Enantioselective friedel-crafts alkylation of furans and indoles with simple α,β-Unsaturated ketones catalyzed by oxazaborolidinone

Article abstract of DOI:10.1055/s-0029-1218821

allo-Threonine-derived oxazaborolidinone (OXB) catalyzes the Friedel-Crafts alkylation of furans and indoles with simple acyclic α,β-unsaturated ketones to give the products in high yields and with high enantioselectivities. With 5-10 mol% of the OXB cata

Full text of DOI:10.1055/s-0029-1218821

2652
FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles with Simple
a,b-Unsaturated Ketones Catalyzed by Oxazaborolidinone
E
nantioselecti
h
i
rafts
A
n
lkylation of
F
y
urans and In
a
doles Adachi, Fumi Tanaka, Kazuya Watanabe, Atsushi Watada, Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax +81(75)7247580; E-mail: harada@chem.kit.ac.jp
Received 17 May 2010
R
Abstract: allo-Threonine-derived oxazaborolidinone (OXB) cata-
chiral catalyst
*
EWG
lyzes the Friedel–Crafts alkylation of furans and indoles with sim-
ple acyclic a,b-unsaturated ketones to give the products in high
yields and with high enantioselectivities. With 5–10 mol% of the
OXB catalyst, enantioselectivities of up to 94% ee could be
achieved for a variety of substrates. The use of N,N-dimethylaniline
(2.5–10 mol%) as an additive is found to be essential for enantiose-
lectivity. The effects of the additive are discussed in terms of the re-
tardation of a proton-catalyzed racemic pathway, which deteriorates
the enantioselectivity of the Friedel–Crafts reactions.
EWG
Ar
H
+
Ar
H
R
H
electron-rich aromatics
Y
H
H
N
O
N
H
Y = OMe,
NMe2
H
H
MeO
electron-deficient alkenes
Key words: asymmetric catalysis, enones, Friedel–Crafts reaction,
furans, indoles
OR'
bidentate
O
O
Z
R
O
R
N
O
R
Z'
R'O
O
Recently, much attention has been focused on the catalyt-
ic enantioselective Friedel–Crafts (F–C) alkylation reac-
tion as an atom-economical method for forming a carbon–
carbon bond between electron-rich aromatics and elec-
2
3
1a–f
O
O
O
N
S
O
P
O
R
R
R
O
tron-deficient alkenes in
a
stereodefined manner
MeO
OMe
R
OR'
(Scheme 1).1 Electron-rich heteroaromatics, such as in-
doles and pyrroles, are ubiquitous constituents in pharma-
cologically important molecules. The enantioselective F–
C alkylation of the heteroaromatics provides a straightfor-
ward and efficient means to incorporate these frameworks
enantioselectively into the target bioactive molecules or
their precursors.
a
b
c
O
O
O
O
N
N
R
OH
R
N
Me
e
f
d
monodentate
O
O
O
In 2001, Jørgensen and co-workers reported the enantio-
selective F–C alkylation catalyzed by a Cu(box)(OTf)2
complex.2 It was shown that b,g-unsaturated a-keto esters
1a, activated by the catalyst, react smoothly with indoles
and other electron-rich aromatics to give the F–C alkyla-
tion products of high enantioselectivities. Following the
first demonstration of the catalytic enantioselective F–C
alkylation, a number of chiral Lewis acid catalyzed reac-
tions of indoles and pyrroles have been developed for oth-
er bidentate chelating substrates, such as alkylidene
malonates 2,3 a,b-unsaturated thioesters 1b,4 acyl phos-
phonates 1c,5 acyl imidazoles 1d,6 acyl pyridine oxides
1e,7 a¢-hydroxy ketones 1f,8 and nitroalkenes 3.9
R
OR'
R
R'
R
H
5
6
4
Scheme 1
tron-rich aromatics with the aid of well-designed chiral
ligands (Scheme 2). In addition, an electron-withdrawing
group adjacent to the alkenoyl moiety notably enhances
their electrophilic reactivity even prior to the coordination
by the metal atoms.
Although the F–C alkylation products derived from some
of these bidentate substrates can be transformed to the
corresponding aldehydes, ketones (for 1f), and esters (for
1b–f and 2), the employment of a,b-unsaturated alde-
hydes 4, ketones 5, and esters 6 would provide more
straightforward entry into the adducts bearing such con-
ventional functionalities. However, for such monodentate
carbonyl compounds, the control of coordination modes,
lone pair discrimination (8a,b vs 8c,d) as well as s-cis, s-
trans control (8a,c vs 8b,d), is more difficult and a higher
Lewis acidity is required for activation. Therefore, the use
The strategy for using such bidentate chelating substrates
is that these should be coordinated by a Lewis acidic met-
al, such as Cu(II), Sc(III), and Pd(II), to form a rigid acti-
vated complex 7a–c, in general with an s-cis-anti
conformation, ideal for the enantioselective attack of elec-
SYNTHESIS 2010, No. 15, pp 2652–2669
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.06.2010
DOI: 10.1055/s-0029-1218821; Art ID: Z12810SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2653
Shinya Adachi was born in the guidance of Prof. P. Sibi at North Dakota
Kobe, Japan in 1980. He Harada at Kyoto Institute of State University and work-
graduated from Kyoto Insti- Technology in 2010. He is ing in the field of asymmet-
tute of Technology in 2003. now a postdoctoral fellow in ric catalysis.
He received his Ph.D. under the group of Prof. Mukund
Fumi Tanaka was born in in 2009 from Kyoto Institute Yushiro Chemical Industry,
Kochi, Japan and received of Technology. She is now a Co., Ltd. Kanagawa, Japan.
her B.Sc. in 2007 and M.Sc. Research Associate at
Kazuya Watanabe was he is working as a master asymmetric reactions cata-
born in Osaka, Japan in course student with Profes- lyzed by oxazaborolidi-
1986 and received his B.Sc. sor Harada at Kyoto Insti- nones.
in 2009 from Kyoto Institute tute of Technology focusing
of Technology. Currently, on the development of
Atsushi Watada was born is working as a master asymmetric reactions cata-
in Kobe, Japan in 1987 and course student with Profes- lyzed by oxazaborolidi-
received his B.Sc. in 2010 sor Harada at Kyoto Insti- nones.
from Kyoto Institute of tute of Technology focusing
Technology. Currently, he on the development of
Toshiro Harada was born Associate in Kyoto Institute Materials Technology, Kyo-
in Kyoto, Japan, in 1952. He of Technology in 1981. He to Institute of Technology.
graduated from Kyoto Uni- spent the year 1982–1983 as His interests are in the de-
versity in 1975. He received a postdoctoral fellow with velopment of chiral Lewis
his Ph.D. from Kyoto Uni- Professor W. Clark Still at acid catalyzed enantioselec-
versity (1980) under the Columbia University. He tive reactions and conver-
guidance
of
Professor was promoted to Full Pro- gent carbon–carbon bond-
Zenichi Yoshida. Then, he fessor in 2002 in the Depart- forming reactions utilizing
was appointed as a Research ment of Chemistry and carbenoid intermediates.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2654
S. Adachi et al.
FEATURE ARTICLE
of simple nonchelating a,b-unsaturated carbonyl com- alytic enantioselective version of the furan F–C alkylation
pounds as electron-deficient alkenes represents a synthet- is much less developed than that of indoles and pyrroles.
ic challenge and has been less studied.
In their study on the copper-catalyzed enantioselective F–
C alkylation, Jørgensen and co-workers reported a few ex-
amples of the reaction of 2-methylfuran with b,g-unsatur-
ated a-keto esters.2b MacMillan et al. reported an
organocatalytic enantioselective cascade process in which
2-methylfuran was added to the b-position of an a,b-un-
saturated aldehyde, via an iminium mechanism, followed
by electrophilic chlorination of the resulting enamine in-
termediate.11a Very recently, the F–C reaction of furans
with highly reactive ethanetricarboxylates has been de-
scribed, but with limited results.3f The enantioselective re-
action of highly nucleophilic 2-methoxyfuran with a,b-
unsaturated 2-acyl imidazoles24 and nitroalkenes25 has
been reported. To date, however, the scope of the reaction
with respect to both furan derivatives and electron-defi-
cient alkenes remains to be expanded.
OR'
ML*n
O
O
N
ML*n
R
O
Z
R
R
O
ML*n
R'O
O
Z'
7a
7b
7c
ML*n
ML*n
O
O
ML*n
Y
ML*n
O
O
Y
Y
R
Y
R
R
R
8a
8b
8c
8d
Y = H, R', OR'
We recently reported that allo-threonine-derived ox-
azaborolidinones (OXB) 9 are efficient catalysts for the
enantioselective Michael reaction26 and Diels–Alder
reaction27 of acyclic a,b-unsaturated ketones.28 The high
enantioselectivities and the absolute stereochemical
course of the reactions with unsaturated ketones are ratio-
nalized in terms of the common activated complex model
10 in which the substrate coordinates to the boron atom in
an s-cis-anti fashion, allowing to be attacked by the nu-
cleophile on the open Si (front) face.
Scheme 2
For the enantioselective F–C alkylation reaction with a,b-
unsaturated aldehydes, an organocatalytic approach has
been revealed to be very effective. The first contribution
was presented by MacMillan and co-workers, who dem-
onstrated that a,b-unsaturated aldehydes are enantioselec-
tively activated by chiral amine catalysts in the form of
iminium salts, undergoing the enantioselective addition of
pyrroles,10a indoles,10b and anilines.10c,11 Other chiral
amine catalysts has been also reported.12
R
The first example of the F–C alkylation with a,b-unsatur-
ated ketones has been reported by Umani-Ronchi et al.13
It was shown that chiral Al(III)-salen complex catalyzes
the reaction of indoles affording the corresponding ad-
ducts with enantiomeric excesses in the 80% range for
most of the substrates. Recently, improved enantioselec-
tivity has been reported by Pedro et al. by using a chiral
Zr(IV)-BINOL catalyst.14 The catalyst system is specifi-
cally effective for alk-1-enyl aryl ketones. At the 20 mol%
catalyst loading, the reaction of pyrroles and indoles af-
forded the products in high yields and high enantioselec-
tivities. Very recently, highly enantioselective reactions
for chalcones (ArCH=CHCOAr¢) catalyzed by a chiral
Sc(III)-N,N¢-dioxide complex (2–10 mol%) has been re-
ported by Feng and co-workers.15 Organocatalytic exam-
ples of the F–C alkylation of indoles and pyrroles with
enones via ketiminine salts has also been reported.16
R1
O
O
O
B
Ph
O
Ar
O
N
O
B
O
H
H
O
R2
Ts
O
O
N
O
S
9
10
Figure 1 Structures of 9 and 10
The present study was aimed at developing the reaction
between the less electrophilic a,b-unsaturated ketones and
the less nucleophilic heteroaromatics such as furans in or-
der to expand the scope of the synthetically useful, cata-
lytic enantioselective F–C alkylation. For this purpose,
attention was focused on the characteristic features of the
OXB catalysts for the enantioselective activation of ke-
tonic carbonyl groups.
Furans also represent an important class of electron-rich
five-membered heterocycles that are broadly found as
structural motifs of many natural products and pharma-
ceutically important substances.17 Moreover, they can be
employed as useful intermediates in synthetic chemis-
try.18–20 Hence, the synthesis and transformation of furans
have attracted significant attention.21
We herein report the full details of the development of an
OXB-catalyzed enantioselective F–C alkylations of
furans and indoles with simple a,b-unsaturated ketones.29
Application to the enantioselective synthesis of g-keto
While furans are less nucleophilic than indoles and pyr-
roles,22 they do undergo the F–C alkylation with a,b-un-
saturated ketones by the catalysis of Brønsted acids or
Lewis acids to give racemic products.23 However, the cat-
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2655
carboxylic acids and a tetrahydropyrano[3,4-b]indole is
also described. The effect of an amine additive is dis-
cussed in terms of the retardation of a proton-catalyzed ra-
cemic pathway, which deteriorates the enantioselectivity
of the F–C alkylation reaction.
Table 1 Enantioselective F–C Alkylation of Furan 11b with Enone
12b Catalyzed by OXB 9aa
Entry
1b,c
2b
Solvent
toluene
EtCN
Et2O
Additive (mol%)
–
Yield (%) ee (%)
69
48
97
97
91
84
96
50
10
73
2
1
4
–
F–C Alkylation of Furans
3
–
2
4
toluene
CH2Cl2
EtCN
Et2O
PhNMe2 (5)
PhNMe2 (5)
PhNMe2 (5)
PhNMe2 (5)
PhNMe2 (5)
4-MeC6H4NMe2 (5)
4-BrC6H4NMe2 (5)
PhNEt2 (5)
44
20
55
69
57
64
44
30
14
32
22
27
22
6
We recently reported that furan (11a) undergoes enantio-
selective Diels–Alder reaction with alkyl vinyl ketones in
the presence of OXB 9a (10 mol%) at –78 °C in toluene
(Equation 1).27b Under similar conditions, the reaction of
2-methylfuran (11b) with vinyl ketone 12a did not afford
the Diels–Alder adduct, but the F–C product 13ba in 8%
yield (Equation 2). The observation prompted us to exam-
ine the possibility of asymmetric induction at the b-posi-
tion of F–C products in the reaction with crotyl ketone
12b.
5
6
7
8
t-BuOMe
Et2O
9
10
11
12
13
14
15
16
17
18
19
20e
21
22f
Et2O
Et2O
O
O
EtCN
EtCN
Et2O
PhN(i-Pr)2 (5)
2,6-lutidine (5)
2,6-lutidine (5)
2,4,6-collidine (5)
DTBPd (10)
PhNMe2 (2.5)
PhNMe2 (7.5)
PhNMe2 (10)
PhNMe2 (10)
PhNMe2 (20)
PhNMe2 (20)
26
72
7
B
Ph
Ph
O
N
O
H
Ts
9a (10 mol%)
O
O
+
O
R
–78 °C, toluene
O
R
11a
EtCN
Et2O
21
12
77
98
92
2
up to 98% ee
Equation 1
Et2O
Et2O
77
80
90
82
75
R1
O
O
9a (10 mol%)
amine additive
+
Et2O
R2
R1
R2
Me
O
O
13ba, 13bb
Et2O
12a; R1 = H, R2 = C5H11
12b; R1 = Me, R2 = Et
11b
Me
Et2O
23
82
Equation 2
Et2O
a Unless otherwise noted, reactions were carried out by using 12b (2.0
mmol, 0.3 M), 11b (5.0 equiv), and OXB 9a (10 mol%) at –40 °C for
18 h.
Initial examination of the reaction of 12b with 11b (5
equiv) in the presence of OXB 9a (10 mol%) resulted in
the nonenantioselective formation of the corresponding
F–C product 13bb irrespective of the solvents employed
(Table 1, entries 1–3). Further examination revealed the
remarkable effect of amine additives. In the presence of an
amine (5–10 mol%), 13bb was obtained in an enantiomer-
ically enriched form (entries 4–16). Of various aniline and
pyridine derivatives examined, N,N-dimethylaniline (5
mol%) was superior, exhibiting the best enantioselectivity
(69% ee) and product yield (96%) at –40 °C in Et2O (entry
7). When the amount of N,N-dimethylaniline was reduced
to 2.5 mol%, the enantioselectivity was decreased consid-
erably (entry 17). On the other hand, increasing the
amount of the additive to 7.5 and 10 mol% brought about
an improved enantioselectivity of 77% and 80% ee, re-
spectively (entries 18 and 19). Further increase (20
mol%), however, resulted in a decrease in the product
yield at –40 °C (entry 21) and led to a decline in the enan-
tioselectivity at –20 °C (entry 22). Although, with 10
b The reaction was carried out for 2 h.
c The reaction was carried out at 0 °C.
d 2,6-Di-tert-butylpyridine.
e The reaction was carried out at –78 °C.
f The reaction was carried out at –20 °C.
mol% of N,N-dimethylaniline 90% ee was obtained at –78
°C, the reaction was very sluggish (entry 20).
The scope of the OXB-catalyzed F–C reaction of furans
was examined in Et2O at –40 °C in the presence of N,N-
dimethylaniline (Equation 3, Table 2). In addition to
R1
O
R4
O
9a (10 mol%)
R2
+
R4
R1
R2
R3
PhNMe2
(10 mol%)
Et2O, –40 °C
O
O
R3
11a–f
12b–g
13
Equation 3
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2656
S. Adachi et al.
FEATURE ARTICLE
Table 2 Enantioselective F–C Alkylation of Furans 11 with Enones
12 Catalyzed by OXB 9aa
Enantioselective Synthesis of g-Keto Carboxylic
Acids
Entry Furan R3
R4
Enone R1
R2 Product Yield ee
(%) (%)b
The enantioselective conjugate addition of a hydroxycar-
bonyl anion equivalent to a,b-unsaturated ketones is one
of the most straightforward methods for the preparation of
enantioenriched g-keto carboxylic acids (Scheme 3).30
The use of cyanide as a hydroxycarbonyl anion equivalent
might be less attractive for this purpose because of possi-
ble racemization in the transformation of the cyano group
to the carboxy group.31 Furans can be oxidatively trans-
formed to carboxylic acids under relatively moderate
conditions32 and could serve as a hydroxycarbonyl anion
equivalent. In order to utilize the present OXB-catalyzed
enantioselective F–C alkylation of furans in the prepara-
tion of enantioenriched g-keto carboxylic acids, oxidative
transformation of the alkylation product 13 was examined
(Equation 4).
1
2
3
4c
5
6
7
8
9
11b Me
11c Et
11d Bu
H
H
H
H
12b Me
12b Me
12b Me
12b Me
Et
Et
Et
Et
Et
Et
Pr
13bb 92
13cb 95
13db 96
13eb 62
80
77
79
85
91
11e
11f
11a
Bn
Me Me 12b Me
13fb
98
H
H
H
H
12b Me
12c Me
12d Me
13ab trace nd
11b Me
11b Me
13bc 79
81
86
93
87
85
89
–
Bu 13bd 92
11f
Me Me 12d Me
Me Me 12e Bu
Bu 13fd
Me 13fe
89
85
81
99
0
10c 11f
R1
O
O
HO
11d 11b Me
12 11f Me Me 12f
13e 11b Me
12g Ph
H
12f
CO2Et Me 13bf
HO
+
R1
R2
R2
O
O
CO2Et Me 13ff
R4
H
Me 13bg
a Unless otherwise noted, reactions were carried out by using 12 (2.0
mmol), 11 (5.0 equiv), PhNMe2 (10 mol%), and OXB 9a (10 mol%)
in Et2O (3.1 mL) at –40 °C for 20 h.
R3
H
O
Scheme 3
b Determined by HPLC on a chiral stationary phase; nd = not deter-
mined.
c The reaction was carried out with 20 mol% of OXB 9a and PhNMe2.
d The reaction was carried out for 44 h.
R1
O
R1
O
RuCl3⋅H2O (1 mol%)
NaIO4 (15 equiv)
HO
e Enone 12g was recovered in 98% yield.
R2
R4
R2
CH2Cl2, MeCN, H2O
O
O
13
14a–d
Me
methyl derivative 11b, the reaction worked well with other
2-substituted furans 11c–e (Table 2, entries 1–4). The re-
actions of the 2-ethyl, 2-butyl, and 2-benzyl derivatives
with enone 12b afforded the corresponding F–C products
with 77–85% ee and in high yields. Of these, benzyl de-
rivative 11e was somewhat less reactive and 20 mol% of
the catalyst was required. 2,3-Dimethylfuran (11f) exhib-
ited high enantioselectivity (91% ee) in the reaction with
enone 12b (entry 5). On the other hand, the parent furan
(11a) hardly reacted with 12b (entry 6).
Equation 4
Oxidation of 13bc (81% ee) with RuCl3·H2O (1 mol%)
and NaIO4 (15 equiv) in CH2Cl2, MeCN, and H2O32 went
to completion in four hours to give the g-keto acid 14a
(R1 = Me, R2 = Pr) in 96% yield (Table 3, entry 1). The
enantiopurity of 14a was determined to be 82% ee by a
chiral phase HPLC analysis of benzylamide derivative,
establishing that no racemization occurs during the oxida-
Aliphatic enones other than 12b, such as crotyl alkyl ke-
tones 12c,d and hex-1-enyl methyl ketone (12e) also
serves as an acceptor, affording the F–C alkylation prod-
ucts of furans 11b and 11f with 81–93% ee and in high
yields (entries 7–10). Enone 12f bearing an ethoxycarbo-
nyl group at the b-position was also a good substrate (en-
tries 11 and 12). The reaction of furan derivatives 11b and
11f gave the corresponding product 13bf and 13ff in 85%
ee and 89% ee, respectively, in high yields. On the other
hand, attempted reaction with benzalacetone (12g) result-
ed in the recovery of the enone (entry 13).
a
Table 3 Oxidation of 13 with RuCl3·H2O and NaIO4
Entry Furan F–C product 13
Yield (%)eeb (%)
R4
R1
R2
Pr
1
2
3
4
13bc
13fb
13fd
13fe
H
Me
Me
Me
Bu
14a
14b
14c
14d
96
81
89
85
82
92
93
88
Me
Me
Me
Et
Bu
Me
a The reactions of 13 were carried out with RuCl3·H2O (1 mol%) and
NaIO4 (15 equiv) in a mixture of CH2Cl2, MeCN, and H2O at r.t. for
4 h.
b Enantioselectivities were determined by HPLC on a chiral stationary
phase after conversion into the corresponding benzylamide.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2657
tion. The absolute structure of 14a was determined to be S
by comparison of the optical rotation sign with literature
data.30 The F–C alkylation products of 2,3-dimethylfuran
were obtained in higher enantioselectivity than those of 2-
methylfuran. Under similar conditions, oxidation of these
products 13 afforded g-keto acids 14b–d of high ee (88–
93% ee) in high yields (entries 2–4).
Me
O
Et
HN
16ab
9a (10 mol%)
+
12b
+
N
Et2O, 20 h
H
NH
15a
N
H
17
F–C Alkylation of Indoles
Equation 5
Catalysis by OXB was examined also for the F–C alkyla-
tion of indoles with a,b-unsaturated ketones because of
the synthetic importance of the transformation. Attempts
were made to optimize the conditions for the reaction of
indole (15a) with enone 12b in the presence of catalyst 9a
(10 mol%) (Equation 5, Table 4).
enantioselectivity was improved to 87% ee (entry 3). In
the presence of 2.5 mol% of N,N-dimethylaniline, high
enantioselectivity comparable to entry 3 was obtained
(entry 4). Unlike the reaction of furans, further increase of
the additive resulted in a decrease in product yields (en-
tries 5 and 6). In the reactions without the amine additive
(entries 1–3), indole dimer 17 was formed as a by-product
in 3% yield while the formation of 17 was not detected in
the presence of the additive (entries 4–6).
Table 4 Enantioselective F–C Alkylation of Indole with Hex-4-en-
3-one Catalyzed by OXB 9aa
Entry Temp
(°C)
Methodb Additive (mol%)
Yield (%)ee (%)
OXB catalyst 9a was prepared prior to use by treatment of
N-tosylamino acid 18 with dichlorophenylborane fol-
lowed by removal of hydrogen chloride in vacuo (Method
A) (Equation 6). Hydrogen chloride, contaminated with
the catalyst, might be responsible for the formation of in-
dole dimer 17.33 Thus, 17 might be formed by a pathway
involving protonation of indole, the attack of another in-
dole to the resulting iminium intermediate, and subse-
quent proton migration leading to dimer salt 17·HCl
(Scheme 4). Judging from the yields of 17 in entries 1–3,
the residual hydrogen chloride is estimated to be about 3
mol%, well consistent with the minimum amount (2.5
mol%) of the amine additive required to suppress the for-
mation of 17.
1c
2c
–40
–85
A
A
A
A
A
A
B
B
B
B
B
–
83
90
90
92
56
27
96
85
68
78
87
87
87
82
77
60
86
29
25
–
3c,d –85
–
4
–85
–85
–85
–85
–40
–85
–85
–85
PhNMe2 (2.5)
5
PhNMe2 (5)
6e
7
PhNMe2 (7.5)
–
–
8
9
PhNMe2·HCl (2.5) 92
O
OH
10
11
AcOH (2.5)
47
61
9a
+ HCl
+
PhBCl2
PhO2C
CH2Cl2
CF3CO2H (2.5)
NHTs
H
a Unless otherwise noted, reactions were carried out by using 12b (2
mmol), 15a (1 equiv), and OXB 9a (10 mol%) in Et2O (3.1 mL) at
–85 °C for 20 h.
18
Equation 6
b OXB 9a was prepared by treatment of 18 with PhBCl2 followed by
removal of HCl in vacuo (Method A) or by treatment with allyltri-
methylsilane (4 equiv) for 14–17 h at r.t. (Method B).
c By-product 17 was obtained in 3% yield.
To avoid contamination by hydrogen chloride, OXB 9a,
prepared according to Equation 6, was treated with allyl-
trimethylsilane (4 equiv) at room temperature for 14–17
hours and used after concentration in vacuo (Method B).
Under these conditions, the formation of dimer 17 was not
detected, confirming the complete removal of hydrogen
chloride (entry 7). F–C alkylation product 16ab was ob-
tained in high yield, but with lower enantioselectivity
(77% ee). The enantioselectivity was comparable to that
in the reaction with Method A in the absence of the amine
additive (entry 2), suggesting that the residual hydrogen
chloride is not influential to the lower enantioselectivity.
d A mixture of 15a and 9a was stirred for 24 h at –85 °C before the
addition of 12b.
e The reaction was carried out for 32 h.
In contrast to the reaction of furans, F–C product 16ab
was obtained in relatively high enantioselectivity (68%
ee) even without an amine additive at –40 °C (Table 4, en-
try 1). The reaction of a stoichiometric amount of 15a
went to completion in 20 h at –85 °C to give 16ab in 78%
ee (entry 2), demonstrating a higher reactivity of indoles
compared to furans.22 When a mixture of 15a and catalyst
9a was stirred for 24 hours before the addition of 12b, the
In the presence of hydrogen chloride, N,N-dimethyl-
aniline forms a hydrochloride salt. Therefore, the effect of
the salt was then examined. When the reaction was carried
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2658
S. Adachi et al.
FEATURE ARTICLE
H
underwent the F–C alkylation reaction without lowering
the reactivity and selectivity (entries 10–12).
N
15a
HCl
Cl
15a
To further investigate the scope of the reaction, the reac-
tions of indole (15a) and 2-methylindole (15i) were car-
ried out with a variety of a,b-unsaturated ketones. The
reaction of 15a with crotyl butyl ketone (12d) proceeded
with high enantioselectivity (92% ee) and in good yield
(entry 13). In comparison with crotyl ketones 12b,d,
enones 12e,g, bearing a butyl and a phenyl group at the b
position, were less reactive. The F–C alkylation of 15a re-
sulted in low or poor product yield (entries 14 and 17).
However, the F–C reaction of 15i proceeded efficiently
with such less reactive enones. Not only 12e but also ben-
zalacetone derivatives 12g,h gave the corresponding F–C
alkylation products 16 in high yields and high selectivities
(entries 15, 18, and 19). Functionalized enones, such as
ethoxycarbonyl derivative 12f, (benzyloxy)methyl deriv-
ative 12i, and, di(methoxy)methyl derivative 12j, could be
used as acceptors of the present F–C alkylation (entries
16, 20, and 21). Of these, 12f and 12j exhibited superior
enantioselectivities. OXB 9a did not exhibit high selectiv-
ity in the reaction with phenyl ketone 12k and cyclic
enone 12l (entries 22 and 23). Such structural limitation of
enones was observed also in the OXB-catalyzed Michael
reaction26 and Diels–Alder reaction.27
N
N
Cl
H
H
H
NH
N
Cl
H2
17⋅HCl
Scheme 4
R5
9a (10 mol%)
PhNMe2 (2.5 mol%)
O
R4
+
R1
12b–l
R2
N
R3
15a–k
Et2O, –85 °C, 20 h
R5
R1
O
R2
N
R4
16
R3
Equation 7
out with catalyst 9a prepared by Method B in the presence
of N,N-dimethylaniline hydrochloride (2.5 mol%), 16ab
was obtained in 86% ee (entry 9). The result shows that
N,N-dimethylaniline exerted the advantageous effect in
the form of the hydrochloride salt. High enantioselectivity
was also obtained in the absence of N,N-dimethylaniline
when catalyst 9a (Method A) was used after treatment
with indole (entry 3). Under these conditions, hydrochlo-
ride salt of indole dimer (17·HCl) might serve as an addi-
tive instead of N,N-dimethylaniline hydrochloride.
Examination of other Brønsted acids such as acetic acid
and trifluoroacetic acid resulted in lowering of the yield
and the enantioselectivity (entries 10 and 11).
One of the characteristic features of the present indole F–
C alkylation reaction is that it can be carried out at rela-
tively low catalyst loadings. A 10 mol% of catalyst 9a is
enough to obtain the results shown in Table 5. Further re-
duction of the amount of the catalyst is possible by the
elongation of the reaction time. Thus, when the reaction of
15a with 12b was carried out at a 5 mol% catalyst loading
for 48 hours, 16ab was obtained in high yield without
lowering enantioselectivity (entry 2).
Catalysis by OXB could be applied successfully to in-
tramolecular F–C alkylation6a,34 as exemplified in enan-
tioselective synthesis of tetrahydropyranoindole 20
(Equation 8). Although indolyl enone 19 was not fully
soluble in cold Et2O, its treatment with 9a (20 mol%) in
the presence of N,N-dimethylaniline for five days gave 20
with 90% ee.
The scope of the OXB-catalyzed F–C alkylation was ex-
plored with respect to indole architecture in the reaction
with hex-4-en-3-one (12b) under the optimized condi-
tions using 10 mol% of 9a (Method A) in the presence of
2.5 mol% of N,N-dimethylaniline (Equation 7). Indole de-
rivatives 15b,c bearing electron-donating substituents at
the 5-position also gave the corresponding adducts 16
enantioselectively in high yields (Table 5, entries 3 and
4). While a chlorine and bromine substituent at the 5 po-
sition lowered conversion, a good level of enantioselectiv-
ity was retained for 15d,e (entries 5 and 6). In the
organocatalytic F–C alkylation of indoles, it has been ob-
served that substitution on the nitrogen atom had a detri-
mental effect on both reactivity and enantioselectivity.16a
The OXB-catalyzed reaction has no such limitation, being
applicable to N-substituted indoles 15f–h (entries 7–9).
Of these, N-methyl derivative 15f exhibited enhanced se-
lectivity of 93% ee in comparison with parent indole. Ster-
ically hindered 2-methyl derivatives 15i–k also
O
Et
Et
9a (20 mol%)
PhNMe2 (7.5 mol%)
O
O
Et2O, –85 °C, 5 d
O
N
Me
N
Me
20; 60%, 90% ee
19
Equation 8
The absolute stereochemistry of indole F–C products
16ab,16a 16af,16a and 16ik13a were determined to be S by
the comparison of their optical rotation signs with litera-
ture data. The selectivity for S-enantiomers, observed
commonly in the F–C alkylation of furans and indoles, is
consistent with activated complex 10, thus ascertaining
further the validity of the model.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2659
Table 5 Enantioselective F–C Alkylation of Indoles 15 with Enones 12 Catalyzed by OXB 9aa
Entry
1
Indole
15a
15a
15b
15c
15d
15e
15f
15g
15h
15i
R3
H
R4
H
R5
H
Enone
12b
12b
12b
12b
12b
12b
12b
12b
12b
12b
12b
12b
12d
12e
12e
12f
R1
R2
Product
16ab
16ab
16bb
16cb
16db
16eb
16fb
16gb
16hb
16ib
16jb
16kb
16ad
16ae
16ie
Yield (%) ee (%)b
Me
Et
92
90
85
73
55
23
93
93
52
91
83
73
81
19
90
96
2
87
87
89
83
85
85
93
85
75
87
81
75
92
72
82
94
nd
84
81
75
92
37
55
2c
H
H
H
Me
Et
3
H
H
MeO
Me
Cl
Br
H
Me
Et
4
H
H
Me
Et
5d
H
H
Me
Et
6d
H
H
Me
Et
7
Me
allyl
Bn
H
H
Me
Et
8
H
H
Me
Et
9
H
H
Me
Et
10
11
12
13
14
15d
16
17d
18d
19d
20e
21e
22
23e
Me
Me
Me
H
H
Me
Et
15j
15k
15a
15a
15i
Me
H
H
Me
Et
MeO
H
Me
Et
H
Me
Bu
Me
Me
Me
Me
Me
Me
Me
C5H11
Ph
H
H
H
Bu
H
Me
H
H
Bu
15a
15a
15i
H
H
EtO2C
Ph
16af
16ag
16ig
H
H
H
12g
12g
12h
12i
H
Me
Me
Me
Me
Me
Me
H
Ph
87
81
70
85
52
47
15i
H
H
4-FC6H4
BnOCH2
(MeO)2CH
Me
16ih
16ii
15i
H
H
15i
H
H
12j
16ij
15i
H
H
12k
12l
16ik
16il
15i
H
H
cyclohex-2-enone
a Unless otherwise noted, reactions were carried out by using 12 (2 mmol), 15 (1 equiv), PhNMe2 (2.5 mol%), and 9a (10 mol%) in Et2O (3.1
mL) at –85 °C for 20 h.
b Determined by HPLC on a chiral stationary phase; nd = not determined.
c The reaction was carried out with 9a (5 mol%) without the addition of PhNMe2 for 48 h. The catalyst prepared by Method A was used after
treatment with 15a for 24 h at –85 °C.
d The reaction was carried out for 96 h.
e The reaction was carried out for 48 h.
Effect of Amine Additive
go 1,3-migration to an enolate carbon to furnish F–C alky-
lation product 13 or 16 with regeneration of the catalyst.
According to the generally accepted mechanism for the The proton migration may proceed either by a concerted
Lewis-acid catalyzed F–C alkylation of electron-rich het- mechanism or by a stepwise mechanism involving depro-
eroaromatics,8b,9b,35 the OXB-catalyzed reaction proceeds tonation/protonation sequence. As a proton-catalyzed ra-
by initial complexation of enone 12 with catalyst 9a fol- cemic background reaction is likely to degrade the overall
lowed by the attack of a heteroaromatic (ArH) to the re- enantioselectivity of the OXB-catalyzed reaction (vide
sulting activated complex 21 to form zwitterionic infra), it is essential to gain mechanistic information on
intermediate 22 (Scheme 5). Then, a proton attached to the proton migration step.
the heteroaromatic ring of intermediate 22 needs to under-
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2660
S. Adachi et al.
FEATURE ARTICLE
syn-isomers were observed for both products. In another
experiment, reaction was quenched before completion af-
ter four hours (entry 2). Under these conditions, H/D
scrambling was observed for products 16fb-d (65%-d)
and 16gb-d (58%-d)36 but not for the recovered indoles
15f-d (90%-d) and 15g (0%-d), excluding the possibility
of a prior H/D scrambling between the substrates. In addi-
tion, scrambling between the F–C products was ruled out
by the absence of d2-products as confirmed by mass spec-
trometric analyses. Extensive H/D scrambling was also
observed when a crossover reaction was carried out with
9a prepared by Method B in the absence of the amine ad-
ditive (entry 3).
O
R2
R1
R1
O
O
O
12
B
Ph
R2
Ar
N
R
H
Ts
13,16
9a
Ts
R
Ts
N
Ph
O
R
N
B
Ph
O
R1
O
O
B
O
O
H
R2
Ar
R2
R1
22
21
16fb-d
9a (10 mol%)
15f-d (0.5 equiv)
+
15g (0.5 equiv)
PhNMe2 (2.5 mol%)
+
Ar -H = indoles and furans
R = (S)-PhCO2CH(Me)-
Ar-H
11, 15
+ 12b
Et2O, –85 °C
Me
O
Scheme 5
Et
D
N
For this purpose, reactions were carried out by using 1-
methyl-3-deuteroindole (15f-d; 90%-d). The reaction of
15f-d with 12b in the presence of 9a (Method A) and N,N-
dimethylaniline afforded F–C product 16fb-d in 86%
yield and with 85% ee (Equation 9). In accord with the re-
16gb-d
Equation 10
Table 6 Crossover Experiments with 15f-d and 15ga
1
action pathway in Scheme 5, H NMR analysis of the
Entry
1
Product
16fb-d
16gb-d
16fb-d
16gb-d
16fb-d
16gb-d
Yield (%) ee (%) d (%)b
syn/antib
85:15
86:14
86:14
84:16
87:13
88:12
product showed that a deuterium was incorporated exclu-
sively at the a position in 84%-d. Compound 16fb-d was
obtained as a 87:13 mixture diastereomers. The major iso-
mer was assigned as syn-16fb-d based on a smaller vicinal
coupling constant (J = 6.2 Hz) relative to the minor anti-
isomer (J = 8.0 Hz) for the a proton of 16fb (Figure 2).
47
48
32
10
41
27
91
84
87
85
78
81
72
22
65
58
57
43
2c
3d
D
Me
O
9a (10 mol%)
PhNMe2 (2.5 mol%)
Et
+
12b
Et2O, –85 °C, 20 h
D
N
N
a Unless otherwise noted, reactions were carried out with 12b, 15f-d
(0.5 equiv), 15g (0.5 equiv), PhNMe2 (2.5 mol%), and 9a (10 mol%,
Method A) in Et2O at –85 °C for 20 h.
Me
Me
15f-d
90%-d
16fb-d
86%, 85% ee, 84%-d,
syn/anti = 87:13
b Determined by 1H NMR spectroscopy.
c Reaction was carried out for 4 h.
Equation 9
d Reaction was performed with 9a prepared by Method B in the ab-
sence of PhNMe2.
H
Me
O
6.2 Hz
The crossover experiments clearly showed that the 1,3-
proton migration in 22 did not proceed by a concerted
mechanism. The result is compatible with a stepwise
mechanism involving deprotonation of 22 by solvent Et2O
to form an ion pair of enol boronate 23 and Et2O+H
(Scheme 6). Subsequent protonation of 23 leading to the
F–C products 13 or 16 (pathway a) would occur, at least
partially, in the solvent cage via an initially produced inti-
mate ion pair. Hence, the observed extensive H/D scram-
bling is difficult to be rationalized by such direct pathway.
It is more probable that 23 undergoes protonation at the
carbonyl oxygen atom to form relatively stable zwitterion
24,37 which furnishes the F–C products with H/D scram-
bling through a bimolecular mechanism (pathway b).38
The selective formation of the syn-diastereomers in
Et
8.0 Hz
Hanti
N
Hsyn
Me
δ 2.50
δ 2.80
16fb
Figure 2 syn/anti-Vicinal couplings in 16fb
A crossover experiment was then examined with a mix-
ture of 15f-d (0.5 equiv) and 1-allyl derivative 15g (0.5
equiv) under similar conditions for 20 hours
(Equation 10). The reaction afforded H/D scrambled
products 16fb-d and 16gb-d enriched with 72% and 22%
deuterium, respectively, as determined by 1H NMR anal-
ysis (Table 6, entry 1). Diastereoselective formations of
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2661
Equations 9 and 10 is well consistent with the deuteration in the absence of the additive, shows that the effect of the
at the less hindered side, anti to the indolyl group of 24.
amine salt is rather small for furans.
The role of N,N-dimethylaniline hydrochloride in the re-
action of indoles could be understood as a catalyst for the
conversion of zwitterion intermediate 24 into the F–C
product 16 [Scheme 7 (a)]. Thus, 24 would react with the
hydrochloride salt by a protonation (at the enolate car-
bon)/deprotonation (of the hydroxy group) sequence to
give 16 with regeneration of catalyst 9a and the amine
salt.39 The catalytic protonation/deprotonation sequence
would prevent the accumulation of 24, which could in-
duce the proton catalyzed racemic pathway via 25. The ef-
fect of free N,N-dimethylaniline, predominant for furans,
could also be rationalized in terms of a catalyst for proton
transfer [Scheme 7 (b)]. For the free amine, deprotonation
24 precedes protonation of the resulting enol boronate 23.
Ts
R
N
Ph
O
B
R1
O
O
pathway a
+
22
Et2O-H
13,16
R2
23
Ar
pathway b
Ts
R
N
Ph
O
Ar-H
B
H
H
11, 15
12
O
O
O
H
R1
Ar
rac-13,16
R2
24
R2
R1
25
H
Scheme 6
H
O
R
O
N
Ph
+
Cl
PhNMe2⋅HCl
PhNMe2
(a)
PhNMe2⋅HCl
B
24
In the OXB-catalyzed F–C alkylations of indoles and
furans, N,N-dimethylaniline as an additive is indispens-
able to obtain high enantioselectivity. In the reaction of in-
dole, the enantioselectivities were about 10% lower
without the amine additive irrespective of Method A and
B for the preparation of OXB 9a (Table 4, entries 2 and 7).
The effect of the additive was more prominent in the furan
F–C alkylations. In the absence of the additive, 9a pre-
pared by Method A, exhibited no enantioselectivity in the
reaction of 2-methylfuran with 12b (Table 1, entry 3). Un-
der similar conditions, the use of 9a, prepared by Method
B and not contaminated with hydrogen chloride, also re-
sulted in the formation of racemic (3% ee) product 13ab
in 61% yield. It is very likely that the racemic product was
produced through a proton catalyzed pathway via inter-
mediate 25 which is formed by protonation of enone 12
with 24 (Scheme 6). In the indole F–C alkylations without
the amine additive, the proton-catalyzed racemic pathway
proceeded in competition with the OXB-catalyzed enan-
tioselective pathway, degrading the overall selectivity of
the reaction.
Ts
16
9a
Ts
R
N
Ph
O
B
R1
O
O
PhNMe2
(b)
PhNMe2
PhNMe2⋅HCl
+
24
R2
Ar
23
9a + 13
Scheme 7
In the reactions of indole (15a) with 13b, the product
yields were decreased considerably by the increase of the
amine additive (5–7.5 mol%) (Table 4, entries 5 and 6).
The results imply that the free amine retards the OXB-cat-
alyzed reaction as well, presumably owing to the revers-
ible formation an amine-OXB complex.40 In the furan F–
C alkylation, 10 mol% of N,N-dimethylaniline efficiently
retarded the proton-catalyzed pathway (Table 1, entry 19)
although, under these conditions, the free amine might
partially deactivate the OXB catalyst by complexation.
Further increase of the amine additive led to a consider-
able decrease in reaction rate by the almost exhaustive
poisoning of the catalyst (entry 21).
Owing to the lower nucleophilic reactivity,22 higher tem-
perature (–40 °C) was required in the reaction of furans.
Under these conditions, the proton-catalyzed racemic
pathway might become predominant. This could be the
reason why increased amount of the amine additive was
necessary to achieve high enantioselectivity. An increase
in the portion of the racemic pathway was observed also
in the reaction of indoles at the higher temperature. Thus,
when the reaction of 15a with 12b was carried out at –40
°C, 16ab was obtained only in moderate enantioselectivi-
ty (Table 4, entries 1 and 8).
The optimal amounts of the amine additive for the F–C
alkylation of indoles and furans are different, being 2.5
and 10 mol%, respectively. As described above, OXB 9a
prepared by Method A was contaminated with ca. 3 mol%
of hydrogen chloride. Accordingly, in the reaction of in-
doles, the amine exerted beneficial effect in the form of
the hydrochloride salt. On the other hand, in the reaction
of furans with 10 mol% of N,N-dimethylaniline, a major
portion of the additive remained as a free base. The poor
selectivity (6% ee) observed with 2.5 mol% additive
(Table 1, entry 17) suggested that the hydrochloride salt is
not much effective for furans. Indeed, when the reaction
of 2-methylfuran (11b) with enone 12b was carried out in
the presence of an increased amount of N,N-dimethyl-
aniline hydrochloride (35 mol%) with catalyst 9a (10
mol%) prepared by Method B (–40 °C, 20 h), F–C product
13ab was obtained in 85% yield and in 19% ee. The low
selectivity, while being slightly better than that obtained
The OXB catalysis is demonstrated to be effective in the
enantioselective F–C alkylation of electron-rich hetero-
aromatics. The enantioselective F–C alkylation of furans
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2662
S. Adachi et al.
FEATURE ARTICLE
1-(5-Methylfuran-2-yl)octan-3-one (13ba)
with a monodentate a,b-unsaturated ketones is realized
for the first time by OXB catalysis. In addition, the F–C
products of furans are successfully converted into the cor-
responding g-keto carboxylic acids without the loss of
enantiopurity. The catalyst system is also applied to the F–
C alkylation of indoles, expanding the scope of substrates.
The observed absolute structures of the F–C products are
consistent with the activated complex model 10 proposed
previously for relevant Michael reaction and Diels–Alder
reaction. The use of N,N-dimethylaniline (2.5 mol% for
indoles and 10 mol% for furans) as an additive is found to
be essential to obtain high enantioselectivity. The effect of
the additives is discussed in terms of the retardation of a
proton-catalyzed racemic pathway, which deteriorates the
enantioselectivity of the F–C alkylation reaction.
1H NMR (500 MHz, CDCl3): d = 0.88 (3 H, t, J = 7.3 Hz), 1.21–1.33
(4 H, m), 1.56 (2 H, m), 2.23 (3 H, s), 2.39 (2 H, t, J = 7.5 Hz), 2.72
(2 H, t, J = 7.1 Hz), 2.84 (2 H, t, J = 7.7 Hz), 5.81–5.84 (2 H, m).
13C NMR (125.8 MHz, CDCl3): d = 13.4, 13.9, 22.3, 22.4, 23.5,
31.3, 40.9, 42.8, 105.7, 105.9, 150.4, 152.8, 209.9.
HRMS (EI): m/z calcd for C13H20O2: 208.14633; found: 208.1466.
(S)-5-(5-Ethylfuran-2-yl)hexan-3-one (13cb)
[a]D18 +3.60 (c 2.50, CHCl3) (77% ee).
1H NMR (500 MHz, C6D6): d = 0.99 (3 H, t, J = 7.3 Hz), 1.17 (3 H,
t, J = 7.6 Hz), 1.28 (3 H, d, J = 6.9), 1.99 (2 H, q, J = 7.3 Hz), 2.26
(1 H, dd, J = 8.1, 16.4 Hz), 2.57 (2 H, q, J = 7.5 Hz), 2.63 (1 H, dd,
J = 5.8, 16.4 Hz), 3.36 (1 H, sext, J = 6.9 Hz), 5.90–5.93 (2 H, m).
13C NMR (125.8 MHz, CDCl3): d = 8.2, 12.7, 19.5, 22.1, 29.7, 36.5,
48.5, 105.0, 105.1, 156.5, 158.1, 208.1.
HRMS (EI): m/z calcd for C12H18O2: 194.1307; found: 194.1313.
1H (500 MHz) and 13C NMR (126 MHz) spectra were recorded on
a Bruker DRX-500 spectrometer. Spectra were referenced to resid-
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.5% i-PrOH in hexane); tR: 5.5 min (ma-
jor S-enantiomer) and 6.2 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
ual CHCl3 (d = 7.26) for 1H resonances and CDCl3 (d = 77.0) for 13
C
resonances. MS measurements were conducted with a JEOL JMS-
700 instrument. Optical rotations were measured with Horiba
SEPA-300 Polarimeter. HPLC analyses were performed on a Beck-
man Gold system. All reactions were performed under an inert at-
mosphere of dry argon. Flash chromatography was carried out with
silica gel C-300 of Wako Pure Chemical Industries, Ltd. CH2Cl2
and EtCN were dried and distilled over CaH2. Et2O and toluene
were distilled from sodium benzophenone ketyl. The following
compounds were prepared according to a literature procedure;
11d,41 11e,42 12c,k,43 12e,44 12f,45 12h,46 12i,47 12j,48 15g,5a 15h,49
15f-d,50 18,26a and N,N-dimethylaniline hydrochloride.51 Dichlo-
rophenylborane and N,N-dimethylaniline were used after distilla-
tion. Furans 11a,b,f were dried and distilled over sodium before
use. Furans 11c–e were passed through basic alumina and distilled
before use.
(S)-5-(5-Butylfuran-2-yl)hexan-3-one (13db)
[a]D27 +3.59 (c 1.00, CHCl3) (79% ee).
1H NMR (500 MHz, CDCl3): d = 0.92 (3 H, t, J = 7.4 Hz), 1.04 (3
H, t, J = 7.3 Hz), 1.22 (3 H, d, J = 6.9 Hz), 1.35 (2 H, sext, J = 7.5
Hz), 1.56–1.61 (2 H, m), 2.38 (2 H, q, J = 7.3 Hz), 2.50 (1 H, dd,
J = 7.9, 16.1 Hz), 2.55 (2 H, t, J = 7.5 Hz), 2.79 (1 H, dd, J = 6.1,
16.1 Hz), 3.35 (1 H, sext, J = 7.2 Hz), 5.82–5.84 (2 H, m).
13C NMR (125.8 MHz, CDCl3): d = 7.7, 13.8, 18.9, 22.3, 27.7, 29.1,
30.2, 36.5, 48.2, 104.1, 104.8, 154.9, 157.1, 210.2.
HRMS (EI): m/z calcd for C14H22O2: 222.1620; found: 222.1623.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.5% i-PrOH in hexane); tR: 5.0 min (ma-
jor S-enantiomer) and 5.4 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
F–C Alkylation of Furans; (S)-5-(5-Methylfuran-2-yl)hexan-3-
one (13bb); Typical Procedure (Table 2, Entry 1)
OXB 9a (0.20 mmol) was prepared as follows (Method A). To a so-
lution of O-benzoyl-N-tosyl-L-allo-threonine (18; 75.5 mg, 0.20
mmol) in anhyd CH2Cl2 (2.0 mL) under argon at r.t. was added
dichlorophenylborane (28.5 mL, 0.220 mmol). After stirring for 30
min, the mixture was concentrated in vacuo. To a mixture of the re-
sulting 9a in anhyd Et2O (3.1 mL) at –40 °C were added 2-methyl-
furan (11b; 821 mg, 10 mmol), N,N-dimethylaniline (24.2 mg, 0.20
mmol), and hex-4-en-3-one (12b; 196 mg, 2 mmol). After stirring
at –40 °C for 18 h, the reaction mixture was quenched with sat. aq
NaHCO3 (10 mL) and filtered. The filtrate was extracted with Et2O
(3 × 20 mL), the combined organic layers were dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash chroma-
tography (SiO2, gradient elution with 1–2% Et2O in hexane) gave
332 mg (92%) of 13bb (80% ee); [a]D28 +4.98 (c 1.33, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.03 (3 H, t, J = 7.3 Hz), 1.21 (3
H, d, J = 6.9 Hz), 2.23 (3 H, s), 2.38 (2 H, q, J = 7.3 Hz), 2.51 (1 H,
dd, J = 8.0, 16.2 Hz), 2.79 (1 H, dd, J = 6.0, 16.2 Hz), 3.34 (1 H,
sext, J = 7.0 Hz), 5.81–5.84 (2 H, m).
13C NMR (125.8 MHz, CDCl3): d = 7.7, 13.5, 19.0, 29.1, 36.4, 48.2,
104.3, 105.7, 150.4, 157.3, 210.2.
(S)-5-(5-Benzylfuran-2-yl)hexan-3-one (13eb)
[a]D27 +4.39 (c 1.00, CHCl3) (85% ee).
1H NMR (500 MHz, CDCl3): d = 1.00 (3 H, t, J = 7.3 Hz), 1.22 (3
H, d, J = 6.9 Hz), 2.32 (2 H, q, J = 7.3 Hz), 2.49 (1 H, dd, J = 7.8,
16.1 Hz), 2.78 (1 H, dd, J = 6.2, 16.1 Hz), 3.35 (1 H, sext, J = 6.9
Hz), 5.85–5.87 (2 H, m), 7.20–7.31 (5 H, m).
13C NMR (125.8 MHz, CDCl3): d = 7.7, 18.9, 29.1, 34.5, 36.4, 48.1,
104.4, 106.6, 126.4, 128.4, 128.6, 138.3, 152.8, 158.0, 210.1.
HRMS (EI): m/z calcd for C17H20O2 256.1463; found: 256.1472.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min 1% i-PrOH in hexane); tR: 6.2 min (major
S-enantiomer) and 6.9 min (minor R-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
(S)-5-(4,5-Dimethylfuran-2-yl)hexan-3-one (13fb)
[a]D27 +5.30 (c = 2.00, CHCl3) (91% ee).
1H NMR (500 MHz, CDCl3): d = 1.04 (3 H, t, J = 7.3 Hz), 1.20 (3
H, d, J = 6.9 Hz), 1.87 (3 H, s), 2.14 (3 H, s), 2.38 (2 H, q, J = 7.3
Hz), 2.49 (1 H, dd, J = 7.9, 16.2 Hz), 2.78 (1 H, dd, J = 6.0, 16.2
Hz), 3.30 (1 H, sext, J = 7.0 Hz), 5.74 (1 H, s).
HRMS (EI): m/z calcd for C11H16O2: 180.1150; found: 180.1157.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.5% i-PrOH in hexane); tR: 6.0 min (ma-
jor S-enantiomer) and 6.7 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
13C NMR (125.8 MHz, CDCl3): d = 7.7, 9.8, 11.2, 19.0, 29.0, 36.4,
48.2, 106.9, 114.1, 145.4, 156.0, 210.2.
HRMS (EI): m/z calcd for C12H18O2: 194.1307; found: 194.1306.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2663
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 0.1% i-PrOH in hexane); tR: 11.3 min (ma-
jor S-enantiomer) and 14.5 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
S-enantiomer) and 10.5 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
Ethyl (S)-2-(5-Methylfuran-2-yl)-4-oxopentanoate (13bf)
[a]D30 +47.7 (c = 2.08, CHCl3) (85% ee).
(S)-2-(5-Methylfuran-2-yl)heptan-4-one (13bc)
[a]D29 +3.30 (c 1.03, CHCl3) (81% ee).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.4 Hz), 1.22 (3
H, d, J = 6.9 Hz), 1.59 (2 H, sext, J = 7.4 Hz), 2.23 (3 H, s), 2.34 (2
H, t, J = 7.3 Hz), 2.50 (1 H, dd, J = 8.1, 16.3 Hz), 2.79 (1 H, dd,
J = 5.9, 16.3 Hz), 3.33 (1 H, sext, J = 7.0 Hz), 5.82–5.83 (2 H, m).
1H NMR (500 MHz, CDCl3): d = 1.23 (3 H, t, J = 7.1 Hz), 2.18 (3
H, s), 2.23 (3 H, s), 2.80 (1 H, dd, J = 4.5, 18.0 Hz), 3.29 (1 H, dd,
J = 10.0, 18.0 Hz), 4.12–4.20 (3 H, m), 5.86 (1 H, m), 6.01 (1 H, m).
13C NMR (125.8 MHz, CDCl3): d = 13.5, 14.0, 29.9, 40.2, 44.1,
61.3, 106.3, 107.4, 149.1, 151.6, 171.2, 205.8.
HRMS (FAB/m-NBA): m/z calcd for C12H17O4 (M + H+): 225.1127;
found: 225.1132.
13C NMR (125.8 MHz, CDCl3): d = 13.5, 13.7, 17.1, 19.0, 28.9,
45.2, 48.5, 104.3, 105.7, 150.3, 157.3, 209.8.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 1% i-PrOH in hexane); tR: 12.1 min (major
S-enantiomer) and 13.4 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C12H18O2: 194.1307; found: 194.1309.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.1% i-PrOH in hexane); tR: 12.3 min
(major S-enantiomer) and 13.7 min (minor R-enantiomer). The ab-
solute configuration of was determined by converting it into (S)-2-
methyl-4-oxoheptanoic acid.
Ethyl (S)-2-(4,5-Dimethylfuran-2-yl)-4-oxopentanoate (13ff)
[a]D25 +62.9 (c = 2.00, CHCl3) (89% ee).
1H NMR (500 MHz, CDCl3): d = 1.24 (3 H, t, J = 7.2 Hz), 1.87 (3
H, s), 2.14 (3 H, s), 2.18 (3 H, s), 2.79 (1 H, dd, J = 4.6, 18.0 Hz),
3.29 (1 H, dd, J = 9.9, 18.0 Hz), 4.09–4.20 (3 H, m), 5.90 (1 H, s).
13C NMR (125.8 MHz, CDCl3): d = 9.7, 11.2, 14.0, 29.9, 40.2, 44.2,
61.2, 109.9, 114.7, 146.8, 147.8, 171.3, 205.9.
(S)-2-(5-Methylfuran-2-yl)octan-4-one (13bd)
[a]D20 +1.59 (c 1.00, CHCl3) (86% ee).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.4 Hz), 1.22 (3
H, d, J = 6.9 Hz), 1.29 (2 H, m), 1.54 (2 H, m), 2.23 (3 H, s), 2.36
(2 H, t, J = 7.5 Hz), 2.51 (1 H, dd, J = 8.0, 16.3 Hz), 2.79 (1 H, dd,
J = 5.9, 16.3 Hz), 3.34 (1 H, sext, J = 7.0 Hz), 5.82–5.83 (2 H, m).
HRMS (EI): m/z calcd for C13H18O4: 238.1205; found: 238.1198.
13C NMR (125.8 MHz, CDCl3): d = 13.5, 13.8, 19.0, 22.3, 25.8,
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 6% i-PrOH in hexane); tR: 6.7 min (mi-
nor R-enantiomer) and 7.2 min (major S-enantiomer). The absolute
stereochemistry was assumed by analogy.
29.0, 43.1, 48.5, 104.3, 105.7, 150.3, 157.3, 209.9.
HRMS (EI): m/z calcd for C13H20O2 208.1463; found: 208.1469.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.5% i-PrOH in hexane); tR: 12.4 min
(major S-enantiomer) and 13.7 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
Enantioselective Synthesis of g-Keto Carboxylic Acids; (S)-2-
Methyl-4-oxoheptanoic Acid (14a);30 Typical Procedure (Table
3, Entry 1)
RuCl3·H2O (1.7 mg, 0.0083 mmol) was added to a mixture of NaIO4
(2.66 g, 12.4 mmol) in CH2Cl2 (11 mL), MeCN (0.64 mL), and H2O
(11 mL) and the mixture was stirred for 1 h at r.t.To the mixture was
added a CH2Cl2 (4.8 mL) solution of 13bc (161 mg, 0.829 mmol)
(82% ee). After stirring for 4 h at r.t., the reaction mixture was acid-
ified to pH 1 with aq 1 N NaHSO4. The mixture was filtered through
a pad of Celite. The organic layer was separated and extracted with
aq 5% K2CO3 (3 × 10 mL). The combined aqueous layers were acid-
ified to pH 1 with solid NaHSO4 and then extracted with CH2Cl2 (3
× 20 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give 126 mg (96%) of (S)-14a. The analyt-
ical sample was prepared after purification by flash chromatogra-
phy (SiO2, gradient elution with 10–50% EtOAc in hexane);
[a]D29 –11.2 (c 0.48, CHCl3) {Lit.30 [a]D25 –14.6 (c 0.48, CHCl3)}
(92% ee).
1H NMR (500 MHz, CDCl3): d = 0.90 (3 H, t, J = 7.5 Hz), 1.21 (3
H, d, J = 7.2 Hz), 1.60 (2 H, sext, J = 7.4 Hz), 2.38 (2 H, m), 2.46
(1 H, dd, J = 5.4, 17.8 Hz), 2.89 (1 H, dd, J = 8.1, 17.8 Hz), 2.97 (1
H, m).
13C NMR (125.8 MHz, CDCl3): d = 13,6, 16.9, 17.2, 34.5, 44.8,
45.4, 181.7, 209.0.
(S)-2-(4,5-Dimethylfuran-2-yl)octan-4-one (13fd)
[a]D29 +6.4 (c 1.22, CHCl3) (93% ee).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.3 Hz), 1.20 (3
H, d, J = 6.9 Hz), 1.28 (2 H, m), 1.54 (2 H, m), 1.87 (3 H, s), 2.14
(3 H, s), 2.35 (2 H, t, J = 7.5 Hz), 2.48 (1 H, dd, J = 8.0, 16.2 Hz),
2.77 (1 H, dd, J = 6.0, 16.2 Hz), 3.29 (1 H, sext, J = 6.9 Hz), 5.73 (1
H, s).
13C NMR (125.8 MHz, CDCl3): d = 9.8, 11.2, 13.8, 19.0, 22.3, 25.8,
28.9, 43.0, 48.5, 107.0, 114.1, 145.4, 156.0, 209.9.
HRMS (EI): m/z calcd for C14H22O2: 222.1620; found: 222.1621.
The ee value was determined by HPLC analysis using a Chiralpak
AS-H column (1 mL/min, 0.1% i-PrOH in hexane); tR: 12.8 min
(major S-enantiomer) and 17.5 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
(S)-4-(4,5-Dimethylfuran-2-yl)octan-2-one (13fe)
[a]D20 +2.60 (c = 2.00, CHCl3) (87% ee).
1H NMR (500 MHz, CDCl3): d = 0.86 (3 H, t, J = 7.0 Hz), 1.17–1.33
(4 H, m), 1.45–1.62 (2 H, m), 1.87 (3 H, s), 2.07 (3 H, s), 2.13 (3 H,
s), 2.58 (1 H, dd, J = 6.6, 16.2 Hz), 2.74 (1 H, dd, J = 7.5, 16.2 Hz),
3.12 (1 H, quint, J = 7.1 Hz), 5.74 (1 H, s).
(S)-2-Methyl-4-oxoheptanoic Acid Benzylamide: To determine the
enantiopurity of (S)-14a, it was converted into the corresponding
benzylamide. To a solution of the acid (22.0 mg, 0.139 mmol) in
THF (3.3 mL) at 0 °C was added benzylamine (26.3 mg, 0.245
mmol), 1-hydroxybenzotriazole hydrate (33.1 mg, 0.245 mmol),
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (31.4 mg, 0.164 mmol). The mixture was stirred at 0 °C for 3 h
and at r.t. for 17 h. After concentration, the residue was partitioned
between EtOAc (20 mL) and aq 1 N HCl (10 mL). The organic layer
13C NMR (125.8 MHz, CDCl3): d = 9.9, 11.2, 13.9, 22.5, 29.3, 30.3,
33.7, 34.5, 48.1, 108.2, 114.0, 145.4, 154.4, 207.9.
HRMS (EI): m/z calcd for C14H22O2: 222.1620; found: 222.1626.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 0.1% i-PrOH in hexane); tR: 8.8 min (major
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2664
S. Adachi et al.
FEATURE ARTICLE
was separated, washed with sat. aq NaHCO3 (10 mL) and concen-
trated in vacuo. Purification of the residue by flash chromatography
(SiO2, gradient elution with 15–30% EtOAc in hexane) gave 27.8
mg (81%) of (S)-2-methyl-4-oxoheptanoic acid benzylamide (82%
ee).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.4 Hz), 1.16 (3
H, d, J = 7.0 Hz), 1.57 (2 H, sext, J = 7.4 Hz), 2.36 (2 H, t, J = 7.5
Hz), 2.40 (1 H, dd, J = 4.3, 17.9 Hz), 2.79 (1 H, m), 2.94 (1 H, dd,
J = 9.1, 17.9 Hz), 4.40 (2 H, m), 6.14 (1 H, br), 7.20–7.33 (5 H, m).
(S)-2-(2-Oxopropyl)hexanoic Acid (14d)
[a]D28 –18.9 (c 1.11, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.88 (3 H, t, J = 6.9 Hz), 1.27–1.32
(4 H, m), 1.51 (1 H, m), 1.65 (1 H, m), 2.15 (3 H, s), 2.51 (1 H, m),
2.84–2.90 (2 H, m).
13C NMR (125.8 MHz, CDCl3): d = 13.8, 22.5, 29.0, 30.0, 31.3,
39.9, 44.6, 181.1, 206.9.
HRMS (EI): m/z calcd for C9H16O3: 172.1100; found: 172.1103.
13C NMR (125.8 MHz, CDCl3): d = 13.6, 17.2, 17.9, 35.8, 43.4,
(S)-2-(2-Oxopropyl)hexanoic Acid Benzylamide: By a procedure
similar to that described for 14a, the acid 14d was converted into
(S)-2-(2-oxopropyl)hexanoic acid benzylamide (54% yield, 88%
ee).
1H NMR (500 MHz, CDCl3): d = 0.87 (3 H, t, J = 7.0 Hz), 1.23–1.41
(5 H, m), 1.62 (1 H, m), 2.14 (3 H, s), 2.48 (1 H, dd, J = 3.6, 18.1
Hz), 2.61 (1 H, m), 2.99 (1 H, dd, J = 9.7, 18.2 Hz), 4.43 (2 H, m),
6.00 (1 H, br), 7.24–7.36 (5 H, m).
44.9, 46.5, 127.3, 127.6, 128.6, 138.4, 175.5, 210.2.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 5% i-PrOH in hexane); tR: 18.0 min (major
S-enantiomer) and 21.3 min (minor R-enantiomer).
(S)-2-Methyl-4-oxohexanoic Acid (14b)52
[a]D29 –11.8 (c 1.05, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.05 (3 H, t, J = 7.3 Hz), 1.21 (3
H, d, J = 7.2 Hz), 2.38–2.49 (3 H, m), 2.87 (1 H, dd, J = 8.1, 17.7
Hz), 2.98 (1 H, m).
13C NMR (125.8 MHz, CDCl3): d = 7.6, 16.9, 34.5, 36.0, 45.0,
181.6, 209.4.
13C NMR (125.8 MHz, CDCl3): d = 13.9, 22.6, 29.6, 30.2, 32.3,
41.8, 43.6, 46.1, 127.4, 127.7, 128.6, 138.3, 174.9, 207.9.
The ee value was determined by HPLC analysis using a Chiralpak
AS-H column (1 mL/min, 4% i-PrOH in hexane); tR: 20.9 min (ma-
jor S-enantiomer) and 23.3 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C7H12O3: 144.0786; found: 144.0793.
(S)-2-Methyl-4-oxohexanoic Acid Benzylamide: By a procedure
similar to that described for 14a, the acid 14b was converted into
(S)-2-methyl-4-oxohexanoic acid benzylamide (80% yield, 92%
ee).
1H NMR (500 MHz, CDCl3): d = 1.02 (3 H, t, J = 7.3 Hz), 1.44 (3
H, d, J = 7.0 Hz), 2.39–2.44 (3 H, m), 2.79 (1 H, m), 2.94 (1 H, dd,
J = 9.1, 17.8 Hz), 4.40 (2 H, m), 6.14 (1 H, br), 7.19–7.32 (5 H, m).
F–C Alkylation of Indoles; (S)-5-(1H-Indol-3-yl)hexan-3-one
(16ab);16a Typical Procedure (Table 5, Entry 1)
To a mixture of OXB 9a (0.20 mmol), prepared by Method A, in
anhyd Et2O (3.1 mL) at –85 °C were added indole (15a; 234 mg, 2.0
mmol), N,N-dimethylaniline (6.09 mg, 0.050 mmol), and hex-4-en-
3-one (12b; 196 mg, 2.0 mmol). After stirring at –85 °C for 20 h,
the reaction mixture was quenched by the addition of sat. aq
NaHCO3 (10 mL) and filtered. The filtrate was extracted with
EtOAc (3 × 20 mL), dried (Na2SO4), and concentrated in vacuo. Pu-
rification of the residue by flash chromatography (SiO2, 8–12%
13C NMR (125.8 MHz, CDCl3): d = 7.6, 17.9, 35.9, 36.1, 43.5, 46.1,
127.3, 127.6, 128.6, 138.4, 175.5, 210.6.
23
EtOAc in hexane) gave 396 mg (92%) of (S)-16ab (87% ee); [a]D
The ee value was determined by HPLC analysis using a Chiralcel
AS-H column (1 mL/min, 5% i-PrOH in hexane); tR: 25.4 min (ma-
jor S-enantiomer) and 31.6 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
r.t.
+8.37 (c 3.01, CHCl3) {Lit.16a [a]D –8.5 (c 0.93, CHCl3) for R-
enantiomer (96% ee)}.
1H NMR (500 MHz, CDCl3): d = 1.02 (3 H, t, J = 7.3 Hz), 1.40 (3
H, d, J = 6.9 Hz), 2.38 (2 H, q, J = 7.3 Hz), 2.71 (1 H, dd, J = 8.3,
15.9 Hz), 2.94 (1 H, dd, J = 6.0, 15.9 Hz), 3.68 (1 H, m), 6.96 (1 H,
d, J = 2.3 Hz), 7.14 (1 H, m), 7.21 (1 H, m), 7.35 (1 H, d, J = 8.1
Hz), 7.67 (1 H, d, J = 7.9 Hz), 8.09 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.6, 21.2, 27.0, 36.4, 50.2,
111.2, 119.09, 119.12, 120.1, 121.0, 121.9, 126.2, 136.5, 211.4.
(S)-2-Methyl-4-oxooctanoic Acid (14c)
[a]D29 –11.2 (c 1.02, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.4 Hz), 1.20 (3
H, d, J = 7.2 Hz), 1.30 (2 H, sext, J = 7.3 Hz), 1.52–1.58 (2 H, m),
2.37–2.43 (2 H, m), 2.47 (1 H, dd, J = 5.4, 17.7 Hz), 2.86 (1 H, dd,
J = 8.0, 17.7 Hz), 2.97 (1 H, m).
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 3% i-PrOH in hexane); tR: 33.6 min (ma-
jor S-enantiomer) and 36.5 min (minor R-enantiomer).
13C NMR (125.8 MHz, CDCl3): d = 13.8, 16.8, 22.2, 25.8, 34.5,
42.6, 45.4, 181.8, 209.0.
HRMS (EI): m/z calcd for C9H16O3: 172.1100; found: 172.1103.
(S)-5-(5-Methoxy-1H-indol-3-yl)hexan-3-one (16bb)
[a]D25 –1.03 (c 3.08, CHCl3) (89% ee).
(S)-2-Methyl-4-oxooctanoic Acid Benzylamide: By a procedure
similar to that described for 14a, the acid 14c was converted into
(S)-2-methyl-4-oxooctanoic acid benzylamide (80% yield, 93% ee).
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.4 Hz), 1.44 (3
H, d, J = 7.0 Hz), 1.28 (2 H, m), 1.51 (2 H, m), 2.37–2.44 (3 H, m),
2.79 (1 H, m), 2.96 (1 H, dd, J = 9.1, 17.9 Hz), 4.41 (2 H, m), 6.07
(1 H, br), 7.24–7.33 (5 H, m).
1H NMR (500 MHz, C6D6): d = 0.96 (3 H, t, J = 7.3 Hz), 1.46 (3 H,
d, J = 6.9 Hz), 2.02 (2 H, m), 2.48 (1 H, dd, J = 7.9, 15.8 Hz), 2.77
(1 H, dd, J = 6.3, 15.8 Hz), 3.68 (3 H, s), 3.81 (1 H, sext, J = 7.1
Hz), 6.67 (1 H, d, J = 2.3 Hz), 7.11–7.15 (2 H, m), 7.34 (1 H, d,
J = 1.4 Hz), 7.42 (1 H, br s).
13C NMR (125.8 MHz, C6D6): d = 8.2, 21.9, 27.8, 36.6, 50.6, 55.9,
101.9, 112.7, 112.8, 121.2, 121.5, 127.7, 132.6, 154.9, 210.2.
13C NMR (125.8 MHz, CDCl3): d = 13.8, 17.9, 22.3, 25.8, 35.8,
42.8, 43.5, 46.5, 127.3, 127.6, 128.6, 138.4, 175.4, 210.3.
HRMS (EI): m/z calcd for C15H19NO2: 245.1416; found: 245.1423.
The ee value was determined by HPLC analysis using a Chiralcel
OB-H column (1 mL/min, 5% i-PrOH in hexane); retention times:
14.3 min (major S-enantiomer) and 19.3 min (minor R-enantiomer).
The absolute stereochemistry was assumed by analogy.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 2.5% i-PrOH in hexane); tR: 78.7 min
(major S-enantiomer) and 84.1 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2665
(S)-5-(5-Methyl-1H-indol-3-yl)hexan-3-one (16cb)
[a]D30 +1.12 (c 3.03, CHCl3) (83% ee).
HRMS (EI): m/z calcd for C15H19NO: 229.1467; found: 229.1462.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 2% i-PrOH in hexane); tR: 17.5 min (major
S-enantiomer) and 20.1 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
1H NMR (500 MHz, CDCl3): d = 1.05 (3 H, t, J = 7.3 Hz), 1.41 (3
H, d, J = 6.9 Hz), 2.41 (2 H, q, J = 7.3 Hz), 2.51 (3 H, s), 2.72 (1 H,
dd, J = 8.4, 15.9 Hz), 2.94 (1 H, dd, J = 5.9, 15.8 Hz), 3.66 (1 H, m),
6.91 (1 H, d, J = 2.3 Hz), 7.05 (1 H, m), 7.25 (1 H, m), 7.46 (1 H,
m), 8.04 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.7, 21.3, 21.6, 27.1, 36.5, 50.3,
111.0, 118.8, 120.4, 120.5, 123.6, 126.5, 128.4, 134.9, 211.6.
(S)-5-(1-Allyl-1H-indol-3-yl)hexan-3-one (16gb)
[a]D28 +10.93 (c 3.00, CHCl3) (85% ee).
1H NMR (500 MHz, CDCl3): d = 1.02 (3 H, t, J = 7.3 Hz), 1.40 (3
H, d, J = 6.9 Hz), 2.37 (2 H, q, J = 7.3 Hz), 2.70 (1 H, dd, J = 8.4,
15.8 Hz), 2.91 (1 H, dd, J = 5.8, 15.8 Hz), 3.66 (1 H, sext, J = 7.0
Hz), 4.68 (2 H, d, J = 5.4 Hz), 5.09 (1 H, m), 5.20 (1 H, m), 5.99 (1
H, m), 6.88 (1 H, s), 7.12 (1 H, m), 7.22 (1 H, t, J = 8.1 Hz), 7.30 (1
H, d, J = 8.2 Hz), 7.66 (1 H, d, J = 7.9 Hz).
1H NMR (500 MHz, C6D6): d = 0.99 (3 H, t, J = 7.3 Hz), 1.48 (3 H,
d, J = 6.9 Hz), 2.02 (2 H, q, J = 7.4 Hz), 2.50 (1 H, dd, J = 8.1, 15.8
Hz), 2.79 (1 H, dd, J = 6.0, 15.8 Hz), 3.84 (1 H, sext, J = 6.9 Hz),
4.16 (2 H, m), 4.85 (1 H, m), 4.95 (1 H, m), 5.65 (1 H, m), 6.68 (1
H, s), 7.22 (1 H, d, J = 8.1 Hz), 7.29 (1 H, m), 7.34 (1 H, m), 7.79
(1 H, d, J = 7.8 Hz).
HRMS (EI): m/z calcd for C15H19NO: 229.1467; found: 229.1463.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 5.0%, i-PrOH in hexane); tR: 25.5 min (ma-
jor S-enantiomer) and 34.3 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
(S)-5-(5-Chloro-1H-indol-3-yl)hexan-3-one (16db)
[a]D31 +3.48 (c 3.04, CHCl3) (85% ee).
1H NMR (500 MHz, CDCl3): d = 1.01 (3 H, t, J = 7.2 Hz), 1.36 (3H,
d, J = 6.9 Hz), 2.37 (2 H, q, J = 7.3 Hz), 2.68 (1 H, dd, J = 8.0, 16.0
Hz), 2.87 (1 H, dd, J = 6.2, 16.0 Hz), 3.59 (1 H, sext, J = 7.0 Hz),
6.97 (1 H, d, J = 2.3 Hz), 7.13 (1 H, dd, J = 1.9, 8.6 Hz), 7.24 (1 H,
d, J = 8.6 Hz), 7.60 (1 H, d, J = 1.6 Hz), 8.14 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.6, 21.2, 26.9, 36.4, 50.0,
112.2, 118.6, 120.8, 121.6, 122.2, 124.9, 127.3, 134.8, 211.0.
13C NMR (125.8 MHz, CDCl3): d = 7.6, 21.3, 27.0, 36.4, 48.6, 50.3,
109.6, 117.1, 118.8, 119.3, 120.1, 121.6, 123.9, 126.8, 133.5, 136.6,
211.1.
HRMS (EI): m/z calcd for C17H21NO: 255.1623; found: 255.1617.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 3.0%, i-PrOH in hexane); tR: 12.0 min (ma-
jor S-enantiomer) and 16.2 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C14H16ClNO: 249.0920; found:
249.0930.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 4%, i-PrOH in hexane); tR: 33.6 min (major
S-enantiomer) and 37.8 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
(S)-5-(1-Benzyl-1H-indol-3-yl)hexan-3-one (16hb)
[a]D31 +10.49 (c 3.01, CHCl3) (75% ee).
1H NMR (500 MHz, CDCl3): d = 1.12 (3 H, t, J = 7.3 Hz), 1.53 (3
H, d, J = 6.9 Hz), 2.41 (2 H, q, J = 7.3 Hz), 2.80 (1 H, dd, J = 8.3,
15.8 Hz), 3.03 (1 H, dd, J = 5.9, 15.8 Hz), 3.81 (1 H, sext, 8.1 Hz),
5.30 (2 H, s), 7.02 (1 H, m), 7.18–7.20 (2 H, m), 7.25–7.31 (2 H, m),
7.34–7.39 (4 H, m), 7.81 (1 H, d, J = 7.6 Hz).
13C NMR (125.8 MHz, CDCl3): d = 7.46, 21.1, 26.9, 36.2, 49.5,
50.1, 109.6, 118.8, 119.2, 120.2, 121.6, 124.2, 126.5, 126.8, 127.3,
128.5, 136.7, 137.5, 210.7.
(S)-5-(5-Bromo-1H-indol-3-yl)hexan-3-one (16eb)
[a]D28 +2.00 (c 3.00, CHCl3) (85% ee).
1H NMR (500 MHz, CDCl3): d = 1.01 (3 H, t, J = 7.3 Hz), 1.35 (3
H, d, J = 6.9 Hz), 2.37 (2 H, q, J = 7.3 Hz), 2.68 (1 H, dd, J = 8.0,
16.0 Hz), 2.86 (1 H, dd, J = 6.2, 16.0 Hz), 3.58 (1 H, m), 6.95 (1 H,
d, J = 2.3 Hz), 7.20 (1 H, d, J = 8.5 Hz), 7.25 (1 H, dd, J = 1.8, 8.6
Hz), 7.76 (1 H, d, J = 1.7 Hz), 8.20 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.6, 21.2, 26.9, 36.4, 50.0,
112.4, 112.7, 120.7, 121.5, 121.6, 124.7, 128.0, 135.1, 211.1.
HRMS (EI): m/z calcd for C21H23NO: 305.1780; found: 305.1780.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 0.5%, i-PrOH in hexane); tR: 25.2 min
(major S-enantiomer) and 28.0 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C14H16BrNO: 293.0415; found:
293.0406.
The ee value was determined by HPLC analysis using a Chiralpak
AS-H (1 mL/min, 7.0%, i-PrOH in hexane); tR: 29.9 min (minor R-
enantiomer) and 45.0 min (major S-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
(S)-5-(2-Methyl-1H-indol-3-yl)hexan-3-one (16ib)
[a]D24 +20.9 (c 3.03, CHCl3) (87% ee).
1H NMR (500 MHz, CDCl3): d = 0.97 (3 H, t, J = 7.3 Hz), 1.48 (3
H, d, J = 7.1 Hz), 2.23 (1 H, m), 2.35 (1 H, m), 2.39 (3 H, s), 2.86
(1 H, dd, J = 6.8, 15.8 Hz), 3.06 (1 H, dd, J = 7.8, 15.8 Hz), 3.65 (1
H, sext, J = 7.2 Hz), 7.11–7.17 (2 H, m), 7.24 (1 H, m), 7.69 (1 H,
m), 7.98 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.5, 11.7, 21.0, 27.1, 36.5, 49.1,
110.5, 114.7, 118.6, 118.8, 120.4, 126.8, 130.4, 135.4, 211.7.
(S)-5-(1-Methyl-1H-indol-3-yl)hexan-3-one (16fb)
[a]D28 +12.7 (c 3.00, CHCl3) (93% ee).
1H NMR (500 MHz, CDCl3): d = 1.02 (3 H, t, J = 7.3 Hz), 1.39 (3
H, d, J = 6.9 Hz), 2.38 (2 H, q, J = 7.3 Hz), 2.69 (1 H, dd, J = 8.3,
15.9 Hz), 2.92 (1 H, dd, J = 6.0, 15.9 Hz), 3.66 (1 H, m), 3.74 (3 H,
s), 6.84 (1 H, s), 7.12 (1 H, m), 7.24 (1 H, m), 7.30 (1 H, d, J = 8.2
Hz), 7.65 (1 H, d, J = 7.9 Hz).
HRMS (EI): m/z calcd for C15H19NO: 229.1467; found: 229.1458.
1H NMR (500 MHz, C6D6): d = 0.99 (3 H, t, J = 7.3 Hz), 1.49 (3 H,
d, J = 6.9 Hz), 2.03 (2 H, m), 2.50 (1 H, dd, J = 8.0, 15.9 Hz), 2.80
(1 H, dd, J = 6.2, 15.8 Hz), 3.06 (3 H, s), 3.84 (1 H, sext, J = 6.9
Hz), 6.53 (1 H, s), 7.14 (1 H, d, J = 8.1 Hz), 7.30 (1 H, m), 7.36 (1
H, m), 7.80 (1 H, d, J = 7.9 Hz).
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 3.0% i-PrOH in hexane); tR: 20.9 min
(major S-enantiomer) and 28.1 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
13C NMR (125.8 MHz, CDCl3): d = 7.7, 21.4, 27.0, 32.5, 36.4, 50.4,
109.3, 118.6, 119.2, 119.6, 121.5, 125.0, 126.6, 137.1, 211.1.
(S)-5-(1,2-Dimethyl-1H-indol-3-yl)hexan-3-one (16jb)
[a]D28 +60.11 (c 2.99, CHCl3) (81% ee).
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2666
S. Adachi et al.
FEATURE ARTICLE
1H NMR (500 MHz, CDCl3): d = 0.96 (3 H, t, J = 7.3 Hz), 1.46 (3
H, d, J = 7.1 Hz), 2.18–2.26 (1 H, m), 2.31–2.39 (1 H, m), 2.42 (3
H, s), 2.86 (1 H, dd, J = 6.8, 16.0 Hz), 3.05 (1 H, dd, J = 7.7, 16.0
Hz), 3.61–3.69 (4 H, m), 7.09 (1 H, t, J = 7.2 Hz), 7.18 (1 H, t,
J = 7.4 Hz), 7.28 (1 H, d, J = 8.1 Hz), 7.68 (1 H, d, J = 7.9 Hz).
13C NMR (125.8 MHz, CDCl3): d = 7.5, 10.3, 21.3, 27.4, 29.3, 36.5,
49.3, 108.8, 114.4, 118.3, 119.0, 120.1, 125.9, 132.2, 136.8, 211.2.
(S)-4-(2-Methyl-1H-indol-3-yl)octan-2-one (16ie)
[a]D26 +30.2 (c 3.01, CHCl3) (82% ee).
1H NMR (500 MHz, CDCl3): d = 0.85 (3 H, t, J = 7.2 Hz), 1.17–1.35
(4 H, m), 1.76 (1 H, m), 1.93 (1 H, m), 1.98 (3 H, s), 2.38 (3 H, s),
2.88 (1 H, dd, J = 6.0, 15.8 Hz), 3.11 (1 H, dd, J = 8.5, 15.8 Hz),
3.42 (1 H, m), 7.09–7.15 (2 H, m), 7.24 (1 H, m), 7.66 (1 H, d,
J = 7.5 Hz), 8.00 (1 H, br s).
HRMS (EI): m/z calcd for C16H21NO: 243.1623; found: 243.1627.
13C NMR (125.8 MHz, CDCl3): d = 11.8, 13.9, 22.5, 30.0, 30.6,
32.6, 34.8, 49.2, 110.4, 113.0, 118.6, 118.8, 120.3, 127.0, 131.4,
135.5, 209.3.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 1.0%, i-PrOH in hexane); retention times:
17.5 min (minor R-enantiomer) and 19.9 min (major S-enantiomer).
The absolute stereochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C17H23NO: 257.1780; found: 257.1784.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 5% i-PrOH in hexane); tR: 18.4 min (minor
R-enantiomer) and 24.1 min (major S-enantiomer). The absolute
stereochemistry was assumed by analogy.
(S)-5-(5-Methoxy-2-methyl-1H-indol-3-yl)hexan-3-one (16kb)
[a]D30 +41.07 (c 2.99, CDCl3) (75% ee).
1H NMR (500 MHz, CDCl3): d = 0.94 (3 H, t, J = 7.3 Hz), 1.43 (3
H, d, J = 7.1 Hz), 2.22 (1 H, m), 2.32 (1 H, m), 2.36 (3 H, s), 2.80
(1 H, dd, J = 6.8, 15.7 Hz), 3.01 (1 H, dd, J = 7.7, 15.7 Hz), 3.58 (1
H, sext, J = 7.2 Hz), 3.89 (3 H, s), 6.78 (1 H, dd, J = 2.2, 8.7 Hz),
7.12–7.14 (2 H, m), 7.76 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 7.5, 12.0, 20.8, 27.1, 36.6, 48.9,
56.1, 102.2, 109.5, 110.9, 114.7, 127.4, 130.7, 131.5, 153.3, 211.4.
Ethyl (S)-2-(1H-Indol-3-yl)-4-oxopentanoate (16af)16a
[a]D +121.9 (c 3.00, CHCl3) (94% ee) {Lit.16a [a]D –106.4 (c
1.04, CHCl3) for R-enantiomer (95% ee)}.
26
r.t.
1H NMR (500 MHz, CDCl3): d = 1.20 (3 H, t, J = 7.1 Hz), 2.19 (3
H, s), 2.86 (1 H, dd, J = 4.3, 18.0 Hz), 3.53 (1 H, dd, J = 10.3, 18.0
Hz), 4.09 (1 H, m), 4.19 (1 H, m), 4.42 (1 H, dd, J = 4.3, 10.3 Hz),
7.03 (1 H, d, J = 2.2 Hz), 7.16 (1 H, t, J = 7.9 Hz), 7.21 (1 H, m),
7.33 (1 H, d, J = 8.2 Hz), 7.74 (1 H, d, J = 7.9 Hz), 8.47 (1 H, br s).
HRMS (EI): m/z calcd for C16H21NO2: 259.1572; found: 259.1573.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 3.0%, i-PrOH in hexane); tR: 24.1 min
(major S-enantiomer) and 27.4 min (minor R-enantiomer). The ab-
solute stereochemistry was assumed by analogy.
13C NMR (125.8 MHz, CDCl3): d = 13.9, 29.8, 37.8, 46.1, 60.9,
111.3, 112.4, 119.0, 119.5, 122.1, 122.2, 126.0, 136.2, 173.8, 207.1.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 10% i-PrOH in hexane); tR: 19.4 min
(major S-enantiomer) and 27.0 min (minor R-enantiomer).
(S)-2-(1H-Indol-3-yl)octan-4-one (16ad)
[a]D31 +2.38 (c 3.02, CHCl3) (92% ee).
4-(1H-Indol-3-yl)-4-phenylbutan-2-one (16ag)16a
1H NMR (500 MHz, CDCl3): d = 2.09 (3 H, s), 3.18 (1 H, dd,
J = 7.8, 16.0 Hz), 3.27 (1 H, dd, J = 7.4, 16.0 Hz), 4.85 (1 H, t,
J = 7.6 Hz), 6.98 (1 H, m), 7.04 (1 H, m), 7.15–7.20 (2 H, m), 7.28
(2 H, m), 7.32–7.33 (3 H, m), 7.45 (1H, d, J = 7.9 Hz), 8.06 (1 H, br
s).
1H NMR (500 MHz, CDCl3): d = 0.90 (3 H, t, J = 7.4 Hz), 1.29 (2
H, sext, J = 7.5 Hz), 1.42 (3 H, d, J = 6.9 Hz), 1.55 (2 H, m), 2.38
(2 H, t, J = 7.5 Hz), 2.73 (1 H, dd, J = 8.3, 16.0 Hz), 2.95 (1 H, dd,
J = 5.9, 16.0 Hz), 3.70 (1 H, m), 6.95 (1 H, d, J = 2.3 Hz), 7.16 (1
H, m), 7.22 (1 H, m), 7.35 (1 H, d, J = 8.1 Hz), 7.69 (1 H, d, J = 7.9
Hz), 8.16 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 13.7, 21.1, 22.2, 25.7, 26.9,
43.0, 50.5, 111.3, 119.0, 119.1, 120.2, 120.9, 121.8, 126.2, 136.5,
211.1.
13C NMR (125.8 MHz, CDCl3): d = 30.4, 38.4, 50.3, 111.6, 118.8,
119.4, 121.4, 122.2, 126.4, 126.5, 127.7, 128.5, 136.6, 144.0, 207.7.
(R)-4-(2-Methyl-1H-indol-3-yl)-4-phenylbutan-2-one (16ig)54
[a]D28 +17.1 (c 3.04, CHCl3) (84% ee).
HRMS (EI): m/z calcd for C16H21NO 243.1623; found: 243.1622.
1H NMR (500 MHz, CDCl3): d = 2.07 (3 H, s), 2.38 (3 H, s), 3.42
(1 H, dd, J = 6.4, 16.2 Hz), 3.52 (1 H, dd, J = 8.5, 16.2 Hz), 4.96 (1
H, m), 7.11 (1 H, m), 7.17 (1 H, m), 7.22–7.25 (2 H, m), 7.31–7.34
(2 H, m), 7.40–7.42 (2 H, m), 7.58 (1 H, m), 7.98 (1 H, br s).
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 3% i-PrOH in hexane); tR: 29.1 min (ma-
jor S-enantiomer) and 33.5 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
13C NMR (125.8 MHz, CDCl3): d = 11.8, 30.5, 36.7, 48.1, 110.5,
112.8, 118.8, 119.0, 120.5, 125.8, 127.16, 127.23, 128.2, 131.7,
135.3, 144.0, 208.1.
(S)-4-(1H-Indol-3-yl)octan-2-one (16ae)53
[a]D28 +13.44 (c 1.22, CHCl3) (72% ee).
1H NMR (500 MHz, CDCl3): d = 0.83 (3 H, t, J = 7.2 Hz), 1.21–1.31
(4 H, m), 1.67–1.82 (2 H, m), 2.03 (3 H, s), 2.81 (1 H, dd, J = 6.8,
15.8 Hz), 2.90 (1 H, dd, J = 7.6, 15.8 Hz), 3.47 (1 H, sext, J = 7.1
Hz), 6.96 (1 H, d, J = 2.4 Hz), 7.12 (1 H, m), 7.19 (1 H, m), 7.35 (1
H, d, J = 8.1 Hz), 7.67 (1 H, d, J = 7.9 Hz), 8.06 (1 H, br s).
The ee value was determined by HPLC analysis using a Chiralpak
AD-H column (1 mL/min, 4% i-PrOH in hexane); tR: 37.3 min (ma-
jor S-enantiomer) and 44.0 min (minor R-enantiomer). The absolute
stereochemistry was assumed by analogy.
13C NMR (125.8 MHz, CDCl3): d = 14.0, 22.6, 29.8, 30.4, 32.8,
35.5, 50.2, 111.3, 119.0, 119.1, 119.3, 121.2, 121.8, 126.5, 136.5,
209.0.
(R)-4-(4-Fluorophenyl)-4-(2-methyl-1H-indol-3-yl)butan-2-one
(16ih)
[a]D27 +15.80 (c 3.03, CHCl3) (81% ee).
1H NMR (500 MHz, CDCl3): d = 2.05 (3 H, s), 2.39 (3 H, s), 3.35
(1 H, dd, J = 6.5, 16.3 Hz), 3.45 (1 H, dd, J = 8.2, 16.3 Hz), 4.88 (1
H, t, J = 7.4 Hz), 6.93–6.97 (2 H, m), 7.06 (1 H, m), 7.12 (1 H, m),
7.24 (1 H, d, J = 8.0 Hz), 7.27–7.30 (2 H, m), 7.47 (1 H, d, J = 7.9
Hz), 7.97 (1 H, br s).
HRMS (EI): m/z calcd for C16H21NO: 243.1623; found: 243.1630.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H (1 mL/min, 1.5%, i-PrOH in hexane); tR: 59.7 min (major S-
enantiomer) and 63.7 min (minor R-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2667
13C NMR (125.8 MHz, CDCl3): d = 11.9, 30.6, 36.0, 48.3, 110.5,
112.8, 114.9 (d, J = 21.1 Hz), 118.8, 119.2, 120.8, 127.1, 128.7 (d,
J = 7.9 Hz), 131.7, 135.4, 139.7 (d, J = 3.4 Hz), 161.1 (d, J = 244
Hz), 207.8.
J = 13.7 Hz), 3.21 (1 H, tt, J = 3.8, 12.9 Hz), 7.07 (1 H, t, J = 7.1
Hz), 7.12 (1 H, t, J = 7.8 Hz), 7.29 (1 H, d, J = 8.0 Hz), 7.66 (1 H,
d, J = 7.8 Hz), 7.76 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 12.1, 26.1, 31.5, 37.3, 41.5,
48.2, 110.6, 113.9, 118.9, 119.1, 121.0, 126.9, 130.1, 135.4, 211.7.
HRMS (EI): m/z calcd for C19H18FNO: 295.1372; found: 295.1367.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H (1 mL/min, 4.0%, i-PrOH in hexane); tR: 36.4 min (major R-
enantiomer) and 41.3 min (minor S-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C15H17NO: 227.1310; found: 227.1315.
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 3.0%, i-PrOH in hexane); tR: 65.0 min (mi-
nor), and 70.0 min (major).
(S)-5-Benzyloxy-4-(2-methyl-1H-indol-3-yl)pentan-2-one (16ii)
[a]D30 +17.39 (c 3.15, CHCl3) (75% ee).
2,3-Dihydro-1H,1¢H-[2,3¢]biindolyl (17)33
1H NMR (500 MHz, CDCl3): d = 3.23 (1 H, dd, J = 8.3, 15.6 Hz),
3.49 (1 H, dd, J = 9.1, 15.6 Hz), 5.27 (1 H, t, J = 8.6 Hz), 6.69 (1 H,
d, J = 7.7 Hz), 6.79 (1 H, t, J = 7.4 Hz), 7.09–7.18 (4 H, m), 7.22 (1
H, m), 7.36 (1 H, d, J = 8.2 Hz), 7.61 (1 H, d, J = 7.9 Hz), 7.99 (1
H, br s)
1H NMR (500 MHz, CDCl3): d = 2.03 (3 H, s), 2.39 (3 H, s), 3.04
(1 H, dd, J = 8.0, 16.4 Hz), 3.15 (1 H, dd, J = 5.3, 16.5 Hz), 3.70 (1
H, m), 3.81–3.90 (2 H, m), 4.54 (2 H, s), 7.05–7.12 (2 H, m), 7.24
(1 H, d, J = 7.9 Hz), 7.29–7.38 (5 H, m), 7.58 (1 H, d, J = 7.8 Hz),
7.89 (1 H, br s).
13C NMR (125.8 MHz, CDCl3): d = 12.0, 30.5, 32.9, 45.7, 72.9,
73.1, 110.5, 110.7, 118.8, 118.9, 120.6, 127.2, 127.46, 127.54,
128.3, 132.0, 135.4, 138.3, 208.4.
13C NMR (125.8 MHz, CDCl3): d = 37.7, 56.4, 109.2, 111.3, 118.8,
119.4, 119.5, 119.6, 121.7, 122.3, 124.7, 125.8, 127.5, 128.9, 136.8,
150.9.
Preparation of OXB 9a by Method B
HRMS (EI): m/z calcd for C21H23NO2: 321.1729; found: 321.1738.
To a solution of 18 (75.5 mg, 0.20 mmol) in CH2Cl2 (2 mL) under
argon r.t. was added dichlorophenylborane (28.5 mL, 0.220 mmol).
The mixture was stirred for 30 min. To the resulting mixture was
added allyltrimethylsilane (91.4 mg, 0.80 mmol) at r.t. After stirring
for 14–17 h, the mixture was concentrated in vacuo to give 9a.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H (1 mL/min, 6.0%, i-PrOH in hexane); tR: 33.8 min (major S-
enantiomer) and 36.4 min (minor R-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
(S)-1,1-Dimethoxy-2-(2-methyl-1H-indol-3-yl)nonan-4-one
(16ij)
6-(1-Methyl-1H-indol-2-ylmethoxy)hex-4-en-3-one (19)
To a solution of 2-allyloxymethyl-1-methyl-1H-indole34b (1.00 g,
5.0 mmol) and hex-4-en-3-one (1.47 g, 15.0 mmol) in CH2Cl2 at r.t.
was added 2nd generation Grubbs catalyst (84.9 mg, 0.1 mmol).
The reaction mixture was heated to reflux for 2 h. The mixture was
concentrated in vacuo and the residue was purified by flash chroma-
tography (SiO2, 10–50% EtOAc in hexane) to give 0.86 g (67%) of
19.
[a]D28 +44.60 (c 1.00, CHCl3) (92% ee).
1H NMR (500 MHz, CDCl3): d = 0.79 (3 H, t, J = 7.3 Hz), 1.05–1.18
(4 H, m), 1.41 (2 H, m), 2.18 (1 H, dt, J = 7.3, 16.7 Hz), 2.30 (1 H,
dt, J = 7.5, 16.7 Hz), 2.42 (3 H, s), 2.97–3.09 (2 H, m), 3.23 (3 H,
s), 3.38 (3 H, s), 3.79 (1 H, m), 4.67 (1 H, d, J = 6.6 Hz), 7.03–7.09
(2 H, m), 7.22 (1 H, m), 7.63 (1 H, d, J = 7.5 Hz), 7.83 (1 H, br s).
1H NMR (500 MHz, CDCl3): d = 1.09 (3 H, t, J = 7.3 Hz), 2.55 (2
H, q, J = 7.3 Hz), 3.79 (3 H, s), 4.15 (2 H, dd, J = 2.0, 4.5 Hz), 4.73
(2 H, s), 6.33 (1 H, td, J = 2.0, 16.0 Hz), 6.49 (1 H, s), 6.78 (1 H, td,
J = 4.5, 16.0 Hz), 7.11 (1 H, t, J = 7.1 Hz), 7.24 (1 H, m), 7.33 (1 H,
d, J = 8.2 Hz), 7.59 (1 H, d, J = 7.9 Hz).
13C NMR (125.8 MHz, CDCl3): d = 7.93, 29.9, 33.7, 64.7, 67.8,
103.4, 109.2, 119.6, 120.8, 122.1, 127.0, 129.2, 134.9, 138.2, 141.4,
200.6.
13C NMR (125.8 MHz, CDCl3): d = 12.1, 13.8, 22.3, 23.2, 31.2,
36.0, 42.7, 43.4, 54.2, 54.8, 106.9, 110.0, 110.4, 119.0, 119.1,
120.6, 127.4, 132.6, 135.4, 210.3.
HRMS (EI): m/z calcd for C20H29NO3: 331.2147; found: 331.2139.
The ee value was determined by HPLC analysis using a Chiralpak
AD-H (1 mL/min, 8.0%, i-PrOH in hexane); tR: 9.7 min (major S-
enantiomer) and 17.3 min (minor R-enantiomer). The absolute ste-
reochemistry was assumed by analogy.
HRMS (EI): m/z calcd for C16H19NO2: 257.1416; found: 257.1417.
(S)-3-(2-Methyl-1H-indol-3-yl)-1-phenylbutan-1-one (16ik)13a
[a]D +23.5 (c 2.50, CHCl3) (37% ee) {Lit.13a [a]D –57.4 (c 1.00,
28
(R)-1-(9-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-4-yl)bu-
tan-2-one (20)
CHCl3) for R-enantiomer (84% ee)}.
To a mixture of OXB 9a (0.10 mmol), prepared by Method A, in an-
hyd Et2O (4.7 mL) at –85 °C were added N,N-dimethylaniline (4.6
mg, 0.038 mmol), and 19 (128.7 mg, 0.50 mmol). After stirring at
–85 °C for 7 d, the reaction mixture was quenched with sat. aq
NaHCO3 (10 mL) and filtered. The filtrate was extracted with
EtOAc (3 × 20 mL), and the combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Purification of the residue by
flash chromatography (SiO2, 2–3% EtOAc in toluene) gave 77 mg
(60%) of 20 (90% ee); [a]D26 –24.6 (c 1.53, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.53 (3 H, d, J = 7.1 Hz), 2.38 (3
H, s), 3.40 (1 H, dd, J = 7.5, 16.2 Hz), 3.56 (1 H, dd, J = 6.5, 16.2
Hz), 3.78 (1 H, sext, J = 7.1 Hz), 7.11 (2 H, m), 7.25 (1 H, m), 7.40
(2 H, m), 7.51 (1 H, m), 7.71 (1 H, m), 7.75 (1 H, br s), 7.90 (2 H,
m).
13C NMR (125.8 MHz, CDCl3): d = 12.0, 21.0, 27.3, 45.6, 110.5,
115.4, 118.9, 119.0, 120.6, 127.0, 128.0, 128.4, 130.3, 132.7, 135.5,
137.2, 200.0.
1H NMR (500 MHz, CDCl3): d = 1.08 (3 H, t, J = 7.3 Hz), 2.43 (2
H, q, J = 7.3 Hz), 2.86 (1 H, dd, J = 9.4, 17.6 Hz), 2.93 (1 H, dd,
J = 4.2, 17.6 Hz), 3.53 (1 H, m), 3.58 (3 H, m), 3.85 (1 H, dd,
J = 3.4, 11.4 Hz), 3.98 (1 H, dd, J = 1.8, 11.4 Hz), 4.78 (1 H, dd,
J = 1.2, 14.6 Hz), 4.87 (1 H, d, J = 14.6 Hz), 7.10 (1 H, t, J = 7.1
Hz), 7.20 (1 H, m), 7.29 (1 H, d, J = 8.2 Hz), 7.47 (1 H, d, J = 7.9
Hz).
The ee value was determined by HPLC analysis using a Chiralcel
OD column (1 mL/min, 6% i-PrOH in hexane); tR: 40.2 min (minor
R-enantiomer) and 46.8 min (major S-enantiomer).
3-(2-Methyl-1H-indol-3-yl)cyclohexanone (16il)55
[a]D31 +11.08 (c 2.02, CHCl3) (55% ee).
1H NMR (500 MHz, CDCl3): d = 1.80 (1 H, m), 2.01 (1 H, m), 2.22
(1 H, m), 2.31–2.38 (4 H, m), 2.47–2.53 (3 H, m), 2.99 (1 H, t,
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

2668
S. Adachi et al.
FEATURE ARTICLE
13C NMR (125.8 MHz, CDCl3): d = 7.8, 28.5, 29.4, 36.7, 45.5, 63.1,
(3) (a) [Sc(III)- Pybox]: Desimoni, G.; Faita, G.; Toscanini, M.;
Boiocchi, M. Chem. Eur. J. 2008, 14, 3630. (b) [Cu(II)-
BOX]: Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124,
9030. (c) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432.
(d) Cao, C.-L.; Zhou, Y.-Y.; Sun, X.-L.; Tang, Y.
Tetrahedron 2008, 64, 10676. (e) Yamazaki, S.; Iwata, Y.
J. Org. Chem. 2006, 71, 739. (f) Yamazaki, S.; Kashima, S.;
Kuriyama, T.; Iwata, Y.; Morimoto, T.; Kakiuchi, K.
Tetrahedron: Asymmetry 2009, 20, 1224. (g) Rasappan, R.;
Hager, M.; Gissibl, A.; Reiser, O. Org. Lett. 2006, 8, 6099.
(h) Liu, Y.; Shang, D.; Zhou, X.; Liu, X.; Feng, X. Chem.
Eur. J. 2009, 15, 2055.
69.7, 108.8, 109.4, 118.1, 119.2, 121.2, 125.7, 133.0, 136.9, 211.1.
HRMS (EI): m/z calcd for C16H19NO2: 257.1416; found: 257.1421.
The ee value was determined by HPLC analysis using a Chiralcel
AS-H column (1 mL/min, 3% i-PrOH in hexane); tR: 20.6 min (ma-
jor) and 31.0 min (minor). The absolute stereochemistry was as-
sumed by analogy.
Crossover Experiment; (S)-4-Deutero-5-(1-methyl-1H-indol-3-
yl)hexan-3-one (16fb-d) and (S)-4-Deutero-5-(1-allyl-1H-indol-
3-yl)hexan-3-one (16gb-d); Typical Procedure (Table 6, entry 1)
To a mixture of OXB 9a (0.10 mmol), prepared by Method A, in an-
hyd Et2O (1.6 mL) at –85 °C were added 1-allylindole (15g; 78.6
mg, 0.500 mmol), 3-deutero-1-methylindole (15f-d; 66.1 mg, 0.500
mmol), N,N-dimethylaniline (3.05 mg, 0.0250 mmol), and hex-4-
en-3-one (12b; 98 mg, 1.00 mmol). After stirring at –85 °C for 20
h, the reaction mixture was quenched with sat. aq NaHCO3 (10 mL)
and filtered. The filtrate was extracted three times with EtOAc (3 ×
20 mL), dried (Na2SO4), and concentrated in vacuo. Purification of
the residue by flash chromatography (SiO2, 5–12% EtOAc in hex-
ane) gave 108 mg (47%) of 16fb-d (91% ee, 72%-d, syn/
anti = 85:15) and 123 mg (48%) of 16gb-d (84% ee, 22%-d, syn/
anti = 86:14).
(4) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A.
Helv. Chim. Acta 2003, 86, 3753.
(5) (a) Evans, D. A.; Scheidt, K. A.; Frandrick, K. R.; Lam, H.
W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780.
(b) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 742.
(6) (a) Evans, D. A.; Fandrick, K. R.; Song, H. J. J. Am. Chem.
Soc. 2005, 127, 8942. (b) Boersma, A. J.; Feringa, B. L.;
Roelfes, G. Angew. Chem. Int. Ed. 2009, 48, 3346.
(7) (a) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121.
(b) Singh, P. K.; Singh, V. K. Org. Lett. 2010, 12, 80.
(8) (a) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (b) Yang,
L.; Zhu, Q.; Guo, S.; Qian, B.; Xia, C.; Huang, H. Chem.
Eur. J. 2009, 16, 1638.
(9) For the reaction of indoles, see: (a) Bandini, M.; Garelli, A.;
Rovinetti, M.; Tommasi, S.; Umani-Ronchi, A. Chirality
2005, 17, 522. (b) Jia, Y. X.; Zhu, S. F.; Yang, Y.; Zhou, Q.
L. J. Org. Chem. 2006, 71, 75. (c) Lu, S.-F.; Du, D.-M.; Xu,
J. Org. Lett. 2006, 8, 2115. (d) Singh, P. K.; Bisai, A.;
Singh, V. K. Tetrahedron Lett. 2007, 48, 1127. (e) Arai, T.;
Yokoyama, N.; Yanagisawa, A. Chem. Eur. J. 2008, 14,
2052. (f) Arai, T.; Yokoyama, N. Angew. Chem. Int. Ed.
2008, 47, 4989. (g) Yuan, Z.-L.; Lei, Z.-Y.; Shi, M.
Tetrahedron: Asymmetry 2008, 19, 1339. (h) Lin, S.-Z.;
You, T.-P. Tetrahedron 2009, 65, 1010. For the reaction of
pyrroles, see: (i) Trost, B. M.; Müller, C. J. Am. Chem. Soc.
2008, 130, 2438. (j) Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M.
Chem. Asian J. 2008, 3, 1111.
(10) (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.
(11) For enantioselective cascade processes initiated by the
organocatalytic F–C alkylation of the unsaturated aldehydes,
see: (a) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (b) Austin,
J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W.
C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.
(S)-16fb-d
1H NMR (500 MHz, C6D6): d = 0.99 (3 H, t, J = 7.3 Hz), 1.48 (3 H,
m), 2.02 (2 H, q, J = 7.3 Hz), 2.46–2.52 (0.39 H for Hsyn, m), 2.77–
2.82 (0.89 H for Hanti, m), 3.06 (3 H, s), 3.84 (1 H, m), 6.52 (1 H, s),
7.14 (1 H, d, J = 8.1 Hz), 7.30 (1 H, m), 7.36 (1 H, m), 7.80 (1 H, d,
J = 7.8 Hz).
+
MS (EI): m/z (%) = 231 (M – d1+ +1 and M+ + 2, 13.0), 230 (M – d1
and M+ + 1, 81.6), 229 (M+, 34.2), 158 (100).
(S)-16gb-d
1H NMR (500 MHz, C6D6): d = 0.96 (3 H, t, J = 7.3 Hz), 1.45 (3 H,
m), 2.00 (2 H, q, J = 7.3 Hz), 2.45–2.50 (0.81 H for Hsyn, m), 2.74–
2.78 (0.97 H for Hanti, m), 3.81 (1 H, m), 4.15 (2 H, m), 4.83 (1 H,
m), 4.93 (1 H, m), 5.63 (1 H, m), 6.66 (1 H, s), 7.19 (1 H, d, J = 8.1
Hz), 7.24–7.76 (2 H, m), 7.77 (1 H, d, J = 7.8 Hz).
+
MS (EI): m/z (%) = 257 (M – d1+ + 1 and M+ + 2, 6.4), 256 (M – d1
and M+ + 1, 41.8), 255 (M+, 90.1), 184 (100).
Acknowledgment
This work was supported partially by KAKENHI (17550101).
References
(1) (a) Catalytic Asymmetric Friedel–Crafts Alkylations;
Bandini, M.; Umani-Ronchi, A., Eds.; Wiley-VCH:
Weinheim, 2009. (b) Poulsen, T. B.; Jørgensen, K. A. Chem.
Rev. 2008, 108, 2903. (c) Bandini, M.; Eichholzer, A.
Angew. Chem. Int. Ed. 2009, 48, 9608. (d) Sheng, Y.-F.;
Zhang, A.-J.; Zheng, X.-J.; You, S.-L. Chin. J. Org. Chem.
2008, 28, 605. (e) Bandini, M.; Melloni, A.; Tommasi, A.
S.; Umani-Ronchi, A. Synlett 2005, 1199. (f) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004,
43, 550. (g) Jørgensen, K. A. Synthesis 2003, 1117.
(h) Bolm, C.; Hildebrand, J. P.; Muñiz, K.; Hermanns, N.
Angew. Chem. Int. Ed. 2001, 40, 3284.
(12) (a) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura,
R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437.
(b) Bonini, B. F.; Capito, E.; Franchini, C.; Fochi, M.; Ricci,
A.; Zwanenburg, B. Tetrahedron: Asymmetry 2006, 17,
3135. (c) Hong, L.; Liu, C.; Sun, W.; Wang, L.; Wong, K.;
Wang, R. Org. Lett. 2009, 11, 2177. (d) Hong, L.; Wang,
L.; Chen, C.; Zhang, B.; Wang, R. Adv. Synth. Catal. 2009,
351, 772.
(13) (a) Bandini, M.; Fagioli, M.; Garavelli, M.; Melloni, A.;
Trigari, V.; Umani-Ronchi, A. J. Org. Chem. 2004, 69,
7511. (b) Bandini, M.; Fagioli, M.; Melchiorre, P.; Melloni,
A.; Umani-Ronchi, A. Tetrahedron Lett. 2003, 44, 5843.
(14) (a) Blay, G.; Fernández, I.; Pedro, J. R.; Vila, C. Org. Lett.
2007, 9, 2601. (b) Blay, G.; Fernández, I.; Pedro, J. R.; Vila,
C. Tetrahedron Lett. 2007, 48, 6731.
(2) (a) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem.
Commun. 2001, 347. (b) Jensen, K. B.; Thorbauge, J.;
Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2001,
40, 160.
Synthesis 2010, No. 15, 2652–2669 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantioselective Friedel–Crafts Alkylation of Furans and Indoles
2669
(15) Wang, W.; Liu, X.; Cao, W.; Wang, J.; Lin, L.; Feng, X.
Chem. Eur. J. 2009, 16, 1664.
(33) (a) Smith, G. F. Adv. Heterocycl. Chem. 1963, 2, 287.
(b) Ishii, H.; Murakami, K.; Sakurada, E.; Hosoya, K.;
(16) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403.
(b) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.-S.;
Chen, Y.-C. Org. Biomol. Chem. 2007, 5, 816. (c) Hong,
L.; Sun, W.; Liu, C.; Wang, L.; Wong, K.; Wang, R. Chem.
Eur. J. 2009, 15, 11105.
(17) Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic
Chemistry II, Vol. 2; Katritzky, A. R.; Rees, C. W.;
Schriven, E. F.; Bird, C. W., Eds.; Pergamon: Oxford, 1996,
395–436.
(18) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Raczko,
J.; Jurczak, J. Stud. Nat. Prod. Chem. 1995, 16, 639.
(19) For oxidation of furans, see: (a) Merino, P.; Tejero, T.;
Delso, J. I.; Matute, R. Curr. Org. Chem. 2007, 11, 1076.
(b) Margaros, I.; Vassilikogiannakis, G. J. Org. Chem. 2008,
73, 2021. (c) Montagnon, T.; Tofi, M.; Vassilikogiannakis,
G. Acc. Chem. Res. 2008, 41, 1001. (d) Robertson, J.; Naud,
S. Org. Lett. 2008, 10, 5445. (e) Noji, M.; Sunahara, H.;
Tsuchiya, K.; Mukai, T.; Komasaka, A.; Ishii, K. Synthesis
2008, 3835.
(20) For rearrangement of furans, see: (a) Kelly, A. R.; Kerrigan,
M. H.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 4097.
(b) Griggs, N. D.; Phillips, A. J. Org. Lett. 2008, 10, 4955.
(21) (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. (b) Du,
X.; Chen, H.; Liu, Y. Chem. Eur. J. 2008, 14, 9495.
(c) Cao, H.; Jiang, H.; Yao, W.; Liu, X. Org. Lett. 2009, 11,
1931.
Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1988, 2377.
(34) (a) Angeli, M.; Bandini, M.; Garelli, A.; Piccinelli, F.;
Tommasi, S.; Umani-Ronchi, A. Org. Biomol. Chem. 2006,
4, 3291. (b) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-
P.; Xiao, W.-J. Org. Lett. 2007, 9, 1847. (c) Cai, Q.; Zhao,
Z.-A.; You, S.-L. Angew. Chem. Int. Ed. 2009, 48, 7428.
(35) Sibi, M. P.; Coulomb, J.; Stanley, L. M. Angew. Chem. Int.
Ed. 2008, 47, 9913.
(36) As 15f-d is more reactive than 15g, the deuterium contents
of the products were influenced by the conversion of the
reaction.
(37) A relevant intermediate has been proposed for an OXB-
catalyzed Mukaiyama aldol reaction: (a) Parmee, E. R.;
Tempkin, O.; Masamune, S.; Abiko, A. J. Am. Chem. Soc.
1991, 113, 9365. (b) Adachi, S.; Harada, T. Org. Lett. 2008,
10, 4999.
(38) Alternatively, protonation of 23 at the enolate oxygen atom
may afford the enol form of product 13 or 16, which
undergoes tautomerization to the keto form with H/D
scrambling. However, the effect of the amine additive is
difficult to be rationalized by this pathway.
(39) A mechanism involving protonation of a Pd-enolate
intermediate by an amine salt has been proposed in the
Pd(II)-catalyzed enantioselective conjugated addition of
amines: Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura,
T.; Sodeoka, M. Org. Lett. 2004, 6, 1861.
(40) Harada, T.; Yamamoto, Y.; Kusukawa, T. Chem. Commun.
2005, 859.
(41) Nolan, S. M.; Cohen, T. J. Org. Chem. 1981, 46, 2473.
(42) Wu, H.-J.; Lin, C.-C. J. Org. Chem. 1996, 61, 3820.
(43) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock,
C. H. J. Org. Chem. 1990, 55, 132.
(22) Gotta, M. F.; Mayr, H. J. Org. Chem. 1998, 63, 9769.
(23) (a) Alder, K.; Schmidt, C.-H. Ber. Dtsch. Chem. Ges. 1943,
76, 183. (b) Bulbule, V. J.; Deshpande, V. H.; Bedekar, A.
V. J. Chem. Res., Synop. 2000, 220. (c) Dyker, G.; Muth,
E.; Hashmi, A. S. K.; Ding, L. Adv. Synth. Catal. 2003, 345,
1247.
(44) Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V.
(24) Evans, D. A.; Fandrick, K. R.; Song, H. J.; Scheidt, K. A.;
Xu, R. S. J. Am. Chem. Soc. 2007, 129, 10029.
(25) Liu, H.; Xu, J.; Du, D.-M. Org. Lett. 2007, 9, 4725.
(26) (a) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.;
Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68,
10046. (b) Harada, T.; Adachi, S.; Wang, X. Org. Lett. 2004,
6, 4877. (c) Harada, T.; Yamauchi, T.; Adachi, S. Synlett
2005, 2151.
J. Org. Chem. 2002, 67, 4615.
(45) McMurry, J. E.; Blaszczak, L. C. J. Org. Chem. 1974, 39,
2217.
(46) (a) Hill, G. A.; Bramann, G. M. Org. Synth. Coll. Vol. 1;
Wiley: New York, 1941, 77. (b) Hill, G. A.; Bramann, G.
M. Org. Synth. Coll. Vol. 1; Wiley: New York, 1941, 81.
(47) Gossauer, A.; Suhl, K. Helv. Chim. Acta 1976, 59, 1698.
(48) Kurangi, R. F.; Tilve, S. G.; Blair, I. A. Lipids 2006, 41, 877.
(49) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
(50) Lane, B. S.; Brown, M.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050.
(27) (a) Singh, R. S.; Harada, T. Eur. J. Org. Chem. 2005, 3433.
(b) Singh, R. S.; Adachi, S.; Tanaka, F.; Yamauchi, T.; Inui,
C.; Harada, T. J. Org. Chem. 2008, 73, 212.
(28) Harada, T.; Kusukawa, T. Synlett 2007, 1823.
(29) Adachi, S.; Tanaka, F.; Watanabe, K.; Harada, T. Org. Lett.
2009, 11, 5206.
(30) For another approach to optically active g-keto carboxylic
acids, see: Hoffman, R. V.; Kim, H.-O. J. Org. Chem. 1995,
60, 5107.
(31) For catalytic enantioselective conjugate addition of cyanide
to enones, see: Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 6072.
(51) Dorogov, K.-Yu.; Yousufuddin, M.; Ho, N.-N.; Churakov,
A.-V.; Kuzmina, L. G.; Schultz, A. J.; Mason, S. A.;
Howard, J. K. A. Inorg. Chem. 2007, 46, 147.
(52) Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org.
Chem. 2003, 68, 7983.
(53) Arcadi, A.; Bianchia, G.; Chiarinia, M.; D’Anniballeb, G.;
Marinellia, F. Synlett 2004, 944.
(54) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700.
(55) Gu, Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175.
(32) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001,
42, 1433.
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