Catalytic enantioselective alkylation of heteroaromatic compounds using alkylidene malonates

Article abstract of DOI:10.1039/b009008p

A catalytic enantioselective alkylation of heteroaromatic compounds using alkylidene malonates has been developed; the reaction proceeds for different heteroaromatic compounds with alkylidene malonates in high yield and enantiomeric excess.

Full text of DOI:10.1039/b009008p

Catalytic enantioselective alkylation of heteroaromatic compounds using
alkylidene malonates
Wei Zhuang, Tore Hansen and Karl Anker Jørgensen*
Center for Metal Catalysed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark.
E-mail: kaj@kemi.aau.dk
Received (in Cambridge, UK) 8th November 2000, Accepted 15th January 2001
First published as an Advance Article on the web 7th February 2001
A catalytic enantioselective alkylation of heteroaromatic
compounds using alkylidene malonates has been developed;
the reaction proceeds for different heteroaromatic com-
pounds with alkylidene malonates in high yield and
enantiomeric excess.
Table 1 Screening of chiral Lewis acids and reaction conditions for the
reaction of indole 1a with alkylidene malonate 2a
Conv.a
(%)
Eebc
(%)
Entry
Catalyst
Solvent
MeCN
X
1
2
3
4
5
6
(S)-4a-CuX
(S)-4a-CuX
(S)-4a-CuX2
(S)-4b-ZnX
(S)-4a-CuX
(S)-4a-CuX
(S)-4a-CuX
(S)-4a-CuX
2
OTf
OTf
OTf
OTf
OTf
OTF
—
—
95
89
91
71
92
93
—
—
60
8d
60 (93)
57
35
The addition of aromatic C–H bonds to alkenes, the Friedel–
2
MeNO
2
Crafts alkylation, is a highly important reaction in synthetic
Et O
2
1
chemistry for the formation of new C–C bonds. A challenge for
2
2
2
2
2
Et
2
O
the Friedel–Crafts alkylation is to perform the reaction in a
catalytic enantioselective fashion as this would be a simple and
attractive method for the synthesis of optically active aromatic
compounds using easily available starting materials. The first
examples of catalytic enantioselective addition reactions of
aromatic compounds to conjugated compounds such as carbon-
THF
CH
CH
2
Cl
Cl
2
2
e
7
2
SbF
OTf
6
f
8
Et
2
O
57
a
Determined by 1H-NMR spectroscopy. b Determined by chiral HPLC.
c
e
d
Number in parentheses is ee after recrystallization. Opposite enantiomer.
f
Reaction performed at 0 °C. No HFIP used.
2
yls and imines have recently appeared. In the following we will
present the first catalytic enantioselective alkylation of hetero-
aromatic compounds using alkylidene malonates catalyzed by
chiral Lewis acids.
2 2
CH Cl giving high conversion at 0 °C, however, the ee of 3a
dropped from 57 to 35% ee (entry 6 and 7). The effect of
addition of HFIP to the reaction was found to be negligible; the
reaction rate decreased only slightly and the ee was essentially
3
The reaction of indole 1a with alkylidene malonate 2a in the
presence of the chiral bisoxazoline–metal(II) complexes, (S)-4a-
4
Cu(II), (S)-4b-Zn(II), as the catalysts proceeds well giving the
5
unchanged in the absence of HFIP (entry 3 vs. 8). The effect of
Friedel–Crafts alkylation adduct 3a in good yield and high ee
other parameters such as lower catalyst loading, concentration
and temperature all gave lower conversion to 3a with very little
increase in ee.
[
eqn. (1)]. Table 1 gives some representative results for the
screening of catalysts and reaction conditions.
A selection of b-substituted alkylidene malonates 2a–e were
examined in this reaction with indole 1b catalyzed by (S)-4a-
Cu(OTf)
Friedel–Crafts alkylation product 3b in 73% yield and 60% ee
entry 1).† The dimethyl benzylidene malonate 2b was
significantly more reactive compared to the diethyl derivative
2a) giving the addition product in 95% isolated yield, however,
2
(Table 2). Indole 1b reacted with 2a to give the
(
(
the ee was lower for 3b (entry 1 vs. 2). The reactivity of
dimethyl p-nitrobenzylidene malonate 2c was comparable to
2
b, and product 3d was formed in high yield and with 56% ee
(1)
Table 2 Reaction of indole 1b with various b-substituted alkylidene
malonates 2a–e catalyzed by (S)-4a-Cu(OTf)
2
The reactions were performed with 2 eq. of hexafluoro-i-
5
PrOH (HFIP) and 10% catalyst loading. No reaction took place
with (S)-4a-Cu(OTf)
Et O high conversion to 3a and good ee was achieved (entries
–3). The catalyst (S)-4b-Zn(OTf) also gave high conversion,
however, the enantioselectivity was low (entry 4). The catalytic
activity of (S)-4a-Cu(OTf) in THF was very good and 3a was
obtained in 91% yield and 60% ee (entry 5). The activity
2 2
in MeCN or MeNO as solvents, while in
2
1
2
2
increased further by changing counterion from OTf to SbF
6
in
DOI: 10.1039/b009008p
Chem. Commun., 2001, 347–348
347
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(
entry 3). The diethyl 2-chlorobenzylidene malonate derivative
e was considerably less reactive compared to the other
In summary, a new catalytic enantioselective alkylation of
2
heteroaromatic compounds using alkylidene malonates cata-
lyzed by chiral bisoxazoline–copper(II) complexes has been
presented. The reactions proceed in high yields and with
moderate ee for different aromatic compounds and alkylidene
malonates. The optical purity of the products can be enhanced
by recrystallization and it is demonstrated that the reaction can
be considered as a formal Friedel–Crafts alkylation of cinna-
mates.
malonates and required a 30 °C reaction temperature for the
reaction to go to completion. The enantioselectivity of 3f was
6
9% ee, the highest enantioselectivity obtained in this selec-
tion.
Dimethyl p-nitrobenzylidene malonate 2c was then used as a
standard substrate to probe the reactivity of different aromatic
compounds 1a, c–f in this Friedel–Crafts alkylation reaction
[eqn. (2)] (Table 3).
We are indebted to The Danish National Research Founda-
tion for financial support.
(2)
Notes and references
†
Representative experimental procedure:
Cu(OTf) (18 mg, 0.05 mmol) and (S)-4a-Cu(OTf)
was dried under vacuum for 1 h. THF (1 mL) was added under N
A
powdered mixture of
(16 mg, 0.054 mmol)
and the
2
2
Table 3 Friedel–Crafts alkylation reaction of different heteroaromatic
compounds 1a, c–g with dimethyl p-nitrobenzylidene malonate 2c cata-
2
solution stirred for 1 h. Compound 2a (113 mL, 0.5 mmol) was added and
stirred for 15 min, followed by addition of 1b (65 mg, 0.55 mmol). After 24
h the reaction mixture was filtered through a plug of silica gel, washed with
lyzed by (S)-4a-Cu(OTf)
2
a
Eebc (%)
Et
solid in 73% yield after purification by chromatography (CH
The ee was determined by HPLC analysis to be 60% (Chiralpack AS, 1.0
2
O, and the solvent removed. The product 3b was obtained as a white
Entry
Ar
Yield (%)
2
Cl as eluent).
2
d
1
5-MeO-indole–1a
4-Cl-indole–1c
N-Me-indole–1d
N-Me-pyrrole–1e
Pyrrole–1f
3g–99
3h–62
3i–99
3j–99
3k–99
3l–99
b
58
46
48
36
28
12
e
mL min , 95:5 hexane–i-PrOH, R
21
t
= 23 (major) and 26 (minor) min).
2
3
4
5
6
a
d
H
(C O, 400 Hz) 10.1 (s, 1H), 7.56 (m, 1H), 7.47 (m, 3H), 7.33 (m, 1H),
7.21 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 5.03 (d, J = 11.6
Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.92 (q, J =
3 6
D
2-Me-furan–1g
7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); d
C
(C
00 Hz) 167.7, 167.6, 142.5, 136.9, 128.6, 128.3, 127.1, 126.6, 121.7,
21.6, 119.0, 118.9, 116.7, 111.4, 60.9, 58.9, 43.0, 13.5; HRMS (ES) calcd
3 6
D O,
1
1
Isolated yield after column chromatography. Determined by chiral
c
d
HPLC. Determined by chiral HPLC. Reaction performed at 0 °C.
Reaction performed at 30 °C.
+
for C22
H
23NO
4
365.1627, found (M + Na) 388.1525; mp 164–167 °C;
e
2
0
21
[a]
D
= +37.1° (69 mg mL CHCl ).
3
The reaction with 5-methoxyindole 1a gave the Friedel–
Crafts alkylation product 3g in excellent yield and with 58% ee
1
For reviews of Friedel–Crafts alkylation reactions see e.g.: (a) G. A.
Olah, R. Krishnamurit and G. K. S. Prakash, Friedel–Crafts Alkylation in
Comprehensive Organic Synthesics, ed. B. M. Trost and I. Flemming,
Pergamon Press, Oxford, (1st Edn.) 1991, Vol III, p. 293; (b) R. M.
Roberts and A. A. Khalaf, Friedel–Crafts Alkylation Chemistry A
Century of Discovery, Dekker, New York, 1984; (c) G. A. Olah, Friedel–
Crafts and Related Reactions, Wiley-Interscience, New York, 1964, Vol.
II, part 1.
(
3
entry 1). 4-Chloroindole 1c reacted to give the desired product
h, although in a lower yield and ee compared to the more
electron-rich indole (entry 2). N-Methylindole 1d and N-
methylpyrrole 1e both yielded the alkylation products 3i and 3j,
respectively, with great efficiency and with a small drop in ee
(entries 3, 4). Both pyrrole 1f and 2-methylfuran 1g reacted in
2
Activated carbonyl compounds: (a) F. Bigi, G. Casiraghi, G. Casnati, G.
Sartori, G. Fava and M. F. Belicchi, J. Org. Chem., 1985, 50, 5018; (b)
A. Ishii, V. A. Soloshonok and K. Mikami, J. Org. Chem., 2000, 65,
a Friedel–Crafts fashion in excellent yields, but the enantiose-
lectivity of the products was low compared to the other
substrates (entries 5, 6).
A further advantage of this Friedel–Crafts alkylation reaction
is that the products all are solid and the optical purity can be
greatly enhanced to > 90% ee by crystallization as shown for
several of the entries in Table 1, 2.
1
597; (c) A. Ishii and K. Mikami, J. Fluorine Chem., 1999, 97, 51; a-
dicarbonyl compounds: (d) G. Erker and A. A. H. Zeijden, Angew.
Chem., Int. Ed. Engl., 1990, 29, 512; (e) N. Gathergood, W. Zhuang and
K. A. Jørgensen, J. Am. Chem. Soc., 2000, 122, 12517; (f) W. Zhuang, N.
Gathergood, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., in press;
imines: (g) M. Johannsen, Chem. Commun., 1999, 2233; (h) S. Saaby, X.
Fang, N. Gathergood and K. A. Jørgensen, Angew. Chem., Int. Ed., 2000,
The Friedel–Crafts adducts such as 3b can undergo decarbox-
6
ylation to give the mono ester 5 in high yield [eqn. (3)],
3
9, 4114.
showing that the present reaction formally can be considered as
a Friedel–Crafts alkylation of cinnamates.
3
4
For enantioselective Lewis acid catalyzed Michael reactions of alkyli-
dene malonates see: D. A. Evans, T. Rovis, M. C. Kozlowski, C. W.
Downey and J. S. Tedrow, J. Am. Chem. Soc., 2000, 122, 9134.
For recent reviews see (a) J. S. Johnson and D. A. Evans, Acc. Chem.
Res., 2000, 33, 325; (b) K. A. Jørgensen, M. Johannsen, S. Yao, H.
Audrain and J. Thorhauge, Acc. Chem. Res., 1999, 32, 605; (c) A. K.
Ghosh, P. Mathivanan and L. Cappiello, Tetrahedron: Asymmetry, 1998,
(3)
9
, 1.
5
6
Addition of HFIP was crucial for catalytic activity in the Micheal addition
of silylketene acetals to alkylidene malonate see ref 4.
A. P. Krapcho, Synthesis, 1982, 805.
348
Chem. Commun., 2001, 347–348