Asymmetric Friedel-Crafts reactions: Catalytic enantioselective addition of aromatic and heteroaromatic C-H bonds to activated alkenes, carbonyl compounds, and imines

Article abstract of DOI:10.1055/s-2003-39176

The development and scope of catalytic enantioselective addition of aromatic and heteroaromatic C-H bonds to α,β-unsaturated alkenes, carbonyl compounds, and imines are presented, α,β-Unsaturated alkenes, 4-substituted 2-oxo-3-butenoate esters and alkylid

Full text of DOI:10.1055/s-2003-39176

FEATURE ARTICLE
1117
Asymmetric Friedel–Crafts Reactions: Catalytic Enantioselective Addition of
Aromatic and Heteroaromatic C–H Bonds to Activated Alkenes, Carbonyl
Compounds, and Imines
A
symmetric Fried
a
R
r
eactionsl Anker Jørgensen*
Danish National Research Foundation: Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
E-mail: kaj@chem.au.dk
Received 4 February 2003
complexes (see Figure 1) have been found to be useful
Abstract: The development and scope of catalytic enantioselective
catalysts for the enantioselective addition of electron-rich
addition of aromatic and heteroaromatic C–H bonds to , -unsatur-
aromatic and heteroaromatic compounds to activated al-
kenes, carbonyl compounds, and imines.
ated alkenes, carbonyl compounds, and imines are presented. , -
Unsaturated alkenes, 4-substituted 2-oxo-3-butenoate esters and
alkylidene malonates react with indoles, furans and electron-rich ar-
omatic compounds in the presence of chiral bisoxazoline-copper(II)
complexes to give the Friedel–Crafts alkylation adduct in moderate
to high yields and with up to >99.5% ee. Chiral bisoxazoline-cop-
per(II) complexes can also catalyze the enantioselective addition of
especially electron-rich aromatic compounds to activated carbonyl
compounds such as glyoxylates and trifluoropyruvate to give e.g.
optically active aromatic mandelic acid esters in good yields and
enantioselectivities. Electron-rich aromatic compounds and het-
eroaromatic compounds react in an enantioselective fashion with
activated N-protected -imino esters to give optically active aromat-
ic and heteroaromatic -amino acid derivatives using chiral
BINAP-copper(I) complexes as the catalyst.
O
O
O
O
N
N
N
N
Cu
(II)
Cu
(II)
Ph
Ph
t-Bu
t-Bu
(S)-t-Bu-BOX-Cu(II)
(S)-t-Bu-BOX-Cu(II)
Tol
Tol
P
Cu(I)
P
Tol
Tol
Key words: asymmetric catalysis, Friedel–Crafts reactions, al-
kenes, carbonyl compounds, imines
(R)-Tol-BINAP-Cu(I)
Figure 1
Friedel–Crafts reactions are fundamental transformations
in organic chemistry and have been widely used for the
synthesis of many different compounds in academia and
industry.1 Depending on the substrates used, alkenes, car-
bonyl compounds, or imines, different types of catalytic
activation can be applied to these substrates, Brønsted and
Lewis acids are among the most frequently used catalysts.
1
Catalytic Enantioselective Addition to Acti-
vated Alkenes
Chiral bisoxazoline3 (BOX)-copper(II) complexes
(Figure 1) have been found to be useful catalysts for a va-
riety of different organic transformations including the
enantioselective Friedel–Crafts alkylation of heteroaro-
matic and aromatic compounds to various types of , -un-
saturated activated compounds. In order to apply the
(BOX)-copper(II) complexes as the catalyst for these re-
actions, a substrate which can coordinate to the catalyst in
a bidentate fashion has to be used. The reactions to be pre-
One of the challenges in organic chemistry is the develop-
ment of synthetic procedures, which allow the formation
of optically active compounds using chiral Lewis acids as
catalysts. Until recently, for the catalytic enantioselective
Friedel–Crafts reactions only a very limited number of re-
actions have been developed.2
In this feature article our recent developments in the field
of catalytic enantioselective Friedel–Crafts-type addition
reactions of aromatic and heteroaromatic C–H bonds to
activated alkenes, carbonyl compounds, and imines are
presented. Our approach to these reactions has been to try
to develop transformations, which use easy-available
chiral ligands in combination with Lewis acids as the cat-
alysts.
sented here are addition reactions to , -unsaturated
-
keto esters (4-substituted 2-oxo-3-butenoate esters) and
alkylidene malonates, which can coordinate to the (BOX)-
copper(II) complex in a bidentate fashion. These reactions
might also be considered as asymmetric Michael-type re-
actions.
The (S)-t-Bu-BOX-Cu(II) and (S)-Ph-BOX-Cu(II) com-
plexes catalyse an enantioselective addition of heteroaro-
The chiral bisoxazoline-copper(II) and BINAP-copper(I)
matic and aromatic C–H bonds to , -unsaturated
-
ketoesters.4 Substituted indoles 1 reacted with 4-substitut-
ed 2-oxo-3-butenoate esters 2 to give the Friedel–Crafts
alkylation adducts 3. A screening of the (S)-t-Bu-BOX-
Cu(II) and (S)-Ph-BOX-Cu(II) in various solvents, using
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1117,1125,ftx,en;Z01703SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1118
K. A. Jørgensen
FEATURE ARTICLE
different counterions and reaction conditions revealed withdrawing (entry 4) substituents on the 4-substituted 2-
that the combination of (S)-t-Bu-BOX and Cu(OTf)2 in oxo-3-butenoate esters 2.
Et2O as the solvent gave the best results in terms of yield
and enantiomeric excess of 3 (Equation 1 and Table 1).
3-butenoate esters 2 proceeded well also for other het-
The Friedel–Crafts alkylation of the 4-substituted 2-oxo-
eroaromatic compounds, e.g. 2-methyl-furan in the pres-
ence of (S)-t-Bu-BOX-Cu(OTf)2 (10 mol%) as the
catalyst in Et2O. The corresponding Friedel–Crafts ad-
ducts (the reaction takes place selectivity at 5-position of
2-methyl furan) were obtained in very high yields (>90%)
and with >79% ee. Quite similar results were obtained for
electron-rich aromatic compounds, e.g. reaction of 1,3-
dimethoxy benzene with the 2-oxo-3-butenoate esters 2
gave 60–89% ee.
The absolute configuration of the Friedel–Crafts alkyla-
tion adducts was assigned using X-ray analysis. The abso-
lute configuration of the chiral carbon atom formed in the
indole derived adduct 3d was found to be (R).
The chiral bisoxazoline-copper(II) complexes have also
been shown to be useful chiral catalysts for other Friedel–
Crafts alkylation reactions. Indoles 1 reacted with alkyl-
Equation 1
idene malonates 4 in an enantioselective reaction
(Equation 2).5 The reaction proceeded at room tempera-
Table 1 Catalytic Enantioselective Friedel–Crafts Reactions of In-
ture in THF and some representative results are given in
Table 2.
doles 1 with 4-Substituted 2-Oxo-3-butenoate Esters 2a,4
Entry
Reaction
Time (h)
Product
Yield (%)
ee (%)
1
2
3
4
5
6
7
64
48
1
3a
3b
3c
3d
3e
3f
77
98
95
69
96
95
98
99.5
96
>99.5
97
16
16
1
95
>99.5
95
1
3g
a Catalyzed by (S)-t-Bu-BOX-Cu(OTf)2 (2–10 mol%) in Et2O.
Equation 2
The results in Table 1 show that (S)-t-Bu-BOX-Cu(OTf)2
catalyses a highly enantioselective addition of indoles 1
with both electron-donating (entries 3,6,7) and electron-
Compared to the reaction of 4-substituted 2-oxo-3-
butenoate esters 2, the reactions of alkylidene malonates 4
with indoles, catalysed by (S)-t-Bu-BOX-Cu(OTf)2 pro-
Biographical Sketch
Karl Anker Jørgensen (b. from Aarhus University The development and un-
1955) is a Professor at the 1984 and a post-doctoral pe- derstanding of catalytic re-
Danish National Research riod with R. Hoffmann, Cor- actions in chemistry is the
Foundation: Center for Ca- nell University he joined the main goal of his research.
talysis. Following a PhD Aarhus University faculty.
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Friedel–Crafts Reactions
1119
Table 2 Catalytic Enantioselective Friedel–Crafts Alkylation Reac-
tions of Alkylidene Malonates 4 with Indoles 1a,5
i-Pr
Entry
Product
5a
Yield (%)
Ee (%)
60 (92)b
56
N
O
1
2
3
4
73
92
87
99
O
O
5b
N
N
5c
69
i-Pr
i-Pr
C3-symmetric
trisoxazoline
5d
58
a Catalyzed by (S)-t-Bu-BOX-Cu(OTf)2 (10 mol%) in THF.
b Ee after recrystallisation.
Figure 2
ceeded with lower enantioselectivity as shown in Table 2.
However, the enantiomeric excess of the Friedel–Crafts
adduct can be improved to >90% ee by crystallisation.
The catalytic enantioselective Friedel–Crafts alkylation of
the alkylidene malonates could also be achieved for het-
eroaromatic compounds, i.e. pyrroles and indoles. For
these heteroaromatic compounds the isolated yields of the
Friedel–Crafts adducts were >95%, however, the enantio-
meric excess was low to moderate.
2
Catalytic Enantioselective Addition to Car-
bonyl Compounds
Catalytic enantioselective Friedel–Crafts reactions have
been found for the reaction of chloral with anisole deriva-
tives catalysed by chiral aluminium complexes.9 Mikami
et al. have also studied the catalytic enantioselective reac-
tions of chloral using BINOL-TiX2 as the catalyst.10 Fur-
thermore, a chiral zirconium complex has been shown to
catalyse the enantioselective addition of 1-napthol to
pyruvate.11
The optically active Friedel–Crafts adducts obtained by
the addition of indoles to alkylidene malonates can under-
go a decarboxylation reaction6 to give mono ester 6 in
74% isolated yield (Equation 3). The product (6) obtained
by this reaction is in principle the optically active Friedel–
Crafts adduct obtained from the reaction of indole with
cinnamic acid ethyl ester.
We have found that especially the (S)-t-Bu-BOX-Cu(II)
complex also is an effective catalyst for the addition of
electron-rich aromatic compounds to activated carbonyl
compounds such as glyoxylate and trifluoropyruvate.12
The catalytic enantioselective Friedel–Crafts reaction
proceeds well for meta-substituted N,N-dimethyl-anilines
7 reacting with ethyl glyoxylate 8 in the presence of (S)-t-
Bu-BOX-Cu(OTf)2 (10 mol%) as the catalyst in a variety
of solvents (Equation 4). Table 3 shows the results for the
reaction of 7 with 8 in CH2Cl2 and THF as the solvents.
Equation 3
Recently, Tang et al. have developed the Friedel–Crafts
alkylation/Michael addition of alkylidene malonates with
indoles as a highly enantioselective reaction as a further
development of the chiral bisoxazoline ligand.7 The use of
the C3-trisoxazoline ligand (Figure 2) in combination with
Cu(ClO4)2 as the Lewis acid gave the optically active ad-
ducts 5 in high yields and very high enantioselectivity (up
to 93% ee)
Equation 4
An interesting new dimension to the catalytic enantiose-
lective addition of aromatic and heteroaromatic com-
pounds to activated alkenes has also recently been
presented by MacMillan et al.8 By using organocatalysis
they have developed the enantioselective addition of pyr-
roles, indoles and anilines to , -unsaturated aldehydes.
These reactions proceed in good yield and with very high
enantioselectivities.
The catalytic enantioselective Friedel–Crafts reactions of
meta-substituted N,N-dimethylanilines 7 with ethyl gly-
oxylate 8 proceeded when both electron-donating and
electron-withdrawing substituents were attached to the ar-
omatic nucleus. The results in Table 3 show that the reac-
tions can proceed in both CH2Cl2 and THF. The yields of
the optically active mandelic acid derivatives range from
low (entry 6) to high (entry 3) depending on the aromatic
substituent. The highest yields were found for aromatic
compounds substituted with electron-withdrawing
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

1120
K. A. Jørgensen
FEATURE ARTICLE
lyst.12b Substituted indoles, pyrroles, furans, thiophenes
and electron-rich aromatic compounds react with ethyl tri-
fluoropyruvate in low (for the thiophenes) to high yields
and with up to 93% ee for the optically active aromatic
and heteroaromatic hydroxy trifluoromethyl esters
formed.
Table 3 Catalytic Enantioselective Friedel–Crafts reactions of N,N-
Dimethylanilines 7 with Ethyl Glyoxylate 8a,12
Entry
Reaction
Time (d)
Product
Yield (%)
CH2Cl2/THF
ee (%)
CH2Cl2/THF
1
2
3
4
5
6
1
1
2
2
1
1
9a
9b
9c
9d
9e
9f
81/71
80/58
84/41
68/36
77/76
21/19
80/90
85/81
93/95
88/89
80/92
77/86
The chiral bisoxazoline catalyst was covalently anchored
to silica and mesoporous MCM-41 to obtain a heteroge-
neous catalyst.13 The Ph-BOX ligand was used for this
purpose and the chiral Ph-BOX-Cu(II) solid support cata-
lyst displayed a high enantioselectivity in the Friedel–
Crafts hydroxyalkylation of 1,3-dimethoxybenzene with
trifluoropyruvate. The enantiomeric excess was higher
than those obtained with the unsupported (S)-t-Bu-BOX-
Cu(OTf)2 complex in solution.
a Catalyzed by (S)-t-Bu-BOX-Cu(OTf)2 (10 mol%) in CH2Cl2 and
THF.
The Friedel–Crafts reactions using the chiral bisoxazoline
catalyst are restricted to activated carbonyl compounds.
However, using other 2-keto esters, such as ethyl pyru-
vate, as the substrate for the reaction with N,N-dimethyl-
aniline in the presence of (S)-t-Bu-BOX-Cu(OTf)2 as the
catalyst gave the homo-aldol, rather that the Friedel–
Crafts adduct.14
groups. It should be noted that the enantioselectivity is rel-
atively independent of the electronic properties of the sub-
stituent and the solvent.
N-Methylindoline (10a) and N-methyltetrahydroquino-
line (10b) reacted smoothly with ethyl glyoxylate 8 using
(S)-t-Bu-BOX-Cu(OTf)2 (10 mol%) as the catalyst
(Equation 5).12 The reaction of 10a gave 11a as the only
isomer in good yield and enantiomeric excess (83% ee),
while the yield of 10b was slightly lower, however, the
enantiomeric excess improved to 93% ee.
An important synthetically useful aspect of the catalytic
enantioselective Friedel–Crafts reactions is that the corre-
sponding anilines can easily be prepared from optically
active adducts obtained in these reactions. Scheme 1
shows the N,N-demethylation of the Friedel–Crafts ad-
duct obtained from the reaction of ethyl glyoxylate with
N,N-dimethylaniline.12a The N,N-demethylation of the
TBS-protected alcohol 13 proceeds in good yield with the
free amine 16 and a variety of different optically active
para-substituted mandelic acid derivatives can be pre-
pared.
TBSO
CO2Et
TBSO
CO2Et
a) PhIO
b) TMSN3
NaHCO3
NMe2
N3
N
N3
Equation 5
13
14
The Friedel–Crafts reactions of N-methylindoline 10a and
N-methyltetrahydroquinoline 10b can give attractive
products, which by oxidation of the unsaturated ring pro-
duced optically active indoles and quinolines, substituted
in the aromatic ring with chiral -hydroxy ester function-
alities.
TBSO
CO2Et
HO
CO2Et
HCl
NH2
NH2
15
16
Other aromatic compounds such as julolidine, N,N-dime-
thylamino-1-naphthalene, N,N-dimethylamino-1-anthra-
cene and 2-substituted furans all reacted with ethyl
glyoxylate to give the corresponding optically active
Friedel–Crafts adducts in moderate to good yield and up
to 89% ee.
Scheme 1
The catalytic enantioselective hydroxyalkylation reaction
of carbonyl compounds with aromatic compounds seems
to be a much more difficult reaction to achieve. We have
shown that pyridinecarbaldehydes can react with the aro-
matic C–H bond in aldehydes mediated by chiral BINOL-
aluminium complexes to give the corresponding alcohols
in moderate yields and enantioselectivities.15
The highly activated carbonyl compound, trifluoropyru-
vate, can also be used as the substrate for these Friedel–
Crafts reactions of activated aromatic and heteroaromatic
compounds using (S)-t-Bu-BOX-Cu(OTf)2 as the cata-
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Friedel–Crafts Reactions
1121
10b, all reacted all with the N-Moc -imino ester
(R1 = R2 = Me) 19 in the presence of (R)-Tol-BINAP-
Cu(ClO4) (10 mol%) as the catalyst to give a highly regio-
3
Catalytic Enantioselective Addition to
Imines
Optically active non-natural aromatic and heteroaromatic selective and enantioselective aza-Fridel–Crafts reaction.
-amino acid derivatives can be prepared from aza- Only one regioisomer (in the para-position relative to the
Friedel–Crafts reactions of aromatic or heteroaromatic nitrogen substituent in the aromatic compound) of the op-
compounds with -imino esters using the (R)-Tol- tically active aromatic -amino acid derivatives was ob-
BINAP-Cu(I) complex (Figure 1) as the catalyst.16 Start- tained with very high enantioselectivities (Table 4, entries
ing from readily available starting materials the optically 1–4). For the reactions of the heteroaromatic compounds
active products are formed with an easily removal N-pro- presented in Table 4, the reaction takes place selectively
tecting groups. The -imino ester electrophiles are at 5-position relative to the substituent on the reagent. For
generated in situ by an aza-Wititig reaction followed by the furans presented the yield of the corresponding furfu-
the catalytic enantioselective addition of the aromatic or ryl- -amino acid derivatives is moderate, however, very
heteroaromatic C–H bond to the N-protected -imino es- high enantiomeric excesses are obtained (entries 5–7). 2-
ter 18 (Scheme 2).
Methoxythiophene (entry 8), as well as other thiophenes,
also react in a highly enantioselective reaction with good
yield of the corresponding thiophene- -amino acid deriv-
ative. Naphthalene and anthracene derived -amino acids
can also be obtained when 2-N,N-dimethylnaphtalene and
2-N,N-dimethyl anthracene were used as substrates (92%
ee and 89% ee, respectively, were obtained for these reac-
tions).
O
O
R1O
N
O
+
H
CO2R2
R1O
NPBnPh2
H
CO2R2
O
PPh3
17
8
18
CO2R1
CO2R2
The two amino functionalities can be selectively depro-
tected and further transformations can be carried out.16b
The N,N-demethylation proceeds well using the proce-
dure described above for the optically active aromatic -
amino acid obtained by reaction of N,N-dimethylaniline
7a reaction with iodosobenzene and TMSN3, and subse-
quent hydrolysis of the bis-azide formed, gave the unpro-
tected aniline derivative in 83% yield. It was
demonstrated that the aromatic amino group could be re-
moved by diazotisation and subsequent copper-catalysed
decomposition of the diazonium salt in saturated aqueous
H3PO2. A variety of synthetic procedures are available for
the transformation of diazonium salts into halogens or hy-
droxyl groups and transformations provide the access to
versatile optically active building blocks.
Ar
H
HN
Ar
(R)-Tol-BINAP-Cu(I)
10 mol%
19
Scheme 2
Optimisation of the aza-Wititig reaction, the formation of
N-protected -imino ester 18 (Scheme 2), revealed that
the best results were obtained for R1 = R2 = Me and some
representative results for the aza-Friedel–Crafts reaction
of some aromatic and heteroaromatic compounds are pre-
sented in Table 4.16b
Table 416 Catalytic Enantioselective aza-Friedel–Crafts Reactions
of some Aromatic and Heteroaromartic Compounds with N-Moc
-
Imino Ester 18a
It was also demonstrated the N-Moc protecting groups, as
well as other N-carbamate groups, could easily be re-
moved by standard procedure.16
Entry
Aromatic
7a
Product
19a
Yield (%) ee (%)
1
2
3
4
5
6
7
8
80
81
56
86
59
40
63
75
98
96
97
88
89
95
96
94
7f
19b
19c
4
Conclusion
10a
This feature article has demonstrated that chiral Lewis ac-
ids catalyse highly enantioselective addition of aromatic
and heteroaromatic C–H bonds to , -unsaturated -keto
esters, activated carbonyl compounds and N-protected -
imino esters. The reactions take place in moderate to high
yields and with high enantioselectivities. These new cata-
lytic processes give access to new classes of optically ac-
tive compounds.
10b
19d
19e
2-Me-furan
2-Bn-furan
2-MeO-furan
2-MeO-thiophene
19f
19g
19h
a R1 = R2 = Me, catalyzed by (R)-Tol-BINAP-Cu(ClO4) (10 mol%).
All reactions were carried out under an atmosphere of N2 using an-
hydrous solvent and flame-dried glassware. Commercially avail-
able compounds were used without further purification. Solvents
were dried according to standard procedures. Purification of the
products, when necessary, was carried out by flash chromatography
The activated anilines, N,N-dimethylaniline 7a and m-
methoxy-N,N-dimethylaniline 7f, and the cyclic amines
N-methylindoline 10a and N-methyltetrahydroquinoline
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

1122
K. A. Jørgensen
FEATURE ARTICLE
(FC) using Merck silica gel 60 (230–400 mesh). TLC was per-
formed using Merck silica gel 60 F254 plates and visualized with
blue stain. Optical rotations were measured on a Perkin–Elmer 241
HRMS: m/z calcd for C21H23NNaO5 [M + Na + MeOH]+, 392.1474;
found, 392.1476.
polarimeter. H NMR and 13C NMR spectra were recorded at 400
3d4
1
MHz and 100 MHz respectively, using CDCl3 as the solvent, and
are reported in ppm downfield from TMS ( = 0) for 1H NMR and
relative to the central CDCl3 resonance ( = 77.0) for 13C NMR.
Yield: 69% yield; mp 158 °C; 97% ee; HPLC (Chiralcel OD col-
umn, hexane–i-PrOH, 85:15, 0.5 mL/min) tR 15.4 min (major),
tR 19.6 min (minor); [ ]Dr.t. –18.5 (c 0.0100, CHCl3).
1H NMR: = 7.95 (br s, 1 H), 7.23–6.89 (m, 9 H), 4.80 (t, J = 7.2
Hz, 1 H), 3.71 (s, 3 H), 3.59 (dd, J = 16.8, 7.2 Hz, 1 H), 3.50 (dd,
J = 16.8, 7.2 Hz, 1 H).
13C NMR: = 37.5, 45.5, 53.0, 111.1, 118.5, 120.3, 120.3, 122.0,
125.0, 126.7, 127.7, 128.3, 128.6, 136.9, 142.9, 161.2, 192.4.
HRMS: m/z calcd for C20H20ClNNaO4 [M + Na + MeOH]+,
396.0979; found, 396.0983.
Catalytic Enantioselective Addition of Indoles 1 to 4-Substitut-
ed 2-Oxo-3-butenoate Esters 2; General Procedure (Table 1)4
To a flame dried Schlenk tube were added Cu(OTf)2 (14.46 mg,
0.04 mmol) and the ligand 2,2 -isopropylidene bis[(4S)-4-tert-bu-
tyl-2-oxazoline] (S)-t-Bu-BOX (12.96 mg, 0.044 mmol) under a
stream of N2. The mixture was dried under vacuum for 1–2 h, the
anhydrous solvent (2.0 mL) was added, and the resulting suspension
was stirred vigorously for 1–2 h. The catalyst is green and heteroge-
neous in Et2O whereas it is homogeneous in other solvents. To the
catalyst in solution was added the 4-substituted 2-oxo-3-butenoate
ester 2 (0.8 mmol). The solution was stirred at r.t. for 15 min, then
cooled to the desired reaction temperature, where the appropriate
indole 1 (0.8 mmol) was added. The solution was then stirred at
–78 °C for 1–64 h depending on the substrate (see Table 1). Pentane
(1.0 mL) was added to the reaction mixture. The heterogeneous
mixture was filtered through a 40 mm plug of silica gel. The silica
was washed with of 60% pentane in Et2O (5–10 mL) followed by
CH2Cl2 (5–10 mL) and the combined fractions were evaporated.
The crude product 3a–g exists both in keto and enol form, however
this equilibrium shifts towards the keto form in MeOH at r.t. The
keto form of 3a–g was purified by FC. In many cases the last puri-
fication is not necessary as the reaction is very clean.
3e4
Yield: 96%; yellow oil; 95% ee; HPLC (Chiralcel OB column, hex-
ane–i-PrOH, 98:2, 0.5 mL/min) tR 26.1 min (major), tR 33.1 min
(minor); [ ]Dr.t. –1.7 (c 0.0100 g/mL, CHCl3).
1H NMR: = 7.95 (br s, 1 H), 7.67 (d, J = 7.2 Hz, 1 H), 7.36 (d,
J = 8.0 Hz, 1 H), 7.18 (t, J = 6.8 Hz, 1 H), 7.13 (t, J = 6.8 Hz, 1 H),
7.02 (s, 1 H), 4.23 (q, J = 6.8 Hz, 2 H), 3.71 (m, 1 H), 3.36 (dd,
J = 16.8, 6.0 Hz, 1 H), 3.12 (dd, J = 16.8, 8.4 Hz, 1 H), 1.44 (d,
J = 6.8 Hz, 3 H), 1.30 (t, J = 7.6 Hz, 3 H).
13C NMR: = 13.8, 20.9, 26.6, 46.8, 62.4, 111.2, 119.0, 119.3,
120.1, 120.4, 122.0, 126.1, 136.4, 161.1, 194.1.
HRMS: m/z calcd for C15H19NNaO4 [M +Na + H2O]+, 300.1212;
found, 300.1200.
3a4
3f4
Yield: 77%; mp 98 °C; 99.5% ee; HPLC (Chiralcel OD-R column,
Yield: 95%; yellow oil; >99.5% ee; HPLC (Chiralcel OJ column,
hexane–i-PrOH, 85:15, 0.5 mL/min) tR 26.5 min (minor), tR 37.2
min (major); [ ]Dr.t. –10.4 (c 0.0100, CHCl3).
1H NMR: = 7.89 (br s, 1 H), 7.23 (d, J = 9.2 Hz, 1 H), 7.09 (d,
J = 2.4 Hz, 1 H), 6.98 (d, J = 2.8 Hz, 1 H), 6.86 (dd, J = 9.2, 2.4 Hz,
1 H), 4.23 (q, J = 7.2 Hz, 2 H), 3.65 (m, 1 H), 3.88 (s, 3 H), 3.33
(dd, J = 16.8, 6.0 Hz, 1 H), 3.09 (dd, J = 16.8, 8.0 Hz, 1 H), 1.41
(d, J = 6.8 Hz, 3 H), 1.29 (t, J = 7.6 Hz, 3 H).
MeOH, 0.5 mL/min) tR 8.9 min (minor), tR 10.1 min (major);
[ ]D –23.9 (c 0.0100, CHCl3).
r.t.
1H NMR: = 8.00 (br s, 1H), 7.44–7.01 (m, 10 H), 4.93 (t, J = 7.6
Hz, 1 H), 3.77 (s, 3 H), 3.69 (dd, J = 16.8, 7.6 Hz, 1 H), 3.60 (dd,
J = 16.8, 7.6 Hz, 1 H).
13C NMR: = 37.7, 45.6, 52.9, 111.1, 118.3, 119.4, 119.5, 121.4,
122.3, 126.4, 126.6, 127.7, 128.5, 136.5, 143.1, 161.3, 192.6.
13C NMR: = 13.9, 20.9, 26.5, 46.8, 56.0, 62.4, 101.0, 111.9, 112.2,
120.1, 121.1, 126.5, 131.6, 153.9, 161.1, 194.1.
HRMS: m/z calcd for calcd for C19H17NNaO3 [M + Na]+, 330.1106;
found, 330.1108.
HRMS: m/z calcd for C16H21NNaO5 [M + Na + H2O]+, 330.1317;
found, 330.1320.
3b4
Yield: 98% yield; mp 100 °C; 96% ee; HPLC (Chiralcel OD-R col-
umn, MeOH, 0.5 mL/min) tR 10.5 min (minor), tR 11.8 min (major),
[ ]Dr.t. –26.6 (c 0.0100, CHCl3).
1H NMR: = 6.88–7.44 (m, 10 H), 4.93 (t, J = 8.0. Hz, 1 H), 3.77
(s, 3 H), 3.74 (s, 3 H), 3.68 (dd, J = 17.2, 8.0 Hz, 1 H), 3.60 (dd,
J = 17.2, 8.0 Hz, 1 H).
13C NMR: = 32.7, 37.6, 45.7, 52.9, 109.2, 116.7, 118.9, 119.4,
121.8, 126.3, 126.5, 126.7, 127.7, 128.5, 137.2, 143.3, 161.2, 192.6.
HRMS: m/z calcd for C21H23NNaO4 [M + Na + MeOH]+, 376.1525;
3g4
Yield: 98%, yellow oil; 95% ee; HPLC, Chiralcel OJ column (hex-
ane–i-PrOH 85:15, 0.5 mL/min) tR 45.2 min (minor), tR 51.0 min
(major), [ ]Dr.t. 23.0 (c 0.0100, CHCl3).
1H NMR: = 7.93 (br s, 1 H), 7.36–7.23 (m, 6 H), 7.09 (d, J = 2.4
Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 6.86 (dd, J = 9.6, 2.4 Hz, 1 H),
4.50 (s, 2 H), 4.19 (m, 2 H), 3.97 (m, 1 H), 3.86 (s, 3 H), 3.81 (dd,
J = 9.2, 4.4 Hz, 1 H), 3.63 (t, J = 9.2 Hz, 1 H), 3.43 (dd, J = 15.6,
8.4 Hz, 1 H), 3.19 (dd, J = 15.6, 6.4 Hz, 1 H), 1.26 (t, J = 6.8 Hz, 3
H).
found, 376.1515.
13C NMR: = 13.9, 34.0, 42.8, 55.9, 62.2, 72.9, 73.5, 100.7, 111.9,
112.5, 115.3, 122.0, 126.8, 127.6, 127.6, 128.3, 131.2, 137.9, 154.0,
161.0, 193.2.
HRMS: m/z calcd for C23H27NNaO6 [M + Na + H2O]+, 436.1736;
found, 436.1738.
3c4
Yield: 95%; semi-crystalline oil; 95% ee; HPLC (Chiralcel OD col-
umn, hexane–i-PrOH, 85:15, 0.5 mL/min) tR 13.1 min (minor),
tR 15.6 min (major); [ ]Dr.t. +5.2 (c 0.0100, CHCl3).
1H NMR: = 7.92 (br s, 1 H), 7.29–6.75 (m, 9 H), 4.82 (t, J = 8.0.
Hz, 1 H), 3.71 (s, 3 H), 3.70 (s, 3 H), 3.62 (dd, J = 16.8, 8.0 Hz, 1
H), 3.54 (dd, J = 16.8, 8.0 Hz, 1 H).
Catalytic Friedel–Crafts Reactions of N,N-Dimethylanilines 7
with Ethyl Glyoxylate; General Procedure12a
To a flame dried Schlenk tube was added Cu(OTf)2 (18.1 mg, 0.05
mmol, 10 mol%) and (S)-t-Bu-BOX (15.5 mg, 0.055 mmol, 11
13C NMR: = 37.6, 45.5, 52.9, 55.7, 101.2, 111.8, 112.2, 117.9,
122.2, 126.6, 126.7, 127.7, 128.5, 131.6, 143.1, 153.8, 161.2, 192.6.
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Friedel–Crafts Reactions
1123
mol%). The mixture was dried under vacuum for 1–2 h and freshly
distilled anhyd CH2Cl2 (2.0 mL) was added and the solution was
stirred for 0.5–1 h. Freshly distilled ethyl glyoxylate (255 mg, 2.5
mmol) and N,N-dimethylaniline (0.5 mmol, 1 equiv) were added.
After stirring at r.t. for the appropriate amount of time (Table 3), the
reaction mixture was filtered through a pad of silica, which was
eluted with Et2O, the eluent was concentrated in vacuo, and the
product was purified by FC.
HRMS: m/z calcd for C13H16BrNO3 [M]+, 301.0314; found,
301.0316.
9e12
Yield: 77%; yellow oil; 80% ee; GC (column Astec B-PM, initial
T = 80 °C, 20 °C/min to 135 °C, 1 °C/min to 140 °C, 1 °C to
160 °C, 0.2 °C/min to 170 °C) tR 38.1 min (major), tR 38.8 min (mi-
nor); [ ]Dr.t. +124.4 (c 8.9, CHCl3).
1H NMR: = 7.12 (d, J = 8.0 Hz, 1 H), 6.57–6.52 (m, 2 H), 5.27 (d,
J = 6.8 Hz, 1 H), 4.28 (dq, J = 10.4, 7.2 Hz, 1 H), 4.20 (dq, J = 10.4,
7.2 Hz, 1 H), 3.22 (d, J = 6.8 Hz, 1 H), 2.94 (s, 6 H), 2.40 (s, 3 H),
1.24 (t, J = 7.2 Hz, 3 H).
13C NMR: = 175.0, 150.7, 137.5, 128.0, 125.0, 114.7, 110.4, 70.5,
62.1, 40.67, 20.0, 14.4.
9a12a
Yield: 81% yield; mp 101–103 °C; 80% ee; GC (column Astec B-
PM, initial T = 80 °C, 20 °C/min to 135 °C, 1 °C/min to 145 °C,
0.2 °C to 158 °C) tR 38.5 min (major), tR 39.2 min (minor);
[ ]Dr.t. +98.7 (c 0.023, CHCl3).
1H NMR: = 7.28–7.23 (m, 2 H), 6.73–6.68 (m, 2 H), 5.07 (d,
J = 6.0 Hz, 1 H), 4.27 (dq, J = 10.5, 7.2 Hz, 1 H), 4.15 (dq, J = 10.5,
7.2 Hz, 1 H), 3.33 (d, J = 6.0 Hz, 1 H), 2.96 (s, 6 H), 1.23 (t, J = 7.2
Hz, 3 H).
13C NMR: =174.4, 150.8, 127.8, 126.4, 112.6, 73.0, 62.2, 40.7,
14.3.
HRMS: m/z calcd for C12H17NO3 [M]+, 223.1208; found, 223.1207.
HRMS: m/z calcd for C13H19NO3 [M]+, 237.1365; found, 237.1368.
9f12
Yield: 21%; colorless oil; 77% ee; HPLC (Chiralpak OD column,
hexane–i-PrOH, 85:15, 0.5 mL/min) tR 24 min (major), tR 28 min
(minor), [ ]Dr.t. +85.4 (c 0.0048, CHCl3).
1H NMR: = 7.08 (d, J = 8.4 Hz, 1 H), 6.27 (dd, J = 8.4, 2.4 Hz, 1
H), 6.21 (d, J = 2.4 Hz, 1 H), 5.16 (d, J = 6.8 Hz, 1 H), 4.25 (dq,
J = 9.2, 7.2 Hz, 1 H), 4.19 (dq, J = 9.2, 7.2 Hz, 1 H), 3.82 (s, 3 H),
3.40 (d, J = 6.8 Hz, 1 H), 2.96 (s, 6 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR: = 174.6, 158.4, 152.4, 130.3, 115.4, 104.7, 96.1, 70.3,
61.8, 55.5, 40.8, 14.4.
HRMS [M]+ calc. for C13H19NO4 253.1314, found 253.1320.
9b12
Yield: 80%; colorless oil; 85% ee; GC (column Astec B-PM, initial
T = 80 °C, 10 °C/min to 140 °C, hold 60 min, 0.5 °C/min to
155 °C) tR 76.3 min (minor), tR 77.0 min (major); [ ]Dr.t. +85.3
(c 0.008, CHCl3).
1H NMR: = 7.14 (dd, JH-F = 8.8 Hz, JH-H = 8.8 Hz, 1 H), 6.44 (dd,
JH-F = 8.8 Hz, JH-H = 2.6 Hz, 1 H), 6.36 (dd, JH-F = 14.0 Hz, JH-
H = 2.6 Hz, 1 H), 5.25 (d, J = 5.6 Hz, 1 H), 4.26 (dq, J = 10.4, 6.8
Hz, 1 H), 4.19 (dq, J = 10.4, 6.8 Hz, 1 H), 3.42 (d, J = 5.6 Hz, 1 H),
2.94 (s, 6 H), 1.22 (t, J = 7.2 Hz, 3 H).
Catalytic aza-Friedel–Crafts Reactions of Aromatic and Het-
eroaromatic Compounds to the N-Moc -Imino Ester 18; Gen-
eral Procedure16
To a flame dried Schlenk tube equipped with a magnetic stirring bar
was added the aza-ylide 17 (R1 = Me) (0.40 mmol), which was
dried under vacuum at r.t. for 1 h before toluene (0.66 mL) was add-
ed by syringe. After stirring for 10 min, the suspension was added
to a 0.42 M solution of methyl glyoxylate 8 (R2 = Me) in toluene
(1.14 mL, 0.48 mmol) and stirred for another 15 min at ambient
temperature before the white milky slurry was cooled to –78 °C
(complete imine formation was checked by 1H NMR spectroscopy,
as full conversion of the aza-ylide is crucial to achieving good re-
sults). A catalyst solution was prepared by drying CuPF6·4MeCN
(15 mg, 0.040 mmol) and (R)-Tol-BINAP (30 mg, 0.044 mmol) in
a flame dried Schlenk tube under vacuum for 1 h, this mixture was
then dissolved in a mixture of CH2Cl2 (0.20 mL) and toluene (2.0
mL) and added via syringe. The resulting mixture was stirred for 30
s, the aromatic or heteroaromatic substrate (0.80 mmol) was added
in one portion. After 44 h the reaction mixture was filtered through
a plug of silica and eluted with Et2O (50 mL). The crude product
was concentrated in vacuo and purified by FC to give directly pro-
tected aromatic or heteroaromatic -amino acid derivative.
13C NMR: = 174.1, 161.8 (d, JC-F = 243.0 Hz), 152.4 (d, JC-
F = 10.7 Hz), 129.4 (d, JC-F = 6.1 Hz), 113.1 (d, JC-F = 15.2 Hz),
108.1 (d, JC-F = 23.0 Hz), 99.3 (d, JC-F = 26.0 Hz), 66.8 (d, JC-F = 2.3
Hz), 62.3, 40.5, 14.3.
HRMS: m/z calcd for C12H16FNO3 [M]+, 241.1114; found,
241.1120.
9c12
Yield: 84%; colorless oil; 93% ee; GC (column Astec B-PM, initial
T = 80 °C, 20 °C/min to 135 °C, hold 120 min, 0.05 °C/min to
140 °C) tR 146.9 min (major), tR 149.9 min (minor); [ ]Dr.t. +117.6
(c 0.0047, CHCl3).
1H NMR: = 7.17 (d, J = 8.8 Hz, 1 H), 6.68 (d, J = 2.4 Hz, 1 H),
6.58 (dd, J = 8.8, 2.4 Hz, 1 H), 5.42 (d, J = 5.6 Hz, 1 H), 4.26 (dq,
J = 10.4, 7.2 Hz, 1 H), 4.20 (dq, J = 10.4, 7.2 Hz, 1 H), 3.40 (d,
J = 5.6 Hz, 1 H), 2.95 (s, 6 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR: = 174.2, 151.8, 134.6, 129.5, 123.4, 113.0, 111.1, 70.5,
62.4, 40.5, 14.3.
19a16
HRMS: m/z calcd for C12H16ClNO3 [M]+, 257.0819; found,
Yield: 80%; 98% ee; HPLC (Daciel Chiralcel OD, hexane–i-PrOH,
90:10, 1 mL/min) tR 17.2 min (minor), tR 22.8 min (major);
[ ]Dr.t. –146.3 (c 0.8, CHCl3).
257.0814.
9d12
1H NMR: = 7.18 (d, J = 8.6 Hz, 2 H), 6.65 (d, J = 8.6 Hz, 2 H),
5.61 (br d, J = 5.8 Hz, 1 H), 5.22 (d, J = 7.0 Hz, 1 H), 3.68 (s, 3 H),
3.64 (s, 3 H), 2.91 (s, 6 H).
Yield: 68%; colorless oil; 88% ee; HPLC (Chiralpak OD column,
hexane–i-PrOH 95:5, 0.5 mL/min) tR 23 min (minor), tR 29 min
(major), [ ]Dr.t. +110.0 (c 0.011, CHCl3).
1H NMR: = 7.08 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 2.5 Hz, 1 H),
6.55 (dd, J = 8.4, 2.5 Hz, 1 H), 5.37 (d, J = 5.2 Hz, 1 H), 4.20 (dq,
J = 10.4, 6.8 Hz, 1 H), 4.12 (dq, J = 10.4, 6.8 Hz, 1 H), 3.32 (d,
J = 5.2 Hz, 1 H), 2.88 (s, 6 H), 1.17 (t, J = 6.8 Hz, 3 H)
13C NMR: = 174.2, 151.4, 129.3, 125.0, 124.8, 116.2, 111.7, 72.5,
62.4, 40.5, 14.3.
13C NMR: = 171.9, 155.9, 150.4, 127.9, 123.6, 112.3, 57.3, 52.5,
52.2, 40.3.
HRMS: m/z calcd for C13H18N2O4 [M + Na]+, 289.1164; found,
289.1168.
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

1124
19b16
K. A. Jørgensen
FEATURE ARTICLE
19h16
Yield: 75%; 94% ee; HPLC (Daicel Chiralpak AS, hexane–i-PrOH,
Yield: 81%; mp 124–126 °C; 96% ee; HPLC (Daciel Chiralcel OD,
hexane–i-PrOH, 85:15) 1 mL/min tR 14.5 min (minor), tR 34.1 min
(major); [ ]Dr.t. –131.0 (c 1, CHCl3).
r.t.
90:10, 1 mL/min) tR 21.8 min (minor), tR 43.1 min (major): [ ]D
131 (c 1, CHCl3).
–
1H NMR: = 7.11 (d, J = 8.5 Hz, 1 H), 6.23 (dd, J = 8.5, 2.3 Hz, 1
H), 6.17 (d, J = 2.3 Hz, 1 H) 5.76 (br d, J = 8.5 Hz, 1 H), 5.36 (d,
J = 8.5 Hz, 1 H), 3.78 (s, 3 H), 3.65 (s, 3 H), 3.63 (s, 3 H), 2.93 (s,
6 H).
13C NMR: = 172.3, 169.8, 157.7, 156.4, 152.0, 130.6, 113.2,
104.3, 95.6, 55.2, 54.4, 53.1, 52.5, 40.4.
1H NMR: = 6.65 (d, J = 3.7 Hz, 1 H), 5.07 (d, J = 4.3 Hz, 1 H),
5.71 (br d, J = 7.1 Hz, 1 H), 5.43 (d, J = 7.7 Hz, 1 H), 3.83 (s, 3 H),
3.76 (s, 3 H), 3.67 (s, 3 H)
13C NMR: = 170.5, 166.5, 155.8, 124.1, 124.0, 103.2, 60.1, 53.9,
52.9, 52.4.
HRMS: m/z calcd for C10H13NO5S [M + Na]+, 282.0412; found,
282.0416.
HRMS: m/z [M + Na]+ calcd for C14H20N2O5, 319.1270; found,
319.1266.
19d16
Acknowledgements
Yield: 86%; 92% ee; HPLC (Daciel Chiralcel OD, hexane–i-PrOH,
85:15, 1 mL/min) tR 11.4 min (minor), tR 17.2 min (major);
[ ]Dr.t. –130.1 (c 1, CHCl3).
1H NMR: = 7.00 (d, J = 8.6 Hz, 1 H), 6.89 (s, 1 H), 6.49 (d, J = 8.6
Hz, 1 H), 5.58 (br d, J = 7.0 Hz, 1 H), 5.16 (d, J = 7.0 Hz, 1 H), 3.69
(s, 3 H), 3.64 (s, 3 H), 3.19 (t, J = 5.6 Hz, 2 H), 2.84 (s, 3 H), 2.71
(t, J = 6.2 Hz, 2 H), 1.95–1.82 (m, 2 H).
This work was made possible by a grant from Danish National Re-
search Foundation. The work presented in this feature article were
performed by a series of dedicated co-workers: Kim B. Jensen, Ja-
cob Thorhauge, Rita G. Hazell, Wei Zhuang, Tore Hansen, Nicolas
Gathergood, Aase S. Gothelf, Steen Saaby, Xiangming Fang, Pau
Bayón and Pompiliu Aburel. Their contributions to our develop-
ment of new catalytic enantioselective reactions are highly acknow-
ledged.
13C NMR: = 172.0, 155.9, 146.8, 127.5, 125.9, 123.7, 122.9,
110.7, 57.4, 52.5, 52.2, 51.0, 38.8, 27.6, 22.0.
HRMS: m/z calcd for C15H20N2O4 [M + Na]+, 315.1321; found,
315.1326.
References
(1) For reviews of Friedel–Crafts alkylation reactions, see:
(a) Olah, G. A.; Krishnamurit, R.; Prakash, G. K. S. Friedel-
Crafts Alkylation In Comprehensive Organic Synthesis, Vol.
3; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
293–339. (b) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts
Alkylation Chemistry: A Century of Discovery; Marcel
Dekker: New York, 1984. (c) Olah, G. A. Friedel-Crafts
and Related Reactions, Part 1, Vol; Wiley-Interscience:
New York, 1964, 2.
(2) For a recent review about catalytic asymmetric Friedel–
Crafts reactions see: Wang, Y.; Ding, K. L. Chin. J. Org.
Chem. 2001, 21, 763.
(3) For reviews of C2-bisoxazoline-Lewis acid complexes as
catalysts see: (a) Ghosh, A. K.; Mathivanen, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1. (b) Jørgensen, K. A.;
Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J. Acc.
Chem. Res. 1999, 32, 605. (c) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325.
19e16
Yield: 59%; 89% ee; HPLC (Daicel Chiralpak AS, hexane–i-PrOH,
97:3, 1 mL/min) tR 19.2 min (minor), tR 25.2 min (major);
r.t.
[ ]D –123.0 (c 1, CHCl3).
1H NMR: = 6.21 (d, J = 3.2 Hz, 1 H), 5.91–5.90 (m, 1 H), 5.69 (br
d, J = 6.9 Hz, 1 H), 5.42 (d, J = 8.2 Hz, 1 H) 3.75 (s, 3 H), 3.68 (s,
3 H), 2.24 (s, 3 H).
13C NMR: = 169.6, 156.0, 152.7, 146.6, 109.4, 106.5, 52.9, 52.4,
51.9, 13.4.
HRMS: m/z calcd for C10H13NO5 [M+Na]+, 250.0691; found,
250.0692.
19f16
Yield: 40% yield; 95% ee; HPLC (Daicel Chiralpak AS, hexane–i-
PrOH, 95:5, 1 mL/min) tR 18.3 min (minor), tR 25.7 min (major),
[ ]Dr.t. –132.0 (c 1, CHCl3).
1H NMR: = 7.32–7.19 (m, 5 H), 6.25 (d, J = 3.2 Hz, 1 H), 5.91 (d,
J = 3.0 Hz, 1 H), 5.64 (br d, J = 7.5 Hz, 1 H) 5.46 (d, J = 8.3 Hz, 1
H), 3.93 (s, 2 H), 3.75 (s, 3 H), 3.69 (s, 3 H).
(4) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2001, 40, 160.
(5) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun.
2001, 347.
13C NMR: = 169.5, 156.0, 155.3, 147.3, 137.5, 128.7, 128.5,
126.6, 109.4, 107.3, 52.9, 52.5, 52.0, 34.4.
HRMS: m/z calcd for C16H17NO5 [M+Na]+, 326.1004; found,
(6) Krapcho, A. P. Synthesis 1982, 805.
(7) Zhou, J.; Tang, T. J. Am. Chem. Soc. 2002, 124, 9030.
(8) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc
2001, 123, 4370. (b) Austin, J. F.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 1172. (c) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
(9) Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Gasparri
Fava, G.; Belicchi, M. F. J. Org. Chem. 1985, 50, 5018.
(10) (a) Ishii, A.; Mikami, K. J. Fluorine Chem. 1999, 97, 51.
(b) Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65,
1597.
326.1005.
19g16
Yield: 63% yield; 95% ee; HPLC (Daicel Chiralpak AS, hexane–i-
PrOH 90/10, 1 mL/min) tR 23.9 min (minor), tR 28.7 min (major);
[ ]Dr.t. –114 (c 1, CHCl3).
1H NMR: = 6.21 (d, J = 3.1 Hz, 1 H), 5.69 (br d, J = 8.2 Hz, 1 H),
5.34 (d, J = 8.2 Hz, 1 H), 5.07 (d, J = 3.44 Hz, 1 H), 3.79 (s, 3 H),
3.74 (s, 3 H), 3.66 (s, 3 H).
(11) Erker, V. G.; van der Zeijden, A. A. H. Angew. Chem., Int.
Ed. Engl. 1990, 29, 517.
(12) (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am.
Chem. Soc. 2000, 122, 12517. (b) Zhuang, W.; Gathergood,
N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66,
1009.
13C NMR: = 169.3, 161.5, 156.0, 138.3, 110.2, 80.2, 57.7, 52.9,
52.4, 51.9.
HRMS: m/z calcd for C10H13NO6 [M + Na]+, 266.0641; found,
266.0633.
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Friedel–Crafts Reactions
1125
(13) Corma, A.; Garcis, H.; Moussaif, A.; Sabater, M. J.; Zniber,
R.; Redouane, A. Chem. Commun. 2002, 1058.
(14) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun.
2000, 2211.
(16) (a) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2000, 39, 4114. (b) Saaby, S.;
Bayon, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem.
2002, 67, 4352.
(15) Gothelf, A. S.; Hansen, T.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 854.
Synthesis 2003, No. 7, 1117–1125 ISSN 1234-567-89 © Thieme Stuttgart · New York