Friedel-Crafts reactions in water of carbonyl compounds with heteroaromatic compounds

Article abstract of DOI:10.1039/b202352k

The development of Friedel-Crafts reaction in H₂O of carbonyl compounds is presented; a series of different heteroaromatic compounds react with ethyl glyoxylate to give the Friedel-Crafts addition adducts in good yields in various H₂O solutions.

Full text of DOI:10.1039/b202352k

Friedel-Crafts reactions in water of carbonyl compounds with
heteroaromatic compounds
Wei Zhuang and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark.
E-mail: kaj@chem.au.dk; Fax: (45)-86196199
Received (in Cambridge, UK) 12th March 2002, Accepted 8th May 2002
First published as an Advance Article on the web 21st May 2002
The development of Friedel-Crafts reaction in H2O of
carbonyl compounds is presented; a series of different
heteroaromatic compounds react with ethyl glyoxylate to
give the Friedel-Crafts addition adducts in good yields in
various H2O solutions.
the Friedel-Crafts reaction in a 1M NaHSO4 solution (pH =
5.5), a 1M NaCl solution (pH = 7) and in distilled H2O (pH =
7) only the double addition adduct 3aa is formed (entries
10–13).
Table 1 Reaction of N-methylindole 1a with ethyl glyoxylate 2 in various
H2O solutions
One of the fundamental challenges and ultimate goals for
reactions of organic molecules is to perform the reaction in
water,1 because the application of water would reduce the use of
harmful organic solvents and lead to the development of
environmentally friendly processes.
A further challenge is to perform catalytic organic reactions
in water, which normally require strict reaction conditions in
organic solvents in order for the catalyst to be usable. In recent
years focus has been on Lewis-acid catalyzed organic reactions
in water and several important reactions are beginning to be
developed.2
The Friedel-Crafts reaction is one of the most important
Lewis-acid catalyzed reactions for the formation of C–C bonds
to aromatic compounds.3 These reactions normally require one
equivalent of a strong Lewis acid, such as AlCl3, and strict
reaction conditions in order to proceed.3 A major step towards
more environmentally friendly conditions for this important
class of reactions would be to perform the reactions in water and
without the use of the traditional Lewis-acid catalysis.4
This communication shows that Friedel-Crafts reactions of
activated carbonyl compounds with heteroaromatic compounds
can successfully take place in H2O without the normally used
Lewis/Brønsted acid catalysts.5,6
Yield 3aa
(%)
Yield 3aaa
(%)
Entry
Solution
pH
1
2
1M Na2CO3
11.3
8.7
8.7
8.0
8.0
8.0
7.5
7.1
6.4
6.0
5.5
7.0
7.0
17
87
95
87
90
74
87
82
63
34
0
0
0
0
0
0
0
0
2
16
54
74
68
62
Sat. NaHCO3
Sat. NaHCO3
1M NaHCO3
1M NaHCO3
1M KHCO3
3b
4
5b
6
7
8
9
10
11
12
13
NaH2PO4–Na2HPO4
NaH2PO4–Na2HPO4
NaH2PO4–Na2HPO4
NaH2PO4–Na2HPO4
1M NaHSO4
1M NaCl
H2O
0
0
a Isolated yield. b Double amount of ethyl glyoxylate 2 relative to N-
methylindole.
The results in Table 1 show that the NaHCO3–H2O solution
has unique properties for the Friedel-Crafts reaction and it
should be noted that no Friedel-Crafts product is formed if e.g.
N-methylindole 1a and ethyl glyoxylate 2 are mixed in an
organic solvent such as CH2Cl2 in the absence of a catalyst. It is
interesting also to compare the reaction conditions for the
present reaction which takes place in water, with e.g. the
reaction of a closely related a-carbonyl ester, ethyl pyruvate,
with aromatic compounds, which proceeds only in dry organic
solvents using AlCl3 or TiCl4 (one equivalent).7 Furthermore, it
should be emphasized that Lewis-acid catalyzed reactions of
glyoxylates normally require that the glyoxylate is freshly
distilled before use. For the present reaction ethyl glyoxylate
can be used directly after preparation from maleate,†from
which it exists to a high extent as a polymer, without taking any
precautions.
The reaction of N-methylindole 1a with ethyl glyoxylate 2†
[eq. (1)] was used for the screening process. Table 1 shows
some results from the screening and optimisation process.
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In a 1M Na2CO3 solution (pH 11.3) N-methylindole 1a reacts
with ethyl glyoxylate 2 to give the Friedel-Crafts addition
adduct 3a in only 17% yield (Table 1, entry 1). However,
reducing the basicity of the Na2CO3–H2O solution (pH 8.7–7.5)
leads to a solvent composition where a smooth Friedel-Crafts
reaction takes place and 3a was isolated in up to 90% yield
(entries 2–7). If the H2O solution is slightly acidic (pH 7.5–6.4)
applying a NaH2PO4–Na2HPO4 buffer system, the amount of
double addition adduct 3aa formed increases (entries 8–10), and
at pH 6, 54% of 3aa is formed in excess (entry 10). Performing
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CHEM. COMMUN., 2002, 1336–1337
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The results for Friedel-Crafts reaction for a series of different
indoles 1b–e with ethyl glyoxylate 2 [eq (2)] and using a buffer
solution (1M NaH2PO4–Na2HPO4) are presented in Table 2.
obtained depending of the amount of ethyl glyoxylate used.
Further work is in progress to develop catalytic enantioselective
Friedel-Crafts reactions in water.
We are indebted to The Danish National Research Founda-
tion for financial support.
Table 2 Reaction of different indoles 1b–e with ethyl glyoxylate 2 in a 1M
NaH2PO4–Na2HPO4
Yielda (%)
Notes and references
Entry
Indole
Reaction time (h)
pH
†
Procedure for preparing ethyl glyoxylate 2: A 500 ml round bottle flask
1
2
3
4
1b
1c
1d
1e
4
4
4
7.1
6.8
6.8
6.8
3b – 67
3c – 84
3d – 70
3e – 62
containing diethyl maleate (40 g) dissolved in 250 ml dry CH2Cl2 was
bubbled with O3 at 278 °C. When the colour of the solution changed to
blue, the reaction was quenched by 1.05 eq. Me2S at 278 °C and then
slowly warmed up to room temperature. After concentration in vacuum at
room temperature, the crude ethyl glyoxylate was kept at 224 °C.
General reaction conditions: Representative experimental procedure: To
a 10 ml tube was added 1M NaH2PO4–Na2HPO4 solution (2 ml).
Subsequently, 5-methylindole 1c (65.6 mg, 0.50 mmol) and non-distilled
ethyl glyoxylate 2 (0.25 ml) were added and reacted for 4 h. The solution
was adjusted to pH = 10 by sat. NaHCO3, then extracted by CH2Cl2, dried
by MgSO4. The product 3c was obtained by flash chromatography (10%
Et2O in CH2Cl2) in 84% yield. 1H NMR (CDCl3, 400 MHz) d 8.19 (s, 1H,
NH), 7.50 (s, 1H; Ar), 7.21 (d, J = 8.4 Hz, 1H; Ar), 7.10 (d, J = 2.8 Hz,
1H; Ar), 7.03 (dd, J = 8.4, 1.2 Hz, 1H; Ar), 5.43 (d, J = 6.0 Hz, 1H; CH),
4.30 (dq, J = 10.8, 6.8 Hz, 1H; CH2CH3), 4.16 (dq, J = 10.8, 6.8 Hz, 1H;
CH2CH3), 3.36 (d, J = 6.0 Hz, 1H; OH), 2.45 (s, 3H; CH3), 1.23 (t, J = 6.8
Hz, 3H; CH2CH3); 13C NMR (100 MHz) d 174.4, 135.0, 129.7, 125.8,
124.4, 123.7, 119.2, 113.4, 111.3, 67.6, 62.3, 21.8, 14.3; HRMS C13H15NO3
[M + Na]+ calculated 256.0950 found 256.0952.
30
a Isolated yield.
The reaction of the indoles having both electron-donating and
electron-withdrawing substituents (1b–e) proceeds well with
ethyl glyoxylate 2 in the 1M NaH2PO4–Na2HPO4 buffered
solution and the Friedel-Crafts adducts 3b–e are all isolated in
good yields (Table 2, entries 1–4).
The Friedel-Crafts reaction also proceeds well for pyrroles in
water; e.g. N-methylpyrrole 4a reacts with ethyl glyoxylate 2 in
a saturated NaHCO3 solution to give the 5a in 87% yield [eq
(3)].8 The Friedel-Crafts reaction of 2 with pyrrole 4b reacts in
a 1M NaHCO3–Na2CO3 solution to give to double addition of
ethyl glyoxylate to both the 2- and 5-positions of 4b and adduct
5b is obtained in 63% yield by using a large excess of 2 [eq
(4)].
1 See e.g.: Organic Synthesis in Water, ed. P. A: Grieco, Blackie Academic
and Professional, London, 1998; C.-J. Li and T. H. Chan, Organic
Reactions in Aqueous Media, John Wiley and Sons, New York, 1997; C.-
J. Li, Chem. Rev., 1993, 93, 2023; R. Breslow, Acc. Chem. Res., 1991, 24,
159.
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2 For recent reviews see e.g.: S. Kobayashi and K. Manabe, Acc. Chem.
Res., 2002, 35, 209 and references therein. See also: R. Sheldon, Chem.
Commun., 2001, 2399.
3 See e.g.: G. A. Olah, R. Khrisnamurti and G. K. S. Prakash,
Comprehensive Organic Synthesis, B. M. Trost and I. Fleming (Eds.),
Pergamon, New York, 1991, Vol. 3, pp. 293–339; R. M. Roberts and A.
A. Khalaf, Friedel-Crafts Alkylation Chemistry, A Century of Discovery,
Marcel Dekker, New York, 1984.
(4)
4 Recently the Sc(DS)3-catalyzed Friedel-Crafts alkylation of electron-
deficient alkenes with indole has been presented: K. Manabe, N. Aoyama
and S. Kobayashi, Adv. Synth. Catal., 2001, 343, 174.
5 Recent studies of the Lewis-acid catalyzed Friedel-Crafts reactions of
indole with carbonyl compounds gave mainly the double-addition
adducts: D. Chen, L. Yu and P. G. Wang, Tetrahedron Lett., 1996, 37,
4467.
6 Palladium-catalyzed reaction of N-methylindole with glyoxylate affords
mono-adduct 3a: J. Hao, S. Taktak, K. Aikawa, Y. Yusa, M. Hatano and
K. Mikami, Synlett,, 2001, 1443.
7 A. Citterio, M. Gandolfi, O. Piccolo, L. Filippini, L. Tinucci and E.
Valoti, Synthesis, 1984, 760.
The results show that the NaHCO3–H2O solution has unique
properties for the Friedel-Crafts reaction. However, at the
present stage of investigations we do not yet have sufficient
mechanistic details to account for the role of the solvent
composition in the selectivity of the reaction.
In summary, we have demonstrated the first Friedel-Crafts
reactions of carbonyl compounds with heteroaromatic com-
pounds in water without the use of the traditional Lewis acid
catalysis. The reactions proceed well for various indoles and the
Friedel-Crafts adducts are obtained in high yields. For pyrroles,
both addition to the 2-, as well as the 2- and 5-positions are
8 When a large excess of ethyl glyoxylate was used, the product of double
addition to both the 2- and 5-position of 4a was found.
CHEM. COMMUN., 2002, 1336–1337
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