(84-89% ee). The presence of a donating group (OMe) in
the ortho position of the diarylketone provided the carbinol
2g with good yield, although the enantioselectivity was
slightly lower (60-66% ee) (entries 7 and 8). The presence
of a linear and electron-withdrawing group (CN) in the ortho
position gave the lowest enantioselectivity (30-32% ee) seen
for this type of substrates (entries 9 and 10). No conversion
was detected when strongly electron-withdrawing ortho
substituents were present (CO2Me or NO2) (entries 11 and
12). The reaction with an alkyl (Et) substituent in the ortho
position gave excellent enantioselectivity (91% ee) (entry
13). With 2-naphthyl as one of the aryl groups of the
diarylketone, the reaction proceeded with excellent enanti-
oselectivity (88% ee) and good yield (70%) (entry 14). No
conversion was detected with the hindered substituted
diarylketones 1m (p-tolyl group in the ortho position) or 1p
(two subtituents in the ortho position) (entries 15, 18).
Finally, we also tested the reaction of diarylketones with an
ortho substituent in one aryl group and a para substituent in
the other aryl group (entries 16 and 17). The reaction of this
type of substrates provided the corresponding carbinols with
good to moderate yields and excellent enantioselectivites
(88-91% ee).
Table 2. Scope of the Reformatsky Reaction with
ortho-Substituted Diarylketones
On the basis of the catalytic cycle proposed by Cozzi for
the imino-Reformatsky reaction7c and the zinc intermediates
proposed by Noyori et al.,11 we suggest a possible mecha-
nism for the Reformatsky reaction with ketones as depicted
in Figure 1.
Figure 1. Proposed catalytic cycle for the Reformatsky reaction
promoted by Me2Zn and air.
In conclusion, we have developed the first enantioselective
Reformatsky reaction to the highly challenging class of
diarylketones with, in several cases, excellent enantioselec-
tivities. The use of ortho-substituted diarylketones is neces-
sary to achieve high levels of stereocontrol. Chiral tertiary
alcohols with two aryl groups were obtained. A readily
available BINOL derivative is used as a chiral catalyst, and
the reactions are performed with ethyl iodoacetate as
a Isolated yield after column chromatography. b Determined by chiral
HPLC. c Conversion determined by GC-MS.
(11) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 4832.
Org. Lett., Vol. 10, No. 18, 2008
4043

nucleophile and Me2Zn as the zinc source while the presence
of air was found to be crucial. Currently, efforts are directed
toward expanding the scope of this new asymmetric trans-
formation.
to the Spanish Ministry of Education and Science for a
postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Dutch Ministry of
Economic Affairs for financial support. M.A.F.-I is grateful
OL801574M
4044
Org. Lett., Vol. 10, No. 18, 2008