Organocatalytic synthesis of α-quaternary amino acid derivatives via aza-Friedel-Crafts alkylation of indoles with simple α-amidoacrylates

Article abstract of DOI:10.1016/j.tet.2011.08.039

The first (organo)catalytic method for regio- and chemoselective aza-Friedel-Crafts (FC) alkylation of indoles and pyrroles with commercially available methyl α-acetamidoacrylates has been discovered. It minimizes/eliminates common competing reactions that occur due to the high and multiatom-nucleophilic character of indole and pyrrole. Diverse quaternary α-amino acids were successfully prepared in good yield and high selectivity using low catalyst loading. The enantioselective variant using BINOL-derived phosphoric acids was also explored with indole providing the desired F-C alkylation product with moderate enantioselectivities.

Full text of DOI:10.1016/j.tet.2011.08.039

Tetrahedron 67 (2011) 7923e7928
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic synthesis of
a-quaternary amino acid derivatives via
aza-FriedeleCrafts alkylation of indoles with simple
a-amidoacrylates
*
Marika Righi, Francesca Bartoccini, Simone Lucarini, Giovanni Piersanti
Department of Biomolecular Sciences, University of Urbino, P.zza Rinascimento 6, 61029 Urbino (PU), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2011
Received in revised form 2 August 2011
Accepted 15 August 2011
Available online 22 August 2011
The first (organo)catalytic method for regio- and chemoselective aza-FriedeleCrafts (FC) alkylation of
indoles and pyrroles with commercially available methyl
minimizes/eliminates common competing reactions that occur due to the high and multiatom-
nucleophilic character of indole and pyrrole. Diverse quaternary -amino acids were successfully pre-
a-acetamidoacrylates has been discovered. It
a
pared in good yield and high selectivity using low catalyst loading. The enantioselective variant using
BINOL-derived phosphoric acids was also explored with indole providing the desired FeC alkylation
product with moderate enantioselectivities.
Keywords:
FriedeleCrafts alkylation
Organocatalysis
Quaternary amino acids
Indoles
Ó 2011 Elsevier Ltd. All rights reserved.
a
-Amidoacrylates
1. Introduction
been published.7 Although a variety of electrophilic systems, such
as activated trifluoro-carbonyl compounds,8
a,b-unsaturated car-
The construction of quaternary stereogenic centers is an ongoing
synthetic challenge.1 In fact, creating these complex fragments
rapidlyand selectivelyis a difficult task because of the inherent steric
bias encountered in the CeC bond-forming event. Also, the de-
velopment of efficient chemical and enzymatic methods for the
bonyl derivatives,9 aldimines,10 and nitroolefins11 catalyzed by
Brønsted acids are available for such purposes, some notable ex-
ceptions can be identified, such as
a-amidoacrylates. They are
poorly reactive with arenes under various conditions but are im-
portant building blocks for organic and medicinal research. The
synthesisof unnatural aminoacids, inparticularquaternary
a
-amino
potential value of a-amidoacrylates or N-acyl-a,b-dehydroamino
acids, is highly desirable. Quaternary -amino acids, also called
disubstituted amino acids, have attracted the interest of organic
chemists due to their biological importance. For example, when
a
a
,
a
-
esters (DHA) in synthetic chemistry is derived mainly from their
ready availability and the unique reactivity of their double bonds.
The presence of acylamino and ester groups on the same carbon
incorporated into peptides,
a
,
a
-disubstituted
a
-amino acids confer
of the double bond facilitates nucleophilic attack at the
-amidoalkylation) after tautomerization to N-acyl ketimines,12 or
the position (Michael-type reactions) giving in both cases
-amino acids that can be readily transformed into a range of dif-
ferent functionalities, or resolved by asymmetric hydrolysis using
-chymotrypsin or carboxypeptidase A.13 As an extension of our
contributions in the field of indolylamino acid synthesis using
stoichiometric amounts of transition metal salts,14 we investigated
the more challenging and appealing (organo)catalytic FC alkylation
a position
increased stability under physiological conditions and stabilize
(a
secondary structure motifs.2 They also have relevance in natural
b
product total synthesis.3 Finally, unnatural
a
-aryl-
a-alkyl
a
-amino
a
acid derivatives have shown strong inhibitory effects on aldose
reductases, a potential target for the treatment of various diabetes-
related diseases.4 Although there is now a wide range of method-
ologies for the synthesis of these compounds,5 few of these methods
a
are useful for the catalytic synthesis of a-alkyl-a-aryl amino acids.
The catalytic FriedeleCrafts (FC) reaction constitutes an impor-
tant CeC bond-forming transformation,6 and several examples
with different electrophiles catalyzed by hydrogen donor catalysts,
in particular Brønsted acid BINOL-derived phosphoric acids, have
of indoles and pyrroles with a-amidoacrylates. Here, we present
the first Brønsted acid catalyzed sequential tautomerization and
aminoalkylation of electron-rich arenes with commercially avail-
able N-acetylated-dehydroalanine methyl ester giving quaternary
a
-amino acids in good yields (Scheme 1).15 To the best of our
knowledge, no examples of catalytic, regio-, and chemoselective a-
amidoalkylation of heteroaromatic compounds with DHA have
been previously disclosed.
* Corresponding author. Tel.: þ39 (0) 722303320; fax: þ39 (0) 722303313; e-mail
address: giovanni.piersanti@uniurb.it (G. Piersanti).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.039

7924
M. Righi et al. / Tetrahedron 67 (2011) 7923e7928
used (entries 9e10). Elimination of acetamide occurred to a lesser
extent when the reaction was performed at lower temperature and
increasing amounts of N-acetyl- -didehydroalanine methyl ester
Ac
Ac
Organocat.
N
NH2
CH3
Het(Ar)
NH
Organocat.
a,b
MeOOC CH3
MeOOC
+
HOOC
was used. The desired product was obtained in poor yields when
phenyl boronic acid (1c) or diphenyl phosphate (1d) were used as
the catalysts (entries 11 and 12). Phenyl phosphinic acid18 (1e)
could also promote this reaction but with low conversion (entry
13). A large screen of Brønsted acids (1) identified phosphoric acid
1f as the best catalyst (entry 16). Lowering the temperature made
the reaction sluggish, but favorably suppressed the side reaction.
Higher conversion of 4a was achieved by the prolonged reaction
time with 1f (5 mol %).19 Importantly, preliminary studies have
revealed that water, generated in the initial condensation step, has
a deleterious impact on both iminium formation and the FC alkyl-
ation step. Therefore, the introduction of Na2SO4 was found to be
critical to achieve useful reaction rates and selectivities. In general,
the presence of molecular sieves is detrimental to the reaction,
which resulted in sharp decrease in reaction rate and yield. The
effect of other solvents, such as 1,2-dichloroethane, acetonitrile,
ethyl acetate, and methyl tert-butyl ether also was examined under
the conditions shown but always lower yield or no reaction was
observed. Having established the optimal conditions for hydrogen
bond catalysis, we next examined the scope of the indole compo-
nent in this unprecedented organocatalytic alkylation. As shown in
Table 2, various substituted indole derivatives 2aeo were suc-
cessfully coupled. Use of 5-halogenated indole derivatives afforded
the products in good yields. However, in the case of 5-chloroindole
(2c), the yield was slightly lower (entry 3) as compared to the 5-
fluoro- or 5-bromo-substituted indoles (68% and 63%, re-
spectively, entries 2 and 4). Electron-rich indoles also reacted
readily. 5-Methoxy- and 5-methyl-indole furnished the desired
products in good yields (entries 10 and 11). Worthy of note is that
the use of 3-methyl-substitued indole20 provided clean formation
Het(Ar)-H
Scheme 1. Organocatalyzed CeC bond formation approach to
(aryl) amino acids via FC alkylation of ketimine.
a-methyl a-hetero
2. Results and discussion
The initial evaluation of the proposed FC alkylation was per-
formed with indole (2a),16 methyl
-acetamidoacrylate (3a), and
a
several classes of established hydrogen-bonding catalysts in tolu-
ene (Table 1).
The newly designed reaction did not proceed in the absence of
catalyst. Stirring the two reagents at room temperature or refluxing
in toluene for almost three days resulted in no detectable quantities
of the desired product 4a (entries 1 and 2). While thiourea 1a and
diol 1b did not induce FC alkylation (entries 3 and 4), stronger
acids, such as trifluoromethanesulfonic acid (TfOH) and 2,4-
dinitrobenzenesulfonic acid (DNSA) did indeed provide the de-
sired alkylation adduct, albeit in low yields (entries 5e8). Under
these strongly acidic conditions, the symmetrical bisindolyl-
methane derivative 5 was the major product.17 Most likely, this
product was obtained by elimination of acetamide and reaction
with a second equivalent of indole via highly electrophilic alkyli-
deneindoleninium ions. In addition, bisindolyl product 5 pre-
dominated upon using other Brønsted acids and it was the only
product obtained when trifluoromethanesulfonimide (Tf2NH) was
Table 1
Identification of an efficient catalyst 1 and reaction conditions for the FC amino-
alkylation of indole (2a) with DHA (3a)
Table 2
Phosphoric acid 1f catalyzed FC alkylation of indoles (2aeq) and DHA (3aed)
Entrya
R1
R2
Yield (%)b
Product
1
2
3
4
5
6
7
8
H (2a)
5-F (2b)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Bz (3b)
Cbz (3c)
Ac(3d)f
Ac (3a)
Ac (3a)
63
68
47
63
58
76
68
65
4a
4b
4c
4d
4e
4f
4g
4h
4i
Entrya
Catalyst
Time (h)
Temp(ꢀC)
Conversionb
Yield 4a (%)c
5-Cl (2c)
5-Br (2d)
4-Br (2e)
5-NO2 (2f)
5-CN (2g)
5-COOMe (2h)
5-B(pin) (2i)
5-OMe (2j)
5-Me (2k)
2-Me (2l)
3-Me (2m)
6-OMe (2n)
H (2o)d
1
2
3
4
5
6
7
8
d
60
60
60
60
2
4
16
2
25
d
d
d
110
110
110
110
70
d
d
1a
1b
d
d
d
d
TfOHd
TfOHd
TfOHd
DNSAe
Tf2NHf
Tf2NHf
1c
>90
>90
d
9
7
d
9
54
76
57
RT
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
110
110
79
110
110
110
110
85
>90
>90
>90
>90
>90
<50
>90
>90
>90
>90
13
Traces
Traces
27
31
21
38
47
72
22
9
2
2
60
10
11
12
13
14
15
16g
17h
31c
43
4m
4n
d
d
d
d
4p
4q
16
16
16
16
60
60
60
1d
1e
1f
1f
1f
1f
NRe
NRe
NRe
NRe
35
H (2a)
H (2a)
H (2a)
85
85
(2p)g
(2q)h
33
a
a
Reaction conditions: 2a (0.6 mmol), 3a (0.66 mmol), Na2SO4 (1.06 mmol), and 1
Reaction conditions: 2 (0.6 mmol), 3 (0.66 mmol), 1 (0.03 mmol), and Na2SO4
(0.06 mmol) in toluene (0.25 M).
(1.06 mmol) in toluene (0.25 M) at 85 ꢀC for 60 h.
b
b
Determined by HPLC-MS.
Yield after flash chromatography.
Yield after flash chromatography.
Formation of methyl 2-acetamido-2-(3-methyl-1H-indol-2-yl)propanoate.
N-methyl indole.
No reaction.
N-methyl acetamidoacrylate.
N-Me-pyrrole.
Dihydroindole.
c
c
d
d
TfOH¼trifluoromethanesulfonic acid.
e
e
DNSA¼2,4-dinitrobenzenesulfonic acid.
f
f
Tf2NH¼trifluoromethanesulfonimide.
g
g
Using 5 mol % of catalyst.
h
h
Reaction carried out without Na2SO4.

M. Righi et al. / Tetrahedron 67 (2011) 7923e7928
7925
of the alkylated product in the 2-position (entry 13), with no
troublesome reaction or indole annulations with dearomatization
of the indole nucleus. On the other hand, the electrophilic alkyl-
ation of indole derivatives was initially selective (at the C3 position)
and then the C2-isomer was formed from 1,2-migration of the C3-
isomer. The results listed in (Table 2 entries 6e9) represent one of
the strong points of this methodology. In fact, electron-poor indoles
are generally recognized as FC-reluctant.21 On the contrary, the
present phosphoric acid catalyzed methodology allowed electron-
deficient indoles to be readily transformed into the correspond-
combined with the relatively high temperature needed to have
good reaction conversion, does not allow energy differences among
the different diastereomeric transition states.
Table 3
Chiral Brønsted acid catalyzed asymmetric FC reaction of 2a and 3a
ing a-methyl-a
-indolylamino acids in moderate to good yields.22 N-
methylindole (2o) proved to be inert under optimal reaction con-
ditions (entry 15), in accordance with findings by others15c re-
garding the existence of a key NeH of the indole to interact with the
phosphoric acid in the present FC-alkylation methodology. Finally,
we tried other N-acylamido acrylates in the reaction to evaluate
their reactivity. Other amino protecting groups, such as benzoyl
(3b) or benzyloxycarbonyl (3c) failed to provide the desired prod-
uct (entries 16 and 17). In addition, the NꢁH group of the amide
seems to be crucial for the reactivity, since tertiary N-methylated 3d
did not react.15c Also, we investigated other suitable substrates for
the present phosphoric acid catalyzed FC alkylation methodology
Entrya
Catalyst
Yield (%)b
erc
1
2
3
4
6a
6b
6c
6d
6e
6f
57
56
52
60
77
64
20
19
NRf
NRf
58:42
72:28
68:32
77:23
73:27
78:22
83:17
64:36
d
with DHA to give a,a-disubstituted a-amino esters.
5
6
Several heteroarenes and electron-rich benzene derivatives
were tested with DHA 3a, but only the more reactive N-Me-pyrrole
(2p) and dihydroindole (2q) were suitable substrates in this re-
action (see Experimental section and Supplementary data). Less
activated arenes like dimethoxybenzene and trimethoxybenzene as
well as different furans, such as methylfurane and methoxyfurane
did not afford the desired coupling products.23 Our success in the
organocatalytic reactions of indoles with dehydroamino acids by
sequential tautomerizationealkylation prompted us to extend this
methodology to catalytic asymmetric reactions (Table 3). A series of
chiral phosphoric acids (6aeh) with different substituents at the
3,30-positions of the binaphthyl ring were prepared and tested in
the reaction of indole (2a) and N-acetylated-dehydroalanine
methyl ester (3a). Although there are several reported examples of
BINOL-phosphoric acid catalyzed enantioselective alkylations of
indoles with aldimines10 and one very recent example with the
more reactive trifluoromethyl ketimines,24 only moderate to good
enantiomeric excess values have been obtained. The sterically
congested phosphoric acid catalysts were found to be crucial for
achieving enantioselectivity, with the catalyst 6f bearing bulky 9-
phenanthryl at the 3,30-positions being the most enantioselective
(entry 7). With the more acidic N-triflyl phosphoramide derivative
6g, the yield of the FC product was only moderate (19%) due to
hydrolysis of the enamide substrate and increasing formation of
bisindolyl derivatives. However, it represents the first example of
catalyzed asymmetric FC alkylation of this class on unreactive
pyruvate-derived ketimine substrates. The low reactivity of keti-
mines, which often exist as a mixture of E and Z isomers, and the
difficulty in differentiating the two substituents on the prochiral
ketimine carbon are the main obstacles that make the development
of a catalytic asymmetric addition of simple ketimines formidably
challenging.25 To date, a non-stereocontrolled catalytic FC reaction
of simple ketimines has yet to be reported. E/Z relative stability of
the imine substrate is an important factor for deciding the stereo-
chemical outcome of the reaction, since reaction with the Z con-
former yields the opposite enantiomer with respect to the E
conformer. The little difference in steric effect between methyl and
carboxymethyl groups (A-values of 1.7 and 1.3, respectively) do not
allow the predominant formation of one imine conformer over the
other. E/Z isomerization of imines would be a slow process if it were
to occur via a planar inversion.26 However, as the first step of the
reaction is tautomerization of the acyl enamine to the N-acyl imine,
both E and Z imine conformers can be readily obtained. This,
7d
8
6f
6g
6g
6h
9e
10
d
a
Reaction conditions: 2a (0.6 mmol), 3a (0.66 mmol), 6 (0.03 mmol), and Na2SO4
(1.06 mmol) in toluene (0.25 M) at 85 ꢀC for 60 h.
b
Yield after flash chromatography.
Determined by chiral HPLC on a Chiralpak AD-H column.
Reaction was run at 60 ꢀC.
Reaction was run at rt.
No reaction.
c
d
e
f
3. Conclusion
We have disclosed the first Brønsted acid catalyzed direct FC-
type addition reaction between indoles and pyrroles with DHA
where phosphoric acids were proven to be highly effective at cat-
alyzing this transformation. High levels of reaction efficiency and
perfect regio- and chemselectivity on both arenes and DHA were
obtained. The effects of the nature of the substituents both on the
indoles and on the DHA components were analyzed. Outstanding
compatibility of the functional groups OMe, Br, Cl, CN, B(pinaco-
late), COOMe, and NO2 is noteworthy. In addition, this methodology
might employ easily available chiral catalysts and provides enan-
tioenriched
a-quaternary amino acids. We speculate that the
moderate enantioselectivity can be attributed to the low intrinsic
electrophilicity of ketimines, combined with the small steric dif-
ference between the two groups flanking the azacarbonyl moiety.
Therefore, we conclude that a novel, operationally simple, metal-
free process and, moreover, catalytic method for the synthesis of
enantioenriched
a-quaternary amino acids has been established.
Our current investigations are focused on expansion of the general
scope and synthetic applications for obtaining bioactive molecules
by this new methodology.
4. Experimental section
4.1. General experimental procedure
All reactions were performed in round-bottom flasks. Column
chromatography purifications were performed in flash conditions
using 230e400 mesh silica gel. Analytical thin layer chromatogra-
phy (TLC) was carried out on silica gel plates (silica gel 60 F254), that

7926
M. Righi et al. / Tetrahedron 67 (2011) 7923e7928
were visualized by exposure to ultraviolet light and an aqueous
solution of cerium ammonium molybdate (CAM).
58.0, 51.4, 22.3, 22.0; Anal. Calcd for C14H15ClN2O3 (294.08): C,
57.05; H, 5.13; N, 9.50. Found: C, 57.36; H, 5.08; N, 9.51.
4.2. Structural analysis
4.3.4. Methyl
(4d). Orange solid by crystallization with ethyl acetate/hexane;
yield 63%; mp: 217e218 ꢀC 1H NMR (200 MHz, CDCl3):
2.05 (s,
2-acetamido-2-(5-bromo-1H-indol-3-yl)propanoate
Instrumentation: 1H NMR and 13C NMR spectra were recorded
d
on a 200/50 MHz on spectrometer. Chemical shifts (
d
scale) are
3H), 2.09 (s, 3H), 3.68 (s, 3H), 6.96e6.98 (br m, 2H), 7.11 (dd, 1H,
J1¼0.5 Hz, J2¼8.5 Hz) 7.21 (dd, 1H, J1¼2 Hz, J2¼8.5 Hz), 7.78 (d, 1H,
reported in parts per million (ppm) relative to the central peak of
the solvent. Coupling constants (J values) are given in hertz (Hz).
ESI-MS spectra were taken on an LC-MS instrument. Only base
peaks (100%) are given. High-performance liquid chromatography
was carried out using following apparatus: only base peaks (100%)
are given. Enantiomeric excesses were determined on an HPLC
instrument (chiracel AD-H column; mobile phase hexane/i-PrOH
J1¼2 Hz), 8.98 (br s, 1H). 13C NMR (50 MHz, CDCl3):
d 173.7, 169.4,
135.3, 126.2, 124.9, 124.7, 121.9, 114.4, 113.2, 113.1, 58.4, 53.2, 24.0,
22.3. The chemical-physical data are in agreement with those
reported in the literature.14
4.3.5. Methyl
2-acetamido-2-(4-bromo-1H-indol-3-yl)propanoate
9:1, flux 1.0 mL minꢁ1
,
l
¼287 nm). Infrared spectra were obtained
(4e). White solid; yield 58%; mp: 262e263 ꢀC; TLC (ethyl acetate),
Rf: 0.3 (UV, CAM). MS (ESI): 280 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1):
on an FTIR spectrometer, absorbances are reported in cmꢁ1
.
Melting points were determined on capillary melting point ap-
paratus. The optical rotation analysis was performed using a po-
3360, 1730; 1H NMR (200 MHz, acetone-d6):
d 1.89 (s, 3H), 2.13 (s,
3H), 3.69 (s, 3H), 6.99 (t, 1H, J¼8 Hz), 7.26 (dd, 1H, J1¼8 Hz, J2¼2 Hz),
larimeter with a sodium lamp (
l
¼589 nm, D-line); ½a D20
ꢂ
value is
7.38 (br s,1H), 7.42e7.47 (m, 2H),10.59 (br s,1H); 13C NMR (50 MHz,
reported in 10ꢁ1 dec cm2 gꢁ1; concentration (c) is in g per 100 mL.
Elemental analyses were within ꢃ0.4 of the theoretical values
(C,H,N).
acetone-d6): d 174.9, 167.4, 126.6126.4124.4122.2, 115.9, 112.5, 111.3,
111.2, 58.3, 52.1, 24.8, 23.1; Anal. Calcd for C14H15BrN2O3 (338.03): C,
49.57; H, 4.46; N, 8.26. Found: C, 49.17; H, 4.2; N, 8.57.
4.3. General procedure for the FriedeleCrafts alkylation
4.3.6. Methyl
2-acetamido-2-(5-nitro-1H-indol-3-yl)propanoate
(4f). Yellow solid; yield 76%; mp: 244e246 ꢀC; TLC (ethyl acetate),
Rf: 0.3 (UV, CAM). MS (ESI): 247 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1):
In a dry, argon-flushed Schlenk tube, the appropriate arenes
2aeq (0.6 mmol), methyl 2-acetamidoacrylate (3a) (95 mg,
0.66 mmol), 1,10-biphenyl-2,20-diyl hydrogen phosphate 1f (7.5 mg,
0.03 mmol, 5 mol %), and Na2SO4 (150 mg, 1.06 mmol) were dis-
solved in dry toluene (2.4 mL, 0.25 M). The solution was stirred at
85 ꢀC for 60 h. The reaction mixture was directly transferred onto
a column and purified by flash chromatography on silica gel (gra-
dient from ethyl acetate/cyclohexane 1:1 to ethyl acetate) affording
desired compounds 4aeq.
3370, 1723; 1H NMR (200 MHz, acetone-d6):
d 2.00 (s, 3H), 2.03 (s,
3H), 3.63 (s, 3H), 7.59 (d, 1H, J¼9.0 Hz), 7.70 (d, 1H, J¼2.5 Hz), 7.87
(br s, 1H), 8.04 (dd, 1H, J1¼9.0 Hz, J2¼2.0 Hz), 8.92 (d, 1H, J¼2 Hz),
11.02 (br s, 1H); 13C NMR (50 MHz, acetone-d6):
d 172.3, 169.1, 141.3,
140.2, 127.3, 124.4, 118.4, 118.0, 116.8, 111.9, 58.0, 51.6, 22.6, 22.0;
Anal. Calcd for C14H15N3O5 (305.1): C, 55.08; H, 4.95; N, 13.76.
Found: C, 54.87; H, 5.28; N, 14.38.
4.3.7. Methyl
2-acetamido-2-(5-cyano-1H-indol-3-yl)propanoate
4.3.1. Methyl 2-acetamido-2-(1H-indol-3-yl)propanoate (4a). White
solid by crystallization with ethyl acetate/hexane; yield 63%. Mp:
197e198 ꢀC (lit. mp 199e202 ꢀC). 1H NMR (200 MHz, CDCl3):
(4g). Off-white solid; yield 68%; mp: 214e216 ꢀC; TLC (cyclohex-
ane/ethyl acetate 2:8), Rf: 0.3 (UV, CAM). MS (ESI): 328
[MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3360, 2951, 1723, 1651; 1H NMR
d
.2.03 (s, 3H), 2.13(s, 3H), 3.70 (s, 3H), 6.74 (br s, 1H), 7.11e7.25 (m,
(200 MHz, CDCl3):
d
2.10 (s, 6H), 3.67 (s, 3H), 6.99 (d, 1H, J¼2.5 Hz),
3H), 7.37 (d, 1H, J¼7.5 Hz), 7.79 (d, 1H, J¼7.5 Hz), 8.62 (br s, 1H). 13C
7.09 (d, 1H, J¼8.5 Hz), 7.25 (d, 2H, J¼1.5 Hz), 7.95 (s. 1H), 9.67 (br s,
NMR (50 MHz, CDCl3):
d
173.5, 169.3, 136.7124.5, 123.3, 122.2,
1H); 13C NMR (50 MHz, CDCl3):
d
173.7, 169.4, 138.4, 126.0, 124.7,
120.0, 119.9, 115.2, 111.8, 58.7, 52.9, 23.7, 22.3. The chemical-
physical data are in agreement with those reported in the
literature.14
124.6, 124.1, 120.8, 115.3, 112.5, 102.5, 58.2, 53.5, 24.2, 22.3; Anal.
Calcd for C15H15N3O3 (285.11): C, 63.15; H, 5.30; N, 14.73. Found: C,
63.46; H, 5.58; N, 14.47.
4.3.2. Methyl
2-acetamido-2-(5-fluoro-1H-indol-3-yl)propanoate
4.3.8. Methyl 3-(2-acetamido-1-methoxy-1-oxopropan-2-yl)-1H-in-
dole-5-carboxylate (4h). White solid by crystallization with ethyl
acetate; yield 65%; mp: 198e200 ꢀC; TLC (cyclohexane/ethyl ace-
tate 2:8), Rf: 0.3 (UV, CAM). MS (ESI): 260 [MþHꢁCOOCH3]þ; IR
(4b). Off-white solid; yield 68%; mp: 158e160 ꢀC; TLC (cyclohex-
ane/ethyl acetate 2:8), Rf: 0.3 (UV, CAM). MS (ESI): 220
[MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3375, 1730, 1652; 1H NMR
(200 MHz, acetone-d6):
d
1.99 (s, 6H), 3.59 (s, 3H), 6.93 (ddd, 1H,
(film, cmꢁ1): 3385, 1720; 1H NMR (200 MHz, DMSO-d6):
d 1.88 (s,
J1¼J2¼9.0 Hz, J3¼2.5 Hz), 7.40 (dd, 1H, J1¼9 Hz, J2¼5 Hz) 7.49 (s, 1H)
3H), 1.89 (s, 3H), 3.53 (s, 3H), 3.86 (s, 3H), 7.45 (d, 1H, J¼9 Hz), 7.52
7.56 (dd, 2H, J1¼11, J2¼2.5 Hz), 10.46 (br s, 1H); 13C NMR (50 MHz,
(s, 1H), 7.73 (d, 1H, J¼9 Hz), 8.50 (br s, 1H), 8.53 (s, 1H), 11.53 (br s,
acetone-d6):
d
172.3, 169.1, 157.2 (d, J¼230 Hz), 133.8, 125.3 (d,
1H); 13C NMR (50 MHz, DMSO-d6):
d 172.8,169.6,167.8, 139.9, 125.9,
124.8, 124.3, 122.6, 120.9, 116.5, 112.0, 58.1, 52.3, 52.2, 23.8, 22.9;
Anal. Calcd for C16H18N2O5 (318.32): C, 60.37; H, 5.70; N, 8.80.
Found: C, 60.17; H, 5.4; N, 8.9.
J¼10 Hz), 115.4 (d, J¼5 Hz), 112.4 (d, J¼10 Hz), 109.7 (d, J¼26 Hz),
106.5, 105.8 (d, J¼26 Hz), 58.0, 51.4, 22.2, 22.0; Anal. Calcd for
C14H15FN2O3 (278.11): C, 60.42; H, 5.43; N,10.07. Found: C, 60.39; H,
5.23; N, 10.04.
4.3.9. Methyl 2-acetamido-2-(5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-indol-3 yl)propanoate (4i). Off-white solid;
yield 54%; mp: 212e213 ꢀC; TLC (cyclohexane/ethyl acetate 2:8), Rf:
0.3 (UV, CAM). MS (ESI): 227 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1):
4.3.3. Methyl
2-acetamido-2-(5-chloro-1H-indol-3-yl)propanoate
(4c). Off-white amorphous solid; yield 47%; TLC (cyclohexane/ethyl
acetate 2:8), Rf: 0.3 (UV, CAM). MS (ESI): 236 [MþHꢁCOOCH3]þ; IR
(film, cmꢁ1): 3365, 2950, 1728, 1655; 1H NMR (200 MHz, acetone-
3364, 2952, 1725, 1653; 1H NMR (200 MHz, CDCl3):
d 1.37 (s, 12H),
d6):
d
1.99 (s, 3H), 2.00 (s, 3H), 3.60 (s, 3H), 7.11 (dd, 1H, J1¼9 Hz,
2.01 (s, 3H), 2.10 (s, 3H), 3.68 (s, 3H), 6.89 (d, 1H, J¼4 Hz), 6.94 (s,
J2¼2 Hz), 7.42 (d, 1H, J¼9 Hz), 7.49e7.50 (m, 1H), 7.66 (br s, 1H), 7.89
1H), 7.32 (d,1H, J¼10 Hz), 7.63 (d,1H, J¼8 Hz), 8.22 (s, 1H), 9.13 (br s,
(d, 1H, J¼2 Hz), 10.60 (br s, 1H); 13C NMR (50 MHz, acetone-d6):
1H); 13C NMR (50 MHz, CDCl3):
d 173.8, 169.7, 138.8, 128.2, 127.3,
d
172.3, 169.0, 135.7, 126.1, 125.2, 124.3, 121.6, 120.5, 115.1, 112.9,
124.3,123.6, 115.3,111.3, 83.5, 58.8, 52.9, 24.9, 23.7, 22.7; Anal. Calcd

M. Righi et al. / Tetrahedron 67 (2011) 7923e7928
7927
for C20H27BN2O5 (386.20): C, 62.19; H, 7.05; N, 7.25. Found: C, 62.49;
H, 7.25; N, 7.15.
J2¼1 Hz), 7.38 (d, 2H, J¼8 Hz), 7.53 (d, 2H, J¼8 Hz), 8.02 (br s, 2H);
13C NMR (50 MHz, CDCl3):
175.9, 136.8, 126.0, 122.9, 121.8, 121.2,
d
119.3, 119.1, 111.2, 52.2, 46.2, 25.9. The chemical-physical data are
in agreement with those reported in the literature.17
4.3.10. Methyl 2-acetamido-2-(5-methoxy-1H-indol-3-yl)propanoate
(4j). Brown amorphous solid; yield 76%; TLC (cyclohexane/ethyl
acetate 2:8), Rf: 0.3 (UV, CAM). MS (ESI): 232 [MþHꢁCOOCH3]þ; IR
(film, cmꢁ1): 3411, 3004, 2360, 2342, 1716; 1H NMR (200 MHz, ac-
4.3.16. Methyl 2-acetamido-2-(1-methyl-1H-pyrrol-2-yl)propanoate
(4p). Yellow solid by crystallization with hexane; yield 35%; mp:
176e177 ꢀC; TLC (cyclohexane/ethyl acetate 3:7), Rf: 0.3 (UV, CAM).
MS (ESI): 166 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3260, 2951, 1739,
etone-d6):
d 2.95 (s, 3H), 2.96 (s, 3H), 4.5 (s, 3H), 4.76 (s, 3H), 7.74
(dd, 1H, J1¼2 Hz, J2¼10 Hz), 8.25 (dd, 1H, J1¼2 Hz, J2¼10 Hz), 8.32
(dd, 2H, J1¼2 Hz, J2¼6 Hz), 8.5 (br s, 1H), 11.2 (br s, 1H); 13C NMR
1655; 1H NMR (200 MHz, CDCl3):
d 1.99 (s, 3H), 2.05 (s, 3H), 3.55 (s,
(50 MHz, acetone-d6):
d
172.4, 169.1, 153.7, 132.3, 125.4, 123.8, 114.8,
3H) 3.76 (s, 3H), 6.08 (dd, 1H, J1¼4 Hz, J2¼3 Hz), 6.28 (dd, 1H,
112.1, 111.7, 103.0, 58.2, 54.9, 51.3, 22.3, 22.1; Anal. Calcd for
C15H18N2O4 (290.13): C, 62.06; H, 6.25; N, 9.65. Found: C, 61.66; H,
6.43; N, 9.41.
J1¼4 Hz, J2¼2 Hz), 6.54 (dd,1H, J1¼3 Hz, J2¼2 Hz), 6.72 (br s,1H); 13
C
NMR (50 MHz, CDCl3): d 173.6, 168.5, 129.7, 124.5, 109.5, 106.8, 58.3,
53.4, 24.0, 23.2; Anal. Calcd for C11H16N2O3 (224.12): C, 58.91; H,
7.19; N, 12.49. Found: C, 58.58; H, 7.45; N, 12.26.
4.3.11. Methyl 2-acetamido-2-(5-methyl-1H-indol-3-yl)propanoate
(4k). Orange amorphous solid; yield 57%; TLC (cyclohexane/ethyl
acetate 4:6), Rf: 0.3 (UV, CAM). MS (ESI): 216 [MþHꢁCOOCH3]þ; IR
(film, cmꢁ1): 3364, 2952, 1725, 1653; 1H NMR (200 MHz, CDCl3):
4.3.17. Methyl 2-acetamido-2-(4,7-dihydro-1H-indol-2-yl)propanoate
(4q). Colorless oil; 33 yield %; TLC (ethyl acetate), Rf: 0.3 (UV, CAM).
MS (ESI): 204 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 325, 2950, 1745,
d
2.03 (s, 3H), 2.11 (s, 3H), 2.48 (s, 3H), 3.69 (s, 3H), 6.75 (br s, 1H),
1650; 1H NMR (200 MHz, CDCl3):
d 1.92 (s, 3H), 2.01 (s, 3H), 3.79 (s,
7.02e7.06 (m, 2H), 7.23 (s, 1H), 7.55 (s, 1H), 8.73 (br s, 1H); 13C NMR
3H), 5.85 (d, 2H, J¼3.5 Hz), 5.94 (s, 1H, J¼2.5 Hz), 6.25 (br s, 1H), 8.89
(50 MHz, CDCl3): 173.5, 169.4, 135.1, 129.2, 124.7, 123.8, 123.4, 119.4,
(br s, 1H); 13C NMR (50 MHz, CDCl3):
d
172.9, 170.4, 129.6, 125.6,
114.5, 111.5, 58.7, 52.9, 23.7, 22.3, 21.7.
C15H18N2O3 (274.13): C, 65.68; H, 6.61; N, 10.21. Found: C, 65.44; H,
6.79; N, 10.61.
d
; Anal. Calcd for for
125.3, 122.8, 113.3, 104.9, 57.8, 53.2, 24.7, 23.9, 23.4, 22.4; Anal. Calcd
for C14H18N2O3 (262.13): C, 64.10; H, 6.92; N, 10.68. Found: 63.9C; H,
6.57; N, 10.35.
4.3.12. Methyl 2-acetamido-2-(2-methyl-1H-indol-3-yl)propanoate
(4l). Brown solid by crystallization with ethyl acetate/hexane; yield
60%; mp: 190e191 ꢀC; TLC (cyclohexane/ethyl acetate 2:8), Rf: 0.4
(UV, CAM). MS (ESI): 216 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3380,
4.4. General procedure for the asymmetric FriedeleCrafts
alkylation
In a dry, argon-flushed Schlenk tube, 2a (0.6 mmol), methyl 2-
acetamidoacrylate (3a) (95 mg, 0.66 mmol), the appropriate chi-
ral Brønsted acid 6aeh (7.5 mg, 0.03 mmol, 5 mol %) and Na2SO4
(150 mg, 1.06 mmol) were dissolved in dry toluene (2.4 mL, 0.25 M).
The solution was stirred at 85 ꢀC for 60 h. The reaction mixture was
directly transferred onto a column and purified by flash chroma-
tography on silica gel (gradient from ethyl acetate/cyclohexane 1:1
to ethyl acetate) affording desired compound 4a as a mixture of
enantiomers. Enantiomeric excesses were determined by HPLC,
major product tR¼21.5 min and minor product tR¼17.1 min. Optical
rotation was measured for compound 4a using chiral Brønsted acid
2924, 1701, 1655; 1H NMR (200 MHz, acetone-d6):
d 1.96 (s, 3H),
2.05 (under solvent peak acetone-d6, 3H), 2.44 (s, 3H), 3.66 (s, 3H),
6.95e7.03 (m, 2H), 7.27 (dd, 1H, J1¼1.5 Hz, J2¼7 Hz), 7.46 (br s, 1H),
7.48 (d, 1H, J¼7 Hz), 10.09 (br s, 1H); 13C NMR (50 MHz, acetone-d6):
d
173.3, 169.1, 135.2, 131.9, 126.8, 124.0, 120.5, 119.8, 118.8, 110.5,
59.4, 51.5, 23.5, 22.3, 12.8; Anal. Calcd for C15H18N2O3 (274.13): C,
65.68; H, 6.61; N, 10.21. Found: C, 65.35; H, 6.83; N, 10.6.
4.3.13. Methyl 2-acetamido-2-(3-methyl-1H-indol-2-yl)propanoate
(4m). Off-white solid by crystallization with ethyl acetate; yield
31%; mp: 176e177 ꢀC; TLC (cyclohexane/ethyl acetate 1:1), Rf: 0.3
(UV, CAM). MS (ESI): 216 [MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3370,
6f; ½a 2D0
þ3.4 (0.89, ee¼66).
ꢂ
1710, 1672; 1H NMR (200 MHz, acetone-d6):
d 1.96 (s, 6H), 2.30 (s,
Acknowledgements
3H), 3.67 (s, 3H), 6.95e7.12 (m, 2H), 7.3 (d, 1H, J¼8 Hz), 7.5 (d, 1H,
J¼8 Hz), 7.78 (br s, 1H), 10.1 (br s, 1H); 13C NMR (50 MHz, acetone-
This work was supported by the Italian M.I.U.R. (Ministero del-
l’Istruzione, dell’Universita’ e della Ricerca). We would like to thank
Prof. Gilberto Spadoni for useful discussion.
d6): d 171.9, 168.9, 135.1, 132.2, 129.5, 121.5, 118.6, 118.0, 111.0, 107.4,
58.7, 52.0, 22.4, 22.1, 8.6; Anal. Calcd for C15H18N2O3 (274.13): C,
65.68; H, 6.61; N, 10.21. Found: C, 65.67; H, 6.38; N, 10.16.
Supplementary data
4.3.14. Methyl 2-acetamido-2-(6-methoxy-1H-indol-3-yl)propanoate
(4n). Orange solid; yield 43%; TLC (cyclohexane/ethyl acetate 4:6),
mp: 175e176 ꢀC; Rf: 0.3 (UV, CAM). MS (ESI): 232
[MþHꢁCOOCH3]þ; IR (film, cmꢁ1): 3365, 2950, 1720, 1656; 1H NMR
1H NMR and 13C NMR spectra for all compounds and HPLC traces
for chiral compounds are reported in Supplementary data. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2011.08.039.
(200 MHz, CDCl3):
d 2.03 (s, 3H), 2.10 (s, 3H), 3.69 (s, 3H), 3.82 (s,
3H), 6.72 (br s,1H), 6.76e6.82 (m, 2H), 6.98 (d,1H, J¼2.5 Hz), 7.65 (d,
1H, J¼9.5 Hz), 8.55 (br s, 1H); 13C NMR (50 MHz, CDCl3):
d 173.5,
References and notes
169.4, 156.4, 137.6, 122.0, 120.5, 118.8, 115.1, 110.1, 94.8, 58.6, 55.6,
52.9, 23.7, 22.2; Anal. Calcd for C15H18N2O4 (290.13): C, 62.06; H,
6.25; N, 9.65. Found: C, 62.27; H, 6.43; N, 9.93.
1. For recent reviews, see: (a) Christoffers, J.; Baro, A. In Quaternary Stereocenters.
Challenges and Solutions in Organic Synthesis; Wiley-VCH: Weinheim, 2006; (b)
Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969e5994; (c)
Trost, B. M.; Chun-hui, J. Synthesis 2006, 369e396; (d) Douglas, C. J.; Overman,
L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363e5367; (e) Riant, O.; Hanne-
douche, J. Org. Biomol. Chem. 2007, 5, 873e888; (f) Bella, M.; Gasperi, T. Syn-
thesis 2009, 1583e1614.
2. (a) Maity, P.; Konig, B. Biopolymers 2008, 90, 8e27; (b) Tanaka, M. Chem. Pharm.
Bull. 2007, 55, 349e358; (c) Venkatraman, J.; Shankaramma, S. C.; Balaram, P.
Chem. Rev. 2001, 101, 3131e3152; (d) Toniolo, C.; Crisma, M.; Formaggio, F.;
Peggion, C. Biopolymers 2001, 60, 396e419; (e) Evans, M. C.; Pradhan, A.;
4.3.15. Methyl 2,2-di(1H-indol-3-yl)propanoate (5). By-product 5
was isolated as white solid by crystallization with methanol; yield
35%; mp: 201e203 ꢀC (lit. mp: 88 ꢀC) TLC (cyclohexane/ethyl ac-
etate 8:2), Rf: 0.3 (UV, CAM): MS (ESI): 260 [MþHꢁCOOCH3]þ. 1H
NMR (200 MHz, CDCl3):
d 2.14 (s, 3H), 3.69 (s, 3H), 6.97 (d, 2H,
J¼2.5 Hz), 7.03 (ddd, 2H, J1¼7 Hz, J2¼1 Hz), 7.19 (ddd, 2H, J1¼7 Hz,

7928
M. Righi et al. / Tetrahedron 67 (2011) 7923e7928
Venkatraman, S.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. J. Med.
Chem. 1999, 42, 1441e1447.
3. Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 512, 5127e5143.
4. Hotta, N.; Touota, T.; Matsuoka, K.; Shigeta, Y.; Kikkiwa, R.; Kaneko, T.; Taka-
hashi, A.; Sugimura, K.; Koike, Y.; Ishii, J.; Sakamoto, N. Diabetes Care 2001, 24,
1776e1782.
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634e5635; (d) Wang, J.;
Hu, X.; Jiang, J.; Gou, S.; Huang, X.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007,
46, 8468e8470; (e) Rueping, M.; Sugiono, E.; Moreth, S. A. Adv. Synth. Catal.
2007, 349, 759e764 (Alkylmetal additions); (f) Lauzon, C.; Charette, A. B. Org.
Lett. 2006, 8, 2743e2745; (g) See Ref. 5i. (Allylmetal additions); (h) Wada, R.;
Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 7687e7691 (Mannich-type additions): (i) Suto, Y.; Kanai, M.; Shi-
basaki, M. J. Am. Chem. Soc. 2007, 129, 500e501; (j) Wieland, L. C.; Vieira, E. M.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 570e576 (arylation):
(k) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
13168e13169.
5. For reviews on the asymmetric synthesis of
a
,a
-disubstituted
a-amino acids,
€
see: (a) Vogt, H.; Brase, S. Org. Biomol. Chem. 2007, 5, 406e430; (b) Cativiela, C.;
Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517e3599; (c) Cati-
viela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645e732; (d)
Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18,
569e623; (e) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2009, 20, 1e63; (f) Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry
2008, 19, 2755e2762 For selected, more recent examples, see: (g) Branca, M.;
Pena, S.; Guillot, R.; Gori, D.; Alezra, V.; Kouklovsky, C. J. Am. Chem. Soc. 2009,
131, 10711e10718; (h) Green, J. E.; Bender, D. M.; Jackson, S.; O’Donnell, M. J.;
McCarthy, J. R. Org. Lett. 2009, 11, 807e810; (i) Fu, P.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2008, 130, 5530e5541; (j) Mitani, M.; Tanaka, Y.; Sawada,
A.; Misu, A.; Matsumoto, Y. Eur. J. Org. Chem. 2008, 1383e1391; (k) Cabrera, S.;
Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2008, 130, 12031e12037; (l) Huang, X. L.; He, L.; Shao, P. L.; Ye, S. Angew.
Chem., Int. Ed. 2009, 48, 192e195; (m) Uraguchi, D.; Asai, Y.; Ooi, T. Angew.
Chem., Int. Ed. 2009, 48, 733e737; (n) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura,
D.; Ishikawa, H. Chem.dAsian J. 2009, 4, 246e249; (o) Dickstein, J. S.; Fennie,
M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130,
15794e15795; (p) Fesko, K.; Uhl, M.; Steinreiber, J.; Gruber, K.; Griengl, H.
Angew. Chem., Int. Ed. 2010, 49, 121e124; (q) Konishi, H.; Lam, T. Y.; Malerich, J.
P.; Rawal, V. H. Org. Lett. 2010, 12, 2028e2031.
13. (a) Porter, J.; Dykert, J.; Rivier, J. Int. J. Pept. Protein Res. 1987, 30, 13e21; (b) Li,
X.-G.; Rantapaju, M.; Kanerva, L. T. Eur. J. Org. Chem. 2011, 9, 1755e1762.
14. Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J. Org. Chem.
2008, 73, 5654e5657.
15. On the other hand, the DHA structure contains an enamine functionality, which
is likely to isomerize to an electrophilic ketimine (or ketiminium) group
through proton transfer under the proper reaction conditions (such as by the
activation of Brønsted or Lewis acids). For the first organocatalytic alkylations
of ketimines, see: to geometrically constrained ketone-derived cyclic imines:
(a) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43,
4476e4478 To activated aryl trifluoromethyl ketimines: (b) Sukach, V. A.;
Golovach, N. M.; Pirozhenko, V. V.; Rusanov, E. B.; Vovk, M. V. Tetrahedron:
Asymmetry 2008, 19, 761e764 For a FC reaction of indoles and a-aryl enamides,
see: (c) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2007, 46, 5565e5567; (d) A FriedeleCrafts reaction of methyl acet-
amidoacrylate with anisole and phenol has been reported: Royo, E.; Lopez, P.;
Cativiela, C. ARKIVOC 2005, 6, 46e61 but stoichiometric amount of Lewis Acid
was used.
6. For reviews on catalytic (Asymmetric) FriedeleCrafts alkylations, see: (a)
Bandini, M.; Umani-Ronchi, A. In Catalytic Asymmetric FriedeleCrafts Alkyl-
ations; Wiley-VCH: Weinheim, 2009; (b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc.
Rev. 2009, 38, 2190e2201; (c) Terrasson, V.; de Figueiredo, R. M.; Campagne, J.
M. Eur. J. Org. Chem. 2010, 2635e2655; (d) Zeng, M.; You, S.-L. Synlett 2010,
1289e1301; (e) Rueping, M.; Nachtsheim, B. J. Beilstein J. Org. Chem. 2010, 6,
2635e2655.
7. For reviews on hydrogen bond mediated catalysis, see: (a) Schreiner, P. R. Chem.
Soc. Rev. 2003, 32, 289e296; (b) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909e3912; (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520e1543; (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713e5743;
(e) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516e532; (f) Knowles, R. R.;
Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678e20686 For recent
reviews on chiral phosphoric acid catalysis, see: (g) Terada, M. Synthesis 2010,
1929e1982; (h) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2010, 291,
395e456; (i) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.dEur. J. 2010, 16,
9350e9365; (j) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2010, 8, 5262e5276.
8. (a) Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2008, 350,
1457e1463; (b) Nie, J.; Zhang, G.-W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem.
Commun. 2009, 2356e2358; (c) Nie, J.; Zhang, G.-W.; Wang, L.; Zheng, D.-H.;
Zheng, Y.; Ma, J.-A. Eur. J. Org. Chem. 2009, 3145e3149; (d) Wang, T.; Zhang, G.-W.;
Teng, Y.; Nie, J.; Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2773e2777; (e)
Kashikura, W.; Itoh, J.; Mori, K.; Akiyama, T. Chem. Asian J. 2010, 5, 470e472.
9. (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed.
2008, 47, 593e596; (b) Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.-F.; He, L.-N.;
Tang, C.-C. Eur. J. Org. Chem. 2008, 1406e1410; (c) Bachu, P.; Akiyama, T. Chem.
Commun. 2010, 4112e4114; (d) Sakamoto, T.; Itoh, J.; Mori, K.; Akiyama, T. Org.
Biomol. Chem. 2010, 8, 5448e5454.
10. (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804e11805; (b) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 8156e8157; (c) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007,
129, 292e293; (d) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129,
1484e1485; (e) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla, J.
C. Org. Lett. 2007, 9, 2609e2611; (f) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla,
J. C. Org. Lett. 2007, 9, 4065e4068; (g) Terada, M.; Yokoyama, S.; Sorimachi, K.;
Uraguchi, D. Adv. Synth. Catal. 2007, 349, 1863e1867; (h) Wanner, M. J.; Hau-
wert, P.; Schoemaker, H. E.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H.
Eur. J. Org. Chem. 2008, 180e185; (i) Enders, D.; Narine, A. A.; Toulgoat, F.;
Bisschops, T. Angew. Chem., Int. Ed. 2008, 47, 5661e5665; (j) Kang, Q.; Zhao,
Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603e1607; (k) Xu, F.; Huang, D.; Han, C.;
Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75, 8677e8680.
16. For a complete and excellent review on selective catalytic functionalization of
indoles, see: (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608e9644 For a recent review on organocatalytic functionalization of indoles,
see: (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39,
4449e4465 For the importance of indoles in the context of medicinal chem-
istry, see for example: (c) Alves, F. R. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev.
Med. Chem. 2009, 9, 782e793; (d) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R.
Curr. Opin. Chem. Biol. 2010, 14, 347e361; (e) Kochanowska-Karamyan, A. J.;
Hamann, M. T. Chem. Rev. 2010, 110, 4489e4497.
17. For examples of Lewis acid catalyzed formation of bis-indoles from DHA, see:
de la Hoz, A.; Diaz-Ortiz, A.; Gomez, M. V.; Mayoral, J. A.; Moreno, A.; Sanchez-
Migallona, A. M.; Vazquez, E. Tetrahedron 2001, 57, 5421e5428; For an excellent
review of bis-indoles: Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z.
Chem. Rev. 2010, 110, 2250e2293.
18. For recent use of phenyl phosphinic acid as Brønsted acid catalyst, see : (a)
Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.;
Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696e15697; (b) Pan, S. C.; Zhou, J.;
List, B. Synlett 2006, 3275e3276; (c) Pan, S. C.; List, B. Angew. Chem., Int. Ed.
2008, 47, 3622e3625.
19. The phosphoric acid acts both to catalyzed the tautomerization to N-acylimine
and the FriedeleCraft reaction. Indeed, no reaction occurs when the catalytic
Barton’s base-tBuTMG (2-tBu-1,1,3,3-tetramethylguanidine), was used to acti-
vate the indole as reported by: Bandini, M.; Sinisi, R. Org. Lett. 2009, 11,
2093e2096 No tautomerization take place in basic condition.
20. (a) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418e14420;
(b) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi,
M.; Spadoni, G. Org. Lett. 2010, 12, 3844e3847.
21. (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. J. Org. Chem. 2002,
67, 5386e5389; (b) Moran, J.; Suen, T.; Beauchemin, A. M. J. Org. Chem. 2006, 71,
676e679; (c) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.dEur. J.
2008, 14, 3630e3636.
22. While the results in Table 1 indicate that the catalyst pKa is certainly important,
there appears to be no direct correlation between catalyst activity and acidity.
23. For a nice example of FriedeleCrafts alkylation of arenes with a glyoxylate
aldimine: Enders, D.; Seppelt, M.; Beck, T. Adv. Synth. Catal. 2010, 352,
1413e1418.
24. With preformed ethyltrifluoropyruvate imines, see: Husmann, R.; Sugiono, E.;
Mersmann, S.; Raabe, G.; Rueping, M.; Bolm, C. Org. Lett. 2011, 13, 1044e1047;
For a previous stereoselective example using triflic acid as a catalyst, see: Abid,
€ €
M.; Teixeira, L.; Torok, B. Org. Lett. 2008, 10, 933e935.
25. For an DFT study on the factors determining the enantioselectivity of Frie-
11. Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016e4018.
12. Studies into catalytic addition reactions of C-based nucleophiles to ketimines,
are rare: (CN additions); (a) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2001, 123, 10784e10785; (b) Vachal, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 10012e10014; (c) Masumoto, S.; Usuda, H.; Suzuki, M.;
deleCrafts reactions of indole with N-acyl-ketimines catalyzed by BINOL-
phosphoric acid derivatives, see: Simon, L.; Goodman, J. M. J. Org. Chem.
ꢀ
2010, 75, 589e597.
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26. Banik, B. K.; Lecea, B.; Arrieta, A.; de Cozar, A.; Cossõo, F. P. Angew. Chem., Int. Ed.
2007, 46, 3028e3032.