Enantioselective 1,3-dipolar cycloaddition of nitrones with ethyl vinyl ether: The difference between Bronsted and Lewis acid catalysis

Article abstract of DOI:10.1002/anie.200705314

(Chemical Equation Presented) Bronsted and Lewis face off: A new chiral N-triflyl phosphoramide is used for asymmetric 1,3-dipolar cycloaddition of diaryl nitrones to ethyl vinyl ether to give the endo products in up to 93% ee (see scheme; Tf = trifluoromethanesulfonyl; Ad = adamantyl). The structure of the chiral phosphoramide was confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1002/anie.200705314

Angewandte
Chemie
DOI: 10.1002/anie.200705314
Asymmetric Synthesis
Enantioselective 1,3-Dipolar Cycloaddition of Nitrones with Ethyl
Vinyl Ether: The Difference between Brønsted and Lewis Acid
Catalysis**
Peng Jiao, Daisuke Nakashima, and Hisashi Yamamoto*
Chiral Brønsted acid catalysis has recently become attractive
because of its wide application in various asymmetric
syntheses.[1] Among these catalysts, chiral phosphoric acids
represent an outstanding example.[2] Whereas phosphoric
acids are used to activate imine type compounds, we reported
the first preparation of chiral N-triflyl phosphoramide 1a
(Scheme 1, Table 1) and its utility in activating a carbonyl
reaction at lower temperatures (À40 to À558C). In sharp
contrast to the exo selectivity of the AlMe–binol catalyzed
cycloaddition of diaryl nitrones with alkyl vinyl ether
reported by Jørgensen and co-workers,[6] our reactions give
the endo products as the major diastereomers.[7]
First, we tested commercially available N,a-diphenyl
nitrone as a substrate for 1,3-dipolar cycloadditions. When
the reaction was carried out between À78 and À208C in
CH2Cl2, the ee value was increased to 64% from 51% at room
temperature. When electron-withdrawing groups were intro-
duced to the nitrone similar results were observed, but the
reaction rate was accelerated significantly. Then, the cyclo-
addition of N-(4-chlorophenyl)-a-phenyl nitrone was con-
ducted in different solvents and at various temperatures with
1a as the catalyst.[8] CHCl3 gave the best results with respect
to both the diastereo- and enantioselectivities of the products
(Table 1, entry 1).
Scheme 1. Chiral phosphoramide-catalyzed 1,3-dipolar cycloaddition of
diaryl nitrones with ethyl vinyl ether. Tf=trifluoromethanesulfonyl.
Next, we compared chiral phosphoramides bearing differ-
ent aryl groups at the 3,3’-positions of the binol backbone
under the optimized reaction conditions (Table 1). On the
group in the asymmetric Diels–Alder reaction of ethyl vinyl
ketone with silyloxydienes.[3] In these reactions, ethyl vinyl
ketone was activated by 1a to give the endo products in up to
92% ee, whereas chiral phosphoric acids failed to give the
Diels–Alder product under the same reaction conditions.
Another example of a chiral N-triflyl phosphoramide serving
as a catalyst for carbonyl group activation is the asymmetric
Nazarov cyclization reported by Rueping et al.[4] Reported
herein is a new application of our chiral phosphoramide in the
asymmetric 1,3-dipolar cycloaddition of diaryl nitrones with
ethyl vinyl ether (Scheme 1). This is the first example of an
asymmetric 1,3-dipolar cycloaddition of nitrones catalyzed by
a chiral Brønsted acid. Wittkopp and Schreiner reported some
pioneering work on 1,3-dipolar cycloadditions between an
N,a-diphenyl nitrone and isopropyl vinyl ether at high
temperature with one equivalent of an achiral thiourea
Table 1: Catalyst screening for the 1,3-dipolar cycloaddition of nitrone
(see Scheme 1).[a,b]
Entry Ar
Yield [%][c] endo:exo[d] ee [%][e]
1
1a 70
79:21
77
2
3
1b 53
1c 86
57:43
81:19
17
7
derivative as
a catalyst, and modest acceleration was
reported.[5] Our phosphoramide can effectively catalyze the
4
5
1d 92
90:10
96:4
76
84
[*] P. Jiao,D. Nakashima,Prof. Dr. H. Yamamoto
Department of Chemistry
The University of Chicago
5735 South Ellis Avenue,Chicago,IL 60637 (USA)
Fax: (+1)773-702-0805
1e 92
E-mail: yamamoto@uchicago.edu
[a] Nitrone substitutents: R1 =4-ClPh and R2 =Ph. Ad=adamantyl.
[b] CHCl3 was used as the solvent and reactions were run at À558C for
1 h. [c] Yield of isolated cycloadduct. [d] Determined by 1H NMR
spectroscopy. [e] Determined for the endo product by chiral HPLC
methods.
[**] Financial support has been provided by the Camille and Henry
Dreyfus Foundation and the University of Chicago. We thank Dr. Ian
Steele for X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Scope of diaryl nitrones in 1,3-dipolar cycloadditions with ethyl
basis of the diastereo- and enantioselectivities of the reaction,
vinyl ether (see Scheme 1).[a,b]
catalysts having 2,6-isopropyl groups on the phenyl ring
attached to the binol backbone (1a, 1d, and 1e) are superior
to those lacking the isopropyl groups (1b and 1c). Gratify-
ingly, the catalyst with the 1-adamantyl group at the para
position of Ar ring (1e) gave a higher ee value than 1a or 1d
(Table 1, entry 5 versus entries 1 and 4). In fact, X-ray
crystollographic analysis of 1e revealed that the adamantyl
groups in the molecule are positioned to create a suitable
chiral environment for the reaction (Figure 1). The crystal
Entry R1
R2
T [8C] Yield [%][c] endo:exo[d] ee [%][e,f]
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
À40
À40
À55
À55
85
78
95
69
91
92
92
74
66
98
95
>99
76
>99
90
96:4
95:5
97:3
96:4
89:11
91:9
96:4
96:4
93:7
89:11
93:7
96:4
87:13
87:13
88:12
93:7
70
56
90
92
90
85
84
90
93
92
89
92
85
87
87
87
2[g]
3
4-ClPh
4-CF3Ph
4-NO2Ph À55
3,5-F2Ph À50
4
5
6
7
8
9
10
11
12[h]
13
14
15
16[h]
4-ClPh Ph
4-ClPh 4-ClPh
4-ClPh 4-CF3Ph
À55
À55
À55
4-ClPh 4-NO2Ph À55
4-ClPh 2-furyl
À50
4-ClPh 2-thienyl À50
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
4-NO2Ph À55
2-furyl
À40
2-thienyl À40
À40
97
[a] Used 0.2 mmol nitrone and 5 mol% 1e. [b] Used CHCl3 as the solvent
and the reaction time was 1 h. [c] Yield of isolated cycloadduct.
[d] Determined by 1H NMR spectroscopy. [e] Determined for endo
product by chiral HPLC methods. [f] For assignment of absolute
configurations,see the Supporting Information. [g] Used tert-butyl vinyl
ether. [h] Reaction time of 6 h.
Figure 1. ORTEP view (50% probability level) of catalyst 1e in anion
form (O red,S yellow,F green,N blue,P purple,C gray).
À
structure of 1e reveals that one P O bond (1.45 Š) is shorter
than the other two bonds (1.60 Š), which implies the
[9]
=
À
existence of P O bond. The observed P N bond (1.61 Š)
is longer than P N bond (1.52Š). [9] Thus, as suggested in the
=
molecular structures of the phosphoramides (Scheme 1), the
proton is located on the N atom, instead of the O atom
bonded to the P center.
The scope of the nitrones in 1,3-dipolar cycloaddition was
examined by using catalyst 1e (Table 2). In most cases (the
exceptions are Table 2, entries 12 and 16) the reaction was
complete within 1 hour and gave the endo products predom-
inantly and with high enantioselectivities. For diphenyl nitro-
nes an electron-withdrawing group (R2) is necessary to ensure
good enantioselectivity.
The diastereoselectivity difference between the above
[3+2] cycloaddition catalyzed by Brønsted acid 1e (up to
96% endo selective) and the reaction catalyzed by a AlMe–
binol complex (up to > 95% exo selective) can be rationalized
by transition-state (TS) structures (Scheme 2).[6] The domi-
nant secondary p-orbital interactions that are responsible for
endo selectivity in the Diels–Alder reaction are weaker in the
1,3-dipolar cycloaddition reaction.[10] The exo approach (TS1)
of the alkyl vinyl ether to the nitrone substrate is more
favored than the endo approach (TS2) for the aluminum-
catalyzed cycloaddition because of the steric repulsion
between the alkoxy group and the bulky Lewis acid.[6,11] For
the Brønsted acid catalyzed reaction, the much smaller acidic
proton allows ethyl vinyl ether to approach in an endo
selective way (TS3). The exo selectivity (TS4) might be
disfavored because of the steric repulsion between the ethoxy
Scheme 2. Transition-state structures showing the diastereoselectivity
of the Brønsted and Lewis acid catalyzed 1,3-dipolar cycloadditions of
nitrones.
and R2 groups. Additionally, hydrogen bonding between the
proton of Brønsted acid and the oxygen atom of ethyl vinyl
ether may stabilize the endo selective transition state (TS3).
In summary, we prepared and used catalyst 1e in the 1,3-
dipolar cycloaddition of diaryl nitrones to ethyl vinyl ether.
Only 5 mol% of this air-stable catalyst leads to complete
reaction within 1 hour. The endo selectivity of the cyclo-
addition is amenable to the previously reported exo selectivity
of the aluminum-catalyzed reaction.[6] These results demon-
strate the usefulness of Brønsted acid catalysts for asymmetric
synthesis, which is complementary to Lewis acid catalysis.[12]
Additionally, the importance of larger alkyl groups in the para
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Chemie
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structure provides important information for future research
into the design of these Brønsted acids.
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Experimental Section
General procedure for 1,3-dipolar cycloaddition of diaryl nitrones
with ethyl vinyl ether catalyzed by 1e: A solution of nitrone
(0.2mmol) in anhydrous CHCl 3 (5 mL) was cooled to the temper-
ature indicated in Table 2. Ethyl vinyl ether (1.0 mmol, 96 mL) was
added by syringe. After stirring the reaction mixture for 10 min, (S)-
phosphoramide 1e (0.01 mmol, 11 mg) was added. The reaction was
monitored by TLC (4:1 hexanes/AcOEt) until all the nitrone was
consumed (usually one hour was sufficient). Saturated aqueous
Na2CO3 (5 mL) was added to the reaction mixture, and the cold
mixture was stirred for 10 min. The aqueous layer was extracted with
CH2Cl2 (2” 10 mL). The combined organic layers were dried over
Na2SO4 and concentrated. The crude product was purified by
chromatography on silica gel with hexanes/Et2O. The endo product
eluted immediately after the exo product. After concentration of the
eluates, the yield of the cycloadduct was determined and the endo:exo
ratio analyzed by 1H NMR spectroscopy.
Received: November 19, 2007
Published online: February 18, 2008
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[4] M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim,
Angew. Chem. 2007, 119, 2143 – 2146; Angew. Chem. Int. Ed.
2007, 46, 2097 – 2100.
Keywords: asymmetric catalysis · cycloaddition ·
organocatalysis · phosphoramides
.
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