Asymmetric intramolecular alkylation of chiral aromatic imines via catalytic C-H bond activation

Article abstract of DOI:10.1055/s-2007-985593

The asymmetric intramolecular alkylation of chiral aromatic aldimines, in which differentially substituted alkenes are tethered meta to the imine, was investigated. High enantioselectivities were obtained for imines prepared from aminoindane derivatives, which function as directing groups for the rhodium-catalyzed C-H bond activation. Initial demonstration of catalytic asymmetric intramolecular alkylation also was achieved by employing a sterically hindered achiral imine substrate and catalytic amounts of a chiral amine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985593

LETTER
2383
Asymmetric Intramolecular Alkylation of Chiral Aromatic Imines
via Catalytic C–H Bond Activation
Alkylation of
Chir
n
al Aromatic
j
s
a Watzke, Rebecca M. Wilson, Steven J. O’Malley, Robert G. Bergman,* Jonathan A. Ellman*
Department of Chemistry and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, University of California,
Berkeley, CA 94720, USA
Fax +1(510)6427714; E-mail: rbergman@berkeley.edu; E-mail: jellman@berkeley.edu
Received 16 April 2007
In previously published work, we evaluated a range of
structurally diverse chiral amine directing groups, with
aminoindane proving to be most effective. Therefore, to
further increase the stereoselectivity of the intramolecular
Abstract: The asymmetric intramolecular alkylation of chiral aro-
matic aldimines, in which differentially substituted alkenes are teth-
ered meta to the imine, was investigated. High enantioselectivities
were obtained for imines prepared from aminoindane derivatives,
which function as directing groups for the rhodium-catalyzed C–H alkylation reaction, we chose to evaluate substituted ami-
bond activation. Initial demonstration of catalytic asymmetric in-
noindane derivatives, which were synthesized from the
tramolecular alkylation also was achieved by employing a sterically
corresponding indanones by one-pot reductive amination
hindered achiral imine substrate and catalytic amounts of a chiral
with tert-butanesulfinamide (Scheme 2 and Scheme 3).6
amine.
Key words: C–H bond activation, asymmetric catalysis, transimi-
nation, cyclization, dihydrobenzofuran
O
1) H2NS(O)t-Bu
Ti(OEt)4
R
R
O
NH2
S
R
HN
HCl
2) NaBH4
The intramolecular alkylation of aromatic imines via
rhodium-catalyzed ortho-directed C–H bond activation1
provides an efficient route to functionalized bicyclic ring
systems.2 A catalytic and highly enantioselective variant
of this intramolecular alkylation has been achieved for
some alkene substitution patterns using chiral phosphor-
amidite ligands.3 However, for other alkene substitution
patterns, alternative approaches for achieving asymmetric
induction may be necessary. In the context of the first total
synthesis of (+)-lithospermic acid,4,5 the first example of
employing a chiral imine as a directing group in catalytic
C–H bond activation was developed. Specifically, imine
2, prepared by condensation of 1 with R-(–)-aminoindane,
was cyclized to give product 3 in 76% ee after auxiliary
hydrolysis (Scheme 1). Herein, improved chiral imine di-
recting groups are reported and evaluated with substrates
containing different alkene substitution patterns.4
4 R = F, 38%
5 R = Me, 24%
6 R = F
7 R = Me
R = F, Me
Scheme 2 Asymmetric synthesis of chiral aminoindane derivatives
6 and 7
Condensation of tert-butanesulfinamide with 7-fluoro-
indanone7 and 7-methylindanone and subsequent reduc-
tion of the N-tert-butanesulfinyl imines with NaBH4
provided sulfinamides 4 and 5 with dr > 99:1. The modest
yields observed in these reactions are presumably the
result of competing enamine formation in the imine
condensation step (Scheme 2). Subsequent removal of
the tert-butanesulfinyl group under acidic conditions
provided the enantiomerically pure amines 6 and 7.
1 mol% Pd(OAc)2
2 mol%
X
O
Br
1) H2NS(O)t-Bu
O
CO2Me
Ti(OPh)4
(t-Bu)2P
PhB(OH)2, KF
THF, 80 °C, 12 h
73%
MeO2C
O
2) NaBH4
32%
OMe
OMe
OMe
OMe
O
O
OMe
OMe
8
1 X = O
2 X = (R)-(–)-aminoindanyl
3
O
S
Scheme 1 Asymmetric cyclization of lithospermic acid precursor
HCl
HN
NH2
9
10
SYNLETT 2007, No. 15, pp 2383–2389
1
7
.0
9
.2
0
0
7
Advanced online publication: 22.08.2007
DOI: 10.1055/s-2007-985593; Art ID: S02307ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Asymmetric synthesis of chiral 7-phenylaminoindane 10

2384
A. Watzke et al.
LETTER
For the introduction of a phenyl group in position 7 of the Table 2 Asymmetric Cyclization of Chiral Imines 14 and 15
aminoindane, 7-bromo-aminoindanone7 was subjected to
Suzuki cross coupling under conditions described by
Buchwald8 to provide 8 in high yield (Scheme 3). At-
tempted condensation of ketone 8 with tert-butanesulfin-
amide using Ti(OEt)4 resulted in Meerwein–Pondorf–
Verley (MPV) reduction to give the undesired corre-
sponding alcohol byproduct. Therefore, Ti(OPh)4,9 which
is not capable of participating in MPV reduction, was used
instead of Ti(OEt)4 and provided sulfinamide 9 with high
selectivity albeit in modest yield. Removal of the tert-
butanesulfinyl group under acidic conditions gave enan-
tiomerically pure amine 10.
O
1) 10 mol% [RhCl(coe)2]2
30 mol% FcPCy2
toluene
CO2Me
Ph
R
N
MeO2C
2) HCl
O
OMe
O
Ph
OMe
14, 15
16
Entry
Imine
R
Temp
(°C)
Time
(h)
Yield
(%)
ee
(%)a
Each 7-substituted 2-aminoindane was condensed with
aldehyde 1 to obtain the corresponding chiral imines 2 and
11–13. Using optimized conditions with ferrocenyl-PCy2
(FcPCy2) as the ligand, the rhodium-catalyzed intra-
molecular alkylation led, after hydrolysis, to dihydro-
1
2
14
15
H
F
75
75
16
16
80
65
70
81
a Enantiomeric excess determined by chiral HPLC after hydrolysis of
imine with 1 M HCl (aq).
benzofuran
3
with good yields and improved
enantioselectivity (Table 1). The enantioselectivity pro-
vided by the 7-fluoroaminoindane chiral auxiliary at 90%
ee was particularly impressive (entry 3).
Table 3 Asymmetric Cyclization of Chiral Imines 17–20
We next focused our efforts on the asymmetric alkylation
of substrates with different alkene substitution patterns to
explore the scope of this method. Cyclization of substrates
14 and 15 with a phenyl group in place of the 3,4-
dimethoxyphenyl group proceeded in good yields but
with appreciable reduction in enantioselectivity (Table 2).
1) 10 mol% [RhCl(coe)2]2
30 mol% FcPCy2
toluene
O
R3
R1
N
*
R2
*
2) HCl
R3
R2
O
O
Imines 17–20 with 1,1- and 1,2-disubstituted double
bonds, respectively, were also evaluated (Table 3). Con-
version of the corresponding aldehyde into chiral imines
17 and 18 followed by cyclization provided dihydrofuran
21 in quantitative yield after auxiliary hydrolysis. Once
17–20
21, 22
Entry Imine
R1
R2
R3
Yield ee
Product
(%)a
>99
>99
34
(%)b
1
2
3
4
17
18
19
20
H
F
Me
Me
H
H
58
68
55
58
21
21
22
22
H
Table 1 Asymmetric Cyclization of Chiral Imines 2, 11–13
H
F
Me
Me
H
50
O
1) 10 mol% [RhCl(coe)2]2
30 mol% FcPCy2
toluene
a Yields based on 1H NMR integration relative to 2,6-dimethoxy-
toluene as an internal standard.
CO2Me
Ar
R
N
b Enantiomeric excess determined by chiral HPLC after hydrolysis of
imine with 1 M HCl (aq).
MeO2C
2) HCl
OMe
O
OMe
O
OMe
Ar = 3,4-dimethoxyphenyl
OMe
again, 7-fluoro-aminoindane provided the highest
enantiomeric excess (entry 2). In contrast, imines 19 and
20, prepared from the 1,2-disubstituted aldehyde, cyclized
significantly less efficiently, with product 22 being ob-
tained in lower yield and with lower enantioselectivity
(entries 3 and 4).
2, 11–13
3
Entry
Imine
R
Temp
(°C)
Time
(h)
Yield
(%)
ee
(%)a
1
2
3
4
2
11
12
13
H
75
16
16
36
16
76
62
70b
90
76
80
90
83
Additionally, asymmetric cyclization of an achiral imine
through imine exchange10 using catalytic amounts of
chiral amine was investigated. Effective imine exchange
was first demonstrated by cyclization of achiral N-tert-bu-
tyl aldimine 23 upon addition of one equivalent of chiral
aminoindane (Table 4, entry 1). The enantiomeric purity
of the product aldehyde 21 establishes that transimination
Me
F
75
60
Ph
75
a Enantiomeric excess determined by chiral HPLC after hydrolysis of
imine with 1 M HCl (aq).
b Includes trace amounts of trans diastereomer.
Synlett 2007, No. 15, 2383–2389 © Thieme Stuttgart · New York

LETTER
Alkylation of Chiral Aromatic Imines
2385
1100 system with a Chiral PAK AS column (250 mm 4.6 mm) with
a flow rate of 1 mL/min and with i-PrOH–hexanes as the mobile
phase. A Perkin-Elmer 241 polarimeter with a sodium lamp was
used to determine specific rotations and concentrations are reported
in g/dL.
Table 4 Catalytic Asymmetric Cyclization of Achiral Imine 24
through Imine Exchange
1) 10 mol% [RhCl(coe)2]2
30 mol% FcPCy2
X mol% (R)-aminoindane
Y mol% Sc(OTf)3
N(t-Bu)
O
Imine Formation
toluene, 75 °C, 16 h
To a 25 mL round-bottom flask equipped with a magnetic stir bar
and septum was added 1.00 mmol of aldehyde, benzene (10 mL),
MS 4 Å (1.0 g), and 1.1 equiv of amine (1.10 mmol). The reaction
flask was then equipped with a reflux condenser, and the mixture
was heated to reflux for 12 h. The reaction mixture was cooled to
r.t., diluted with benzene, dried over Na2SO4, filtered, and concen-
trated.
*
2) HCl
O
O
23
21
Entry Imine
X (mol%) Y (mol%) Yield (%) ee (%)a
1
2
23
23
100
30
0
88
75
58
45
Cyclization of Aromatic Imines
10
In a dry box, a solution of [RhCl(coe)2]2 (3.59 mg, 5 mmol, 0.1
equiv) and FcPCy2 (5.73 mg, 15.0 mmol, 0.3 equiv) in toluene-d8
(0.25 mL) was added to a solution of imine (50.0 mmol, 1.0 equiv)
in toluene (0.25 mL) and then transferred to an NMR tube. The tube
was sealed, and the solution was stirred at 75 °C for 16 h. The reac-
tion solution was cooled to r.t., transferred to a round-bottom flask
with EtOAc rinses, and concentrated under reduced pressure. The
a Enantiomeric excess was determined by chiral HPLC after
hydrolysis of imine with 1 M HCl (aq).
occurs considerably faster than cyclization of the sterical-
ly hindered achiral imine, which would lead to racemic
product. Catalytic asymmetric cyclization of 23 was next residue was washed with 1 N HCl (aq) and stirred for 20 min. The
mixture was diluted with EtOAc, the layers were separated, and the
demonstrated by addition of 30 mol% of chiral aminoin-
aqueous layer was extracted with EtOAc. The combined organic
dane along with 10 mol% Sc(OTf)3, which was required
layers were dried, filtered, and concentrated under reduced pres-
sure. The crude material was chromatographed on SiO2.
to accelerate the imine exchange process. Only a minor
drop in the yield and enantiomeric excess of product 22
was observed (entry 2).
Deprotection of tert-Butanesulfinamide Derivatives
To the tert-butanesulfinamide derivatives was added 1:1 (v/v)
MeOH and HCl–dioxane solution (4 M, 3 equiv). The mixture was
stirred at r.t. for 30 min and then concentrated to near dryness. The
amine hydrochloride was precipitated in a mixture of MeOH and
tert-butyl methyl ether. The precipitate was then filtered off and
washed with tert-butyl methyl ether. The amine hydrochloride was
In conclusion, asymmetric intramolecular alkylation of
chiral aromatic aldimines was evaluated for differentially
substituted alkene substrates. The highest enantioselectiv-
ities were obtained using the 7-fluoro-aminoindane as the
chiral auxiliary with cyclization providing product in 90%
ee for the most favorable substrate. Additionally, initial dissolved in 1 N NaHCO3 solution, which was subsequently ex-
tracted three times with EtOAc. The combined organic layers were
demonstration of catalytic asymmetric intramolecular
dried over MgSO4, filtrated, and concentrated to provide each
amine in quantitative yields.
alkylation was accomplished by employing a sterically
hindered achiral imine substrate and catalytic amounts of
a chiral amine.
3-(3,4-Dimethoxyphenyl)-3-[5-(indan-1-yliminomethyl)-2-
methoxyphenoxy]acrylic Acid Methyl Ester (2)
This compound was prepared according to the general procedure for
Unless otherwise noted, materials were obtained from commercial
imine formation with 1 equiv of aldehyde (18.6 mg, 0.0500 mmol)
suppliers and used without further purification. THF was distilled
1
and 1.5 equiv of amine (7.32 mg, 0.0550 mmol). H NMR (400
under N2 from sodium benzophenone ketyl, pyridine from CaH2,
MHz, CDCl3): d = 8.18 (s, 1 H, CH=NCH), 7.38 (d, 1 H, J = 8.4 Hz,
and MeOH from Mg(MeO)2 immediately prior to use. Degassed
toluene was purified by passage through an activated alumina col-
umn. All organic reactions were performed under an atmosphere of
N2 in flame-dried or oven-dried glassware unless otherwise stated.
ArH), 7.31–7.11 (m, 6 H, ArH × 6), 7.00 (d, 1 H, J = 7.3 Hz, ArH),
6.90 (d, 1 H, J = 8.4 Hz, ArH), 6.73 (d, 1 H, J = 8.5 Hz, ArH), 5.97
(s, 1 H, CHCO2CH3), 4.78 (t, 1 H, J = 7.2 Hz, CH2CHN=CH), 3.93
(s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.64 (s, 3
All C–H activation experiments were prepared in an N2-filled Vac
H, CO2CH3), 3.07–3.01 (m, 1 H, one of ArCH2CH2), 2.92–2.84 (m,
inert atmosphere box. The following compounds were prepared ac-
11
1 H, one of ArCH2CH2), 2.39–2.35 (m, 1 H, one of ArCH2CH2),
2.19–2.09 (m, 1 H, one of ArCH2CH2). 13C NMR (100 MHz,
CDCl3): d = 164.6, 162.6, 159.0, 151.3, 150.8, 148.6, 146.0, 144.1,
143.4, 129.2, 128.0, 127.2, 126.0, 124.4, 124.0, 124.0, 120.5, 116.1,
111.6, 110.6, 109.5, 103.6, 74.5, 55.8, 55.5, 55.4, 50.9, 33.9, 30.7.
[a]D25 7.7 (c 1.12, CH2Cl2). HRMS–FAB: m/z calcd for C29H30NO6
[M + H]+: 488.2073; found: 488.2079.
cording to referenced literature procedures: [RhCl(coe)2]2 and
FcPCy2.12 Thin-layer chromatography was performed on Merck 60
F254 250 mm silica gel plates. Visualization of the developed chro-
matogram was performed by fluorescence quenching, KMnO4
stain, or p-anisaldehyde stain. Flash chromatography was carried
out according to the general procedure of Still13 using Merck 60
230–240 mesh silica gel or basic Al2O3 (activity grade I) as noted.
Organic extracts were dried over MgSO4 or Na2SO4 and were con-
centrated using a Büchi rotary evaporator under high vacuum pres-
sure. Melting points were determined on a Mel-Temp apparatus and
2-Methylpropane-2-sulfinic Acid (7-Fluoroindan-1-yl)amide
(4)
1
are uncorrected. Unless otherwise noted, H NMR and 13C NMR
To a 25 mL round-bottom flask equipped with a magnetic stir bar
and septum were added 7-fluoroindan-1-one (190 mg, 1.23 mmol),
2 equiv of (R)-2-methylpropane-2-sulfinic acid amide (297 mg,
2.45 mmol), and 2.5 mL of THF. Under argon atmosphere, 4 equiv
of Ti(OEt)4 (1.12 g, 4.90 mmol) was added to the reaction mixture.
spectra were obtained in CDCl3. NMR chemical shifts are reported
in ppm and referenced to residual protonated solvent. Mass spectra
were performed by the University of California, Berkeley Micro-
Mass Facility. Chiral HPLC analyses were performed on an Agilent
Synlett 2007, No. 15, 2383–2389 © Thieme Stuttgart · New York

2386
A. Watzke et al.
LETTER
The reaction flask was then equipped with a reflux condenser and
the mixture was heated to reflux for 12 h. The reaction mixture was
cooled to –78 °C and 4 equiv of NaBH4 (185 mg, 4.90 mmol) was
added. The reaction mixture was stirred for 30 min at –78 °C and al-
lowed to warm to r.t. The reaction mixture was quenched with NaCl
solution, and the precipitate was filtered off and washed with
EtOAc. After phase separation, the aqueous phase was extracted
with EtOAc. The combined organic phases were washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude material
was chromatographed on SiO2 (10–50% EtOAc–hexanes) to afford
compound 4 as a yellow oil (120 mg, 0.470 mmol, 38%). 1H NMR
(400 MHz, CDCl3): d = 7.19–7.14 (m, 1 H, ArH), 6.97 (d, 1 H,
J = 7.2 Hz, ArH), 6.81 (t, 1 H, J = 8.8 Hz, ArH), 5.08–5.05 (m, 1 H,
HNCHCH2CH2), 3.76 [br s, 1 H, NHS(O)t-Bu], 3.11–3.03 (m, 1 H,
one of ArCH2CH2), 2.86–2.79 (m, 1 H, one of ArCH2CH2), 2.44–
2.35 (m, 1 H, one of ArCH2CH2), 2.19–2.11 (m, 1 H, one of
ArCH2CH2), 1.12 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):
d = 160.5, 158.0, 147.5, 147.4, 130.1, 130.1, 128.9, 128.8, 120.5,
120.4, 113.2, 113.0, 56.7, 56.7, 55.3, 33.3, 30.6, 30.6, 22.2 (multiple
s, 2 H, NH2). 13C NMR (100 MHz, CDCl3): d = 145.3, 143.2, 133.9,
25
127.9, 127.7, 122.3, 55.9, 35.7, 30.2, 18.4. [a]D –2.08 (c 0.5,
CH2Cl2).
7-Phenylindan-1-one (8)
In a dry box, 7-bromoindan-1-one (105 mg, 0.500 mmol), 3 equiv
of KF (87.2 mg, 1.50 mmol), 1.5 equiv of phenylboronic acid (91.5
mg, 0.750 mmol), 1 mol% of Pd(OAc)2 (1.1 mg, 0.0050 mmol),
2 mol% of biphP(t-Bu)2 (3.0 mg, 0.010 mmol), and 0.5 mL of THF
were added to a Schlenk flask. The flask was sealed, and the solu-
tion was stirred at 80 °C for 14 h. The reaction solution was cooled
to r.t., diluted with EtOAc, and washed with brine and H2O. The
aqueous layer was extracted with EtOAc, and the combined organic
layers were dried, filtered, and concentrated under reduced pres-
sure. The crude material was chromatographed on SiO2 (0–10%
EtOAc–hexanes) to afford compound 8 as a white solid (76.0 mg,
0.365 mmol, 73%); mp 91–92 °C. 1H NMR (400 MHz, CDCl3): d =
7.60 (t, 1 H, J = 7.6 Hz, ArH), 7.52–7.41 (m, 6 H, ArH × 6), 7.28 (d,
1 H, J = 7.6 Hz, ArH), 3.16–3.13 (m, 2 H, ArCH2CH2), 2.71–2.68
(m, 2 H, ArCH2CH2). 13C NMR (100 MHz, CDCl3): d = 205.2,
156.1, 141.1, 137.8, 133.6, 132.7, 129.1, 129.1, 127.5, 127.4, 125.5,
36.6, 25.0. HRMS–FAB: m/z calcd for C15H13O [M + H]+:
209.0966; found: 209.0966.
25
C’s coupled to F). [a]D –6.1 (c 2.8, CH2Cl2). HRMS–FAB: m/z
calcd for C13H19FNOS [M + H]+: 256.1171; found: 256.1171.
Propane-2-sulfinic Acid (7-Methylindan-1-yl)amide (5)
To a 25 mL round-bottom flask equipped with a magnetic stir bar
and septum were added 7-methylindan-1-one (179 mg, 1.23 mmol),
2 equiv of (R)-2-methylpropane-2-sulfinic acid amide (297 mg,
2.45 mmol), and 2.5 mL of THF. Under argon atmosphere, 4 equiv
of Ti(OEt)4 (1.12 g, 4.90 mmol) was added to the reaction mixture.
The reaction flask was then equipped with a reflux condenser and
the mixture was heated to reflux for 12 h. The reaction mixture was
cooled to –78 °C and 4 equiv of NaBH4 (185.4 mg, 4.90 mmol) was
added. The reaction mixture was stirred for 30 min at –78 °C and al-
lowed to warm to r.t. The reaction mixture was quenched with NaCl
solution, and the precipitate was filtered off and washed with
EtOAc. After phase separation, the aqueous phase was extracted
with EtOAc. The combined organic phases were washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude material
was chromatographed on SiO2 (10–50% EtOAc–hexanes) to afford
compound 5 as a white solid (73.9 mg, 0.294 mmol, 24%); mp 67–
2-Methylpropane-2-sulfinic Acid (7-phenylindan-1-yl)amide
(9)
To a 25 mL round-bottom flask equipped with a magnetic stir bar
and septum were added 7-phenylindan-1-one (200 mg, 0.960
mmol), 2 equiv of (R)-2-methylpropane-2-sulfinic acid amide (233
mg, 1.92 mmol), and 2.5 mL of THF. Under an argon atmosphere,
4 equiv of Ti(OPh)4 (1.61 g, 3.84 mmol) was added to the reaction
mixture. The reaction flask was then equipped with a reflux con-
denser, and the mixture was heated to reflux for 12 h. The reaction
mixture was then cooled to –78 °C, and 4 equiv of NaBH4 (145 mg,
3.84 mmol) were added. The reaction mixture was stirred for 30 min
at –78 °C and allowed to warm to r.t. The reaction mixture was
quenched with NaCl solution, and the precipitate was filtered off
and washed with EtOAc. After phase separation, the aqueous phase
was extracted with EtOAc. The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentrated.
The crude material was chromatographed on SiO2 (10–40%
EtOAc–hexanes) to afford compound 9 as a white solid (95.0 mg,
0.303 mmol, 32%); mp 109–110 °C. 1H NMR (400 MHz, CDCl3):
d = 7.51–7.45 (m, 4 H, ArH × 4), 7.36–7.41 (m, 1 H, ArH), 7.33 (d,
1 H, J = 7.6 Hz, ArH), 7.27–7.29 (m, 1 H, ArH), 7.18 (d, 1 H,
J = 7.2 Hz, ArH), 5.29 (t, 1 H, J = 6.0 Hz, HNCHCH2), 3.42 [s, 1 H,
NHS(O)t-Bu], 3.14–3.08 (m, 1 H, one of ArCH2CH2), 3.01–2.93
(m, 1 H, one of ArCH2CH2), 2.60–2.53 (m, 1 H, one of ArCH2CH2),
1
68 °C. H NMR (400 MHz, CDCl3): d = 7.17 (t, 1 H, J = 7.2 Hz,
ArH), 7.08 (d, 1 H, J = 7.6 Hz, ArH), 6.99 (d, 1 H, J = 7.2 Hz, ArH),
4.94 (br s, 1 H, HNCHCH2CH2), 3.18–3.09 [m, 2 H, NHS(O)t-Bu,
one of ArCH2CH2], 2.83–2.77 (m, 1 H, one of ArCH2CH2), 2.37 (s,
3 H, ArCH3), 2.21–2.16 (m, 2 H, ArCH2CH2), 1.15 [s, 9 H,
C(CH3)3]. 13C NMR (100 MHz, CDCl3): d = 145.0, 141.3, 134.5,
128.8, 128.0, 122.2, 58.2, 55.3, 33.6, 30.3, 22.4, 18.4. [a]D25 –9.2 (c
1.5, CH2Cl2). HRMS–FAB: m/z calcd for C14H22NOS [M + H]+:
252.1422; found: 252.1422.
2.14–2.07 (m, 1 H, one of ArCH2CH2), 0.89 [s, 9 H, C(CH3)3]. 13
C
Amines 6 and 7 were prepared according to the general procedure
for the deprotection of tert-butanesulfinamide derivatives.
NMR (100 MHz, CDCl3): d = 144.8, 140.4, 139.7, 138.6, 129.0,
25
128.4, 128.4, 127.8, 127.8, 124.0, 57.3, 54.8, 32.7, 30.5, 22.1. [a]D
–16.8 (c 0.6, CH2Cl2). HRMS–FAB: m/z calcd for C19H24NOS
7-Fluoroindan-1-ylamine (6)
[M]+: 314.1579; found: 314.1579.
1H NMR (400 MHz, CDCl3): d = 7.18–7.11 (m, 1 H, ArH), 6.96 (d,
1 H, J = 10.0 Hz, ArH), 6.82 (t, 1 H, J = 12.0 Hz, ArH), 4.63 (t, 1
H, J = 8.4 Hz, H2NCHCH2), 3.08–3.01 (m, 1 H, one of ArCH2CH2),
2.86–2.76 (m, 1 H, one of ArCH2CH2), 2.25–2.41 (m, 1 H, one of
ArCH2CH2), 1.95–1.75 (m, 3 H, one of ArCH2CH2, NH2). 13C NMR
(100 MHz, CDCl3): d = 161.2, 158.7, 146.7, 146.6, 133.3, 133.1,
129.3, 129.2, 120.5, 113.2, 113.0, 55.0, 35.5, 30.6 (multiple Cs cou-
pled to F). [a]D25 –0.4 (c 3.5, CH2Cl2).
7-Phenylindan-1-ylamine (10)
This compound was prepared according to the general procedure for
1
the deprotection of tert-butanesulfinamide derivatives. H NMR
(400 MHz, CDCl3): d = 7.49–7.44 (m, 4 H, ArH × 4), 7.38–7.36 (m,
1 H, ArH), 7.31–7.22 (m, 2 H, ArH × 2), 7.07 (d, 1 H, J = 10.0 Hz,
ArH), 4.74 (t, 1 H, J = 8.4 Hz, H2NCHCH2), 3.14–3.08 (m, 1 H, one
of ArCH2CH2), 3.13–3.03 (m, 1 H, one of ArCH2CH2), 2.94–2.84
(m, 1 H, one of ArCH2CH2), 2.54–2.43 (m, 1 H, one of ArCH2CH2),
7-Methylindan-1-ylamine (7)
1.81–1.70 (m, 1 H, one of ArCH2CH2), 1.47 (br s, 2 H, NH2). 13
C
1H NMR (400 MHz, CDCl3): d = 7.17–7.05 (m, 2 H, ArH × 2), 6.99
(d, 1 H, J = 9.2 Hz, ArH), 4.50–4.46 (dd, 1 H, J = 9.6, 3.6 Hz,
H2NCHCH2), 3.17–3.06 (m, 1 H, one of ArCH2CH2), 2.84–2.75 (m,
1 H, one of ArCH2CH2), 2.40 (s, 3 H, ArCH3), 2.40–2.29 (m, 1 H,
one of ArCH2CH2), 1.96–1.88 (m, 1 H, one of ArCH2CH2), 1.55 (br
NMR (100 MHz, CDCl3): d = 143.9, 140.8, 138.7, 128.6, 128.3,
25
127.8, 127.7, 127.2, 124.0, 56.1, 35.2, 30.2. [a]D –3.5 (c 3.5,
CH2Cl2).
Synlett 2007, No. 15, 2383–2389 © Thieme Stuttgart · New York

LETTER
Alkylation of Chiral Aromatic Imines
2387
3-(3,4-Dimethoxyphenyl)-3-{2-methoxy-5-[(7-methylindan-1-
ylimino)methyl]phenoxy}acrylic Acid Methyl Ester (11)
128.2, 126.4, 125.3, 119.4, 111.5, 110.3, 109.4, 87.7, 56.0, 55.8,
55.7, 54.1, 51.7. [a]D25 –112.9 (c 0.95, CH2Cl2). HRMS–FAB: m/z
calcd for C20H20O7 [M]+: 372.1209; found: 372.1213. HPLC analy-
sis [AS column, hexanes–i-PrOH (70:30), 40 min run time]: peak 1,
tR = 16.6 min (minor enantiomer) and peak 2, tR = 31.0 min (major
enantiomer).
This compound was prepared according to the general procedure for
imine synthesis with 1 equiv of aldehyde (18.6 mg, 0.0500 mmol)
and 1.5 equiv of amine (8.1 mg, 0.0550 mmol). 1H NMR (400 MHz,
CDCl3): d = 8.08 (s, 1 H, CH=NCH), 7.33 (d, 1 H, J = 8.5 Hz, ArH),
7.20–7.18 (m, 2 H, ArH × 2), 7.15–7.09 (m, 3 H, ArH × 3), 6.94 (d,
1 H, J = 7.0 Hz, ArH), 6.80 (d, 1 H, J = 8.5 Hz, ArH), 6.77 (d, 1 H,
J = 8.5 Hz, ArH), 5.96 (s, 1 H, CHCO2CH3), 4.98–4.95 (m, 1 H,
CH2CHN=CH), 3.96 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 3.79 (s,
3 H, OCH3), 3.67 (s, 3 H, CO2CH3), 3.14–3.10 (m, 1 H, one of
ArCH2CH2), 2.89–2.86 (m, 1 H, one of ArCH2CH2), 2.39–2.34 (m,
1 H, one of ArCH2CH2), 2.10 (s, 3 H, ArCH3), 2.06–2.02 (m, 1 H,
one of ArCH2CH2). 13C NMR (100 MHz, CDCl3): d = 165.0, 162.9,
158.2, 151.4, 151.0, 148.8, 146.2, 144.6, 142.0, 135.4, 129.6, 128.3,
127.9, 127.8, 126.4, 124.1, 122.2, 120.7, 116.3, 111.8, 110.8, 109.8,
3-(3-Formylphenoxy)-3-phenylacrylic Acid Methyl Ester
To a sealed tube equipped with a magnetic stir bar was added
MeOH (42 mL) followed by Na metal (1.58 g, 68.8 mmol, 1.6
equiv, cut into small pieces). Once all the Na had dissolved, isovan-
illin (48.4 g, 318 mmol, 7.6 equiv) was added, and the reaction mix-
ture became a thick, yellow slurry. After stirring at r.t. for 5 min,
pyridine (42 mL) was added, followed by phenylpropynoic acid
methyl ester (5.00 g, 43.0 mmol, 1.0 equiv), and the reaction mix-
ture was stirred at 120 °C for 1.75 h. The mixture was cooled to r.t.,
diluted with EtOAc, and sat. aq NH4Cl solution was added. The lay-
ers were separated, and the organic layer was washed several times
with sat. aq K2CO3 solution to remove excess isovanillin. The com-
bined organic layers were dried, filtered, and concentrated under re-
duced pressure. The crude material was chromatographed on basic
alumina (0–20% EtOAc–hexane) to afford the Z-alkene as a white
solid (5.20 g, 18.4 mmol, 42%); mp 98–99 °C. 1H NMR (400 MHz,
CDCl3): d = 9.68 (s, 1 H, CHO), 7.57 (dd, 2 H, J = 2.0, 6.4 Hz,
ArH), 7.45 (dd, 1 H, J = 2.0, 8.4 Hz, ArH), 7.35–7.25 (m, 4 H,
J = 2.0 Hz, ArH), 7.00 (d, 1 H, J = 8.4 Hz, ArH), 6.15 (s, 1 H,
CHCO2Me), 4.00 (s, 3 H, OCH3), 3.64 (s, 3 H, OCH3). 13C NMR
(100 MHz, CDCl3): d = 190.2, 164.3, 162.1, 154.4, 146.5, 133.1,
130.8, 129.7, 128.7, 127.5, 126.8, 114.9, 111.5, 105.8, 56.2, 51.2.
HRMS–FAB: m/z calcd for C18H17O5 [M + H]+: 313.1076; found:
313.1076.
25
103.9, 73.7, 56.1, 55.9, 55.7, 51.2, 33.9, 31.0, 18.8. [a]D +4.2 (c
2.0, CH2Cl2).
3-(3,4-Dimethoxyphenyl)-3-{5-[(7-fluoroindan-1-ylimino)meth-
yl]-2-methoxyphenoxy}acrylic Acid Methyl Ester (12)
In a dry box, 1 equiv of aldehyde (20.8 mg, 0.0559 mmol), 1.1 equiv
of amine (9.3 mg, 0.0615 mmol), and 0.5 mL of benzene were com-
bined in a vial and stirred overnight at r.t. The resulting reaction
mixture was diluted with 2 mL of Et2O, filtered through Celite, and
concentrated to yield a colorless oil (28.0 mg, 0.0554 mmol, 99%).
1H NMR (400 MHz, CDCl3): d = 8.16 (s, 1 H, CH=NCH), 7.38–
7.36 (m, 2 H, ArH × 2), 7.27–7.10 (m, 3 H, ArH × 3), 7.04 (d, 1 H,
J = 7.2 Hz, ArH), 6.90 (d, 1 H, J = 8.4 Hz, ArH), 6.82–6.76 (m, 2
H, ArH × 2), 5.96 (s, 1 H, CHCO2CH3), 5.05 (m, 1 H,
CH2CHN=CH), 3.95 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.79 (s,
3 H, OCH3), 3.67 (s, 3 H, CO2CH3), 3.21–3.17 (m, 1 H, one of
ArCH2CH2), 2.95–2.85 (m, 1 H, one of ArCH2CH2), 2.45–2.35 (m,
3-[5-(Indan-1-yliminomethyl)-2-methoxyphenoxy]-3-phenyl-
acrylic Acid Methyl Esters (14)
1 H, one of ArCH2CH2), 2.25–2.15 (m, 1 H, one of ArCH2CH2). 13
C
NMR (100 MHz, CDCl3): d = 165.0, 163.0, 161.6, 159.1, 151.4,
151.0, 148.7, 148.1, 148.0, 146.1, 130.1, 130.0, 129.7, 129.7, 129.5,
128.3, 126.3, 124.0, 120.7, 120.4, 120.4, 116.7, 113.2, 113.0, 111.8,
110.8, 109.7, 103.7, 71.6, 71.6, 56.1, 56.0, 55.9, 55.8, 55.7, 51.2,
34.0, 31.4 (multiple C’s coupled to F).
This compound was prepared according to the general procedure for
imine synthesis with 1 equiv of aldehyde (14.1 mg, 0.0500 mmol)
and 1.5 equiv of amine (7.3 mg, 0.0550 mmol). 1H NMR (400 MHz,
CDCl3): d = 8.20 (s, 1 H, CH=NCH), 7.59 (d, 2 H, J = 7.6 Hz,
ArH × 2), 7.43 (d, 1 H, J = 8.0 Hz, ArH), 7.37–7.32 (m, 3 H,
ArH × 3), 7.20–7.16 (m, 4 H, ArH × 4), 7.02 (d, 1 H, J = 7.6 Hz,
ArH), 6.93 (d, 1 H, J = 8.4 Hz, ArH), 6.05 (s, 1 H, CHCO2CH3),
4.81 (t, 1 H, J = 7.2 Hz, CH2CHN=CH), 3.98 (s, 3 H, OCH3), 3.68
(s, 3 H, OCH3), 3.12–3.07 (m, 1 H, one of ArCH2CH2), 2.94–2.88
(m, 1 H, one of ArCH2CH2), 2.45–2.39 (m, 1 H, one of ArCH2CH2),
2.20–2.15 (m, 1 H, one of ArCH2CH2). 13C NMR (100 MHz,
CDCl3): d = 164.9, 163.0, 159.1, 151.4, 148.1, 146.0, 133.9, 130.5,
129.7, 129.4, 128.6, 127.1, 123.9, 120.4, 120.4, 116.6, 113.2, 113.1,
3-(3,4-Dimethoxyphenyl)-3-{2-methoxy-5-[(7-phenylindan-1-
ylimino)methyl]phenoxy}acrylic Acid Methyl Ester (13)
This compound was prepared according the general procedure for
imine synthesis with 1 equiv of aldehyde (18.6 mg, 0.0500 mmol)
1
and 1.5 equiv of amine (11.5 mg, 0.0550 mmol). H NMR (400
MHz, CDCl3): d = 7.37–7.05 (m, 13 H, ArH × 12, CH=NCH), 6.83
(m, 2 H, ArH × 2), 5.96 (s, 1 H, CHCO2CH3), 4.93 (m, 1 H,
CH2CHN=CH), 3.94 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.79 (s,
3 H, OCH3), 3.69 (s, 3 H, CO2CH3), 3.20–3.18 (m, 1 H, one of
ArCH2CH2), 3.00–2.90 (m, 1 H, one of ArCH2CH2), 2.41–2.32 (m,
1 H, one of ArCH2CH2), 2.15–2.00 (m, 1 H, one of ArCH2CH2).
[a]D25 +7.7 (c 1.5, CH2Cl2).
25
112.0, 105.1, 71.6, 56.2, 51.3, 34.1, 31.4. [a]D +1.3 (c 2.9,
CH2Cl2).
3-{5-[(7-Fluoroindan-1-ylimino)methyl]-2-methoxyphenoxy}-
3-phenylacrylic Acid Methyl Ester (15)
This compound was prepared according to the general procedure for
imine synthesis with 1 equiv of aldehyde (14.1 mg, 0.0500 mmol)
and 1.5 equiv of amine (8.3 mg, 0.0550 mmol). 1H NMR (400 MHz,
CDCl3): d = 8.12 (s, 1 H, CH=NCH), 7.59 (d, 2 H, J = 6.8 Hz,
ArH × 2), 7.36–7.27 (m, 4 H, ArH × 4), 7.18–7.13 (m, 2 H,
ArH × 2), 7.02 (d, 1 H, J = 5.6 Hz, ArH), 6.87 (d, 1 H, J = 6.8 Hz,
ArH), 6.78 (t, 1 H, J = 6.8 Hz, ArH), 6.00 (s, 1 H, CHCO2CH3), 5.03
(m, 1 H, CH2CHN=CH), 3.92 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3),
3.20–3.14 (m, 1 H, one of ArCH2CH2), 2.89–2.85 (m, 1 H, one of
ArCH2CH2), 2.40–2.36 (m, 1 H, one of ArCH2CH2), 2.17–2.14 (m,
1 H, one of ArCH2CH2). 13C NMR (100 MHz, CDCl3): d = 164.8,
162.9, 159.4, 151.5, 146.1, 144.4, 143.7, 130.6, 129.4, 128.6, 127.4,
127.1, 126.3, 124.7, 124.3, 123.9, 116.4, 111.9, 105.3, 74.7, 56.2,
2-(3,4-Dimethoxyphenyl)-4-formyl-7-methoxy-2,3-dihydroben-
zofuran-3-carboxylic Acid Methyl Ester (3)
The C–H activation reactions of imines 2 and 11–13 were per-
formed following the general procedure for the cyclization of aro-
matic imines. The crude material was chromatographed on SiO2 (2–
50% EtOAc–hexanes) to afford compound 6 as a white solid with
yields and ee as described in the text. The ee was determined by
HPLC analysis; mp 119–120 °C. 1H NMR (400 MHz, CDCl3): d =
9.82 (s, 1 H, CHO), 7.39 (d, 1 H, J = 8.3 Hz, ArH), 6.98 (d, 1 H,
J = 8.3 Hz, ArH), 6.96–6.62 (m, 2 H, ArH × 2), 6.82 (d, 1 H,
J = 8.2, ArH), 6.00 (d, 1 H, J = 10.2 Hz, ArOCHAr), 4.89 (d, 1 H,
J = 10.2 Hz, ArCHCO2CH3), 3.97 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 3.23 (s, 3 H, CO2CH3). 13C NMR (100
MHz, CDCl3): d = 190.6, 169.7, 149.9, 149.5, 149.0, 148.5, 128.7,
25
51.3, 34.2, 30.9 (multiple C’s coupled to F). [a]D +1.8 (c 1.1,
CH2Cl2).
Synlett 2007, No. 15, 2383–2389 © Thieme Stuttgart · New York

2388
A. Watzke et al.
LETTER
Indan-1-yl-(3-isopropenyloxybenzylidene)amine (17)
7-Formyl-4-methoxy-2-phenylindan-1-carboxylic Acid Methyl
Ester (16)
One equiv of aldehyde (8.1 mg, 0.0500 mmol) and 1.5 equiv of
1
The C–H activation reactions of imines 14 and 15 were performed
following the general procedure for the cyclization of aromatic imi-
nes. The crude material was chromatographed on SiO2 (2–30%
EtOAc–hexanes) to afford compound 16 as a white solid with yields
and ee as described in the text. The ee was determined by HPLC
analysis; mp 135–136 °C. 1H NMR (400 MHz, CDCl3): d = 9.82 (s,
1 H, CHO), 7.41–7.28 (m, 6 H, ArH × 6), 6.99 (d, 1 H, J = 8.4 Hz,
ArH), 6.07 (d, 1 H, J = 10.4 Hz, ArOCHAr), 4.95 (d, 1 H, J = 10.0
amine (7.32 mg, 0.0550 mmol) were condensed. H NMR (400
MHz, CDCl3): d = 8.43 (s, 1 H, CH=NCH), 7.55 (d, 1 H, J = 7.6 Hz,
ArH), 7.51 (s, 1 H, ArH), 7.39 (t, 1 H, J = 8.0 Hz, ArH), 7.30 (d, 1
H, J = 7.2 Hz, ArH), 7.26–7.13 (m, 2 H, ArH × 2), 7.12 (m, 2 H,
ArH × 2), 4.95 (t, 1 H, J = 7.2 Hz, CH2CHN=CH), 4.21 [s, 1 H, one
of CH2=C(O)CH3], 4.01 [s, 1 H, one of CH2=C(O)CH3], 3.18–3.12
(m, 1 H, one of ArCH2CH2), 3.02–2.94 (m, 1 H, one of ArCH2CH2),
2.53–2.47 (m, 1 H, one of ArCH2CH2), 2.32–2.23 (m, 1 H, one of
ArCH2CH2), 2.00 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3): d =
159.8, 159.4, 155.7, 144.1, 143.8, 138.0, 129.6, 127.6, 126.4, 124.8,
124.3, 124.0, 123.0, 120.1, 90.3, 74.9, 34.2, 31.0, 20.0. [a]D25 +14.6
(c 1.0, CH2Cl2).
Hz, ArCHCO2CH3), 3.97 (s, 3 H, OCH3), 3.13 (s, 3 H, OCH3). 13
C
NMR (100 MHz, CDCl3): d = 190.7, 169.5, 150.4, 149.6, 136.0,
128.8, 128.51, 128.1, 126.6, 126.5, 125.3, 111.7, 87.8, 56.2, 54.3,
51.6. HRMS–FAB: m/z calcd for C18H16O5 [M]+: 312.0998; found:
312.0998. HPLC analysis [AS column, hexane–i-PrOH (75:25), 45
min run time]: peak 1, tR = 10.8 min (minor enantiomer) and peak
2, tR = 20.0 min (major enantiomer).
(7-Fluoroindan-1-yl)-(3-isopropenyloxybenzylidene)amine (18)
One equiv of aldehyde (8.3 mg, 0.0500 mmol) and 1.5 equiv of
amine (7.3 mg, 0.0550 mmol) were condensed. 1H NMR (400 MHz,
CDCl3): d = 8.48 (s, 1 H, CH=NCH), 7.50–7.43 (m, 2 H, ArH × 2),
7.34 (t, 1 H, J = 10.4 Hz, ArH), 7.25–7.17 (m, 1 H, ArH), 7.09–7.05
(m, 2 H, ArH × 2), 6.82 (t, 1 H, J = 11.2 Hz, ArH), 5.17–5.15 (m, 1
H, CH2CHN=CH), 4.17 [s, 1 H, one of CH2=C(O)CH3], 3.97 [s, 1
H, one of CH2=C(O)CH3], 3.30–3.20 (m, 1 H, one of ArCH2CH2),
2.99–2.89 (m, 1 H, one of ArCH2CH2), 2.51–2.41 (m, 1 H, one of
ArCH2CH2), 2.29–2.23 (m, 1 H, one of ArCH2CH2), 1.97 (s, 3 H,
CH3). [a]D25 +2.2 (c 1.3, CH2Cl2).
3-Isopropenyloxybenzaldehyde
To a 100 mL round-bottom flask equipped with a magnetic stir bar
and septum were added 1.5 equiv (7.98 g, 24.6 mmol) of Cs2CO3,
0.25 equiv of CuCl (405 mg, 4.10 mmol), 0.5 equiv of acetylacetone
(819 mg, 8.19 mmol), and 50 mL of THF. The suspension was
stirred for 5 min at r.t. Under an argon atmosphere, 3-hydroxyben-
zaldehyde (2.0 g, 16.38 mmol) and 1.3 equiv of 2-bromopropene
(1.86 mL, 21.29 mmol) were added to the reaction mixture. The re-
action flask was then equipped with a reflux condenser, and the
mixture was heated to reflux for 12 h. The reaction mixture was
cooled to r.t., filtered, and concentrated under reduced pressure. The
crude material was chromatographed on SiO2 (0–10% EtOAc–hex-
anes) to afford the title compound as a yellow oil (690 mg, 4.26
mmol, 26%). 1H NMR (400 MHz, CDCl3): d = 9.92 (s, 1 H, CHO),
7.56 (dd, 1 H, J = 1.2, 10.0 Hz, ArH), 7.49 (t, 1 H, J = 1.6 Hz, ArH),
7.44 (t, 1 H, J = 7.6 Hz, ArH), 7.24 (dd, 1 H, J = 1.2, 10.8 Hz, ArH),
4.23 (d, 1 H, J = 2.0 Hz, CH2=CCH3), 3.99 (d, 1 H, J = 2.0 Hz,
CH2=CCH3), 1.93 (s, 3 H, CH2=CCH3). 13C NMR (100 MHz,
CDCl3): d = 191.3, 158.7, 156.0, 137.8, 130.0, 126.4, 125.2, 120.1,
91.5, 19.5. HRMS–FAB: m/z calcd for C10H10O2 [M]+: 162.0681;
found: 162.0681.
Indan-1-yl-(3-propenyloxybenzylidene)amine (19)
One equiv of aldehyde (8.1 mg, 0.0500 mmol) and 1.5 equiv of
amine (7.3 mg, 0.0550 mmol) were condensed. 1H NMR (400 MHz,
CDCl3): d = 8.43 (s, 1 H, CH=NCH), 7.49 (s, 1 H, ArH), 7.43 (d, 1
H, J = 6.0 Hz, ArH), 7.36 (t, 1 H, J = 6.0 Hz, ArH), 7.32 (d, 1 H,
J = 5.6 Hz, ArH), 7.26 (t, 1 H, J = 5.2 Hz, ArH), 7.21 (t, 1 H, J = 6.0
Hz, ArH), 7.12 (d, 1 H, J = 5.6 Hz, ArH), 7.07 (d, 1 H, J = 6.0 Hz,
ArH), 6.49 [d, 1 H, J = 9.6 Hz, HC(CH3)=CHOAr], 5.45–5.38 [m,
1 H, HC(CH3)=CHOAr], 4.96 (t, 1 H, J = 5.6 Hz, CH2CHN=CH),
3.18–3.13 (m, 1 H, one of ArCH2CH2), 3.02–2.96 (m, 1 H, one of
ArCH2CH2), 2.51–2.49 (m, 1 H, one of ArCH2CH2), 2.33–2.26 (m,
1 H, one of ArCH2CH2), 1.69 (d, 3 H, J = 5.6 Hz, CH3). 13C NMR
(100 MHz, CDCl3): d = 160.0, 157.7, 144.1, 143.8, 141.7, 137.8,
129.7, 127.6, 126.4, 124.8, 124.3, 123.0, 119.1, 114.6, 108.7, 74.9,
34.2, 31.0, 12.2. [a]D25 +2.1 (c 1.9, CH2Cl2).
3-Propenyloxybenzaldehyde
To a 100 mL round-bottom flask equipped with a magnetic stir bar
and septum were added 1.5 equiv (7.98 g, 24.6 mmol) of Cs2CO3,
0.25 equiv of CuCl (405 mg, 4.10 mmol), 0.5 equiv of acetylacetone
(819 mg, 8.19 mmol), and 50 mL of THF. The suspension was
stirred for 5 min at r.t. Under an argon atmosphere, 1 equiv of 3-
[1,3]dioxolan-2-yl-phenol (2.72 g, 16.38 mmol) and 1.5 equiv of 1-
bromopropene were added to the reaction mixture. The reaction
flask was then equipped with a reflux condenser and the mixture
was heated to reflux for 12 h. The reaction mixture was cooled to
r.t., filtered, and concentrated under reduced pressure. The acetal
was hydrolyzed by stirring in 6 N HCl–MeOH for 1 h. The mixture
was extracted with EtOAc and concentrated, and the crude material
was chromatographed on SiO2 (0–10% EtOAc–hexanes) to afford
(7-Fluoroindan-1-yl)-(3-propenyloxybenzylidene)amine (20)
One equiv of aldehyde (8.11 mg, 0.05 mmol) and 1.5 equiv of amine
(8.31 mg, 0.055 mmol) were condensed. 1H NMR (400 MHz,
CDCl3): d = 8.39 (s, 1 H, CH=NCH), 7.40–7.37 (m, 2 H, ArH × 2),
7.32 (t, 1 H, J = 7.6 Hz, ArH), 7.25–7.16 (m, 1 H, ArH), 7.08 (d, 1
H, J = 7.2 Hz, ArH), 7.02 (d, 1 H, J = 8.0 Hz, ArH), 6.84 (t, 1 H,
J = 8.8 Hz, ArH), 6.46 [d, 1 H, J = 12.4 Hz, HC(CH3)=CHOAr],
5.41–5.36 [m, 1 H, HC(CH3)=CHOAr], 5.18–5.17 (m, 1 H,
CH2CHN=CH), 3.31–3.23 (m, 1 H, one of ArCH2CH2), 2.98–2.97
(m, 1 H, one of ArCH2CH2), 2.52–2.47 (m, 1 H, one of ArCH2CH2),
2.29–2.28 (m, 1 H, one of ArCH2CH2), 1.68 [d, 3 H, J = 6.8 Hz,
C(CH3)3]. 13C NMR (100 MHz, CDCl3): d = 159.9, 159.2, 157.7,
148.2, 148.1, 141.7, 137.9, 130.0, 129.9, 129.9, 129.6, 122.9, 120.5,
120.5, 119.0, 114.8, 113.3, 113.1, 108.6, 71.8, 34.1, 31.5, 31.5, 12.3
(multiple C’s coupled to F). [a]D25 +6.0 (c 1.0, CH2Cl2).
1
the E-alkene as a yellow oil (584 mg, 3.60 mmol, 22%). H NMR
(400 MHz, CDCl3): d = 9.90 (s, 1H, CHO), 7.45 (dd, 1 H, J = 1.2,
8.0 Hz, ArH), 7.41–7.37 (m, 2 H, ArH), 7.16 (dd, 1 H, J = 1.2, 5.2
Hz, ArH), 6.40–6.35 (m, 1 H, CH3CH=CH), 5.42–5.34 (m, 1 H,
CH3CH=CH), 1.63 (dd, 3 H, J = 1.6, 6.8 Hz, CH3CH=CH). 13C
NMR (100 MHz, CDCl3): d = 191.6, 157.8, 140.9, 137.7, 130.1,
124.4, 122.6, 114.9, 109.9, 12.1. HRMS–FAB(+): m/z calcd for
C10H10O2 [M]+: 162.0681; found: 162.0680.
The C–H activation reactions of imines 17–20 were prepared fol-
lowing the general procedure for the cyclization of aromatic imines.
The crude material was chromatographed on SiO2 (0–1% EtOAc–
hexanes) to afford compounds 21 and 22 as colorless oils with
yields and ee as described in the text. The ee was determined by
HPLC analysis.
Imines 17–20 were prepared according to the general procedure for
imine synthesis.
Synlett 2007, No. 15, 2383–2389 © Thieme Stuttgart · New York

LETTER
Alkylation of Chiral Aromatic Imines
2389
2-Methyl-2,3-dihydrobenzofuran-4-carbaldehyde (21)
References and Notes
1H NMR (400 MHz, CDCl3): d = 10.03 (s, 1 H, CHO), 7.30–7.26
(m, 2 H, ArH × 2), 7.01–6.98 (m, 1 H, ArH), 5.06–4.97 [m, 1 H,
CH3CH(CH2)OAr], 3.70–3.64 [dd, 1 H, J = 17.6, 8.8 Hz, one of
CH3CH(CH2)OAr], 3.15–3.09 [dd, 1 H, J = 17.6, 7.6 Hz, one of
CH3CH(CH2)OAr], 1.48 (d, 3 H, J = 6.0 Hz, CH3CH). 13C NMR
(100 MHz, CDCl3): d = 192.5, 160.6, 132.9, 128.5, 128.0, 124.1,
114.7, 80.7, 36.8, 21.8. HPLC analysis [AS column, hexanes–
i-PrOH (99:1), 20 min run time]: peak 1, tR = 9.3 min (minor enan-
tiomer) and peak 2, tR = 8.9 min (major enantiomer).
(1) For recent reviews of C–H activation, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(b) Kakiuchi, F.; Chatani, N. Top. Organomet. Chem. 2004,
11, 45. (c) Labinger, J. A.; Bercaw, J. E. Nature (London)
2002, 417, 507. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
Res. 2003, 102, 1731. (e) Jia, C. G.; Kitamura, T.; Fujiwara,
Y. Acc. Chem. Res. 2001, 34, 633.
(2) (a) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J.
A. J. Am. Chem. Soc. 2001, 123, 9692. (b) Ahrendt, K. A.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2003, 5, 1301.
(3) (a) Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2004, 126, 7192. (b) Wilson, R. M.; Thalji, R. K.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2006, 8, 1745.
(4) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496.
(5) (a) Kelley, C. J.; Mahajan, J. R.; Brooks, L. C.; Neubert, L.
A.; Breneman, W. R.; Carmack, M. J. Org. Chem. 1975, 40,
1804. (b) Kelley, C. J.; Harruff, R. C.; Carmack, M. J. Org.
Chem. 1976, 41, 449.
(6) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem.
2007, 72, 626.
(7) Nguyen, P.; Corpuz, E.; Heidelbaugh, T. M.; Chow, K.;
Garst, M. E. J. Org. Chem. 2003, 68, 10195.
(8) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 2892.
(9) Ti(OPh)4 was prepared in situ by the addition of 4 equiv of
phenol to 1 equiv of Ti(Oi-Pr)4 in THF at r.t. Ti(OPh)4 was
obtained as an orange solid after removal of the solvent.
(10) For an example of C–H activation with transimination, see:
Jun, C. H.; Moon, C. W.; Lee, D. Y. Chem. Eur. J. 2002, 8,
2422.
3-Methyl-2,3-dihydrobenzofuran-4-carbaldehyde (22)
1H NMR (400 MHz, CDCl3): d = 10.06 (s, 1 H, CHO), 7.34–7.28
(m, 2 H, ArH × 2), 7.05–7.02 (m, 1 H, ArH), 4.60 [t, 1 H, J = 11.2
Hz, CH3CH(CH2)OAr], 4.34–4.29 [m,
1
H, one of
CH3CH(CH2)OAr], 3.98–3.92 [m, 1 H, one of CH3CH(CH2)OAr],
1.30 (d, 3 H, J = 9.2 Hz, CH3CH). 13C NMR (100 MHz, CDCl3):
d = 192.1, 160.6, 133.4, 132.7, 128.7, 124.8, 115.2, 79.3, 36.1, 20.5.
HPLC analysis [AS column, hexanes–i-PrOH (99:1), 20 min run
time]: peak 1, tR = 10.0 min (minor enantiomer) and peak 2, tR = 8.9
min (major enantiomer).
tert-Butyl-(3-isopropenyloxybenzylidene)amine (23)
Imine 23 was prepared following the general procedure for imine
formation. 1H NMR (400 MHz, CDCl3): d = 8.22 (s, 1 H,
CH=NCH), 7.49 (d, 1 H, J = 7.6 Hz, ArH), 7.44 (s, 1 H, ArH),
7.34 (t, 1 H, J = 8.0 Hz, ArH), 7.06 (d, 1 H, J = 7.6 Hz, ArH), 4.17
[s, 1 H, one of CH2=C(CH3)OAr], 3.97 [s, 1 H, one of
CH2=C(CH3)OAr], 1.98 (s, 3 H, CCH3), 1.28 [s, 9 H, C(CH3)3]. 13
C
NMR (100 MHz, CDCl3): d = 159.4, 155.6, 154.4, 138.9, 129.5,
123.5, 122.5, 119.8, 89.9, 57.3, 29.6, 20.0. HRMS–FAB: m/z calcd
for C14H20NO [M + H]+: 218.1545; found: 218.1545.
(11) Van der Ent, A.; Onderdelinden, A. L. Inorg. Synth. 1973,
14, 92.
(12) Guillaneaux, D.; Kagan, H. J. Am. Chem. Soc. 1995, 60,
2502.
(13) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
292.
Acknowledgment
This work was supported by the NIH, GM069559 (to J.A.E.) and
5F32GM071207-02 (to S.O.M.), by the German Academic Ex-
change Service – DAAD (to A.W.), and by the Director and Office
of Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under contract DE-
AC03-76SF00098 (to R.G.B.).
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