Enantioselective enolate protonations: Friedel-crafts reactions with α-substituted acrylates

Article abstract of DOI:10.1002/anie.200804221

(Chemical Equation Presented) Templates rule: A Zn(NTf₂) ₂/1 catalyzed tandem Friedel-Crafts alkylation/enantioselective protonation of pyrroles with isoxazolidinone-derived α-substituted a,b-unsaturated imides, provides high levels

Full text of DOI:10.1002/anie.200804221

Angewandte
Chemie
DOI: 10.1002/anie.200804221
Asymmetric Catalysis
Enantioselective Enolate Protonations: Friedel–Crafts Reactions with
a-Substituted Acrylates**
Mukund P. Sibi,* Julien Coulomb, and Levi M. Stanley
In recent decades, enantioselective protonation of prochiral
enolates has become a practical means of accessing a-chiral
carbonyl compounds with high enantiomeric purity.[1] The
majority of work in this area has focused on the enantiose-
lective protonation of isolated enolate precursors, such as silyl
enol ethers.[2] Silyl enol ethers derived from a-substituted
cyclic ketones have been most widely studied, owing to the
fixed enolate geometry inherent in cyclic systems. Enantio-
selective protonations of acyclic enolate derivatives have also
been developed, although to a lesser extent.[2a,b,3] The involve-
ment of acyclic enolates is more challenging, especially in the
context of transient enolate generation, because strict control
of enolate geometry is essential for enantioselectivity.
The issues associated with enantioselective protonation of
acyclic enolates are directly relevant to tandem sequences
involving a 1,4-addition of a nucleophile to an a-substituted
a,b-unsaturated carbonyl compound, such as A (Scheme 1),
followed by enantioselective protonation of the resulting
transient enolate. Several tandem 1,4-addition/enantioselec-
tive protonation sequences have been reported for nitrogen,[4]
sulfur,[5] phosphorous,[5b] and carbon nucleophiles.[6] However,
these current sequences are somewhat limited and significant
work remains necessary to access catalyst/substrate combina-
tions that will prove general across nucleophile classes.
The use of carbon-based nucleophiles was of particular
enantioselective protonation sequences is currently limited to
rhodium-catalyzed additions of aryl boronic acids and potas-
sium aryltrifluoroborates.[6] Thus, we identified the Friedel–
Crafts (F–C) reaction, one of the more important and widely
[7]
ꢀ
studied C C bond-forming reactions, as a valuable candi-
date for development of a 1,4-addition/enantioselective pro-
tonation process. However, only in the past decade have
highly enantioselective variants[8] using chiral Lewis acids[9] or
organocatalysts[10] been reported for F–C alkylations of
aromatic and heterocyclic nucleophiles with a variety of
electrophilic acceptors. In all reported enantioselective F–C
alkylations that use a,b-unsaturated carbonyl compounds as
acceptors, the stereochemistry has been established at the b-
carbon of the acceptor during the nucleophilic addition step.
In contrast, there are no known examples wherein stereocen-
ters are installed a to the carbonyl carbon, as it would require
an enantioselective protonation step after nucleophile addi-
tion [A!C, Scheme 1, Eq. (1)], which would be possible only
if the enolate formed with a single E or Z geometry [D or E,
Scheme 1; Eq. (2)].
Based on our previous work with a-substituted acrylates
in enantioselective transformations,[11] our starting hypothesis
was that rotamer control of the enoyl geometry (s-cis F or s-
trans G) would impact both reactivity and enolate config-
uration. Thus, a judicious choice of an achiral template is
important. Herein we report the first examples of highly
enantioselective enolate protonation in Friedel–Crafts alky-
lations using pyrrole nucleophiles and a-substituted a,b-
unsaturated imide electrophiles. Critical to the success of the
tandem sequence is the development of a new achiral
isoxazolidinone auxiliary which enhances reactivity and
incorporates all the features necessary for efficient control
of rotamer geometry.[11e]
ꢀ
interest to us because C C bond formation in 1,4-addition/
Our work began with the aim of identifying a combination
of achiral template and chiral Lewis acid that provided high
reactivity and selectivity in the model alkylation of N-
methylpyrrole[12] 5 (5 equivalents, to minimize the formation
of the dialkylation product) with a-methyl acrylate acceptors
(Table 1). After initial studies on the model reaction system
(data not shown), we identified chiral Lewis acids prepared
from the Ph–dbfox ligand[13] 6 (Ph–dbfox = (R,R)-4,6-diben-
zofurandiyl-2,2ꢀ-bis(4-phenyloxazoline)), and zinc(II) salts as
promising leads for further reaction optimization. The
reaction of 5 with the oxazolidinone-derived substrate 1 in
the presence of Zn(NTf2)2 and 6 gave the addition product in
good yield and good enantioselectivity when the reaction was
performed at room temperature (Table 1, entry 1). In con-
trast, the same reaction at ꢀ308C gave trace amounts of the
alkylation product (Table 1, entry 2). In an attempt to
improve reactivity and selectivity, we evaluated the use of
Scheme 1. Enantioselective protonation in Friedel–Crafts alkylations.
[*] Prof. Dr. M. P. Sibi, Dr. J. Coulomb, Dr. L. M. Stanley
Department of Chemistry and Molecular Biology
North Dakota State University, Fargo, ND 58105 (USA)
Fax: (+1)701-231-1057
E-mail: mukund.sibi@ndsu.edu
Homepage: http://www.ndsu.nodak.edu/sibi_research/
Sibi_Group/Welcome.html
[**] We thank the National Science Foundation (NSF-CHE-0719061) for
financial support and Digamber Rane for experimental assistance.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804221.
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Table 1: Template identification and optimization of reaction conditions.[a]
reactivity and selectivity. Control
experiments suggest that the reac-
tion is under kinetic control and
external proton donors such as
phthalimide or succinimide had
negligible impact on selectivity.[16]
We propose that intermediate B
(Scheme 1) is the most likely
proton source in these experiments.
We have evaluated the scope of
the reaction, with respect to the a-
substituent on the a,b-unsaturated
imide acceptor, using the optimal
conditions identified in Table 1. The
results are presented in Table 2. As
noted earlier, the reaction of a-
methyl acrylate 4 with 5 gave the
corresponding product in high yield
Entry
SM
Lewis Acid
T [8C]
t
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1
1
2
2
3
4
4
4
4
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(ClO4)2
Zn(NTf2)2
Zn(NTf2)2
25
ꢀ30
25
2 h
16 h
2 h
16 h
8 h
10 min
1 h
7
7
8
8
9
10
10
10
10
89
<10
98
14
36
98
62
98
96
83
ND
77
ND
60
84
90
93
93
ꢀ30
25
25
25
and
high
enantioselectivity
(Table 2, entry 1). An even higher
level of enantioselectivity was
obtained with an a-ethyl-substi-
tuted acceptor (Table 2, entry 2).
Substrates containing functional-
ized a substituents were also com-
petent acceptors, furnishing the
ꢀ30
1 h
16 h
ꢀ50
[a] For detailed reaction conditions, see the Supporting Information; SM=starting material. [b] Yield of
isolated products after purification by column chromatography. [c] Determined by HPLC on a chiral
stationary phase; ND=not determined.
ꢀ
pyrazolidinone and N H imide auxiliaries in the model
reaction system. These auxiliaries were chosen because,
unlike oxazolidinone, they have been shown to increase
reactivity by minimizing A1,3 strain when appended to a-
substituted a,b-unsaturated carbonyl substrates.[11] Pyrazoli-
dinone substrate 2 reacted well at room temperature with
Zn(NTf2)2/6 (Table 1, entry 3) as the chiral Lewis acid, but
again gave poor reactivity at ꢀ308C (Table 1, entry 4). The
products in high yields and selectivities (Table 2, entries 3
and 4). A styrene derivative 14 also gave the alkylated
product with high selectivity (Table 2, entry 5). Thus, the new
methodology is tolerant of a variety of substituents at the
a carbon with respect to chemical efficiency (68–98% yield)
as well as enantioselectivity (93–98% ee).
The scope of the pyrrole nucleophile in the F–C alkyla-
tion/enantioselective protonation reaction was also investi-
gated (Table 3). A variety of pyrroles were evaluated under
the optimal reaction conditions using substrate 4 as the
acceptor. The reaction of the parent pyrrole gave the
alkylated product in excellent yield and selectivity (Table 3,
entry 1). N-Alkyl pyrroles were even more efficient (Table 3,
entries 2–5). A variety of alkyl substituents on the pyrrole
ꢀ
N H imide template 3, which nearly eliminates the potential
for A1,3 strain, gave surprisingly low reactivity and reduced
selectivity relative to substrates 1 and 2 (Table 1, entry 5).
At this point we sought an achiral auxiliary that would
minimize A1,3 interactions and provide enhanced reactivity
under the low-temperature reaction conditions required for
improved enantioselectivity. To this end, we have designed a
new and easily prepared achiral isoxazolidinone[14] template,
(substrate 4), in which incorporation of oxygen avoids A1,3
interactions and also provides electronic activation relative to
oxazolidinone 1. The room-temperature reaction of 4 with 5
in the presence of Zn(NTf2)2/6 gave improved reactivity (98%
yield in 10 min, as compared to 89% yield in 2 h for 1, Table 1,
entry 6 vs entry 1) with comparable selectivity (84% ee vs
83% ee). Notably, the use of Zn(ClO4)2/6 as the chiral Lewis
acid led to improved enantioselectivity, but lower reaction
efficiency (Table 1, entry 7 vs entry 6). However, the
improved reactivity of isoxazolidinone 4 enabled the Zn-
(NTf2)2/6-catalyzed reaction with 5 to proceed efficiently at
lower temperatures (ꢀ30 and ꢀ508C), with superior enantio-
selectivity (93% ee, Table 1, entries 8 and 9). These experi-
ments constitute the first examples of successful enantiose-
lective protonation during Friedel–Crafts alkylations.[15] Fur-
thermore, they demonstrate that the achiral template plays a
key role in the outcome of the reaction, with respect to
Table 2: Evaluation of the scope of the acceptor.[a]
Entry
SM
t [h]
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
4
11
12
13
14
1
2
3
4
48
10
15
16
17
18
98
89
90
68
74
93
97
98
98
97
[a] For detailed reaction conditions, see the Supporting Information.
TIPS=triisopropylsilyl. [b] Yield of isolated products after purification by
column chromatography. [c] Determined by HPLC on a chiral stationary
phase.
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Chemie
Table 3: Evaluation of the scope of the nucleophile.[a]
[1] For a recent review on enolate protonation, see: L. Duhamel, P.
Duhamel, J.-C. Plaquevent, Tetrahedron: Asymmetry 2004, 15,
3653.
[2] For examples, see: a) S. Nakamura, M. Kaneeda, K. Ishihara, H.
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Angew. Chem. Int. Ed. 2007, 46, 7090; e) C. H. Cheon, H.
Yamamoto, J. Am. Chem. Soc. 2008, 130, 9246.
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Sakata, M. Stec, E. Suna, J. Am. Chem. Soc. 2000, 122, 4602, and
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Org. Lett. 2000, 2, 3773; c) N. T. Reynolds, T. Rovis, J. Am.
Chem. Soc. 2005, 127, 16406.
Entry R1
R2 Nuc t [h] Product Yield [%][b] ee [%][c]
1
H
H
H
H
H
H
H
19
5
20
21
22
23
1
1
1
2
3
26
10
27
28
29
30
31
32
75
98
92
84
84
70
98
98
81
93
91
90
91
73
43
88
2
Me
3
Et
4
CH2CH2Br
5
Bn
Ph
H
6[d]
7
16
1
Et 24
Et 25
8
Me
1
[a] For detailed reaction conditions, see the Supporting Information.
[b] Yield of isolated products after purification by column chromatog-
raphy. [c] Determined by HPLC on a chiral stationary phase. [d] Reaction
at room temperature.
[4] Y. Hamashima, H. Somei, Y. Shimura, T. Tamura, M. Sodeoka,
Org. Lett. 2004, 6, 1861.
[5] a) K. Nishimura, M. Ono, Y. Nagaoka, K. Tomioka, Angew.
Chem. 2001, 113, 454; Angew. Chem. Int. Ed. 2001, 40, 440; b) D.
Leow, S. Lin, S. K. Chittimalla, X. Fu, C.-H. Tan, Angew. Chem.
2008, 120, 5723; Angew. Chem. Int. Ed. 2008, 47, 5641.
[6] a) L. Navarre, S. Darses, J.-P. Genet, Angew. Chem. 2004, 116,
737; Angew. Chem. Int. Ed. 2004, 43, 719; b) M. P. Sibi, H.
Tatamidani, K. Patil, Org. Lett. 2005, 7, 2571; c) C. G. Frost, S. D.
Penrose, K. Lambshead, P. R. Raithby, J. E. Warren, R. Gleave,
Org. Lett. 2007, 9, 2119; d) L. Navarre, R. Martinez, J.-P. Genet,
S. Darses, J. Am. Chem. Soc. 2008, 130, 6159.
[7] a) G. A. Olah, Friedel–Crafts Chemistry, Wiley, New York, 1973;
b) M. Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi,
Synlett 2005, 1199.
[8] For a recent review on asymmetric Friedel–Crafts chemistry, see:
T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903.
[9] a) K. B. Jensen, J. Thorhauge, R. G. Hazell, K. A. Jørgensen,
Angew. Chem. 2001, 113, 164; Angew. Chem. Int. Ed. 2001, 40,
160; b) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W. Lam, J.
Wu, J. Am. Chem. Soc. 2003, 125, 10780.
[10] a) J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
1172; b) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc.
2001, 123, 4370.
[11] a) M. P. Sibi, N. Prabagaran, S. G. Ghorpade, C. P. Jasperse, J.
Am. Chem. Soc. 2003, 125, 11796; b) M. P. Sibi, G. Petrovic, J.
Zimmerman, J. Am. Chem. Soc. 2005, 127, 2390; c) M. P. Sibi,
L. M. Stanley, T. Soeta, Org. Lett. 2007, 9, 1553; d) M. P. Sibi,
J. B. Sausker, J. Am. Chem. Soc. 2002, 124, 984; e) M. P. Sibi, Z.
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2349.
nitrogen were tolerated and gave products in good to
excellent yields with > 90% enantioselectivities. In contrast,
the reaction of the less nucleophilic N-phenylpyrrole with 4
was less efficient and gave product 28 with lower selectivity
(Table 3, entry 6). Using 2-ethyl pyrrole as the nucleophile
gave the product in nearly quantitative yield, but with modest
enantioselectivity (Table 3, entry 7). Gratifyingly, the reaction
of 2-ethyl-N-methylpyrrole gave a single alkylated product in
very high yield and high selectivity (Table 3, entry 8).
The absolute stereochemistry of product 10 was deter-
mined to be S by correlation.[16] Molecular models of the
enolate intermediates D and E suggest that the S absolute
configuration resulted from protonation of the Z enolate E
rather than E enolate D (Scheme 1). The intermediacy of the
Z enolate E in turn implies that nucleophilic addition occurs
on the s-cis rotamer F. The preferred reactivity of the s-cis
over the s-trans rotamer has been observed in related systems
and appears to have some generality.[11e] While this s-cis
preference is not fully understood, it appears likely to be
electronic rather than steric in origin.[17] The extension of the
present methodology to different classes of nucleophiles and
a,b-disubstituted acceptors is underway.
[12] For the use of pyrroles in enantioselective Friedel–Crafts
reactions, see: a) B. M. Trost, C. Muller, J. Am. Chem. Soc.
2008, 130, 2438; b) M. Abid, L. Teixeira, B. Tꢂrꢂk, Org. Lett.
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Garcia, A. Linden, J. Am. Chem. Soc. 2005, 127, 4154; d) D. A.
Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt, R. Xu, J. Am.
Chem. Soc. 2007, 129, 10029; e) G. Li, G. B. Rowland, E. B.
Rowland, J. C. Antilla, Org. Lett. 2007, 9, 4065.
[13] U. Iserloh, Y. Oderaotoshi, S. Kanemasa, D. P. Curran, Org.
Synth. 2003, 80, 46.
[14] a) A. S. Reddy, M. S. Kumar, G. R. Reddy, Tetrahedron Lett.
2000, 41, 6285; b) S. Wolfe, M.-C. Wilson, M.-H. Cheng, G. V.
Shustov, C. I. Akuche, Can. J. Chem. 2003, 81, 937.
Experimental Section
General Procedure for Friedel–Crafts Alkylation/Enantioselective
Protonation Reactions: A mixture of Zn(NTf2)2 (0.060 mmol) and
Ph–dbfox ligand 6 (0.066 mmol) in CH2Cl2 (1 mL) was stirred at room
temperature for 30 min. 4 ꢁ molecular sieves (100 mg) were then
added, followed by the a-substituted acrylate acceptor (0.20 mmol)
and the pyrrole nucleophile (1.0 mmol). The reaction was monitored
by 1H NMR spectroscopy. When the reaction was complete, the
reaction mixture was concentrated and purified by flash column
chromatography on silica, using mixtures of hexane and ethyl acetate
as the eluent.
[15] Reducing the catalytic loading from the optimal 30 mol% led to
lower yield, selectivity, and longer reaction time.
[16] See the Supporting Information for details.
Received: August 26, 2008
Published online: November 17, 2008
[17] D. M. Birney, K. N. Houk, J. Am. Chem. Soc. 1990, 112, 4127.
Keywords: alkylation · asymmetric catalysis · chiral auxiliaries ·
.
enantioselectivity · nitrogen heterocycles
Angew. Chem. Int. Ed. 2008, 47, 9913 –9915
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