Catalytic, asymmetric, interrupted Feist-Benary reactions of α-tosyloxyacetophenones

Article abstract of DOI:10.1021/ol2026697

A new variant of the Interrupted Feist-Benary (IFB) reaction uses α-tosyloxyacetophenones as electrophiles and proceeds in good yields and excellent enantioselectivities.

Full text of DOI:10.1021/ol2026697

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6328–6330
Catalytic, Asymmetric, Interrupted
ꢀ
r-Tosyloxyacetophenones
Michael A. Calter* and Alexander Korotkov
FeistÀBenary Reactions of
Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459,
United States
mcalter@wesleyan.edu
Received October 4, 2011
ABSTRACT
ꢀ
A new variant of the Interrupted FeistÀBenary (IFB) reaction uses R-tosyloxyacetophenones as electrophiles and proceeds in good yields and
excellent enantioselectivities.
Substituted furanoids are common building blocks for
the synthesis of many natural products and useful inter-
mediates in organic synthesis.1 Among other methods, the
asymmetric IFB reaction involve β-bromo-R-ketoesters as
electrophiles.4
We decided to expand the scope of the catalytic, asym-
metric IFB reaction to include less highly functionalized
electrophiles. We chose acetophenone derivatives as our
initial set of substrates (Scheme 1). In analogy to the previous
work, we chose to use bromide as the leaving group. How-
ever, these simple R-bromoketones, without the adjacent,
activating ester, did not afford appreciable product.
Fortunately, we then discovered that ketones bearing an
R-tosyloxy (OTs) group were much more reactive, and
therefore we decided to explore the catalytic, asymmetric
reactions of R-tosyloxyacetophenones.
We began our study using the reaction between
R-tosyloxy-p-nitroacetophenone5 and 1,3-cyclohexyldione
to screen for the optimal catalyst (Table 1). Under stan-
dard conditions using Proton Sponge (PS) as a base and
quinuclidine as a catalyst the reaction went to the comple-
tion in about 10 min and the desired product was isolated
in moderate yield. As bis(cinchona alkaloid)pyrimidines
proved to be effective in the parent reaction, we decided to
screen the quinidine catalysts previously synthesized in our
group.3,6 These initial results indicated that catalysts with
R2 = tBu (entries 1 and 2) lead to low enantioselectivity,
ꢀ
Interrupted FeistÀBenary (IFB) reaction;the condensa-
tion of R-haloketones and 1,3-dicarbonyl compounds;
provides quick access to highly substituted hydroxyfura-
noids from simple and easily accessible starting materials.2
We found several years ago that β-bromo-R-ketoesters were
suitable electrophiles for a asymmetric version of the IFB
reaction catalyzed by bis(cinchona alkaloid)pyrimidines.3
The ester moiety of the β-bromo-R-ketoester presumably
activates the ketone carbonyl carbon for nucleophilic
attack, allowing the reaction to proceed rapidly at low
temperature. We also postulated that the ester carbonyl
provides a second hydrogen-bond acceptor, further orga-
nizing the transition state and allowing for high enantio-
selectivity.3 Indeed, all reported examples of the catalytic,
(1) Kilroy, T. G.; O’Sullivan, T. P.; Guiry, P. J. Eur. J. Org. Chem.
2005, 4929–4949.
ꢀ
(2) (a) Feist, F. Chem. Ber. 1902, 35, 1537–1544. (b) Benary, E. Chem.
Ber. 1911, 44, 489–492. (c) Dunlop, A. P.; Hurd, C. D. J. Org. Chem.
1950, 15, 1160–1164. (d) Cantlon, I. J.; Cocker, W.; McMurry, T. B. H.
Tetrahedron 1961, 15, 46–52. (e) Calter, M. A.; Zhu, C. Org. Lett. 2002,
4, 205–208. (f) Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002,
4, 209–212.
(3) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc.
2005, 127, 14566–14567.
(4) Chen, H.; Jiang, R.; Wang, Q. F.; Sun, X. L.; Luo, J.; Zhang, S. Y.
(5) Kose, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L; Wettach,
R. H. J. Org. Chem. 1982, 47, 2487–2489.
Chin. Chem. Lett. 2010, 21, 167–170.
r
10.1021/ol2026697
Published on Web 11/04/2011
2011 American Chemical Society

These cinchona alkaloid-derived catalysts can be synthe-
sized in two steps starting from commercially available 4,6-
dichloro-2-methylthio-5-phenylpyrimidine (Scheme 2).
LiebeskindÀSrogl coupling of this substrate with aryl
boronic acids allows the introduction of different aryl groups
at the R1 position.7 The resulting dichloropyrimidines react
with quinine or quinidine in the presence of KOH in refluxing
toluene to afford bis(cinchona alkaloid)pyrimidine catalysts
3f and 4aÀd.
ꢀ
Scheme 1. Interrupted FeistÀBenary Reaction
Scheme 2. Synthesis of New Catalysts
while a catalystwithphenylatboth the R1 and R2 positions
(entry 5) gives a promising result (74% ee). For further
improvement of ee toward a synthetically useful level, we
decided to synthesize new catalysts containing different
aryl groups at the R1 position.
Screening of these newly synthesized quinine catalysts
showed that the 2,3-dimethylphenyl group noticeably im-
proves the ee of the product (82%, Table 2). Gratifyingly, a
similar catalyst containing a 1-naphthyl group gave over
90% ee in the test reaction. Other large aryl groups, like
9-phenanthryl, 3-benzothiophene, or 2-naphthyl, did not
significantly improve enantioselectivity. The quinidine
version of the catalyst with the 1-naphthyl substituent
was also synthesized (3f) and gave the opposite enantiomer
of the product in 96% ee.
Table 1. Target IFB Reaction
Table 2. IFB Reaction of 1a and 2a in CH2Cl2 in the Presence of
PS and 10 mol % of Catalyst at À42 °C
entry
catalyst
yield %
ee %a
1
2
3
4
6
4a
4b
4c
4d
3f
83
80
73
79
81
82 (S)
92 (S)
84 (S)
69 (S)
96 (R)
a Determined by HPLC analysis of the purified product.
While the IFB reaction of R-tosyloxy-p-nitroacetophe-
none proceeds smoothly at À42 °C, the less reactive R-
tosyloxy-p-bromoacetophenone (1f) affords the desired
product in an unsatisfying 51% yield at this temperature
(Table 3, entry 1). The significant fall in the yield was
caused by competing C-alkylation. To optimize the reac-
tion conditions, we varied solvent, base, and temperature.
The yield improves if the reaction is run at higher tem-
perature (0 °C), but the enantioselectivity drops signifi-
cantly in both CH2Cl2 and CH3CN in the presence of PS.
entry
catalyst
yield %
ee %a
1
2
3
4
5
3a
3b
3c
3d
3e
79
69
72
81
74
46
11
10
60
74
a Determined by HPLC analysis of the purified product.
(6) (a) Calter, M. A.; Wang, J. Org. Lett. 2009, 11, 2205–2208.
(b) Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z. M.; Xe, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785–3786.
(7) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979–981.
Org. Lett., Vol. 13, No. 23, 2011
6329

Switching from PS to K2CO3 allowed us to perform the
reaction at higher temperature (0 °C) in acetonitrile with-
out any loss of stereoinduction. Although reaction in
CH2Cl2 gives a better ratio of IFB vs C-alkylation product,
and as a result a better yield, the ee of the product is too low
at 0 °C.
Table 4. Substrate Scope of IFB Reaction
Table 3. Optimization of Reaction Conditions for Reaction of
1b and 2a
electro-
%
%
entry
phile
X1
X2
R
catalyst product yield eea
1
1a
1a
1a
1b
1c
1d
1d
1e
1e
1f
NO2
NO2
NO2
CN
CF3
F
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4b
3f
5a
5a
5a
5b
5c
5d
5d
5e
5e
5f
98
97
95
82
87
76
73
69
71
65
66
70
64
66
78
77
61
90
69
91
94b
95c
94
96
90
93
84
96
96
96b
99
84
90
82
90
91
98
94
2
H
H
H
H
H
H
H
H
H
H
H
H
H
3
4b
4b
4b
4b
4c
4b
4c
4b
3f
4
5
6
temp
5f:
% yield % ee
7
F
entry
base
PS
solvent
(°C)
alkylationa
of 5f
of 5fb
8
Cl
9
Cl
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH3CN
CH3CN
À42
0
1.2:1
9.0:1
1.1:1
3.2:1
8.9:1
32:1
51
76
47
67
73
85
50
69
95
82
97
88
86
80
96
94
10
11
12
13
14
15
16
17
18
19
Br
Br
I
PS
PS
PS
1f
5f
À28
0
1g
1h
1h
1i
4b
4b
4c
4b
4c
4c
4b
4b
5g
5h
5h
5i
H
K2CO3 CH2Cl2
K2CO3 CH2Cl2
K2CO3 CH3CN
K2CO3 CH3CN
À28
0
H
H
NO2 Me
NO2 Me
À28
0
1.2:1
5.0:1
1i
H
5i
1j
H
Br
H
Me
H
5j
a Determined by 1H NMR analysis of the unpurified reaction
mixture. b Determined by HPLC analysis of the purified product.
1c
1f
CF3
Br
5k
5l
H
H
a Determined by HPLC analysis of the purified product. b The (R)-
enantiomer is the major product. c Reaction run at À42 °C.
With optimized reaction conditions in hand, we then
tested the scope of the reaction by varying the substituents
on the phenyl ring of the electrophile. We found that the
electronic nature of the aryl group has some effect on the
rate and yield but, at the same time, a very small influence
on the stereochemical outcome of the reaction. Electron-
withdrawing groups accelerate the reaction so that it is
done faster and yields of the products are generally higher
(Table 4, entries 1À5).
We assigned the absolute stereochemistry of IFB pro-
duct 5f, made in the reaction catalyzed by the quinine-
catalyst 4b, by anomalous dispersion analysis of single
crystal X-ray data. By analogy, the remaining IFB pro-
ducts were assigned as S-isomers if 4b was used and R with
quinine-derived catalyst 3f .
ꢀ
In conclusion, the interrupted FeistÀBenary reaction of
Most of the p-halo-substituted-R-tosyloxyacetophenones
give IFB products in excellent ee’s (entries 6À12) and good
yields with the catalyst 4b. The reaction of p-chloro and
unsubstituted R-tosyloxyacetophenone showed reduced
enantioselectivity, but it can be significantly improved by
switching to the catalyst 4c containing a 9-phenanthryl
group at the R1 position (entries 7 and 14). Meta-substi-
tuted substrates also react with only slightly reduced ee and
yields. In general, in order to increase the enantioselectivity
the reaction can be carried out at lower temperature
(entries 3 and 16), but the yield can worsen for substrates
with no electron-withdrawing group on an aromatic ring.
Finally, both dimedone 2b and cyclohexyldione 2a func-
tion as satisfactory nucleophiles for the reaction, giving
very similar results in terms of yields and enantioselectiv-
ities of the IFB products.
R-tosyloxy-acetophenones and cyclic 1,3-diketones pro-
ceeds in good to excellent yields under mild conditions.
Newly synthesized bis(cinchona alkaloid)pyrimidines af-
ford the IFB product with excellent asymmetric induction.
Acknowledgment. The authors thank the NIH for fi-
nancial support of this project. We acknowledge Dr. Ryan
Phillips (IRIX Pharmaceuticals) for preliminary experi-
ments. We thank Dr. Christopher Incarvito of the Yale
University X-ray Crytallographic Facility for completing
the X-ray structure of 5f.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
6330
Org. Lett., Vol. 13, No. 23, 2011