Recoverable PEG-supported copper catalyst for highly stereocontrolled nitroaldol condensation

Article abstract of DOI:10.1021/ol070636w

A new polyethylene glycol)-modified DAT2-Cu(OAc)₂ complex smoothly catalyzes a base-free nitroaldol condensation in a highly enantioselective manner (ee up to 93%) also in reagent-grade solvent and in the presence of air. Effective recovery and

Full text of DOI:10.1021/ol070636w

ORGANIC
LETTERS
2
007
Vol. 9, No. 11
151-2153
Recoverable PEG-Supported Copper
Catalyst for Highly Stereocontrolled
Nitroaldol Condensation
2
Marco Bandini,*,† Maurizio Benaglia, Riccardo Sinisi, Simona Tommasi, and
‡
†
†
Achille Umani-Ronchi*,
†
Dipartimento di Chimica “G. Ciamician”, UniVersit a` di Bologna, Via Selmi 2,
40126 Bologna, Italy, and Dipartimento di Chimica Organica e Industriale,
UniVersit a` degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
marco.bandini@unibo.it; achille.umanironchi@unibo.it
Received March 15, 2007
ABSTRACT
2
A new poly(ethylene glycol)-modified DAT2−Cu(OAc) complex smoothly catalyzes a base-free nitroaldol condensation in a highly enantioselective
manner (ee up to 93%) also in reagent-grade solvent and in the presence of air. Effective recovery and recycling (up to five runs) of supported
catalysts are documented.
4
Nitroaldol condensations (commonly termed Henry reac-
tions) represent one of the most versatile and employed
in asymmetric Henry condensations. This aspect, in com-
1
5
bination with the peculiar atom economy of the reaction,
carbon-carbon forming transformations in natural product
synthesis. As a consequence, particular emphasis has been
would certainly expand the utility of enantioselective Henry
protocols for large-scale production of fine chemicals. During
our ongoing research focused on the stereoinductive proper-
2
2
addressed to the discovery of catalytic enantioselective
variants of this protocol, through the use of both bio- and
ties of C -symmetric diaminobithiophenes (DAT2, 1, Figure
3
6
7
chemocatalysis (organic as well as organometallic).
1) in metallo-catalyzed transformations, we demonstrated
8
Despite this flurry of activity, very little has been done
toward the recovering and reutilization of the active species
that the combination of 1 with Cu(OAc)2 (0.1-5 mol %)
smoothly promoted the condensation of nitromethane with
9
a variety of aldehydes in excellent enantiomeric excess. The
*
Corresponding author. Fax: 39 051 2099456. Tel: 39 51 2099509.
Universit a` di Bologna.
Universit a` degli Studi di Milano.
†
ready synthetic accessibility and facile manipulation of
‡
(
1) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
(
2) (a) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
(4) For studies regarding stereoselective Henry reactions under hetero-
geneous conditions, see: (a) Choudary, B. M.; Ranganath, K. V. S.; Pal,
U.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167. (b)
Bhatt, A. P.; Pathak, K.; Jasra, R. V.; Kureshy, R. I.; Khan, N. H.; Abdi,
S. H. R. J. Mol. Catal. A: Chem. 2006, 244, 110. (c) Arai, T.; Watanabe,
M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew. Chem., Int. Ed.
2006, 45, 5978.
Ed.; Pergamon: Oxford, 1996. (b) Luzzio, F. A. Tetrahedron 2001, 57,
9
15. (b) Ono, N. In The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
3) (a) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed.
004, 43, 5442. (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
(
2
Tetrahedron: Asymmetry 2006, 17, 3315. (c) Palomo, C.; Oiarbide, M.;
Laso, A. DOI: 10.1002/ejoc.200700021.
(5) Trost, B. M. Science 1991, 254, 1471.
1
0.1021/ol070636w CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/05/2007

Table 1. Scope of Methoda
entry
RCHO
4
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
3a R ) 4F-C6H4
3a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
tracesd
89
85
75
71
75
89
81
90
89 (S)
88 (S)
93 (S)
90 (S)
90 (S)
92 (S)
84 (S)
89 (S)
83 (S)
3b R ) C6H5
3c R ) C7H15
3d R ) 2NO2-C6H4
3e R ) 4Cl-C6H4
3f R ) t-Bu
3g R ) C6F5
3h R ) Cy
3i R ) 3,5(OMe) -C H
3
Figure 1. DAT2 ligand 1 and PEG-supported analogues 2.
thiophene-based compounds allowed us to prepare in few
10
65
2
6
steps a C
(
1
-symmetric DAT2 analogue tethered to poly-
a
The reactions were carried out under a nitrogen atmosphere in dry EtOH
ethylene glycol) (MeO-PEG5000, 2, Figure 1)10 that was
for 40 h. Aldehyde/MeNO 1:40 elsewhere otherwise reported. b Isolated
yields after flash chromatography. Determined by HPLC with a chiral
2
c
effectively employed in Pd-catalyzed asymmetric allylic
alkylations. Here, the recovery of the supported ligand for
several runs without any loss of activity was demonstrated.
Prompted by these promising findings, we decided to ex-
plore the potential of 2 as the chiral ligand in copper-
catalyzed base-free Henry reactions. Poly(ethylene glycol)-
modified chiral catalysts have already found numerous
applications in asymmetric organic and metallo-organic-
based reactions.
However, a very few examples12 of effective recovery of
organometallic catalysts, through the use of PEG chemistry,
have been reported. An initial drawback to circumvent was
the poor solubility of 2 in EtOH (optimal reaction media)
that prevented homogeneous conditions from operating
column. Absolute configuration was assigned by comparison of the HPLC
retention times with known samples (see ref 8). d Aldehyde/MeNO2 1:10.
that, by increasing the MeNO
2
/4F-C
0:1, 2 was successfully solubilized, furnishing (S)-4a in
excellent conversion (>98%) and good enantiomeric excess
89%, entry 2). The adopted reagents’ ratio is the best
compromise to obtain higher chemical and optical outcomes.
In fact, if lower amounts of MeNO caused a poor solubi-
lization of the catalyst (slow reaction rates), higher quantities
6 4
H CHO (3a) ratio to
1
4
4
(
1
1
2
1
5
13
of MeNO
of aromatic (electron-rich and electron-poor) and aliphatic
linear and branched) aldehydes (3b-i) was screened. Under
2
led to a drop of stereoselection. Then, a range
(
optimal conditions (EtOH, 0 °C, 40 h) nitroalcohols 4b-i
were obtained in excellent conversions (85-98%) and high
enantiomeric excesses (83-93%). The erosion in stereoin-
duction observed (∆ee ≈ 1-7) with respect to the Henry
(Table 1, entry 1). However, we were delighted to find out
(6) Melucci, M.; Barbarella, G.; Gazzano, M.; Cavallini, M.; Biscarini,
F.; Bongini, A.; Piccinelli, F.; Monari, M.; Bandini, M.; Umani-Ronchi,
A.; Biscarini, P. Chem.sEur. J. 2006, 12, 7304.
2
condensation in the presence of 1-Cu(OAc) can be
(
7) (a) Albano, V. G.; Bandini, M.; Melucci, M.; Monari, M.; Piccinelli,
F.; Tommasi, S.; Umani-Ronchi, A. AdV. Synth. Catal. 2005, 347, 1502.
b) Albano, V. G.; Bandini, M.; Barbarella, G.; Melucci, M.; Monari, M.;
Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A. Chem.sEur. J. 2006, 12,
67. (c) Albano, V. G.; Bandini, M.; Monari, M.; Piccinelli, F.; Tommasi,
S.; Umani-Ronchi, A. Inorg. Chim. Acta 2007, 360, 1000.
8) Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici,
C. Chem. Commun. 2007, 616.
9) For previous uses of chiral copper-based weak Lewis acids in
tentatively ascribed to the higher amount of nitromethane
needed with PEG-modified DAT2.
Focusing on operational simplicity, we endeavored to run
the present nitroaldol condensation (3e+MeNO ) in an open-
2
air vial with reagent-grade EtOH as the solvent. Remark-
(
6
(
(
enantioselective Henry reactions, see: (a) Evans, D. A.; Seidel, D.; Rueping,
M.; Lam, H. W.; Shaw, J. T.; Downey, C. D. J. Am. Chem. Soc. 2003,
(12) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo,
M. J. Org. Chem. 2001, 66, 3160. (b) Glos, M.; Reiser, O. Org. Lett. 2000,
2, 2045. (c) Reger, T. S.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 6929.
(d) Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325. (e) Zhao,
D.; Sun, J.; Ding, K. Chem.sEur. J. 2004, 10, 5952.
(13) For the recycle of PEG-supported organometallic chiral catalysts
in water, see: (a) Benaglia, M.; Danelli, T.; Pozzi, G. Org. Biomol. Chem.
2003, 1, 454. (b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, F. Org.
Biomol. Chem. 2004, 2, 3401. (c) Li, X.; Wu, X.; Chen, W.; Hancock, F.
E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321.
(14) In the case of 1-based catalysis, the optimal MeNO2/3 ratio was
10:1.
(15) The model reaction (MeNO2/4F-C6H4CHO) carried out in nitro-
methane as the solvent led to (S)-4a in 96% conversion and 50% ee.
1
25, 12692. (b) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M.-M.
Tetrahedron: Asymmetry 2006, 17, 725. (c) Maheswaran, H.; Prasanth, K.
L.; Krishna, G. G.; Ravikumar, K.; Sridhar, B.; Lakshmi Kantam, M. Chem.
Commun. 2006, 4066. (d) Blay, G.; Climent, E.; Fern a´ ndez, I.; Hern a´ ndez-
Olmos, V.; Pedro, J. R. Tetrahedron: Asymmetry 2006, 17, 2046. (e) Xiong,
Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem.sEur. J. 2007, 13,
8
29.
10) Bandini, M.; Benaglia, M.; Quinto, T.; Tommasi, S.; Umani-Ronchi,
A. AdV. Synth. Catal. 2006, 348, 1521.
11) (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002,
02, 3325. (b) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345. (c) Benaglia,
M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003, 103, 3401.
(
(
1
2152
Org. Lett., Vol. 9, No. 11, 2007

ably, 4e was obtained in >98% conversion (40 h, 0 °C) and
Noticeably, after five runs, 81% of the initial amount of
catalyst was recovered.
84% ee.
The high reaction conversions and the possibility of
removing solvent and excess MeNO easily from the reaction
2
crude under vacuum called for a ready recovering of the
To prove the integrity of the ligand after the experi-
ments, the recovered PEG-supported catalyst was dissolved
in CH Cl (0.3 mL/0.1 g of polymer) and treated dropwise
2 2
whole metal-ligand system. To this aim, we initially isolated
with a 0.3 M solution of KCN (5 mol/equiv) in water. The
mixture was stirred at room temperature for 15 min, then
diluted with CH Cl , dried, filtered, and concentrated under
2 2
vacuum to give a solid residue that was analyzed by NMR
as such. Further purification of this material was possible
by the usual procedure to afford a ligand identical by NMR
to a sample freshly prepared.
the precatalytic PEG-DAT2-Cu(OAc)
from 2. Equimolar amounts of 2 and Cu(OAc)
overnight under nitrogen at room temperature in degassed
CH Cl , furnishing the desired copper complex 5 as a pale
2
5 species starting
2
were stirred
2
2
green solid in 84% yield (Figure 2).
2
PEG-DAT2-Cu(OAc) formed in situ was also subjected
to the recovering/reusing experiment with different substrates.
In particular, five aldehydes (3a-e) were consecutively
condensed with MeNO
2
in the presence of the same batch
of 2-Cu(OAc) (5 mol %, 0 °C, 40 h). Interestingly, the
2
chemo/stereochemical outputs recorded (see Supporting
Information) were consistent with those obtained with fresh
catalyst. Such evidence underlines the effectiveness of our
workup procedure (purification/recovering/recycling) and
recommends the present copper catalyst for applications in
combinatorial synthetic approaches such as “one-pot multi-
2
Figure 2. Synthesis of MeO-PEG5000-DAT2-Cu(OAc) 5.
1
6
substrate screening” methods.
In conclusion, we have successfully demonstrated the
suitability of PEG-modified DAT2 ligand 2 in promoting
highly stereoselective copper-catalyzed Henry reactions.
Excellent conversions and ees up to 93% were obtained under
mild and operationally simple conditions. Finally, unique
properties of preformed complex 5 allowed the reusability
of the entire organometallic species for several iterations
without any significant loss in activity. Studies addressing
the use of this type of catalytic system in environmentally
friendly stereocontrolled transformations are underway.
Then, preformed 5 (5 mol %) was employed in several
consecutive runs of the nitroaldol reaction between MeNO
and PhCHO. After each iteration, elimination of the volatiles
and repeated washings of the catalyst with Et O allowed 5
to be recovered and reused in the next run without the need
for further additions of copper salt.
Gratifyingly, the stereochemical induction of 5 over five
runs remained unaltered, furnishing constant values of
enantiomeric excesses (84-87%), with a slight erosion in
chemical conversions by the fourth iteration (Figure 3).
2
2
Acknowledgment. Acknowledgment is made to the
MIUR (Rome), FIRB Project (Progettazione, preparazione
e valutazione biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci innovativi), Consorzio
C.I.N.M.P.I.S. (Bari), and University of Bologna.
Supporting Information Available: Experimental pro-
1
13
cedures, H/ C NMR spectra, chiral HPLC analyses of the
known molecules, and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070636W
(16) (a) Gao, X.; Kagan, H. B. Chirality 1998, 10, 120. (b) Brouwer, A.
J.; Van der Linden, H. J.; Liskamp, R. M. B. J. Org. Chem. 2000, 65,
Figure 3. Proof of recoverability of 5 (up to five times) in the
catalytic enantioselective condensation of MeNO with PhCHO.
2
1750. (c) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2002,
58, 5773. (d) Satyanarayana, T.; Kagan, H. B. AdV. Synth. Catal. 2005,
347, 737.
Org. Lett., Vol. 9, No. 11, 2007
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