Switchable reactivity of acylated α,β-dehydroamino ester in the Friedel-Crafts alkylation of indoles by changing the lewis acid

Article abstract of DOI:10.1021/jo800881u

(Chemical Equation Presented) Highly regioselective electrophilic substitution of indoles with N-acetylated α,β-dehydroalanine methyl ester, promoted by different transition metal salts was achieved. The orthogonal regioselectivity provides an efficient p

Full text of DOI:10.1021/jo800881u

dition with these unsaturated residues can lead to the formation
of Dha adducts, including intramolecular lanthionine cross-
links.5
Switchable Reactivity of Acylated
r, ꢀ-Dehydroamino Ester in the Friedel-Crafts
Alkylation of Indoles by Changing the Lewis
Acid
The indole nucleus is found in a number of biologically active
natural and unnatural compounds, and the synthesis of its
derivatives continues to be an intriguing subject in organic
synthesis.6 Friedel-Crafts (F-C) alkylation of indoles with an
R,ꢀ-unsaturated carbonyl compound such as the Michael ac-
ceptor is a straightforward approach for the synthesis of
substituted indoles. Several conjugate additions of indoles to
various Michael acceptors, some of which are highly enanti-
oselective, have been developed by using either Lewis acids
(LA) or organic catalysts.7
Elena Angelini, Cesarino Balsamini, Francesca Bartoccini,
Simone Lucarini, and Giovanni Piersanti*
Institute of Medicinal Chemistry, UniVersity of Urbino
“Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino (PU),
Italy
gioVanni.piersanti@uniurb.it
ReceiVed April 24, 2008
Although remarkable achievements have been made using
the F-C alkylation of indole substrates with R,ꢀ-unsaturated
carbonyl compounds, to the best of our knowledge there have
been no reports in which N-acylated dehydroamino esters (R-
amidoacrylates) have been employed.
The potential value of the N-acyl-R,ꢀ-dehydroamino esters
in synthetic chemistry is derived mainly from their ready
availability and unique reactivity.8 The contemporary presence
of acylamino and ester groups on the same carbon of the double
bond can promote the nucleophilic attack at the R and ꢀ
positions (Figure 1), providing R-amino acids that can be readily
transformed into a range of different functionalities, or even
Highly regioselective electrophilic substitution of indoles
with N-acetylated R,ꢀ-dehydroalanine methyl ester, promoted
by different transition metal salts was achieved. The or-
thogonal regioselectivity provides an efficient protocol
toward highly functionalized 3-indolyl-R-amino acids. The
mechanism of the reactions was explored by NMR studies.
(3) For reviews, see: (a) Chatterjee, C.; Paul, M.; Xie, L. L.; van der Donk,
W. A. Chem. ReV. 2005, 105, 633–683. (b) Bonauer, C.; Walenzyk, T.; Ko¨nig,
B. Synthesis 2006, 1, 1–20. For representative examples see: (c) Burrage, S. A.;
Raynham, T.; Brandley, M. Tetrahedron Lett. 1998, 39, 2831–2834. (d) Ferreira,
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9578. (e) Miao, Z.; Tam, P. J. Org. Lett. 2000, 2, 3711–3711.
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788. (b) Cotter, P. D.; Hill, C.; Ross, R. P. Curr. Protein Pept. Sci. 2005, 6,
61–72.
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9, 5997–6006. (b) Zhu, Y.; van der Donk, W. A. Org. Lett. 2001, 3, 1189–
1192. (c) Zhu, Y. T.; Gieselman, Y. T.; Zhou, H.; Averin, O.; van der Donk,
W. A. Org. Biomol. Chem. 2003, 1, 3304–3315.
Amino acids and their derivatives are well-known as versatile
building blocks for pharmaceutical applications, as well as
essential starting material for the generation of molecular
diversity.1 Therefore, we have focused our attention on develop-
ing methodologies to generate nonproteinogenic amino acids,2
using readily available N-protected dehydroamino esters, such
as dehydroalanine.
The amino acid dehydroalanine (Dha) is found in a number
of proteins and nonribosomal natural products, and is typically
revealed by the activation and ꢀ-elimination of serine or
cysteine.3 R,ꢀ-Unsaturated amino acids can alter the conforma-
tion, rigidity, and proteolytic susceptibility of the polypeptide
backbone.4 Intra- or intermolecular electrophilic Michael ad-
(6) (a) Sundberg, R. J. Indoles; Academic Press: London, UK, 1996. (b)
Saxton, J. E. Nat. Prod. Rep. 1997, 559–590. (c) Borschberg, H.-J. Curr. Org.
Chem. 2005, 9, 1465–1492. (d) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert,
D. Pharmaceutical Substances, 4th ed.; Thieme: New York, 2001. (e) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873–2920.
(7) For reviews see: (a) Jørgensen, K. A. Synthesis 2003, 1117–1125. (b)
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
550–556.
(8) For representative examples of reactivity of 1, see: Asymmetric
hydrogenation: (a) Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.; Kobs,
U.; Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649–6667. Cycload-
dittion: (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron Asymmetry 2000,
11, 645–732, Heck reaction. (c) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.;
McGlacken, G. P.; Weissburger, F.; de Vries, A. H. M.; Schmieder-van de
Vondervoort, L. Chem. Eur. J. 2006, 12, 8750–8761. With thiolates: (d) Sridhar,
P. R.; Prabhu, K. R.; Chandrasekaran, S. Eur. J. Org. Chem. 2004, 4809–4815.
With phosphite: (e) Meyer, F.; Laaziri, A.; Papini, A. M.; Uzieland, J.; Juge`, S.
Tetrahedron 2004, 60, 3593–3597. With enamines: (f) Desmaele, D.; Delarue-
Cochin, S.; Cave´, C.; d’Angelo, J.; Morgant, G. Org. Lett. 2004, 14, 2421–
2424. With trifluoroorganoborate: (g) Navarre, L.; Darses, S.; Genet, J. P. Angew.
Chem., Int. Ed. 2004, 43, 719–723. With boronic acid: (h) Reetz, M. T.; Moulin,
D.; Gosberg, A. Org. Lett. 2001, 25, 4083–4085. With anisole and phenol: (i)
Royo, E.; Lo´pez, P.; Cativiela, C. ARKIVOC 2005, Vi, 46–61. With furan and
pyrrole: (j) de la Hoz, A.; Diaz-Ortiz, A.; Gomez, M. V.; Mayoral, J. A.; Moreno,
A.; Sanchez-Migallona, A. M.; Vazquez, E. Tetrahedron 2001, 57, 5421–5428.
Reaction of 1 with indole was also reported, employing Silica-supported LA
(Al,Ti) in conjunction with microwave irradiation, but the polysubstituted bis-
indolyl derivative was the main product.
* Address correspondence to this author. Fax: +39-0722-303313. Phone: +39-
0722-303320.
(1) (a) Gordon, E. M. Combinatorial Chemistry and Molecular DiVersity in
Drug DiscoVery; Gordon, E. M., Kerwin, J. F., Jr., Eds.; Wiley-Liss: New York,
1998. (b) Sawyer, T. K. Structure Based Drug Design: Disease, Targets,
Techniques and DeVelopment; (Ed.: Veerapandian P), Marcel Dekker: New York,
1997, p 559.
(2) (a) Ballini, R.; Balsamini, C.; Diamantini, G.; Savoretti, N. Synthesis
2005, 7, 1055–1057. (b) Ballini, R.; Balsamini, C.; Bartoccini, F.; Gianotti, M.;
Martinelli, C.; Savoretti, N. Synthesis 2005, 2, 296–300. (c) Balsamini, C.;
Diamantini, G.; Duranti, A.; Spadoni, G.; Tontini, A. Synthesis 1995, 4, 370–
372.
5654 J. Org. Chem. 2008, 73, 5654–5657
10.1021/jo800881u CCC: $40.75 2008 American Chemical Society
Published on Web 06/18/2008

TABLE 1. Effect of LA in the F-C Reaction of 1 and Indole
FIGURE 1. Contributing structures of R,ꢀ-dehydroamino esters.
more importantly they can be resolved by asymmetric hydrolysis
with use of R-chymotrypsin or carboxypeptidase A.9
In this paper, we document the first efficient regioselective
LA-promoted addition of indoles to methyl R-methylacetami-
doacrylate (1),10 one of the simplest compounds of the N-acyl-
R,ꢀ-dehydroamino ester family. The procedure is straightforward
and allows rapid access to a broad range of 3-indolyl-R-amino
acids derivatives. In particular, the successful regioselective
activation strategy to enester-enamide substrate 1 was achieved
by appropriate choice of LA in terms of hardness and softness.11
The proposed F-C alkylation strategy was first examined by
reacting indole with 1 in the presence of a series of LAs in
dichloromethane for 2 h. (Table 1). Using a catalytic amount
or less than 1 equiv of the highly reactive and commercially
available LA EtAlCl2 in hexane solution did not provide any
of the desired substituted indole product. When the reaction
was carried out with 1 equiv of EtAlCl2, the yield was low
(Table 1, entry 1). The presence of 2 equiv of EtAlCl2 was
required to obtain N-acetyl tryptophan methyl ester 4a in high
yield as the only regioisomer (Table 1, entry 2). Higher
temperatures gave lower yields, most likely due to polym-
erization (Table 1, entry 4).
The effects of various other LAs belonging to the aluminum
group such as BF3, GaCl3, and InCl3 were also studied, but they
were found to be ineffective for this conversion (Table 1, entries
5-8). Although LiClO4,12 MgBr2,13 and Sc(OTf)314 are known
to be efficient catalysts for F-C and for Michael addition
reactions, surprisingly they showed no reactivity in our system
(Table 1, entries 9-11). Compound 4a was obtained in low
yield when TiCl4 was employed using the same conditions
(Table 1, entry 12). Instead, we were delighted to find that ZrCl4,
a safe, economical, and environmentally benign LA,15 furnished
the desired product in good yield even though a longer reaction
time was needed (Table 1, entry 13).
entry
1a
MXn
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
BF3 ·OEt2
GaCl3
InCl3
InCl3
LiClO4
MgBr2
Sc(OTf)3
TiCl4
ZrCl4
ReCl5
IrCl4
NaAuCl4•2H2O
Cu(OTf)2
Zn(OTf)2
Bi(OTf)3
CF3SO3H
HCl
T (°C)
yield (%)
3a/4a
0
0
0
83
0
10
75
58
50
0/100
0/100
0/100
0/100
2
3b,e
4b
5
NRc
NRc
NRc
NRc
NRc
NRc
NRc
30
6
rt
rt
0
rt
rt
rt
rt
0
rt
rt
rt
rt
rt
rt
0
7d
8
9
10
11
12e
13f
14e
15
16e
17
18
19e
20
21g
22
23
0/100
0/100
100/0
65
55
NRc
46
100/0
100/0
NRc
NRc
62
NRc
NRc
NRc
NRc
0
0
0
Amberlyst
Montmorillonite
a 1 equiv of LA was used. b 1,2-Dichloroethane was used as a solvent.
c No reaction occurred. d H2O/THF 9:1 mixture was used as a solvent.
e The reaction was carried out for 4 h. f The reaction was carried out for
24 h. g 4 M HCl solution in dioxane was used.
Next, we explored late transition metal salts with more
azaphilic/soft characteristics as the LAs under similar reaction
conditions. Using ReCl5, NaAuCl4 · 2H2O, and Bi(OTf)3, we
obtained complete regioselectivity to provide the other isomer
3a in good yield (Table 1, entries 14, 16, and 19). The indole
nucleus preserved C3 regioselectivity while 1 no longer behaved
as an electron-deficient olefin but as an enamide, performing
(9) Porter, J.; Dykert, J.; Rivier, J. Int. J. Peptide Protein Res. 1987, 30,
13–21. Racemic tryptophanes were prepared by nucleophilic addition of
diethylacetamidomalonate to acrolein, subsequent addition of appropiate phe-
nylhydrazine, and final cyclization of the substituted hydrazone with sulfuric
acid by Fisher synthesis.
FIGURE 2. Plausible reaction mechanism of 1 and indole catalyzed
by 2 equiv of EtAlCl2.
(10) Snyder, H. R.; MacDonald, J. A. J. Am. Chem. Soc. 1955, 77, 1257–
1259. Acetyl Tryptophan already has been prepared from R-acetamidoacrylic
acid and indole in the presence of acetic acid and acetic anhydride. However,
the yield and the substrate scope from the method described above were far
from satisfactory (58% yield and only two indole substrates) and this procedure
cannot be used for practical synthesis.
the R-amidoalkylation reaction (Figure 3). Rhenium pentachlo-
ride is very air and moisture sensitive making it unattractive
for use in synthetic organic chemistry. Similarly, the relatively
high cost and toxicity preclude the use of gold compounds in
stochiometric amount, although catalysis by gold compounds
has rapidly become a hot topic in chemistry.16 On the other
hand, bismuth compounds have recently attracted attention due
to their low cost, ease of handling, and remarkably low toxicity,
rendering them suitable for green chemistry.17 Among the metal
salts tested IrCl4, Cu(OTf)2, and Zn(OTf)2 were found to be
ineffective (Table 1, entries 15, 17, and 18). No reaction
(11) (a) Ferraris, D.; Drury, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998,
63, 4568–4569. (b) Woodward, S. Tetrahedron 2002, 58, 1017–1050. (c)
Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 19, 3491–3494.
(12) Gunanathan, C. Synlett 2002, 4, 649–650.
(13) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett.
2002, 4, 1127–1130.
(14) Kobayashi, S. Eur. J. Org. Chem. 1999, 15–27.
(15) Hashemi, M. M.; Eftekhari-Sis, B.; Abdollahifar, A.; Khalili, B.
Tetrahedron 2006, 62, 672–677, and references cited therein.
J. Org. Chem. Vol. 73, No. 14, 2008 5655

TABLE 2. Substrate Scope for the F-C Reaction
FIGURE 3. Plausible reaction mechanism of 1 and indole catalyzed
by 1 equiv of Bi(OTf)3.
occurred with Bro¨nsted acids triflic acid or hydrogen hydro-
chloride, nor heterogeneous LAs such as Amberlyst or mont-
morillonite (Table 1, entries 20-23).
entry
indole
MXn
product yield (%)
1
2
3
4
5
6
7
8
indole (2a)
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
4a
4b
4c
4d
4e
4f
75
60
66
52
35
77
65
80
63
57
62
50
61
N-methylindole (2b)
2-methylindole (2c)
2-phenylindole (2d)
To explain the switchable regioselectivity of the reaction by
changing the characteristics of the LA, we carried out 1H NMR
experiments. First, we examined the Michael addition reaction
(ꢀ-regioselectivity) performed with EtAlCl2. The 13C NMR
N-methyl-2-methyl indole (2e) EtAlCl2
5-methoxyindole (2f)
5-bromoindole (2g)
5-fluoroindole (2h)
4-methoxyindole (2i)
6-chloroindole (2j)
indole (2a)
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
4g
4h
4i
experiments reported by Avenoza et al.18 and our H NMR
1
9
experiments (see the Supporting Information) suggest that the
nucleophilic oxygen of the amide is the coordination site of
the metal without activating the electron-deficient alkene. In
the EtAlCl2:1 complex (1:1) spectrum we observed line
broadening of the H3b, methyl amide, and NH signals (Figure
2) due to rapid chemical exchange between the free and bonded
substrate. These changes provide further evidence of aluminum
coordination of the amide carbonyl. A similar study on the
EtAlCl2:1 complex (2:1) showed the broadening of all the
protons. These facts can be interpreted in terms of coordination
of the second equivalent of EtAlCl2 to the ester carbonyl oxygen,
which probably causes a decrease in the LUMO energy of
this olefin and therefore makes the reaction more effective
(Figure 2).
10
11
12
13
4j
3a
3b
3c
N-methylindole (2b)
5-bromoindole (2g)
under the optimal reaction conditions (Table 2). All the
substituted indole derivatives underwent the F-C reaction
smoothly to give the corresponding ꢀ-substituted alanines (4a-j)
in good to excellent yields. The presence of a substituent either
on the indole nitrogen ring or on the aromatic ring did not affect
the Michael addition. With regard to the substituent effect on
the indole ring, neither electron-donating groups (Table 2, entries
6 and 9) nor electron-withdrawing groups (Table 2, entries 7,
8, and 10) on the indole affected the efficiency of the reaction.
In addition, N-methylindole, as well as indoles substituted with
methyl and phenyl group in the 2 position, provided the desired
products (Table 2, entries 2-5).
In conclusion, we have developed for the first time an efficient
reaction between R-amidoacrylates and indoles in the presence
of transition metal salts where the regioselectivity outcome can
be modulated by tuning the oxo- and aza-philic nature of the
LA. The process highlights the use of R,ꢀ-dehydroamino acids
as versatile substrates in C-C bond forming reactions, opening
new opportunities for applications in synthesis and biology. The
reaction was even further extended to include several mono-
substituted indoles and was applied to the synthesis of different
natural and unnatural tryptophanes.
Second, regarding the R-regioselective addition (product 3a),
we imagined that the more azaphilic LA initially facilitates the
tautomerization of enamide to N-acylimine, with the latter
reacting with indole. A similar intermediate already has been
proposed in the Bro¨nsted acid-catalyzed enantioselective F-C
reaction of indoles and R-arylenamides.19 To obtain insight into
1
the reaction mechanism, we performed a H NMR experiment
on the Bi(OTf)3:1 complex (1:1) (see the Supporting Informa-
tion). The spectrum showed the full conversion of the olefinic
protons to three singlets corresponding to the three methyl
groups of the N-acylimine tautomer (Figure 3). Clearly, the more
azaphilic LA plays an important role in the inversion of the
regioselectivity of the F-C reaction.
It is noteworthy that while enamides have generally been used
as nucleophiles in acid-catalyzed reactions, compound 1 plays
the role of the electrophile in this reaction system with indoles.
Remarkably, this represents an easy route to unnatural R-amino
acids containing quaternary carbon centers bearing a nitrogen
atom (R,R-disubstituted glycine). Therefore, the present activa-
tion mode is regarded as an efficient alternative to the generation
of aliphatic N-acylimines, which are generally labile and difficult
to isolate.
Experimental Section
A Typical Procedure for the Preparation of 3-Tryptophane
Derivatives (4a-j). A 1 M solution of EtAlCl2 in hexane (2 mmol,
2 mL) was added dropwise to a stirred and cooled (0 °C) mixture
of methyl 2-acetamidoacrylate 1 (143 mg, 1 mmol) and indole (2a)
or substituted indoles 2b-j (1,5 mmol) in dry CH2Cl2 (4 mL) under
a nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h,
then carefully poured into an ice-cold saturated aqueous sodium
hydrogen carbonate solution (10 mL). The resulting suspension of
Al(OH)3 was filtered through Celite and the aqueous layer was
extracted with dichloromethane. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(column size: 15 × 1.5 cm2) on silica gel to give the product 4a-j.
To demonstrate the scope and potential of the present reaction,
we next examined a series of indole derivatives 2a-j with 1
(16) For an outstanding review, see: Stephen, A.; Hashmi, K.; Hutchings,
G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936.
(17) Gaspard-Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004, 12,
2517–2532, and references cited therein.
1
For compound 4b: TLC (EtOAc 100%), Rf 0.49 (UV, CAM); H
(18) Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M.; Perez-Fernandez,
M. Org. Lett. 2005, 16, 3597–3600.
NMR (200 MHz, CDCl3) δ 1.97 (s, 3H, NHCOCH3), 3.30 (dd,
2H, J1 ) 5.3 Hz, J2 ) 1.1 Hz, CH2), 3.71 (s, 3H, COOCH3), 3.75
(s, 3H, NCH3), 4.89-4.98 (m, 1H, CH), 5.98 (br d, 1H, J ) 7.5
(19) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2007, 46, 5565–5567.
5656 J. Org. Chem. Vol. 73, No. 14, 2008

Hz, NHCOCH3), 6.83-7.53 (m, 5H, ArH); 13C NMR (50 MHz,
CDCl3) δ 172.3, 169.6, 136.7, 128.1, 127.2, 121.6, 119.0, 118.4,
della Ricerca). We would like to thank Prof. Gilberto Spadoni
for useful discussions.
109.2, 108.3, 53.0, 52.1, 32.5, 27.3, 23.0; FTIR (CH2Cl2) νmax
/
cm-1 3293 (br), 2951 (m), 1743 (s), 1655 (s), 1545 (s); MS (ESI)
275 (M + 1). Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N,
10.21. Found: C, 65.69; H, 6.62; N, 10.22.
Supporting Information Available: Experimental proce-
dures, characterization, and spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was partially supported by the
Italian M.I.U.R. (Ministero dell’Istruzione, dell’Universita` e
JO800881U
J. Org. Chem. Vol. 73, No. 14, 2008 5657