Carbon-carbon bond formation in neutral aqueous medium by modification of the Nozaki-Hiyama reaction

Article abstract of DOI:10.1016/S0040-4039(01)01638-0

A carbon-carbon bond forming reaction has been developed by modifying the Nozaki-Hiyama reaction using a chromium(II)-aminopolycarboxylate complexes in a neutral aqueous medium at room temperature. Aldehydes and ketones can be coupled with aralkyl and aryl halides in good yields.

Full text of DOI:10.1016/S0040-4039(01)01638-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7711–7713
Carbonꢀcarbon bond formation in neutral aqueous medium by
modification of the Nozaki–Hiyama reaction
K a´ roly Micskei,* Attila Kiss-Szikszai, Julianna Gyarmati and Csongor Hajdu
Department of Chemistry, Faculty of Natural Sciences, University of Debrecen, H-4010 Debrecen, Egyetem t e´ r 1,
PO Box 21, Hungary
Received 19 June 2001; revised 24 August 2001; accepted 30 August 2001
Abstract—A carbonꢀcarbon bond forming reaction has been developed by modifying the Nozaki–Hiyama reaction using a
chromium(II)-aminopolycarboxylate complexes in a neutral aqueous medium at room temperature. Aldehydes and ketones can be
coupled with aralkyl and aryl halides in good yields. © 2001 Elsevier Science Ltd. All rights reserved.
2−
A selective carbonꢀcarbon bond forming reaction was
Cr(EDTA)
medium.
complex in the so-called biomimetic
1
15
described by Nozaki and Hiyama in 1977 based on the
addition of alkenyl, alkynyl, allyl or vinylchromium(III)
compounds to aldehydes in a mild anhydrous medium.
In this work we demonstrate that the Nozaki–Hiyama
reaction after modification, can be used in a neutral
2
The use of CrCl in anhydrous DMF resulted in well
2
2
established reaction conditions. A catalytic amount of
aqueous medium. The selectivity of these reactions can
10,13,15
NiCl in the reaction mixture increased the chemoselec-
be regulated by added ligands.
2
tivity of numerous CꢀCꢀbond forming reactions (the
3
,4
5
Nozaki–Hiyama–Kishi reaction ). F u¨ rstner proposed
a catalytic solution for Cr(II) using reactive Mn powder
as the electron source reducing the cost of the reagent
and the amount of toxic salts. The detailed evaluation
and wide-ranging applications of the use of
organochromium(III) reagents for CꢀC bond formation
To get the best reaction conditions, benzaldehyde (1)
II
and benzyl bromide (3) were reacted with Cr L com-
plexes (L=acetate (OAc); imino-diacetate (IDA);
nitrilo-triacetate (NTA); ethylenediaminetetra-acetate
(EDTA) in neutral aqueous/DMF solution at room
temperature. 1,2-Diphenylethanol (7) as well as the
by-products, toluene (11), benzyl alcohol (12), 1,2-
6–9
have been abundantly reviewed.
Our recent results have shown, that Cr(II)-based syn-
thetic chemistry can be transferred to a neutral aqueous
diphenylethane (13) and 1,2-diphenyl-1,2-ethanediol
(14) were detected in the crude product mixtures (see
Table 1).
1
0,11
12
medium
and that the chemo as well as the
13,14
enantioselectivity
can be regulated carefully by
added ligands. Intramolecular carbonꢀcarbon bond for-
In a typical experiment, Na EDTA·2H O (4.66 g, 12.5
2
2
3
mation was executed on the morphine skeleton using a
mmol) was dissolved in 7.2 cm aqueous 2.78 M KOH
−
3
solution (40 mmol OH ) and 7.8 cm water at room
temperature in a three-necked flask using standard
Keywords: Nozaki–Hiyama reaction; chromium(II) complex; car-
bonꢀcarbon bond; organochromium(III) complexes.
3
Schlenk-techniques. DMF (15 cm ) was then added and
the magnetically stirred solution was deoxygenated by
*
Corresponding author. Tel.: +36-52-512-900; fax: +36-52-489-667;
bubbling with argon for 15 min. Then [Cr(OAc) ·H O]
e-mail: kmicskei@delfin.klte.hu
2
2
2
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01638-0

7
712
K. Micskei et al. / Tetrahedron Letters 42 (2001) 7711–7713
II
Table 1. Reaction of benzaldehyde and benzyl bromide with Cr L complexes
II
%a,b,e,f
12
Entry
1 (mmol)
3 (mmol)
Ligand
Cr L (mmol)
pH
Method
7
1
14
II
c
c
c
c
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
10
10
10
10
10
10
10
5
OAc
IDA
NTA
EDTA
EDTA
EDTA
EDTA
EDTA
20
20
20
20
20
20
20
10
5.5
6.5
6.5
6.0
6.0
6.0
6.0
6.0
Cr L+(1+3)
–
8
26
32
6
5
87
89
69
49
22
19
10
19
–
31
43
49
25
50
61
8
–
–
3
24
34
15
5
II
Cr L+(1+3)
II
Cr L+(1+3)
II
Cr L+(1+3)
II
d
Cr L+1+3
II
d
Cr L+3+1
II
(1+3)+Cr L
(1+3)+Cr L
II
–
6
5
a
Calculated from the 1H NMR spectra and HPLC chromatograms.
b
c
d
e
f
Calculated for 1.
Mixture of 1 and 3 was added dropwise within 10 min as suggested by Nozaki and Hiyama.
First 1 or 3 was added to Cr L in one portion and after 60 seconds 1 or 3 in one portion.
II
1
3<5%.
1
1 not measured (can be calculated from the mass balance).
(
1.88 g, 10 mmol Cr(II)) was added in one portion
highest conversion of (7) was reached when the
2−
under argon, and the color of the solution immediately
turned blue indicating the formation of the reactive
Cr(EDTA) complex was added slowly to the mixture
of (1) and (3) (entry 7). The 1:2:4 carbonyl:halide:Cr(II)
ratio suggested by Nozaki and Hiyama (entries 1–7)
could be decreased to 1:1:2 under then reaction condi-
tions (entry 8).
†
II
2−
complex [Cr (EDTA)] . The pH of the solution was
.0 (checked by pH-potentiometry) and the solution
was poured into a dropping funnel under argon. In
6
3
3
another three-necked flask, 10 cm water and 10 cm
Using the optimal reaction conditions further car-
bonꢀcarbon bond formation reactions can be realized
with good or moderate yields (Table 2). Acetophenone
(2) as well as the less reactive chlorides (4, 6) can also
be coupled as a result of the increased reactivity pro-
vided by the EDTA ligand.
DMF was deoxygenated with argon and then 0.53 g (5
mmol) benzaldehyde and 0.86 g (5 mmol) benzyl bro-
mide were added into the solvent mixture. The
II
2−
[
Cr (EDTA)] solution was added dropwise to the
benzaldehyde-benzyl bromide mixture under argon
within 60 min. The color of the reaction mixture
changed slowly to dark violet. The reaction vessel was
than stoppered under a slight overpressure of argon,
Our results open new possibilities in the development of
the classical Nozaki–Hiyama reaction. The neutral
aqueous medium seems to be ideal for application in
various natural product synthesis. The selectivity con-
trolled by the complex reagents may allow chiral lig-
ands to lead to the enantioselective reactions. This
work is in progress in our laboratory.
‡
and stirring was continued for 6 h.
Using Cr(OAc) as reductant (entry 1) unchanged start-
2
ing aldehyde (1) and side products (11, 12, 13) were
found in the crude mixture. Modifying the coordination
sphere of the Cr(II) reagent by adding ligands to give
−
2−
the Cr(IDA), Cr(NTA) and Cr(EDTA) complexes,
gave the coupled product (7) in low–moderate quanti-
ties (entries 2–4). The formation of (7) fell when the
substrates were added separately (entries 5, 6). The
Acknowledgements
Financial support of this work are acknowledged to the
Hungarian Scientific Research Foundation (Grants
OTKA, No. T33130 and No. T32429) and the Hungar-
†
‡
II
For the preparation of the Cr L complexes solution equilibrium
calculations16 using the known formation constants17 gave the
desired pH.
The mixture was extracted with ether (5×), the ethereal phase was
washed with water (3×), than dried with Na SO . The solvent was
evaporated under diminished pressure. The analyses were also
controlled by isolating (3). The main product was separated using
column chromatography, (Kieselgel 60, hexane/acetone (6:1)) and
was identified by H and C NMR (Bruker AM 360) spectra. The
isolated products had all characteristics identical with that of an
authentic sample. The raw mixtures were analysed by HPLC per-
formed on a Chiralcel OJ (250×4.6 mm) column equipped with a
BST-silica precolumn (40×4.6 mm). The column was attached to a
Jasco PU-980 solvent delivery system and pressure moderator.
Peaks were monitored by UV detection using a Jasco MD-910
diode array detector. Solvent mixture hexene/2-propanol 95:5 (v/v)
2−
Table 2. Coupling reactions with the Cr(EDTA) com-
plex
2
4
Entry
Substrate
Product
Yield (%)a
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
3
4
5
6
3
4
5
6
7
7
9
9
8
8
10
10
78
72
70
66
68
64
61
59
1
13
3
−1
a
was used, the flow rate was 0.8 cm min
.
Isolated yields calculated for the carbonyl compounds.

K. Micskei et al. / Tetrahedron Letters 42 (2001) 7711–7713
7713
ian Ministry of Education (Grant: FKFP 0614/2000).
The J a´ nos Bolyai Research Scholarship (K. Micskei) was
8. Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36.
9. F u¨ rstner, A. Chem. Rev. 1999, 99, 991–1045.
also supported by the Hungarian Academy of Sciences.
10. Kov a´ cs, G.; Gyarmati, J.; Soms a´ k, L.; Micskei, K. Tet-
rahedron Lett. 1996, 37, 1293–1296.
1
1
1
1. Kov a´ cs, G.; Micskei, K. Tetrahedron Lett. 1997, 38,
References
9055–9056.
2. Kov a´ cs, G.; T o´ th, K.; Dinya, Z.; Soms a´ k, L.; Micskei,
K. Tetrahedron 1999, 55, 5253–5264.
3. Gyarmati, J.; Hajdu, C.; Dinya, Z.; Micskei, K.; Zuc-
chi, C.; P a´ lyi, G. J. Organomet. Chem. 1999, 586, 106–
1
2
3
4
. Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 3179–3181.
. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki,
H. Tetrahedron Lett. 1983, 24, 5281–5284.
. Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem.
Soc. 1986, 108, 5644–5646.
. Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Uti-
moto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108,
048–6050.
. F u¨ rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118,
2349–12357.
109.
1
1
4. Patonay, T.; Hajdu, C.; Jeko, J.; L e´ vai, A.; Micskei, K.;
Zucchi, C. Tetrahedron Lett. 1999, 40, 1373–1374.
5. Micskei, K.; Gyarmati, J.; Kov a´ cs, G.; Makleit, S.;
Simon, C.; Szab o´ , Z.; Marton, J.; Hosztafi, S.; Reinke,
H.; Drexler, H.-J. Eur. J. Org. Chem. 1999, 149–153.
6. Z e´ k a´ ny, L.; Nagyp a´ l, I. In Computational Methods for the
Determination of Formation Constants; Leggett, D. J.,
Ed.; Plenum Press: New York, 1985; pp. 291–353.
6
5
1
1
6
7
. Cintas, P. Synthesis 1992, 11, 248–257.
. Saccomano, N. A. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: London,
17. Micskei, K.; Debreczeni, F.; Nagyp a´ l, I. J. Chem. Soc.,
Dalton Trans. 1983, 1335–1338.
1
991; Vol. 1, pp. 173–208.