Phosphonium ion tagged chiral phosphoric acids and their application in Friedel-Crafts reactions of indoles

Article abstract of DOI:10.1016/j.tet.2011.03.105

The attachment of phosphonium ion phase tags to chiral binapthyl-based phosphoric acid catalysts, and the use of these materials in a range of organocatalytic asymmetric Friedel-Crafts reactions of indoles has been studied. Placement of the tags at the 3

Full text of DOI:10.1016/j.tet.2011.03.105

Tetrahedron 67 (2011) 4103e4109
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Tetrahedron
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Phosphonium ion tagged chiral phosphoric acids and their application in
FriedeleCrafts reactions of indoles
*
Julia Hermeke, Patrick H. Toy
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The attachment of phosphonium ion phase tags to chiral binapthyl-based phosphoric acid catalysts, and
the use of these materials in a range of organocatalytic asymmetric FriedeleCrafts reactions of indoles
has been studied. Placement of the tags at the 3 and 30 positions of the phosphoric acid, so that they
could serve as steric blocking groups, failed to produce an active catalyst. However, moving the phos-
phonium ion groups to the 6 and 60 positions produced an efficient and enantioselective catalyst. Aided
by the presence of the phase tags, the chiral catalyst was easily removed at the end of the reactions, and
could be reused several times, albeit with somewhat decreased efficiency and enantioselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 February 2011
Received in revised form 24 March 2011
Accepted 30 March 2011
Available online 8 April 2011
Keywords:
Organocatalysis
Asymmetric catalysis
Chiral phosphoric acid
Phosphonium salt
FriedeleCrafts reactions
1. Introduction
steric blocking groups also serve as handles to aid in its recovery
from reaction mixtures. Illustrative of this methodology is the
Since the first publications regarding the concept of asymmetric
Brønsted acid organocatalysis using chiral phosphoric acids by
Akiyama1 and Terada,2 a large body of work has emerged in the
organic chemistry literature examining various aspects and appli-
cations of such catalysis.3 While this general field of asymmetric
organocatalysis has been explored intensively, only a single report
by Rueping describes the synthesis and utility of a chiral phos-
phoric acid catalyst, that is, easily recoverable, and readily reused
without loss of reactivity or selectivity.4 In this work, the chiral
phosphoric acid was incorporated into a heterogeneous, cross-
linked polystyrene framework so that it could be removed for re-
use simply by filtration.
report that 27a can be used as a soluble reagent in triphenyl-
phosphine mediated transformations, such as Mitsunobu re-
actions, and then it and its oxidized by-product can be separated
from the desired reaction product by precipitation and filtration.
Thus, we set out to synthesize (R)-3 and examine its utility as
a recyclable asymmetric organocatalyst. Herein we describe the
results of our research regarding this concept.
During a survey of this topic, we noted that all of the effective
binapthyl-based chiral phosphoric acid organocatalysts reported
in the literature were functionalized at the 3 and 30 positions by
sterically bulky groups. For example, (R)-1a (Akiyama’s
catalyst),1 (R)-1b (Terada’s catalyst),2 and what is referred to as the
TRIP catalyst (R)-1c,3d all possess substituted aryl groups at these
positions (Fig. 1). Furthermore, MacMillan5 and Gong6 introduced
(R)-1d, which bears triphenylsilyl groups at the 3 and 30 positions.
This later example caused us to consider if it might be possible to
use Charette’s phosphonium ion phase tag technology7 to prepare
a homogeneous chiral phosphoric acid organocatalyst in which the
Fig. 1. Chiral phosphoric acids and Charette’s phosphonium ion tagged phosphine
reagent.
2. Results and discussion
For the synthesis of (R)-3, diol (R)-4 was prepared from
(R)-BINOL according to literature procedures.8e10 Phosphonium
ions were then added to (R)-4 in good yield using a Pd2(dba)3
mediated coupling reaction with PPh3 in ethylene glycol at high
* Corresponding author. Tel.: þ852 2589 2167; fax: þ852 2587 1586; e-mail
address: phtoy@hku.hk (P.H. Toy).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.105

4104
J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
temperature, to afford tagged diol (R)-5 (Scheme 1). Subsequent
reaction of (R)-5 with POCl3 in pyridine at 80 ꢀC, followed by
treatment with water and acidification afforded phosphoric acid
(R)-6 in 83% overall yield. Finally, (R)-6 was converted into (R)-3 in
quantitative yield by counter ion exchange using KPF6.
partner to a,b-unsaturated carbonyl compound 10a using similar
conditions (Scheme 2b).17 However, once again, none of the desired
product11a wasformed. Acid(R)-3 also failedto catalyzethe reaction
between 7a and nitroalkene 12 to produce 13 (Scheme 2c).14f Finally,
we attempted to use (R)-3 to catalyze the DielseAlder reaction be-
tween aldimine 14 and vinyl ether 15 in toluene at room temperature
(Scheme 2d).18 However, even after 7 days none of the expected
product 16 was observed, and only the starting materials and catalyst
were present in the reaction mixture.
We believed that there were two possible explanations for our
disappointing results; that the phosphonium groups were too bulky,
and thereby sterically inhibited (R)-3 from interacting with the sub-
stratesinthenecessarywayforcatalysis tooccur, orthattheircationic
natureelectronicallyaffectedtheabilityof thephosphoricacidgroups
to activate the substrates in thedesiredmanner. In order to determine
which of these possibilities was responsible for the failure of (R)-3 to
catalyze the reactions studied in Scheme 2, we felt that moving the
phosphonium ion phase tags from the 3 and 30 positions of the BINOL
skeleton to the 6 and 60 positions might be informative. Thus, we
designed and synthesized (R)-17 as outlined in Scheme 3. For (R)-17
we chose to install 2,4,6-triisopropylphenyl groups at the 3 and 30
positions since they are the basis for the TRIP catalyst (R)-1c, which
has been shown to be an excellent catalyst for asymmetric transfer
hydrogenation,19,20 and FriedeleCrafts reactions.21
Scheme 1. Synthesis of the phosphonium ion tagged chiral phosphoric acid (R)-3.
To begin with, diol (R)-18 was synthesized from (R)-BINOL
according to literature procedures8,9,22 and was subsequently bro-
minated in CH2Cl2 at ꢁ78 ꢀC to afford (R)-19 in quantitative yield
(Scheme 3). It should be noted that this reaction is very sensitive to
both the quantity of Br2 used, and the time allowed for the reaction
to occur, since over-bromination at 4 and 40 positions occurred if
the reaction was not carefully controlled and monitored. The
phosphonium ion groups were then added to (R)-19 as before,
using a palladium-catalyzed coupling reaction with PPh3 in hot
ethylene glycol, to afford diol (R)-20 in 79% yield. Conversion of
(R)-20 into the corresponding phosphoric acid (R)-21 in 84% yield
was achieved by treating it with POCl3 in pyridine at 80 ꢀC, followed
by water and acidification. Finally, exchange of the counter ion of
(R)-21 was accomplished by treatment with KPF6 to afford phos-
phoric acid (R)-17 in quantitative yield. It should be noted that
purification of (R)-17, (R)-20 and (R)-21 was accomplished simply
by precipitation and filtration. These products were found to be
soluble in solvents, such as CH2Cl2, acetonitrile, dimethyl sulfoxide,
dimethylformamide, but insoluble in solvents, such as diethyl ether
and n-hexane. Thus, addition of one of these later solvents to the
reaction mixture caused the phosphonium ion tagged species to
precipitate, so that it could be isolated by filtration and purified by
washing with additional solvent.
With thesynthesis of phosphoric acid (R)-3 completed, we moved
on to examine its potential as an enantioselective organocatalyst in
a range of asymmetric FriedeleCrafts and DielseAlder reactions for
which (R)-1d was previously reported to be an excellent catalyst
(Scheme 2). In regards to the construction of carbonecarbon bonds,
the catalytic asymmetric FriedeleCrafts reaction is a highly effective
method that provides direct access to enantiomerically enriched
arene derivatives.11 This is especially true for indoles substrates,12
due to their significant nucleophilic reactivity,13 and chiral phos-
phoric acids have been reported to be a very efficient and highly
stereoselective catalyst for such reactions.14e16 First we set up a re-
action with indole 7a and a-aryl enamide 8a using 0.1 equiv of (R)-3
with molecular sieves in CH2Cl2 at room temperature (Scheme 2a).14e
Unfortunately, none of the desired product 9awas formed, even after
5 days. In the next reaction we changed the electrophilic reaction
Once the phosphonium ion tagged phosphoric acid (R)-17 was
synthesized, we tested its catalytic utility in asymmetric Frie-
deleCrafts reactions. Gratifyingly, when we attempted to use (R)-17
to catalyze the same reaction that (R)-3 failed to promote between
7a and 8a (Scheme 2a), we obtained the desired product 9a in
excellent yield with moderate enantioselectivity using molecular
sieves in CH2Cl2 at 0 ꢀC (Table 1, entry 1). Encouraged by this result,
we next used (R)-17 to catalyze a series of similar reactions, using
indoles 7aec and enamides 8aed. The reactions between unsub-
stituted 7a and enamides bearing an electron-withdrawing group
in the para-position (8bec) also proceeded to afford excellent yield
of the products 9b and 9c, respectively, but with slightly higher
enantioselectivity than before (Table 1, entries 2 and 3). When an
electron-donating group was placed in the para-position, as in 8d,
the yield of the alkylated indole 9d was somewhat lower, as was the
enantioselectivity (Table 1, entry 4). The use of substituted indoles 7b
and 7c as the reacting partner with unsubstituted enamide 8a affor-
ded products 9e and 9f, respectively, in yields and enantioselectivities
similar to the other products (Table 1, entries 5 and 6). Overall, these
Scheme 2. Attempts to use (R)-3 as an asymmetric organocatalyst.

J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
4105
Scheme 3. Synthesis of phosphonium ion tagged chiral phosphoric acid (R)-17.
Table 2
Table 1
Enantioselective FriedeleCrafts reactions of indoles with enamidesa
Enantioselective FriedeleCrafts reactions of indoles with
b
,
g
-unsaturated
a
-keto
estersa
NHAc
R1
Ar
*
O
O
Ar
*
(R)-17 (5 mol%)
R1
+
CO2Et
Ar
CO2Et
(R)-17 (10 mol%)
Ac
4 Å MS
N
H
R1
+
R1
Ar
N
H
CH2Cl2, - 78 °C
HN
4 Å MS,
N
H
N
H
CH2Cl2, 0 °C
7a: R1 = H-
10a: Ar = C6H5-
11a: R1 = H, Ar = C6H5-
7a: R1 = H-
8a: Ar = C6H5-
9a: R1 = H-, Ar = C6H5-
7b: R1 = 5-Br- 10b: Ar = 4-Me-C6H4-
7c: R1 = 5-F- 10c: Ar = 4-Br-C6H4-
10d: Ar = 4-OMe-C6H4-
11b: R1 = H, Ar = 4-Br-C6H4-
11c: R1 = H, Ar = 4-F-C6H4-
11d: R1 = H, Ar = 4-OMe-C6H4-
11e: R1 = 5-Br, Ar = C6H5
11f: R1 = 5-F, Ar = C6H5
7b: R1 = 5-Br-
7c: R1 = 5-F-
8b: Ar = 4-Br-C6H4-
8c: Ar = 4-F-C6H4-
8d: Ar = 4-OMe-C6H4-
9b: R1 = H-, Ar = 4-Br-C6H4-
9c: R1 = H-, Ar = 4-F-C6H4-
9d: R1 = H-, Ar = 4-OMe-C6H4-
9e: R1 = 5-Br-, Ar = C6H5-
9f: R1 = 5-F-, Ar = C6H5-
-
-
Yieldb (%)
erc
Entry
Substrates
Product
Reaction time (h)
Yieldb (%)
erc
Entry
Substrates
Products
Reaction time (h)
1
2
3
4
5
6
7aþ10a
7aþ10b
7aþ10c
7aþ10d
7bþ10a
7cþ10a
11a
11b
11c
11d
11e
11f
24
24
24
48
24
24
98
94
92
89
90
92
80:20
75:25
80:20
75:25
73:27
77:23
1
2
3
4
5
6
7aþ8a
7aþ8b
7aþ8c
7aþ8d
7bþ8a
7cþ8a
9a
9b
9c
9d
9e
9f
24
24
24
48
24
24
95
98
98
81
95
82
87:13
95:5
91:9
85:15
93:7
87:13
a
a
Reactions were conducted using 0.21 mmol 7aec, 0.1 mmol 10aed and
0.005 mmol of (R)-17.
Reactions were conducted using 0.14 mmol of 7aec, 0.1 mmol of 8aed and
0.01 mmol of (R)-17.
b
b
Isolated yields.
Isolated yields.
c
c
Enantiomer ratios were determined by HPLC using a chiral stationary phase
Enantiomer ratios were determined by HPLC using a chiral stationary phase
column.
column.
Thus, since we demonstrated the catalytic activity of (R)-17, we next
examined its recyclability. The reaction arbitrarily chosen for this
exercise was the FriedeleCrafts reaction between 7a with enamide
8b to form 9b. As can be seen in Table 3, 9b was isolated in similar
results are generally similar, albeit with slightly lower selectivity, to
what was reported by Zhou in his related pioneering work.14e
In ordertofurther demonstratethe utility of (R)-17 as a catalyst in
asymmetric FriedeleCrafts reactions, weexamined anotherreaction
that (R)-3 failed to promote, specifically that between 7a and
b,g-
Table 3
Recyclability of phosphoric acid (R)-17a
unsaturated -keto ester 10a (Scheme 2b). Such reactions were
a
previously studied by Desimoni using a scandium(III) triflate cata-
lyst.23 The only use of an organocatalysts in such reactions with N-
methylindole substrates was described by Rueping, and these were
catalyzed by a chiral N-triflylphosphoramide.17 Satisfyingly, in the
reaction between 7a and 10a, using molecular sieves in CH2Cl2 at
ꢁ78 ꢀC, product 11a was formed in nearly quantitative yield and
with moderate enantioselectivity (Table 2, entry 1). We then reacted
7a with substituted substrates 10bed, and obtained similar results
for products 11bed (Table 2, entries 2-4). When substituted indoles
7b and 7c were reacted with 10a, both 11e and 11f were obtained in
excellent yield, respectively. However, the enantioselectivities of
these reactions were only moderate (Table 2, entries 5 and 6).
As described above, the impetus for incorporating phosphonium
ion groups into both (R)-3 and (R)-17 was to allow them to serve as
recyclable homogeneous catalysts that could be easily separated
from reaction mixtures by precipitation and filtration operations.
NHAc
Ar
∗
(R)-17 (10 mol%)
4 Å MS, CH2Cl2
0 °C, 24-48 h
Ac
+
Ar
N
H
N
H
N
H
8b
7a
9b
Ar = 4-Br-C6H4-
Cycle
1
2
3
4
Reaction time (h)
Yield (%)
24
30
73
93:8
95
48
74
85:15
93
48
72
76
96:4
98
erb
87:13
93
Recovered catalyst (%)c
a
Reactions were conducted using 2.8 mmol of 7a, 2.0 mmol of 8b and 0.2 mmol of
(R)-17. At the end of each reaction, (R)-17 was precipitated by the addition of diethyl
ether to the reaction mixture, washed and then reused in the next cycle.
b
EnantiomerratiosweredeterminedbyHPLCusingachiralstationaryphasecolumn.
Catalyst recovery was calculated based on the previous experiment.
c

4106
J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
yield (76e72% yield) in reactions that took progressively longer to
complete, and with decreased enantioselectivity (Table 3). Thus, it
is clear that (R)-17 has limited reusability.
dissolving it in CH2Cl2 (3.0 mL) and precipitating it by the addition
of cold Et2O (60 mL). Filtration and washing of the precipitate
afforded pure phosphonium salt (R)-5 (1.50 g, 95%) as a yellow
solid. 1H NMR (400 MHz, CD3Cl):
d
7.83e7.53 (m, ArH, 32H),
7.40e7.36 (m, ArH, 4H), 7.34e7.26 (m, ArH, 4H), 7.23e7.19 (m, ArH,
2H); 13C NMR (126 MHz, CD3Cl):
3. Conclusion
d
162.0 (d, J¼9.0 Hz, 2C), 138.9 (d,
In summary, we used the phosphonium ion phase tag tech-
nology to prepare a pair of phase tagged chiral binapthyl-based
phosphoric acids, (R)-3 and (R)-17 and studied their catalytic ac-
tivity in a range of asymmetric FriedeleCrafts reactions with in-
doles substrates. Unfortunately, our attempt to use the phase tags
as steric blocking groups at the 3 and 30 positions of the binapthyl
skeleton in (R)-3 failed to produce an active catalyst. On the other
hand, when we placed the phosphonium ion phase tags at the
6 and 60 positions of the binapthyl skeleton and used conventional
2,4,6-triisopropylphenyl steric blocking substituents at the 3 and
30 positions, (R)-17 proved to be an active and stereoselective
catalyst. These contrasting sets of results lead us to believe that
the lack of catalytic activity exhibited by (R)-3 can be ascribed to
steric hindrance by the phosphonium ion groups, which should be
larger than the previously studied triphenylsilyl groups, and is not
due to any electronic effect that the phase tags impart on the
phosphoric acid group. As for the less than optimal results in the
recycling experiments, perhaps the decreased enantioselectivity
observed with recovered (R)-17 was due to an undetected impu-
rity that co-precipitated with it during the recycling process, and
that inhibited enantioselective catalysis by (R)-17, allowing the
J¼8.0 Hz, 2C), 138.6 (s, 2C), 134.2 (d, J¼10.4 Hz, 18C), 129.8 (d,
J¼12.9 Hz,12C),129.6 (s, 2C),128.9 (s, 2C),126.6 (s, 2C),122.8 (s, 2C),
120.8 (d, J¼11.5 Hz, 2C), 120.7 (d, J¼7.3 Hz, 2C), 118.6 (d, J¼86.6 Hz,
6C), 111.1 (d, J¼95.8 Hz, 2C); 31P NMR (162 MHz, CD3Cl):
d 23.0;
HRMS for C56H41O2P2: calcd 807.2571, found 807.2555.
4.2.2. Phosphoric acid (R)-6. To
a solution of (R)-5 (1.2 g,
1.41 mmol) in pyridine (19.0 mL) was added POCl3 (1.05 mL,
11.3 mmol) at room temperature under a N2 atmosphere. The re-
action mixture was then heated at 80 ꢀC and stirred at this tem-
perature for 13 h. At this time water (9.5 mL) was added and
stirring was continued for an additional 4 h at 80 ꢀC. The reaction
mixture was then cooled using an ice bath and 3 M HCl was slowly
added to the reaction mixture. Extraction with CH2Cl2 was followed
by additional washing with 3 M HCl, drying over anhydrous MgSO4,
filtration and solvent removal. The crude product was purified by
dissolving it in CH2Cl2 (3 mL) and precipitating it with chilled Et2O
(60 mL) to afford (R)-6 (1.06 g, 85%) as a yellow solid. 1H NMR
(400 MHz, CD3Cl):
d
8.03 (d, J¼16.3 Hz, ArH, 2H), 7.90 (d, J¼7.9 Hz,
ArH, 2H), 7.80e7.74 (m, ArH, 18H), 7.69e7.64 (m, ArH, 12H),
7.59e7.53 (m, ArH, 4H), 7.30 (d, J¼7.9 Hz, ArH, 2H); 13C NMR
non-selective background reaction to occur to
a
greater
(126 MHz, CD3Cl):
d
150.8 (d, J¼9.4 Hz, 2C), 141.1 (d, J¼8.3 Hz, 2C),
extent.24,25 However, we cannot rule out the possibility that the
electronic properties of the phosphonium groups play a role in
limiting the recyclability of (R)-17. Regardless, we hope that our
observations in this study can aid others as they work to develop
more stereoselective and recyclable versions of these important
organocatalysts.
136.3 (s, 2C), 135.1 (d, J¼10.8 Hz, 12C), 135.1 (d, J¼3.2 Hz, 6C), 131.1
(s, 2C), 130.1 (d, J¼13.3 Hz, 12C), 129.9 (s, 2C), 129.3 (d, J¼14.3 Hz,
2C), 127.1 (s, 2C), 126.6 (s, 2C), 124.6 (d, J¼6.6 Hz, 2C), 118.9 (d,
J¼91.2 Hz, 6C), 110.8 (d, J¼91.7 Hz, 2C); 31P NMR (162 MHz, CD3Cl):
d
23.0, 0.5; HRMS for C56H40O4P3: calcd 869.2128, found 869.2113.
4.2.3. Phosphoric acid (R)-3. A solution of KPF6 (0.66 g, 3.56 mmol)
in CH3CN (64 mL) was added dropwise to a solution of (R)-6 (1.00 g,
0.89 mmol) in CH2Cl2 (64 mL) and the resulting reaction mixture
was stirred at room temperature for 3 h. Afterwards, the mixture
was washed with water and 3 M HCl, dried over anhydrous MgSO4,
filtered and evaporated to dryness to afford (R)-3 (0.68 g, 100%) as
a yellow solid. If necessary, the product could be purified by dis-
solving it in CH2Cl2 and precipitating it with Et2O. 1H NMR
4. Experimental
4.1. General
All reagents were obtained from the Acros, Aldrich, In-
ternational Laboratory or Lancaster chemical companies and were
used as received. Diethyl ether and CH2Cl2 were dried using
a Solv-Tek purification system employing activated Al2O3. All re-
actions were carried out in dry glassware under N2 atmosphere,
and monitored by TLC analysis using GF254 silica gel coated plates.
Merck silica gel 60 (230e400 mesh) was used for chromatogra-
phy. 1H, 13C, 31P and 19F NMR spectra were recorded in CDCl3 on
a Bruker DRX-300, DRX-400 or DRX-500 spectrometer operating
at 300/400/500 MHz for 1H, 75/100/125 MHz for 13C, 162 MHz for
31P, and 376 MHz for 19F analysis. Chemical shift data is expressed
in parts per million with reference to TMS. HR EI-MS data was
recorded on a Finnigan MAT 96 mass spectrometer and HR ESI-MS
data was recorded on a ABI Q-STAR Pulsar i mass spectrometer.
HPLC analyses were performed using a Waters 2998 chromatog-
raphy system.
(400 MHz, CD3Cl):
d
8.01 (d, J¼16.3 Hz, ArH, 2H), 7.86e7.84 (m, ArH,
2H), 7.78e7.73 (m, ArH, 18H), 7.66e7.61 (m, ArH, 12H), 7.56e7.48
(m, ArH, 4H), 7.27e7.30 (m, ArH, 2H); 13C NMR (126 MHz, CD3Cl):
d
150.7 (d, J¼9.1 Hz, 2C), 141.1 (d, J¼7.3 Hz, 2C), 136.4 (s, 2C), 135.0
(d, J¼10.2 Hz, 12C), 135.0 (d, J¼3.2 Hz, 6C), 131.1 (s, 2C), 130.1 (d,
J¼15.5 Hz, 12C), 129.8 (s, 2C), 129.3 (d, J¼14.5 Hz, 2C), 127.0 (s, 2C),
126.6 (s, 2C),124.5 (d, J¼7.5 Hz, 2C),119.0 (d, J¼91.1 Hz, 6C),110.7 (d,
J¼90.9 Hz, 2C); 31P NMR (162 MHz, CD3Cl):
d
23.0, 0.9, ꢁ144.3
(septet, J¼713 Hz, PF6); 19F NMR (376 MHz, CD3Cl):
d
ꢁ73.4 (d,
J¼712 Hz, PF6); HRMS for C56H40O4P3: calcd 869.2128, found
869.2117.
4.2.4. (R)-6,60-Dibromo-3,30-bis(2,4,6-triisopropylphenyl)-1,10-bi-
naphthyl-2,20-diol (19). The synthesis of (R)-19 was based on liter-
ature procedures.26 A solution of (R)-18 (1.0 g, 1.45 mmol)8,9,22 in
dry CH2Cl2 (10 mL) was cooled to ꢁ78 ꢀC and a solution of Br2
(0.51 g, 3.18 mmol) in CH2Cl2 (5.0 mL) was added dropwise. The
reaction mixture was stirred at ꢁ78 ꢀC for 2.5 h and then at room
temperature for 1 h. If the reaction was not complete, it was cooled
to ꢁ78 ꢀC and an additional 0.3 equiv of Br2 (0.07 g, 0.43 mmol) in
CH2Cl2 (0.7 mL) was added to the reaction mixture. After con-
firming the completeness of the reaction by 1H NMR, the reaction
mixture was quenched by an aqueous solution of sodium bisulfate
to destroy the excess Br2, extracted with CH2Cl2 (3ꢂ20 mL), washed
4.2. Synthesis of (R)-3 and (R)-17
4.2.1. Diol (R)-5. Starting material (R)-4 was prepared according to
literature procedures.8e10 (R)-4 (0.80 g, 1.49 mmol), Pd2(dba)3
(0.08 g, 6 mol %, 0.09 mmol) and PPh3 (1.17 g, 4.46 mmol) were
added to a 2-necked flask under a N2 atmosphere, followed by
ethylene glycol (0.57 g, 0.51 mL). The reaction mixture was then
heated at 130 ꢀC for 24 h. At this time CH2Cl2 was added, and then
the mixture was filtered through Celite, and the filtrate was con-
centrated to afford the crude product. This was purified by

J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
4107
with brine, dried over anhydrous MgSO4, filtered and concentrated.
The crude product was purified by chromatography (2% ethyl ace-
tate/hexane) to obtain (R)-19 (1.23 g, 100%) as a yellow solid. 1H
4.2.7. Phosphoric acid (R)-17. A solution of KPF6 (0.29 g,1.59 mmol)
in CH3CN (28 mL) was added dropwise to a solution of (R)-21
(0.57 g, 0.40 mmol) in CH2Cl2 (28 mL) and the resulting reaction
mixture was stirred at room temperature for 3 h. Afterwards, the
mixture was washed with 3 M HCl, dried over anhydrous MgSO4,
filtered and evaporated to dryness to afford (R)-17 (0.32 g, 100%). If
necessary, the product could be purified by dissolving it in CH2Cl2
NMR (400 MHz, CD3Cl):
d 8.00 (s, ArH, 2H), 7.66 (s, ArH, 2H),
7.39e7.36 (m, ArH, 2H), 7.15e7.11 (m, ArH, 6H), 4.90 (s, OH, 2H),
2.98e2.94 (m, CH(CH3)2, 2H), 2.79e2.75 (m, CH(CH3)2, 2H),
2.65e2.61 (m, CH(CH3)2, 2H), 1.31 (d, J¼8.0 Hz, ArCH(CH3)2, 12H),
1.20 (d, J¼4.0 Hz, ArCH(CH3)2, 6H), 1.12e1.08 (m, ArCH(CH3)2, 12H),
and precipitating it with Et2O. 1H NMR (400 MHz, CD3Cl):
d 8.00 (d,
1.03 (d, ArCH(CH3)2, 6H); 13C NMR (100 MHz, CD3Cl):
d
150.8, 149.8,
J¼14.9 Hz, ArH, 2H), 7.87e7.83 (m, ArH, 8H), 7.75e7.67 (m, ArH,
28H), 6.98 (d, J¼7.0 Hz, ArH, 4H), 2.87e2.86 (m, CH(CH3)2, 2H),
2.54e2.50 (m, CH(CH3)2, 4H), 1.22 (d, J¼6.9 Hz, ArCH(CH3)2, 12H),
1.06 (d, J¼6.8 Hz, ArCH(CH3)2, 6H), 1.00 (d, J¼6.7 Hz, ArCH(CH3)2,
6H), 0.94 (d, J¼6.7 Hz, ArCH(CH3)2, 6H), 0.90 (d, J¼6.4 Hz,
148.1, 148.0, 132.2, 130.4, 130.3, 130.3, 130.0, 129.6, 129.4, 126.4,
121.6, 121.6, 117.7, 113.7, 34.5, 31.1, 31.0, 24.5, 24.2, 24.2, 24.1, 23.9;
HRMS for C50H56Br2O2: calcd 846.2647, found 846.2628.
4.2.5. Diol (R)-20. (R)-19 (0.90 g, 1.06 mmol), Pd2(dba)3 (0.06 g,
6 mol %, 0.06 mmol) and PPh3 (0.83 g, 3.18 mmol) were added to
a 2-necked flask under a N2 atmosphere, followed by ethylene
glycol (0.40 g, 0.36 mL). The reaction mixture was heated at 130 ꢀC
for 24 h. At this time CH2Cl2 was added, the mixture was filtered
through Celite and the filtrate was concentrated to afford the crude
product. This was purified by dissolving it in CH2Cl2 (2.3 mL) and
precipitating it by the addition of cold Et2O (45 mL). Filtration and
washing of the precipitate afforded pure phosphonium salt (R)-20
ArCH(CH3)2, 6H); 13C NMR (126 MHz, CD3Cl):
d 151.7 (s, 2C), 148.7
(s, 2C),147.8 (s, 2C),147.0 (s, 2C),137.6 (d, J¼2.0 Hz, 6C),136.8 (s, 2C),
135.6 (s, 2C), 134.9 (d, J¼9.0 Hz, 12C), 134.6 (d, J¼10.3 Hz, 2C), 132.1
(d, J¼9.9 Hz, 2C),130.9 (d, J¼12.1 Hz,12C),130.7 (s, 2C),130.2 (s, 2C),
130.0 (d, J¼13.1 Hz, 2C), 128.6 (d, J¼12.4 Hz, 2C), 122.0 (s, 2C), 121.2
(s, 2C), 120.3 (s, 2C), 117.9 (d, J¼89.6 Hz, 8C), 34.3 (s, 2C), 31.1 (s, 2C),
31.1 (s, 2C), 29.7 (s, 2C), 26.6 (s, 2C), 25.3 (s, 2C), 24.1 (s, 2C), 23.6 (s,
2C), 23.2 (s, 2C); 31P NMR (162 MHz, CD3Cl):
d
23.2, 1.5, ꢁ144.5
(septet, J¼713 Hz, PF6) 19F NMR (376 MHz, CD3Cl):
d
ꢁ73.4 (d,
(1.15 g, 79%) as
a
yellow solid. 1H NMR (400 MHz, CD3Cl):
J¼713 Hz, PF6); HRMS for C86H85O4P32þ: calcd 637.2825, found
d
7.92e7.88 (m, ArH, 8H), 7.82e7.80 (m, ArH, 15H), 7.75e7.63 (m,
637.2779; HRMS for
1273.5518.
C
86H84O4P3
þ
:
calcd 1273.5577, found
ArH, 15H), 7.12 (d, J¼7.3 Hz, ArH, 4H), 3.64 (s, OH, 2H), 2.96e2.90 (m,
CH(CH3)2, 2H), 2.72e2.70 (m, CH(CH3)2, 2H), 2.61e2.59 (m,
CH(CH3)2, 2H), 1.28 (d, J¼6.9 Hz, ArCH(CH3)2, 12H), 1.16 (d, J¼6.3 Hz,
ArCH(CH3)2, 6H), 1.11e0.90 (m, ArCH(CH3)2, 18H); 13C NMR
4.3. FriedeleCrafts reaction procedures
(126 MHz, CD3Cl):
d
154.6 (s, 2C), 150.7 (s, 2C), 148.3 (s, 2C), 148.2 (s,
4.3.1. General procedure for FriedeleCrafts reaction of indoles with
enamides (Table 1). Phosphoric acid catalyst (R)-17 (15.6 mg,
0.01 mmol, 10 mol %), enamide 8 (0.1 mmol, 1.0 equiv) and 4 A MS
(90 mg) were added to a flame dried Schlenck tube under a N2
atmosphere, followed by dry CH2Cl2 (1.5 mL). The reaction mixture
was then cooled to 0 ꢀC and indole 7 (0.14 mmol, 1.4 equiv) was
added. After TLC analysis indicated that the reaction was com-
pleted, the reaction mixture was purified directly by chromatog-
raphy (50% ethyl acetate/hexane) to afford product 9.
2C), 137.7 (d, J¼12.1 Hz, 2C), 136.6 (s, 2C), 135.8 (d, J¼2.4 Hz, 6C),
134.5 (d, J¼10.5 Hz, 12C), 132.1 (d, J¼10.2 Hz, 2C), 132.0.0 (s, 2C),
131.6 (s, 2C), 130.9 (d, J¼12.8 Hz, 12C), 128.6 (d, J¼8.5 Hz, 2C), 128.5
(d, J¼12.2 Hz, 2C),127.4 (s, 2C), 121.8 (s, 2C), 121.8 (s, 2C), 117.9 (d,
J¼89.9 Hz, 6C), 117.5 (d, J¼89.6 Hz, 2C), 114.2 (s, 2C), 34.4 (s, 2C),
31.0 (s, 2C), 30.9 (s, 2C), 24.3 (s, 2C), 24.3 (s, 2C), 24.1 (s, 2C), 24.0 (s,
ꢀ
2C), 24.0 (s, 2C), 23.9 (s, 2C); 31P NMR (162 MHz, CD3Cl):
HRMS for C86H86O2P22þ: calcd 606.3046, found 606.3067.
d 23.2;
4.2.6. Phosphoric acid (R)-21. To
a
solution of (R)-20 (0.4 g,
4.3.1.1. N-(1-(3-Indolyl)-1-phenylethyl)acetamide (9a). This was
0.29 mmol) in pyridine (4.0 mL) was added POCl3 (0.08 mL,
0.87 mmol) at room temperature under a N2 atmosphere. The re-
action mixture was heated at 80 ꢀC and stirred at this temperature
for 13 h. At this time water (1.9 mL) was added and stirring was
continued for 4 h more at 80 ꢀC. The reaction mixture was then
cooled using an ice bath and 3 M HCl was slowly added to the re-
action mixture. Extraction with CH2Cl2 was followed by additional
washing with 3 M HCl, drying over anhydrous MgSO4, filtration and
solvent removal. The crude product was purified by dissolving it in
CH2Cl2 (1.5 mL) and precipitating it with chilled Et2O (30 mL) to
afford (R)-21 (0.31 g, 84%) as a yellow solid. 1H NMR (400 MHz,
obtained in 91% yield and 75% ee. 1H NMR (400 MHz, CD3Cl):
d 8.19
(s, NH, 1H), 7.48 (d, J¼8.0 Hz, ArH, 1H), 7.41 (d, J¼8.1 Hz, ArH, 2H),
7.36e7.31 (m, ArH, 3H), 7.27e7.23 (m, ArH, 1H), 7.18 (dt, J¼7.3,
1.0 Hz, ArH, 1H), 7.06 (dt, J¼7.4, 0.9 Hz, ArH, 1H), 6.69 (d, J¼2.3 Hz,
ArH, 1H), 6.31 (s, NH, 1H), 2.34 (s, CH3, 3H), 2.02 (s, CH3, 3H); 13C
NMR (126 MHz, CD3Cl):
d 169.3, 145.4, 137.1, 128.2, 126.8, 126.2,
124.8, 123.1, 122.7, 122.2, 120.2, 119.8, 111.7, 59.3, 26.7, 24.5; HRMS
for C18H18N2O: calcd 278.1419, found 278.1416; HPLC conditions:
IPA/hexane¼10:90, flow rate¼1.0 mL/min, AD-H column, minor
21.0 min, major 33.2 min.
CD3Cl):
d
7.92e7.88 (m, ArH, 8H), 7.80e7.70 (m, ArH, 26H),
4.3.1.2. N-(1-(4-Bromophenyl)-1-(3-indolyl)ethyl)acetamide
7.55e7.54 (m, ArH, 2H), 7.40 (t, ArH, 2H), 7.09 (s, ArH, 2H), 6.94 (s,
ArH, 2H), 3.04e3.01 (m, CH(CH3)2, 2H), 2.89e2.86 (m, CH(CH3)2,
2H), 2.51 (m, CH(CH3)2, 2H), 1.32e1.26 (m, ArCH(CH3)2, 18H), 1.11 (d,
J¼6.7 Hz, ArCH(CH3)2, 6H), 1.06 (d, J¼6.7 Hz, ArCH(CH3)2, 6H), 0.88
(9b). This was obtained in 94% yield and 91% ee. 1H NMR (400 MHz,
CD3Cl):
d
8.41 (s, NH, 1H), 7.49 (d, J¼8.0 Hz, ArH, 1H), 7.43 (d,
J¼8.6 Hz, ArH, 2H), 7.34e7.28 (m, ArH, 3H), 7.19 (t, J¼7.6 Hz, ArH,
1H), 7.08 (t, J¼7.5 Hz, ArH, 1H), 6.61 (d, J¼2.6 Hz, ArH, 1H), 6.36 (s,
NH, 1H), 2.30 (s, CH3, 3H), 2.01 (s, CH3, 3H); 13C NMR (101 MHz,
(d, J¼6.4 Hz, ArCH(CH3)2, 6H); 13C NMR (126 MHz, CD3Cl):
d 153.5
(s, 2C), 148.3 (s, 2C), 148.0 (s, 2C), 146.6 (s, 2C), 137.9 (s, 2C), 137.5 (d,
J¼10.7 Hz, 2C), 135.8 (d, J¼2.3 Hz, 6C), 135.3 (s, 2C), 134.7 (d,
J¼9.9 Hz, 2C), 134.5 (d, J¼10.4 Hz, 12C), 132.9 (s, 2C), 131.4 (s, 2C),
130.9 (d, J¼12.3 Hz, 2C), 130.9 (d, J¼12.7 Hz, 12C), 129.6 (d,
J¼10.7 Hz, 2C), 122.2 (s, 2C), 121.3 (s, 2C), 120.0 (s, 2C), 117.8 (d,
J¼89.9 Hz, 6C), 117.5(d, J¼89.6 Hz, 2C), 34.3 (s, 2C), 31.2 (s, 2C), 30.9
(s, 2C), 26.6 (s, 2C), 25.1 (s, 2C), 24.1 (s, 2C), 24.1 (s, 2C), 23.7 (s, 2C),
CD3Cl): d 169.6, 144.5, 137.3, 131.4, 128.3, 124.6, 123.1, 122.5, 122.2,
120.9, 120.1, 120.0, 112.0, 59.1, 26.6, 24.5; HRMS for C18H17BrN2O:
calcd 356.0524, found 356.0502; HPLC condition: IPA/
hexane¼10:90, flow rate¼1.0 mL/min, AD-H column, minor
20.0 min, major 25.3 min.
4.3.1.3. N-(1-(4-Flourophenyl)-1-(3-indolyl)ethyl)acetamide
23.3 (s, 2C); 31P NMR (162 MHz, CD3Cl):
d
23.1, 2.0; HRMS for
calcd 637.2825, found 637.2873; HRMS for
: calcd 1273.5577, found 1273.5535.
(9c). This was obtained in 71% yield and 80% ee. 1H NMR (400 MHz,
C
C
86H85O4P32þ
86H84O4P3
:
CD3Cl):
d
8.19 (s, NH, 1H), 7.49 (d, J¼8.0 Hz, ArH, 1H), 7.40e7.35 (m,
þ
ArH, 3H), 7.20 (t, J¼7.6 Hz, ArH, 1H), 7.10 (t, J¼7.6 Hz, ArH, 1H), 7.00

4108
J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
(t, J¼8.7 Hz, ArH, 2H), 6.67 (d, J¼2.3 Hz, ArH, 1H), 6.31 (s, NH, 1H),
2.32 (s, CH3, 3H), 2.02 (s, CH3, 3H); 13C NMR (126 MHz, CD3Cl):
126.6, 122.4, 121.7, 119.7, 119.5, 118.5, 111.3, 62.6, 45.7, 37.9, 14.0;
HRMS for C20H19NO3: calcd 321.1365, found 321.1356; HPLC con-
dition: IPA/hexane¼10:90, flow rate¼1.0 mL/min, AD-H column,
major 22.5 min, minor 28.4 min.
d
169.3 (s, 1C), 161.7 (d, J¼246 Hz, 1C), 141.0 (d, J¼2.9 Hz, 1C), 137.1
(s, 1C), 128.0 (s, 1C), 127.9 (s, 1C), 124.6 (s, 1C), 122.9 (d, J¼11.8 Hz,
2C), 122.4 (s, 1C), 120.2 (s, 1C), 120.0 (s, 1C), 114.9 (d, J¼21.4 Hz, 2C),
111.8 (s, 1C), 58.9 (s, 1C), 26.7 (s, 1C), 24.4 (s, 1C); HRMS for
4.3.2.2. 4-(1H-Indol-3-yl)-2-oxo-4-(4-methylphenyl)butyric acid
C
18H17FN2O: calcd 296.1325, found 296.1319; HPLC condition: IPA/
ethyl ester (11b). This was obtained in 94% yield and 50% ee. 1H
hexane¼10:90, flow rate¼1.0 mL/min, AD-H column, minor
NMR (400 MHz, CD3Cl):
d
8.01 (s, NH, 1H), 7.43 (d, J¼7.9 Hz, ArH,
18.7 min, major 23.7 min.
1H), 7.30 (d, J¼8.1 Hz, ArH, 1H), 7.20 (d, J¼8.0 Hz, ArH, 2H), 7.15 (t,
J¼7.8 Hz, ArH, 1H), 7.07e7.00 (m, ArH, 4H), 4.88 (t, J¼7.5 Hz, CH, 1H),
4.20 (dq, J¼1.1, 4.1 Hz, CH2, 2H), 3.63 (dd, J¼7.3, 18.9 Hz, CHaHb, 1H),
3.59 (dd, J¼7.3, 18.9 Hz, CHaHb, 1H), 2.27 (s, CH3, 3H), 1.26 (t,
4.3.1.4. N-(1-(3-Indolyl)-1-(4-methoxyphenyl)ethyl)acetamide
(9d). This was obtained in 65% yield and 61% ee. 1H NMR (300 MHz,
CD3Cl):
d
8.08 (s, NH, 1H), 7.49 (d, J¼8.1 Hz, ArH, 1H), 7.38e7.32 (m,
J¼7.1 Hz, CH3, 3H); 13C NMR (126 MHz, CD3Cl):
d 193.3, 161.2, 140.3,
ArH, 3H), 7.19 (t, J¼7.5 Hz, ArH, 1H), 7.06 (t, J¼7.4 Hz, ArH, 1H), 6.86
(d, J¼8.8 Hz, ArH, 2H), 6.74 (d, J¼2.4 Hz, ArH, 1H), 6.27 (s, NH, 1H),
3.80 (s, MeO, 3H), 2.31 (s, CH3, 3H), 2.01 (s, CH3, 3H); 13C NMR
136.7, 136.2, 129.4, 127.8, 126.6, 122.4, 121.6, 119.6, 119.6, 118.7, 111.3,
62.6, 45.9, 37.6, 21.1, 14.0; HRMS for C21H21NO3: calcd 335.1521,
found 335.1521; HPLC condition: IPA/hexane¼10:90, flow
rate¼1.0 mL/min, AD-H column, major 22.2 min, minor 30.3 min.
(126 MHz, CD3Cl):
d 169.3, 158.3, 137.7, 137.1, 129.2, 127.4, 124.8,
123.1, 122.7, 122.1, 120.3, 119.7, 113.5, 113.5, 111.7, 58.9, 55.3, 26.8,
24.5; HRMS for C19H20N2O2: calcd 308.1525, found 308.1524; HPLC
condition: IPA/hexane¼17:83, flow rate¼1.0 mL/min, AS-H column,
major 14.7 min, minor 20.3 min.
4.3.2.3. 4-(1H-Indol-3-yl)-2-oxo-4-(4-bromophenyl)butyric acid
ethyl ester (11c). This was obtained in 92% yield and 60% ee. 1H
NMR (400 MHz, CD3Cl):
d 8.04 (s, NH, 1H), 7.40e7.32 (m, ArH, 4H),
7.21e7.15 (m, ArH, 3H), 7.05e7.01 (m, ArH, 2H), 4.87 (t, J¼7.5 Hz, CH,
1H), 4.24 (dq, J¼0.6, 7.1 Hz, CH2, 2H), 3.65 (dd, J¼7.0, 12.1 Hz, CHaHb,
1H), 3.56 (dd, J¼8.0, 12.6 Hz, CHaHb, 1H), 1.29 (t, J¼7.1 Hz, CH3, 3H);
4.3.1.5. N-(1-(5-Bromo-3-indolyl)-1-phenylethyl)acetamide
(9e). This was obtained in 83% yield and 89% ee. 1H NMR (400 MHz,
CD3Cl):
d
8.29 (s, NH, 1H), 7.53 (s, ArH, 1H), 7.38e7.31 (m, ArH, 4H),
13C NMR (126 MHz, CD3Cl):
d 192.7, 160.9, 142.3, 136.6, 131.6, 129.6,
7.29e7.28 (m, ArH, 1H), 7.24 (dd, J¼8.6, 1.8 Hz, ArH, 1H), 7.17 (d,
126.2, 122.5, 121.5, 120.4, 119.7, 119.3, 117.9, 111.2, 62.6, 45.3, 37.2,
13.9; HRMS for C20H18BrNO3: calcd 399.0470, found 399.0464;
HPLC condition: IPA/hexane¼10:90, flow rate¼1.0 mL/min, AD-H
column, major 23.2 min, minor 38.4 min.
J¼8.6 Hz, ArH, 1H), 6.78 (d, J¼2.6 Hz, ArH, 1H), 6.21 (s, NH, 1H), 2.28
(s, CH3, 3H), 2.04 (s, CH3, 3H); 13C NMR (126 MHz, CD3Cl):
d 169.4,
145.2, 135.7, 128.4, 127.2, 126.7, 126.1, 125.0, 124.5, 122.7, 121.5, 113.1,
112.9, 59.1, 27.2, 24.5; HRMS for C18H17BrN2O: calcd 356.0524,
found 356.0502; HPLC condition: IPA/hexane¼10:90, flow
rate¼1.0 mL/min, AD-H column, minor 17.3 min, major 35.4 min.
4.3.2.4. 4-(1H-Indol-3-yl)-2-oxo-4-(4-methoxyphenyl)butyric
acid ethyl ester (11d). This was obtained in 89% yield and 50% ee. 1H
NMR (400 MHz, CD3Cl):
d
8.02 (s, NH, 1H), 7.41 (d, J¼7.9 Hz, ArH,
4.3.1.6. N-(1-(5-Flouro-3-indolyl)-1-phenylethyl)acetamide
1H), 7.31 (d, J¼8.1 Hz, ArH, 1H), 7.20 (d, J¼8.5 Hz, ArH, 2H), 7.15 (t,
J¼7.5 Hz, ArH, 1H), 7.07e7.01 (m, ArH, 2H), 6.79 (d, J¼8.5 Hz, ArH,
2H), 4.86 (t, J¼7.5 Hz, CH, 1H), 4.24 (q, J¼6.9 Hz, CH2, 2H), 3.75 (s,
eOCH3, 3H), 3.64 (dd, J¼7.2, 16.7 Hz, CHaHb, 1H), 3.57 (dd, J¼8.0,
16.7 Hz, CHaHb, 1H), 1.27 (t, J¼7.0 Hz, CH3, 3H); 13C NMR (101 MHz,
(9f). This was obtained in 80% yield and 58% ee. 1H NMR (500 MHz,
CD3Cl):
d
8.07 (s, NH, 1H), 7.39e7.36 (m, ArH, 2H), 7.33 (t, J¼7.6 Hz,
ArH, 3H), 7.30e7.28 (m, ArH, 1H), 7.04 (dd, J¼2.0, 9.0 Hz, ArH, 1H),
6.93 (dt, J¼2.5, 9.0 Hz, ArH, 1H), 6.87 (d, J¼2.5 Hz, ArH, 1H), 6.19 (s,
NH, 1H), 2.30 (s, CH3, 3H), 2.03 (s, CH3, 3H); 13C NMR (126 MHz,
CD3Cl):
d 193.4, 161.1, 158.3, 136.7, 135.5, 135.5, 128.9, 126.6, 122.4,
CD3Cl):
d
169.3 (s, 1C), 157.6 (d, J¼230 Hz, 1C), 145.2 (s, 1C), 133.5 (s,
121.5, 119.6, 119.6, 118.9, 114.0, 111.3, 62.6, 55.6, 45.9, 37.2, 14.0;
HRMS for C21H21NO4: calcd 351.1471, found 351.1467; HPLC condi-
tion: IPA/hexane¼17:83, flow rate¼1.0 mL/min, AS-H column, ma-
jor 15.3 min, minor 17.9 min.
1C), 130.9 (d, J¼3.0 Hz, 1C), 128.8 (s, 1C), 128.4 (s, 2C), 127.1 (s, 1C),
126.1 (s, 1C),124.8 (s, 2C),112.3 (d, J¼9.7 Hz,1C),110.6 (d, J¼26.6 Hz,
1C), 105.3 (d, J¼24.2 Hz, 1C), 59.2 (s, 1C), 26.8 (s, 1C), 24.5 (s, 1C);
HRMS for C18H17FN2O: calcd 296.1325, found 296.1320; HPLC
condition: IPA/hexane¼10:90, flow rate¼1.0 mL/min, AD-H column
minor 18.5 min, major 30.6 min.
4.3.2.5. 4-(1H-5-Bromoindol-3-yl)-2-oxo-4-phenylbutyric
ethyl ester (11e). This was obtained in 90% yield and 46% ee. 1H
NMR (400 MHz, CD3Cl): 8.08 (s, NH, 1H), 7.53 (s, ArH, 1H),
acid
d
4.3.2. General procedure for FriedeleCrafts Reaction of indoles with
7.31e7.24 (m, ArH, 4H), 7.22e7.17 (m, ArH, 3H), 7.05 (d, J¼2.0 Hz,
ArH, 1H), 4.85 (t, J¼7.5 Hz, CH, 1H), 4.23 (dq, J¼1.0, 8.4 Hz, CH2, 2H),
3.64 (dd, J¼7.6, 17.1 Hz, CHaHb, 1H), 3.56 (dd, J¼7.6, 17.0 Hz, CHaHb,
1H), 1.28 (t, J¼7.1 Hz, CH3, 3H); 13C NMR (101 MHz, CD3Cl): 193.0,
161.0, 142.9, 135.3, 128.8, 128.3, 127.8, 126.9, 125.4, 122.9, 122.0,
118.1, 113.0, 112.8, 62.7, 45.7, 37.7, 14.1; HRMS for C20H18BrNO3:
calcd 399.0470, found 399.0464; HPLC condition: IPA/
hexane¼10:90, flow rate¼1.0 mL/min, AD-H column, major
16.8 min, minor 20.6 min.
b,
g
-unsaturated
a-keto esters (Table 2). Phosphoric acid catalyst
(R)-17 (5.5 mg, 0.005 mmol, 5 mol %),
b
,
g
-unsaturated -keto ester
a
ꢀ
10 (0.07 mmol,1.0 equiv) and 4 A MS (90 mg) were added to a flame
dried Schlenk tube under a N2 atmosphere, followed by dry CH2Cl2
(1.0 mL). The reaction mixture was then cooled to ꢁ78 ꢀC and in-
dole 7 (0.15 mmol, 2.1 equiv) was added. After TLC analysis in-
dicated that the reaction was completed, the reaction mixture was
purified directly by chromatography (20% ethyl acetate/hexane) to
afford product 11.
4.3.2.6. 4-(1H-5-Flouroindol-3-yl)-2-oxo-4-phenylbutyric
ethyl ester (11f). This was obtained in 92% yield and 54% ee. 1H NMR
(400 MHz, CD3Cl): 8.07 (s, NH, 1H), 7.29e7.19 (m, ArH, 6H),
acid
4.3.2.1. 4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid ethyl ester
(11a). This was obtained in 98% yield and 61% ee. 1H NMR
d
(400 MHz, CD3Cl):
d
8.01 (s, NH, 1H), 7.42 (d, J¼8.0 Hz, ArH, 1H), 7.32
7.07e7.02 (m, ArH, 2H), 6.88 (t, J¼7.5 Hz, ArH, 1H), 4.83 (t, J¼7.3 Hz,
CH, 1H), 4.22 (q, J¼6.8 Hz, CH2, 2H), 3.65 (dd, J¼7.5, 16.9 Hz, CHaHb,
1H), 3.56 (dd, J¼7.5, 16.9 Hz, CHaHb, 1H), 1.28 (t, J¼7.1 Hz, CH3, 3H);
(t, J¼6.8 Hz, ArH, 3H), 7.26 (t, J¼7.5 Hz, ArH, 2H), 7.15 (q, J¼6.0 Hz,
ArH, 2H), 7.02 (t, J¼7.5 Hz, ArH, 2H), 4.91 (t, J¼7.5 Hz, CH, 1H), 4.20
(dq, J¼1.2, 5.6 Hz, CH2, 2H), 3.67 (dd, J¼7.4, 16.9 Hz, CHaHb, 1H), 3.59
(dd, J¼7.4, 16.9 Hz, CHaHb, 1H), 1.26 (t, J¼7.1 Hz, CH3, 3H); 13C NMR
13C NMR (101 MHz, CD3Cl):
d 193.1 (s, 1C), 161.1 (s, 1C), 157.7 (d,
J¼230 Hz, 1C), 143.0 (s, 1C), 133.2 (s, 1C), 128.8 (s, 2C), 127.8 (s, 2C),
(126 MHz, CD3Cl):
d 193.2, 161.1, 143.4, 136.7, 128.7, 127.9, 126.7,
127.0 (s, 1C), 126.9 (s, 1C), 123.4 (s, 1C), 118.6 (d, J¼3.5 Hz, 1C), 111.9

J. Hermeke, P.H. Toy / Tetrahedron 67 (2011) 4103e4109
4109
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(d, J¼9.7 Hz, 1C), 110.9 (d, J¼26.3 Hz, 1C), 104.5 (d, J¼23.5 Hz, 1C),
62.7 (s, 1C), 45.6 (s, 1C), 37.8 (s, 1C), 14.0 (s, 1C); HRMS for
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C
20H18FNO3: calcd 339.1271, found 339.1266; HPLC condition: IPA/
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18.0 min, major 22.9 min.
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4.3.3. Recycling experiments (Table 3). These reactions were per-
formed using 7a (2.8 mmol), 8b (2.0 mmol) and (R)-17 (0.2 mmol)
as described above using catalyst recovered from the previous
experiment. Recovery of the catalyst was achieved by precipitation
from the reaction mixture using diethyl ether, and the morphology
and 1H NMR spectra of the recovered material was essentially
identical to that of newly synthesized (R)-17.
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Acknowledgements
This research was supported financially by the University of
Hong Kong and the Research Grants Council of the Hong Kong SAR,
PR of China (Project No. HKU 705209P), and Mr. Jun Ou performed
some preliminary experiments.
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Supplementary data
Supplementary data associated with this article, including 1H,
13C, 19F and 31P NMR spectra and HPLC graphs. Supplementary data
associated with this article can be found in the online version at
doi:10.1016/j.tet.2011.03.105.
ꢁ
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J.; Lin, L.; Feng, X. Chem.dEur. J. 2010, 16, 1664.
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J.-G.; Jin, J.; Lv, X.; Bao, W. Synthesis 2009, 23, 3994; (d) Qian, Y.; Ma, G.; Lv, A.;
Zhu, H. L.; Zhao, J.; Rawal, V. H. Chem. Commun. 2010, 3004.
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