Nitrophenylacetonitriles as versatile nucleophiles in enantioselective organocatalytic conjugate additions

Article abstract of DOI:10.1021/ol101178u

Arylacetonitriles are able to participate in organocatalytic Michael additions to α,β-unsaturated aldehydes by incorporating a nitro group at the phenyl ring, which acts as a temporary activating group in a remote position and allows further transformations. The sequential protocol Michael addition/NaBH₄ reduction/lactonization allows the synthesis of diastereomerically pure disubstituted lactones in high yield and optical purity.

Full text of DOI:10.1021/ol101178u

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3586-3589
Nitrophenylacetonitriles as Versatile
Nucleophiles in Enantioselective
Organocatalytic Conjugate Additions
M. Bele´n Cid,* Sara Duce, Sara Morales, Eduardo Rodrigo, and
Jose´ Luis Garc´ıa Ruano*
Department of Organic Chemistry, UniVersidad Auto´noma de Madrid, Cantoblanco 28049
belen.cid@uam.es; joseluis.garcia.ruano@uam.es
Received May 21, 2010
ABSTRACT
Arylacetonitriles are able to participate in organocatalytic Michael additions to r,ꢀ-unsaturated aldehydes by incorporating a nitro group at
the phenyl ring, which acts as a temporary activating group in a remote position and allows further transformations. The sequential protocol
Michael addition/NaBH4 reduction/lactonization allows the synthesis of diastereomerically pure disubstituted lactones in high yield and optical
purity.
Although asymmetric organocatalysis has proven to be a
powerful tool for the efficient synthesis of complex mol-
ecules,1 some challenges remain unsolved. With the excep-
tion of the nitroderivatives,1f the pro-nucleophilic species
usually require the presence of two geminal electron-
withdrawing groups to get the appropriate acidity of the
methylenic protons for being able to intervene in organo-
catalytic processes.2,3 As the second group is not usually
required, it should be removed once it exerted its activating
function, which reduces the scope of the process and
produces epimerization, making the stereoselective formation
of compounds bearing stereogenic centers at the nucleophilic
carbon very difficult.
We reasoned that the incorporation of an appropriate
electron-withdrawing group (EWG) to an aromatic ring could
increase the acidity of the benzylic protons, allowing the use
of any arylacetic acid derivative in organocatalytic processes.
Elimination or transformation of the EWG group would not
have any consequence on the possible chirality created at
the nucleophilic center.4
(1) For recent reviews on organocatalysis see, for example: (a) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175. (b) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724. (c) Berkessel, A.; Gro¨ger,
H. Asymmetric OrganocatalysissFrom Biomimetic Concepts to Powerful
Methods for Asymmetric Synthesis: WILEY-VCH: Weinheim, 2005. (d)
Pellisier, H. Tetrahedron 2007, 63, 1733. (e) MacMillan, D. W. C. Nature
2008, 455, 304–308. (f) Dalko, P. I. EnantioselectiVe Organocatalysis:
Reactions and Experimental Procedures; WILEY-VCH: Weinheim, 2007.
In this paper, we report the first example of the use of
arylacetonitriles bearing an EWG at the phenyl ring, as
prochiral nucleophiles in their reactions with R,ꢀ-unsaturated
(2) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218
.
(4) To our knowledge, the only paper related to the organocatalytic use
of prochiral nucleophiles derived from monofunctionalized compounds deals
with the reactions of trifluoroethyl thioesters derived from phenylacetic acid
and was reported by Barbas III: Alonso, D. A.; Kitagaki, S.; Utsumi, N.;
Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47, 4588.
(3) For examples of nonprochiral monofunctionalized enolates, see: (a)
Ricci, A.; Pettersen, D.; Bernardi, L.; Fini, F.; Fochi, M.; Pe´rez Herrera,
R.; Sgarzani, V. AdV. Synth. Catal. 2007, 349, 1037. (b) Lubkoll, J.;
Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841
.
10.1021/ol101178u  2010 American Chemical Society
Published on Web 07/28/2010

aldehydes catalyzed by prolinol ethers.5,6 The nitro group
at para (compound 1) and ortho (compound 2) have been
chosen as EWGs because of its known influence for
increasing the acidity at the benzylic position.7 Moreover, 1
and 2 are both cheap and commercially available, have
nucleophilicities similar to those of cyanoesters,8 widely used
in organocatalysis,9 and have demonstrated a high synthetic
versatility10 (Scheme 1).
Table 1. Screening for the Addition of p-Nitrophenylacetonitrile
1 to Crotonaldehyde
Scheme 1
.
Nitrophenylacetonitriles as Versatile Nucleophiles in
Organocatalytic Michael Additions
t
yielda deb, ref 12 ee (%) ee (%)
entry cat. additive (h)
(%)
4a:4′a
4a
4′a
1
2
3
4
5
6
7
8
9
I
I
I
I
PhCO2H 40
90
95
63
65
60
59:41
63:37
60:40
63:37
61:39
63:37
60:40
60:40
61:39
90
90
84
84
64
89
89
88
88
78
AcOLi
AcONa
20
24
DABCO 24
I
TMAF
AcOLi
AcOLi
40
40
24
24
24
Ic
II
93
91
86
90
70
84e
82e
54e
III AcOLi
IV AcOLi
-50d
15
-62d
16
Additionally, the high acidity transferred by the nitro group
to the benzylic position has been exploited to epimerize the
center to the most stable diastereoisomer by cyclization into
lactones. These lactones can be obtained in a highly enantio-
and diastereoselective manner. Once the temporary activating
group has exerted its function, it can be transformed into
other fuctional groups without affecting the integrity of the
created stereogenic centers (Scheme 1).
Crotonaldehyde (3a) was chosen as a starting aldehyde
for optimizing reactions with compound 1 (Table 1). The
use of the Jørgensen-Hayashi catalyst I11 allowed us to
obtain a 59:41 diastereomeric mixture of Michael adducts
in 90% yield under standard conditions, using benzoic acid
as additive and THF/H2O as solvent12 (entry 1). The easy
decomposition of these aldehydes in the HPLC columns
a After flash chromatography. b By HPLC. c Reaction at 0 °C. d The
other enantiomer was obtained with catalyst III. e Conversion.
made necessary their transformation into alcohols (4a and
4′a) before determining their optical purity. NaBH4 reduction
on the reaction crude of the Michael addition,13 once the
solvent (THF and H2O) was eliminated under vacuum,
allowed us to determine by HPLC an ee next to 90% for
both alcohols (entry 1).
In the absence of additive, the reaction did not take place.
The use of nonacidic additives reduced the reaction times
(entries 2-5), with AcOLi providing the best results (entry
2).14 Different additives, solvents,12 or a decrease in the
temperature did not produce any significant improvement
in the ee (entry 6). The use of other catalysts like II-IV
provided lower yields and enantiomeric excesses (entries
7-9).
(5) For a review of iminium catalysis, see: Erkkila¨, A.; Majander, I.;
Pihko, P. M. Chem. ReV. 2007, 107, 5416
.
(6) Review articles about organocatalytic Michael addition, see: (a)
Almasi, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18,
299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Vicario, J. L.;
To control the configuration at the benzylic carbon, we
took advantage of its intrinsic acidity to epimerize it to the
most stable isomer in a cyclic substrate.15 To our delight,
when the epimeric mixture of alcohols 4a and 4′a was treated
with H2SO4 in AcOH,16 diastereomerically pure lactone 6a
Bad´ıa, D.; Carrillo, L. Synthesis 2007, 14, 2065
.
(7) 12.3 is the pKa value of p-nitrophenylacetonitrile in DMSO. See:
Bordwell, F. G.; Cheng, J.-P.; Bausch, M. J.; Bares, J. E. J. Phys. Org.
Chem. 1988, 1, 209.
(8) Kaumanns, O.; Appel, R.; Lemek, T.; Seeliger, F.; Mayr, H. J. Org.
Chem. 2009, 74, 75–81.
(9) (a) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120. (b) Lo´pez-Cantarero, J.; Cid, M. B.; Poulsen, T. B.; Bella, M.;
Garc´ıa Ruano, J. L.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 7062.
(10) (a) Gaudemer, A.; Nguyen-Van-Duong, K.; Shahkarami, N.; Achi,
S. S.; Frostin-Rio, M.; Pujol, D. Tetrahedron 1985, 41, 4095. (b) Sheppeck,
J. E., II; Gilmore, J. L.; Tebben, A.; Xue, C.-B.; Liu, R.-Q.; Decicco, C. P.;
Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2007, 17, 2769. (c) Boedeker, J.;
Fieblinger, D.; Koeppel, H.; Radeglia, R. Z. Chem. 1988, 183. (d) Allen,
C. F. H. J. Am. Chem. Soc. 1925, 47, 1733.
(13) NaBH4 reduction of the diastereomerically pure aldehydes, separated
from the crude by flash chromatography, produce epimerization into their
thermodinamic mixture of 4a/4′a.
(14) For other examples where AcOLi has been used, see: (a) Wang,
Y.; Li, P.; Liang, X.; Zhang, Y.; Ye, J. Chem. Commun. 2008, 1232. (b)
Garc´ıa Ruano, J. L.; Marcos, V.; Alema´n, J. Chem. Commun. 2009, 4435.
(15) This strategy has been previously used. See, for example: (a) Garc´ıa
Ruano, J. L.; de Haro, T.; Singh, R.; Cid, M. B. J. Org. Chem. 2008, 73,
1150. (b) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (c) Valero, G.; Schimer, J.; Cisarova,
I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 1943.
(16) Corrie, J. E. T.; Munasinghe, V. R. N. J. Labelled Compd.
Radiopharm. 2005, 48, 231.
(11) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. For a review of chiral
diarylprolinol ether catalysis, see: Palomo, C.; Mielgo, A. Angew. Chem.,
Int. Ed. 2006, 45, 7876.
(12) For more details see the Supporting Information.
Org. Lett., Vol. 12, No. 16, 2010
3587

was obtained in quantitative yield, without erosion of the
enantiomeric purity (90% ee, Scheme 2).
is lower (entries 6-9). It seems that electron-donating groups,
like p-OMe, seriosly reduced the ee (entry 7), whereas it is
slighly improved by electron withdrawing groups like p-NO2
(entry 8).
ortho-Nitrophenylacetonitrile 2 also reacted with aldehydes
3a (R ) alkyl) and 3f (R ) aryl), under the same sequential
procedure used for 1 (entries 10 and 11) affording 7a and
7f, respectively. Reaction times for cyclization (t2) are longer
than those required for 1, and the ee is slightly lower
(compare entries 1 and 10 or 6 and 11), probably due to the
steric hindrance of the ortho substituent.
Scheme 2. Formation of Diastereomerically Pure Lactone 6a
It is remarkable that m-nitrophenylacetonitrile did not react
under the same conditions. As the pKa for this compound
is 18.1 in DMSO,7 this lack of reactivity is in agreement
with the requirements established for the nucleophile
activation using amine organocatalysts, which fix the pKa
values below 17.17
To illustrate the versatility of these nucleophiles, several
transformations have been carried out. The reduction of the
NO2 into the NH2 group is fundamental for decreasing the
acidity of the benzylic possition, thus minimizing its tendency
to epimerize. It can be easily performed in quantitative yield
by treatment of 6a with Zn/AcOH.18 The so-obtained 8a was
transformed into the acyclic diol 9a without epimerization
(Scheme 3). Analogously, iodide 10a, a useful starting
We then searched a sequential procedure Michael addition/
reduction/lactonization, to afford the direct synthesis of
lactone 6a from compounds 1 and 3a without isolation of
the intermediates. It required the elimination of the solvents
under vacuum after the first step (see above) and the filtration
through a short pad of silica gel after the reduction. Under
these conditions, 6a could be obtained as only one diaste-
reoisomer (de > 98%) in 95% yield and 90% ee (entry 1,
Table 2). The enantiomeric excess could be increased until
98% ee by simple crystallization, and the reaction was scaled
up until 1 g of product.
Table 2. Scope for the Addition of p-Nitrophenylacetonitriles 1
and 2
Scheme 3
.
Transformation of 6a into Acyclic Compounds
without Epimerization
b
c
t1
t2
overall yield eed
entrya
R
(h) (h) product
(%)
(%)
1
2
3
4
5
6
7
8
3a (Me)
3b (Et)
3c (n-Pr)
3d (n-Bu)
3e (iPr)
3f (Ph)
20
24
48
48
120
48
1
1
1
1
3
8
6ae
6be
6ce
6de
6ee
6fe
95
89
92
89
90
79
82
86
84
78
76
90
92
92
90
96
80
30
85g
70
84
50
material for metal-catalyzed cross coupling reactions and
easily obtained from 8a,19 can also be opened to the ester
11a (Scheme 3).12
As 9a and 11a can be considered as the optically enriched
acyclic compounds which would result in an organocatalytic
asymmetric Michael reaction with monoactivated benzylic
3g (p-OMe-C6H4) 72 30
6ge
6he
6ie
3h (p-NO2-C6H4)
3i (p-Br-C6H4)
3a (Me)
48 48
72 3.5
24
40 25
9
10
11
8
7af
7ff,h
3f (Ph)
(17) Malonates with a pKa of 16.4 are used in enantioselective
organocatalysis with chiral amines. See: (a) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661. (b) Wang, J.; Li,
H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc.
2006, 128, 12652. Nevertheless, ketones with a pKa around 18 need
activation via enamine, see also ref 4.
a Reactions performed on 1 mmol scale. b Michael addition. c Cyclization.
d Determined by HPLC. e 1 was used as starting material. f 2 was used as
starting material. g Estimated from the ee of the mixture of alcohols.12
h Obtained as a 94:6 mixture of epimers.
(18) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.;
Kawasaki, T. Org. Lett. 2009, 11, 197.
(19) Peretto, I.; Radaelli, S.; Parini, C.; Zandi, M.; Raveglia, L. F.;
Dondio, G.; Fontanella, L.; Misiano, P.; Bigogno, C.; Rizzi, A.; Riccardi,
B.; Biscaioli, M.; Marcello, M.; Marchetti, S.; Puccini, P.; Catinella, S.;
Rondelli, I.; Cenacchi, V.; Bolzoni, P. T.; Caruso, P.; Villetti, G.; Facchinetti,
F.; Del Giudice, E.; Moretto, N.; Imbimbo, B. P. J. Med. Chem. 2005, 48,
5705.
This sequential procedure (Table 2) was applied with
similar efficiency for synthesizing the presumably most stable
trans-lactones 6a-6e with R ) alkyl (entries 1-5). When
R is aromatic, diastereoselectivity remains complete, but ee
3588
Org. Lett., Vol. 12, No. 16, 2010

prochiral nucleophiles, we can consider our strategy as an
indirect way for getting these transformations.
The absolute configuration of the lactone 10a was un-
equivocally established as (3S, 4S) by X-ray diffraction
studies (Figure 1). This configuration was assumed for the
rest of the lactones 8a, 6, and 7.12
Particularly, the para-nitrophenylacetonitrile (cheap and
commercially available) is able to react with ꢀ-alkyl-
substituted acroleines in a highly enantioselective manner.
Performing three sequential reactions (Michael/reduction/
lactonization) affords diastereomerically pure lactones in a
very high yield and optical purity (up to 96% ee) with
minimal laboratory manipulation. These results open a new
route to study the behavior of other benzylic versatile
nucleophiles.
Acknowledgment. We thank the Spanish Government
(CTQ2009-12168/BQU), Comunidad Auto´noma de Madrid
(S2009/PPQ-1634), and Universidad Auto´noma de Madrid
(CCG08-UAM/PPQ-4235) for financial support. S.D. thanks
the Comunidad Auto´noma de Madrid for a predoctoral
fellowship. We also thank Rachel Holcomb for her help in
the elaboration of this manuscript.
Figure 1. X-ray structure of 10a.
Supporting Information Available: Experimental pro-
cedures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallographic data of 10a. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have demonstrated that the nitro group
at an aromatic ring can be used as a temporary activating
group of benzylic nucleophiles in organocatalytic processes.
OL101178U
Org. Lett., Vol. 12, No. 16, 2010
3589