Cu-catalysed asymmetric 1,4-addition of Me3Al to nitroalkenes. Synthesis of (+)-ibuprofen

Article abstract of DOI:10.1016/j.tetlet.2005.01.007

Trimethylaluminium undergoes enantioselective (ee up to 93%) copper-catalysed Michael addition to various nitroalkenes. Copper thiophenecarboxylate (CuTC) (2 mol %) and 4 mol % of a chiral phosphoramidite ligand are sufficient for a complete and clean reaction. The synthesis of (+)-ibuprofen is described with 82% ee.

Full text of DOI:10.1016/j.tetlet.2005.01.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1529–1532
Cu-catalysed asymmetric 1,4-addition of Me3Al to nitroalkenes.
Synthesis of (+)-ibuprofen
Damien Polet and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
Received 9 December 2004; revised 22 December 2004; accepted 5 January 2005
Available online 20 January 2005
Abstract—Trimethylaluminium undergoes enantioselective (ee up to 93%) copper-catalysed Michael addition to various nitroalk-
enes. Copper thiophenecarboxylate (CuTC) (2 mol %) and 4 mol % of a chiral phosphoramidite ligand are sufficient for a complete
and clean reaction. The synthesis of (+)-ibuprofen is described with 82% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
The nitro group is of remarkable synthetic importance,
as it can be readily available and the synthetic interme-
diates containing it can be transformed to a wide variety
of valuable organic compounds such as aldehydes,
amines, carboxylic acids, nitriles and nitrile oxides.1
Therefore, it is of great interest to be able to get access
to optically enriched molecules containing this moiety.
The asymmetric conjugate addition reaction2 is one
of the widely used method for this purpose as it allows
the enantioselective creation of carbon–carbon bonds
from nitroalkenes.3 Both rhodium3a,b and copper3c–o
have been found to efficiently catalyse this reaction,
the first one with aryl boronates, the latter with dialkyl-
zinc reagents. In the copper-catalysed version, several
dialkylzinc reagents have been added to a variety of
nitroalkenes, bearing aryl or alkyl substituents, func-
tionalized or not. The only difficult group to introduce
is the methyl group, though it is the most valuable from
a synthetic point of view. Although excellent results
have been obtained by Hoveyda and Feringa,4 the
poor reactivity of dimethylzinc generally results either
in lower enantioselectivity or lower yields.
ticularly, ligand L1 (Table 1) was found to be the best
ligand for substrates such as nitroalkenes under our
classical conditions, in Et2O with 2% copper thiophene-
carboxylate (CuTC) and 4% chiral ligand (Table 1, entry
1). In comparison, ligands L23d (entry 2) and L33f (entry
4) gave moderate to good eeÕs. However, using L1, the
less reactive dimethyl zinc did not allow us to get good
enantioselectivities (entries 4 and 5), even at ꢀ15 °C
(entry 6).
Recently, triorganoaluminium reagents have been
shown to be good candidates for the asymmetric cop-
per-catalysed conjugate addition, in place of dialkyl-
zincs.6 The increased Lewis acidity of Al versus Zn
allows the reaction to occur on more demanding
systems. There is also one example of the use of
trimethylaluminium copper-catalysed 1,4-addition to
b-nitroacrylates, which constitute a particular class of
nitroolefins.7
R
2% CuTC, 4% L1
NO2
RxM
+
Ph
NO2
Et2O
Ph
We have recently disclosed new phosphoramidite li-
gands, which afforded the highest reported enantioselecti-
vities (up to 96%) in the copper-catalysed conjugate
addition of diethylzinc to nitrostyrene derivatives.5 Par-
1a
2a
Ph
Ph Ph
O
O
Ph
P
N
O
O
O
O
O
P
N
P Ph
Ph
Keywords: Copper; Aluminium; Nitro; Conjugate addition; Asymme-
try; Ibuprofen.
O
Ph
Ph Ph
*
Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32
15; e-mail: alexandre.alexakis@chiorg.unige.ch
L1
L2
L3
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.007

1530
D. Polet, A. Alexakis / Tetrahedron Letters 46 (2005) 1529–1532
Table 1. Addition of different organometallic species to nitrostyrene
Entry
RxM
Ligand
Conditiona
Temp. (°C)
Yield (%)b
ee%c
1d
2e
3g
4
Et2Zn
Et2Zn
Et2Zn
L1
L2
L3
L1
L1
L1
L1
A
Af
Af
A
A
A
B
ꢀ30
ꢀ78
ꢀ30
ꢀ30
0
(>99)
(90)
100
(0)
95(S)
48(S)
81(S)
Nd
Me2Zn
Me2Zn
Me2Znh
Me3Al
5
(63)
(71)
61
42(S)
59(S)
78(S)
6
ꢀ15
ꢀ30
7
a Method A: CuTC (0.008 mmol) and ligand (0.016 mmol) were dissolved in diethylether (2 mL) and stirred at room temperature for 0.3 h. The
mixture was then cooled to the indicated temperature and dialkylzinc (0.49 mmol, 2 M in hexane) was added dropwise before nitrostyrene
(0.4 mmol, in solution in 0.5 mL toluene). The reaction mixture was stirred for 16 h. Method B: CuTC (0.008 mmol) and ligand (0.016 mmol) were
dissolved in diethylether (2 mL) and stirred at room temperature for 0.3 h prior to nitrostyrene addition (0.4 mmol, in solution in 0.5 mL toluene).
The mixture was then cooled to the indicated temperature and Me3Al (1 mmol, 2 M in toluene) was added dropwise within 1 min. The reaction
mixture was stirred for 16 h at the indicated temperature.
b Isolated yields. In parentheses, conversion measured by GC.
c Measured by chiral GC or SFC. In parentheses, absolute configuration.
d Taken from Ref. 5a.
e Taken from Ref. 3d.
f In toluene with Cu(OTf)2 as copper salt.
g Taken from Ref. 3f.
h 10 equiv of dimethylzinc.
Table 2. Addition of trimethylaluminium onto various nitroalkenesa
In order to explore more thoroughly the behaviour of
triorganoaluminium species, we wondered if trimethylalu-
minium could afford good enantioselectivities on sim-
ple unactivated nitroalkenes. By using 2.5 equiv of
trimethylaluminium at ꢀ30 °C and slightly changing
the experimental conditions, we were able to introduce
the methyl group in good yield (61%) and good enantio-
selectivity (78%, Table 1, entry 7).
Me
2% CuTC, 4% L1
Et2O, -30 °C
NO2
Me Al
+
3
R
NO2
R
1
2
Entry
Substrate
Yield (%)b
ee (%)c
NO2
1
61
66
60
73
73
50
77
78 (S)
86 (ꢀ)
93 (ꢀ)
56 (ꢀ)
91 (ꢀ)
84 (ꢀ)
78 (+)
NO2
Following this successful attempt, we screened several
other nitroalkenes as well. The results are shown in
Table 2. The electron-donating properties of the substi-
tuent on the phenyl moiety gave proportional improve-
ment in terms of enantioselectivity: the para-methyl
improved to 86% and the para-methoxy to 93% !
(entries 2 and 3). A contrario, an electron-withdrawing
substituent such as para-chloro was deleterious in terms
of ee (entry 4). Heteroaryl (thienyl and furyl) substrates
could also give good eeÕs (entries 5 and 6). In addition to
aryl substituted substrates, an alkyl substituted one was
tested (cyclohexyl, entry 7) and the corresponding 1,4-
adduct was obtained with an ee of 78%, identical to
nitrostyrene. The acetal substituent also gave an im-
proved ee (88%, entry 8) compared to the nitrostyrene,
confirming that an electron-rich group should be
attached to the nitroolefin.
2
3
4
5
6
7
Me
NO2
MeO
NO2
Cl
S
NO2
NO2
NO2
O
MeO
NO2
8
64
88 (ꢀ)
OMe
a Cond. CuTC (0.008 mmol) and ligand (0.016 mmol) were dissolved in
diethylether (2 mL) and stirred at room temperature for 0.3 h prior to
nitroalkene addition (0.4 mmol, in solution in 0.5 mL toluene). The
mixture was then cooled to ꢀ30 °C and Me3Al (1 mmol, 2 M in
toluene) was added dropwise within 1 min. The reaction mixture was
stirred for 16 h at ꢀ30 °C.
The nitro group could be transformed into many other
functionalities. The reduction to the amino group has
been described on substrates 2, with Raney nickel.8 As
another example of the numerous transformations de-
scribed in the literature to convert the nitro group,1a
the oxidation of the primary nitroalkanes to the corre-
sponding carboxylic acids was envisaged (Scheme 1).
b Isolated yields after silicagel chromatography.
c Measured by chiral SFC or chiral GC.
Using the MioskowskiÕs variant of KornblumÕs transform-
ation,9 we were able to do this oxidation without race-
mization, affording 3 in nearly quantitative yield and
with complete conservation of the enantiomeric excess.
With this transformation in hands, we thought that
the whole sequence could be profitable to the synthesis
of the molecules belonging to the profen family.
This sequence was applied to the synthesis of (+)-ibu-
profen, a well-known nonsteroidal anti-inflammatory

D. Polet, A. Alexakis / Tetrahedron Letters 46 (2005) 1529–1532
1531
Nagaoka, Y. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 2000; p 1105; (d) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033–8061; (e) Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171–196; (f)
Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236; (g) Alexakis, A. In Methodologies in Asymmetric
Catalysis, Malhotra, S. V., Ed. ACS Symposium Series
880; Washington, 2004; Chapter 4, pp 43–59.
NO2
NaNO2, AcOH
DMSO, 35 °C, 24h
95%
COOH
2a, 77% ee
3a, 78% ee
Scheme 1. Oxidation of nitroalkane 2a into carboxylic acid according
to Ref. 9b.
3. For Rh-catalysed 1,4-addition of aryl boronates onto
nitroalkenes, see: (a) Hayashi, T. Synlett 2001, 879–887;
(b) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem.
Soc. 2000, 122, 10716–10717; For Cu-catalysed 1,4-addi-
tion of alkylzinc reagents onto nitroalkenes, see: (c)
Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett.
1997, 38, 7745–7748; (d) Sewald, N.; Wendisch, V.
Tetrahedron: Asymmetry 1998, 9, 1341–1344; (e) Verslei-
jen, J. P. G.; Van Leusen, A. M.; Feringa, B. L.
Tetrahedron Lett. 1999, 40, 5803–5806; (f) Alexakis, A.;
Benhaim, C. Org. Lett. 2000, 2, 2579–2581; (g) Ongeri, S.;
Piarulli, U.; Jackson, R. F. W.; Gennari, C. Eur. J. Org.
Chem. 2001, 803–807; (h) Alexakis, A.; Rosset, S.;
Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett
2001, 1375–1378; (i) Alexakis, A.; Benhaim, C.; Rosset, S.;
Humam, M. J. Am. Chem. Soc. 2002, 124, 5262–5263; (j)
Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron
2002, 58, 5773–5778; (k) Kang, J.; Lee, J. H.; Lim, D. S.
Tetrahedron: Asymmetry 2003, 14, 305–315; (l) Alexakis,
A.; Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.;
Mangeney, P. Adv. Synth. Catal. 2003, 345, 345–348; (m)
Rimkus, A.; Sewald, N. Synthesis 2004, 135–146; (n)
Arink, A. M.; Braam, T. W.; Keeris, R.; Jastrzebski, J. T.
B. H.; Benhaim, C.; Rosset, S.; Alexakis, A.; Van Koten,
G. Org. Lett. 2004, 6, 1959–1962; (o) Choi, H.; Hua, Z.;
Ojima, I. Org. Lett. 2004, 6, 2689–2691.
NO2
i
O
ii
3
4
NO2
iii
COOH
5, 81% ee
6, 82% ee
Scheme 2. Reagents and conditions: (i) MeNO2, AcONH4, AcOH,
55%; (ii) 2.5 equiv Me3Al, 2 mol % CuTC, 4 mol % L1, Et2O, ꢀ30 °C,
81%; (iii) NaNO2, AcOH, DMSO, 35 °C, 80%.
drug (NSAID) (Scheme 2).10 We had first to synthesize
the corresponding nitroolefin from the commercially
available 4-isobutylbenzaldehyde 3.11 The one-pot
Henry condensation followed by dehydration afforded
4 in 55% yield after distillation. We then proceeded to
the copper-catalysed 1,4-addition of trimethylalumin-
ium onto 4 affording 5 in good yield (81%) as well as
with acceptable enantioselectivity (ee 82%). The trans-
formation of the primary nitroalkane 5 to (+)-ibuprofen
6 (80%, ee 82%) was then achieved following the elegant
literature procedure.9b
4. For successful attempts, see: (a) Luchaco-Cullis, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192–8193;
(b) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2003, 125, 3700–3701; (c) Mampreian, D. M.;
Hoveyda, A. H. Org. Lett. 2004, 6, 2829–2832.
5. (a) Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org.
Chem. 2004, 69, 5660–5667; (b) Alexakis, A.; Polet, D.;
Benhaim, C.; Rosset, S. Tetrahedron: Asymmetry 2004, 15,
2199–2203.
6. (a) Woodward, S.; Fraser, P. K. Chem. Eur. J. 2003, 9,
776–783; (b) Liang, L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2002, 13, 1393–1396; (c) Alexakis, A.;
DÕAugustin, M.; Palais, L. Angew. Chem., Int. Ed. 2005,
44, in press.
7. Recently, Wendisch reported the use of trimethylalumin-
ium in the copper-catalysed 1,4-addition to nitro acrylates:
Eilitz, U.; Lessmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 3095–3097.
In summary, we have shown that trimethylaluminium
could advantageously replace dimethylzinc in the cop-
per-catalysed conjugate addition to a wide variety of
nitroalkenes. Yields and enantioselectivities are gener-
ally good to excellent (up to 93%). Coupled with the oxi-
dative transformation of the nitro group, the sequence
could provide with an excellent entry to the family of
aryl propionic acid derivatives.
Acknowledgements
8. Schafer, H.; Seebach, D. Tetrahedron 1995, 51, 2305–2324.
9. (a) Kornblum, N.; Blackwood, R. K.; Mooberry, D. D. J.
Am. Chem. Soc. 1956, 78, 1501–1504; (b) Matt, C.;
Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62,
234–235.
10. For a review on ibuprofen and congeners syntheses see:
Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G.
Tetrahedron 1986, 42, 40954131.
The authors thank the BASF company for the generous
gift of chiral amines, the Swiss National Research Foun-
dation No. 20-068095.02 and COSTaction D24/0003/01
(OFES contract No. C02.0027) for financial support.
References and notes
11. Typical procedure: CuTC (0.021 g, 0.110 mmol) and L1
(0.121 g, 0.221 mmol) were dissolved in diethylether
(28 mL) at room temperature. The mixture was stirred
1. (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001; (b) Berner, O. M.; Tedeschi, L.;
Enders, D. Eur. J. Org. Chem. 2002, 1877–1894.
2. Key reviews on 1,4-addition: (a) Rossiter, B. E.; Swingle,
N. M. Chem. Rev. 1992, 92, 771–806; (b) Feringa, B. L.
Acc. Chem. Res. 2000, 33, 346–353; (c) Tomioka, K.;
for 0.3 h and charged with nitroalkene
4 (1.132 g,
5.515 mmol) before being cooled down to ꢀ35 °C (cryo-
stat). Due to the scale of the reaction, trimethylaluminium
(13.8 mmol, 2 M solution in toluene) was added dropwise
over 4 h via a syringe pump. The reaction mixture was

1532
D. Polet, A. Alexakis / Tetrahedron Letters 46 (2005) 1529–1532
stirred for an additional 12 h at ꢀ35 °C. The flask was
44.9 mmol) were dissolved in 10 mL of freshly distilled
dimethylsulfoxide. The resulting mixture was stirred at
35 °C for 24 h, before being acidified with a 10% aqueous
solution of HCl. The product was then extracted with
diethylether and the combined extracts dried over sodium
sulfate and concentrated in vacuo. Purification by distil-
lation under reduced pressure (Kugelrohr 0.2 mmHg,
140 °C) afforded 0.742 g (80 %) of (+)-ibuprofen 6 as a
removed from the cooling bath, and 5 mL of an aq satd
solution of NH4Cl were added dropwise, followed by
10 mL of a 10% aq solution of HCl. After the solution
reached room temperature, the latter was extracted with
diethylether. The organic phase was dried over magnesium
sulfate, concentrated and the crude product was purified
by chromatography (pentane/diethylether 7:3) to afford
0.993 g (81%) of 5 as a colorless oil. 1H NMR (CDCl3,
400 MHz) d: 7.14 (d of AB sys, 2H, J = 8.6 Hz), 7.11 (d of
AB sys, 2H, J = 8.6 Hz), 4.54 (dd, 1H, J = 11.9, 7.1 Hz),
4.46 (dd, 1H, J = 11.8, 8.3 Hz), 3.61 (m, 1H), 2.45 (d, 2H,
J = 7.1 Hz), 1.85 (sept, 1H, J = 6.8 Hz), 1.37 (d, 3H,
J = 6.8 Hz), 0.90 (d, 6H, J = 6.6 Hz). 13C NMR (CDCl3,
100 MHz) d: 141.1, 138.1, 129.7, 126.6, 82.1, 45.0, 38.3,
30.2, 22.4, 18.8. MS (EI) 221 (M+., 8), 174 (81), 147 (13),
131 (100), 117 (58), 105 (19), 91 (45). HRMS (HR) calcd
1
colorless oil. H NMR (CDCl3, 400 MHz) d: 10.0–8.0 (br
s, 1H), 7.22 (d, 2H, J = 8.1 Hz), 7.10 (d, 2H, J = 8.1 Hz),
3.71 (q, 1H, J = 7.1 Hz), 2.45 (d, 2H, J = 7.0 Hz), 1.83
(sept., 1H, J = 6.8 Hz), 1.50 (d, 3H, J = 7.3 Hz), 0.89 (d,
6H, J = 6.8 Hz). 13C NMR (CDCl3, 100 MHz) d: 180.8,
140.9, 137.0, 129.4, 127.3, 45.1, 45.0, 30.2, 22.4, 18.1. MS
(EI) 207 (8), 206 (M+Å, 46), 163 (100), 161 (95), 119 (65),
115 (16), 107 (43), 91 (68), 77 (14). MS (HR) calcd for
20
D
[C13H18O2Na]+ 229.1204, found 229.1199. ½aŠ +38.5
20
D
for [C13H19NO2Na]+ 244.13135, found 244.13067.
(c = 1.075, CHCl3) for 82% ee, lit. ½aŠ +54.5 (c = 1.1,
20
D
½aŠ ꢀ40.8 (c = 1.165, CHCl3) for 81% ee. Ee was
CHCl3) for 97.2% ee (Harrington-Frost, N.; Leuser, H.;
Calaza, M. I.; Kneisel, F. F.; Knochel, P. Org. Lett. 2003,
5, 2111–2114). Ee was measured by chiral SFC (Chiralcel
OJ column, 5% MeOH during 2 min, then 1%/min 2
mL/min): R-(ꢀ) enantiomer: 3.310. S-(+) enantiomer:
3.600.
measured by chiral SFC (Chiralcel OD-H column, 1%
MeOH 2 mL/min): S-(ꢀ) enantiomer: 3.420; R-(+) enan-
tiomer: 3.660.
(+)-Ibuprofen (6). Compound 5 (0.993 g, 4.487 mmol),
sodium nitrite (0.93 g, 13.5 mmol) and acetic acid (2.6 mL,