Organocatalyzed Michael addition reaction by novel (2 R,3a S,7a S)-octa-hydroindole-2-carboxylic acid, a new fused proline

Article abstract of DOI:10.1055/s-0030-1259296

We present here the results obtained in our study on organocatalytic enantioselective Michael addition reaction of acetone to different nitroolefines using (2R,3aS,7aS)-octahydroindole-2-carboxylic acid [(R,S,S)-Oic] as a new and suitable catalyst for thi

Full text of DOI:10.1055/s-0030-1259296

LETTER
249
Organocatalyzed Michael Addition Reaction by Novel (2R,3aS,7aS)-Octa-
hydroindole-2-carboxylic Acid, a New Fused Proline
O
rganocatalyze
d
M
a
ichael Add
v
itionReactio
i
nbya
d
N
ew
F
usedProlineRoca-López,a Pedro Merino,*a Francisco J. Sayago,b Carlos Cativiela,b Raquel P. Herrera*a,c
a
b
c
Laboratorio de Síntesis Asimétrica, Dpto. de Química Orgánica, ICMA (CSIC-UZ), 50009 Zaragoza, Spain
Laboratorio de Aminoácidos y Péptidos, Dpto. de Química Orgánica, ICMA (CSIC-UZ), 50009 Zaragoza, Spain
ARAID, Fundación Aragón I+D, 50004 Zaragoza, Spain
Fax +34(976)762075; E-mail: raquelph@unizar.es
Received 27 November 2010
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday
Recently, some of us reported the syntheses of enantio-
merically pure proline analogues (2S,3aS,7aS)- and
(2R,3aS,7aS)-octahydroindole-2-carboxylic acid [(S,S,S)-
Oic, 48 and (R,S,S)-Oic, 5],9 respectively (Figure 1), using
Abstract: We present here the results obtained in our study on or-
ganocatalytic enantioselective Michael addition reaction of acetone
to different nitroolefines using (2R,3aS,7aS)-octahydroindole-2-
carboxylic acid [(R,S,S)-Oic] as a new and suitable catalyst for this
process. Computational calculations support the results obtained semipreparative chiral HPLC resolution.
with (R,S,S)-Oic versus its diastereomeric form (S,S,S)-Oic. The fi-
nal products are obtained in good yields and moderate enantioselec-
tivities (up to 58% ee).
These structures possess particular conformational prop-
erties, and they are the core structure of compounds with
applications in medicinal chemistry.10 For instance, they
exhibit interesting biological activity as antithrombotics,
and they are suitable molecules for the prevention of car-
diovascular disorders, antiamnesic, anti-inflammatory,
antiallergic, and analgesic drugs.11 However, despite of
their similarity to L-proline, their ability as organocata-
lysts is still unexplored.
Key words: Michael addition, nitroolefines, ketones, Oic, organo-
catalysis, enantioselectivity
In the last ten years asymmetric organocatalysis has be-
come one of the most active and growing fields of re-
search in asymmetric catalysis, and it has represented a
powerful tool for performing stereoselective transforma-
tions which were classically achieved using transition-
metal or enzymatic catalysis.1 The Michael addition reac-
tion is widely recognized as one of the most important car-
bon–carbon bond-forming reactions in organic synthesis.2
Several reagent systems for this type of transformation
that rely on asymmetric catalysts have been developed to
date.2–4 In particular, the interest for environmentally
friendly and nonmetal-catalyzed asymmetric syntheses1
has focused considerable attention on the development of
efficient organocatalyzed Michael reactions.3,4 In the par-
ticular case of nitroalkenes,2a the Michael adducts with
ketones are versatile synthetic intermediates, since the ni-
tro moiety is a strong electron-withdrawing group that can
be readily derived into a range of different functional-
ities.5
CO2H
H
CO2H
N
H
N
H
1
2
H
H
CO2H
CO2H
CO2H
N
H
N
H
N
H
H
3
4
5
(S,S,S)-Oic
(R,S,S)-Oic
Figure 1
It is well known that a chiral secondary amine catalyzes
the asymmetric conjugate addition of ketones to nitroalk-
enes by transforming the carbonyl group to an enamine in-
termediate.12 The substituents and geometries of the
Among the several studies concerning Michael addition enamine and nitroolefine control the stereochemical out-
of ketones to nitroalkenes5,6 most of them are focused on come of the reaction. Compared with proline catalyst, pe-
cyclic ketones, particularly six-membered ones, which rhydroindole derivatives 413,14 and 5 possess two more
have been reported to afford best results. On the contrary,
stereogenic centers in the backbone, and may exert stron-
less attention has been paid to acyclic ketones which usu- ger influences on the orientation of enamine and the ni-
ally lead to lower ee values. In this respect the develop- troolefin. Hence we have undertaken a project to study the
ment of this process using the simplest acetone is still relation between absolute stereochemistry of the modified
remained,6,7 and new effective catalysts are still desired proline and enantioselectivity trying to understand the in-
for the development of that reaction.4
fluence of the different aspects of the reaction.
We started our investigation of this asymmetric Michael
addition between acetone 6 and (E)-b-nitrostyrene 7a cat-
alyzed by organocatalysts 1–5 (Figure 1) leading to the
corresponding g-nitro ketone 8a, as a test reaction. The re-
sults for the initial screening are reported in Table 1.
SYNLETT 2011, No. 2, pp 0249–0253
Advanced online publication: 04.01.2011
DOI: 10.1055/s-0030-1259296; Art ID: G36210ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

250
D. Roca-López et al.
LETTER
Table 1 Screening to Optimize the Reaction Conditions15
was DMF (Table 1, entry 9). Further exploration regard-
ing concentration (Table 1, entry 12), catalyst loading
(Table 1, entries 10 and 11) and reagents ratio (Table 1,
entry 13) did not improve the enantioselectivity of the
process. We did not consider the possibility of performing
the reaction at lower temperatures due to the long reaction
times.
O
Ph
*
O
catalyst 1–5
solvent
r.t.
+
NO2
NO2
Ph
6
Entry
1c
7a
8a
Catalyst Solvent
Time (d) Yield(%)a
ee (%)b
1
2
3
4
5
5
5
5
5
5
5
5
5
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
NMP
4.5 h
10
10
2
89
4 (R)
n.r.d
Notably, a preliminary result using isopropanol as an ad-
ditive resulted in a considerable acceleration of the reac-
tion furnishing a promising yield. To explore this effect,
we tried different amounts of i-PrOH as well as other al-
cohols as additives (Table 2).
2
n.r.d
n.r.d
85
3
n.r.d
4
22 (S)
38 (R)
n.r.d
5
4
74
Table 2 Screening of Reaction Conditions15
6
5
n.r.d
48
O
Ph
O
5 (10 mol%)
NO2
+
NO2
7
8
36 (R)
n.r.d
Ph
DMF
additive
6
7a
8a
8
MeOH
DMF
5
n.r.d
71
Entry Additive (equiv)
Time (d) Yield (%)a
ee (%)b
9
4
46 (R)
32 (R)
37 (R)
38 (R)
39 (R)
10e
11f
12g
13h
DMF
4
80
1
2
i-PrOH (0.5)
i-PrOH (1)
i-PrOH (2)
i-PrOH (4)
i-PrOH (8)
MeOH (2)
EtOH (2)
3
3
4
5
5
4
4
4
4
4
67
70
89
83
77
83
70
89
14
15
40
36
34
35
33
36
36
35
42
43
DMF
8
77
3
DMF
7
77
4
DMF
7
70
a Isolated yields after column chromatography.
b Determined by chiral HPLC analysis (Chiralpak IA).
c Ref. 6a.
5
6
d No reaction observed.
7
e 20 mol% of catalyst.
f 5 mol% of catalyst.
8
t-BuOH (2)
i-PrOH (1)
i-PrOH (2)
g 2 mL of solvent.
h 0.5 mL of acetone.
9c
10c
We performed this study by comparing our results with
the previously reported one using L-proline for the same
reaction, as a model catalyst (Table 1, entry 1),6 and fol-
lowing the course of the reaction until consumption of the
nitroalkene. The low catalytic ability observed with cata-
lyst 216 (Table 1, entry 2) was probably due to the influ-
ence previously observed by conformational preferences
of a-substituted proline analogues.17 We thought that the
lack of reactivity shown by catalyst 318 can be explained
due to the less remarkable nucleophilic character of the
electron pair placed on the nitrogen atom (Table 1, entry
3). To our surprise the best catalyst was (R,S,S)-Oic 5
(Table 1, entry 5) affording the final product with a slight
improvement in the enantioselectivity compared with the
diastereomeric form (S,S,S)-Oic 4, which, interestingly,
afforded the opposite enantiomer (Table 1, entry 4). Since
(R,S,S)-Oic 5 provided the best results, we decided to use
this unexplored catalyst for further examinations. We con-
tinued the screening of our reaction model testing differ-
ent solvents. Dichloromethane (Table 1, entry 6) and
methanol (Table 1, entry 8) showed a complete lack of re-
activity probably due to the poor solubility of the catalyst
for the former and the well-known H-bond inhibition ca-
pability for the latter. For the rest, the solvent of choice
a Isolated yields after column chromatography.
b Determined by chiral HPLC analysis (Chiralpak IA).
c Reaction performed at 0 °C.
We were pleased to observe a strong rate-acceleration of
the reaction using a small amount of i-PrOH as an addi-
tive, although accompanied of a slight decreasing in the
enantioselectivity (Table 2, entry 1). Variations in the sto-
ichiometry (Table 2, entries 1–5) and nature (Table 2, en-
tries 6–8) of the alcohols, or even performing the reaction
at lower temperature (entries 9 and 10) did not improve
the result obtained in absence of additive, even when sim-
ilar enantioselectivities were observed but with very poor
yields (entries 9 and 10). Therefore, we considered that
the improvement in the reaction rate did not justify the use
of isopropanol as an additive of the reaction.
Under the best optimized reaction conditions a variety of
nitroalkenes, bearing electron-donating and electron-
withdrawing groups, were explored and investigated in
order to establish the scope of our Michael addition reac-
tion, and the results are summarized in Table 3.
All reactions were performed at room temperature in the
presence of 10 mol% of 5, and for the reaction time indi-
Synlett 2011, No. 2, 249–253 © Thieme Stuttgart · New York

LETTER
Organocatalyzed Michael Addition Reaction by a New Fused Proline
251
Table 3 Michael Addition of Acetone 6 to Nitroolefines 7a–l15
To gain insight on the origin of the enantioselectivity of
the studied reaction, computational studies24 were carried
out by employing DFT methods at B3LYP/6-31+G(d,p)
and M062X/6-311+G(d,p)//B3LYP/6-31+G(d,p) levels
considering in all instances a PCM solvent model for DM-
SO.25 In spite of the levels used no determinant data could
be obtained due to the close values calculated even at the
highest level. The energy values obtained for the transi-
tion structures leading to S- and R-enantiomers are given
O
R
O
5 (10 mol%)
+
NO2
NO2
R
DMF, r.t.
6
7a–l
8a–l
Entry Product (R)
Time (d)
Yield (%)a ee (%)b
1
2
8a Ph
4
71
75
64
87
52
71
60
73
62
68
74
67
46
42
35
53
41
40
40
58
45
33
36
44
8b 4-MeC6H4
8c 4-MeOC6H4
8d 2-MeOC6H4
8e 2-F3CC6H4
8f 4-ClC6H4
6
in Table 4, while the optimized geometries [PCMDMSO
/
3
10
3
B3LYP/6-31+G(d,p)] are illustrated in Figure 2. Al-
though the calculations correctly predicted an opposite
enantioselectivity for 4 and 5, differences less than 0.7
kcal/mol (M062X) were obtained between the corre-
sponding transition structures leading to both enantiomers
for each catalyst. Admittedly, these differences are only
indicative that low enantioselectivities will be obtained.
Accordingly, the values shown in Table 4 cannot be used
as predictive values since they are within a mean error of
about 2 kcal/mol following previous observations report-
ed by Houk for M062X functional.26
4
5
4
6
3
7
8g 4-FC6H4
4
8
8h 2-furyl
4
9
8i 4-BrC6H4
4
10
11
12
8j 4-HOC6H4
8k 4-BnOC6H4
8l 3,4-Cl2C6H3
10
10
2
Table 4 Total and Relative Electronic Energy Values for Transition
Structures TS1–TS4
Total energy (hartrees)
Relative energy (kcal/mol)
a Isolated yields after column chromatography.
b Determined by chiral HPLC analysis.
ΔG (B3LYP)a ΔG (M062X)b ΔG (B3LYP)a ΔG (M062X)b
TS1c –1187.782666 –1187.528351 0.62
TS2d –1187.783649 –1187.527877 0.00
TS3e –1187.784652 –1187.528192 0.00
TS4f –1187.781419 –1187.572184 2.03
0.00
0.30
0.00
0.63
cated in Table 3. As shown above, all aromatic b-nitroalk-
enes react smoothly with acetone to give the desired
Michael adducts 8a–l in moderate to good yields and
moderate enantioselectivities (up to 58% ee). Unfortu-
nately, attempts using aliphatic nitroalkenes gave lower
yields and ee (for R = PhCH2CH2, ee 34% and 30%
yield). No significant dependence on the enantioselectivi-
ty was observed on electronic or steric features of the sub-
strates. On the other hand, the reaction rate seems to have
a Optimized structures at (PCM = DMSO)/B3LYP/6-31+G(d,p) lev-
el.
b Single point calculations at (PCM = DMSO)/M062X/6-
311+G(d,p)/B3LYP/6-31+G(d,p) level.
a slight dependence on the electronic properties of the ni- c Re attack (from 4) leading to R-isomer.
d Si attack (from 4) leading to S-isomer.
troalkene showing a lower acceleration with electron-do-
nating groups (Table 3, entries 2, 3, 10, and 11). This
observation is in agreement with the fact that the rate-lim-
e Si attack (from 5) leading to S-isomer.
f Re attack (from 5) leading to R-isomer.
iting step in this reaction is the C–C bond formation, re-
sponsible of the origin of the enantioselectivity that
accounts during the addition of the enamine to the ni-
troalkene. Indeed, both experimental19 and theoretical20
studies demonstrate that the C–C bond-forming step is the
rate-determining one. Nevertheless, a recent study re-
vealed that in addition to the reaction of the enamine with
the nitroalkene, the hydrolysis of the enamine is also rate
limiting in some extent.21 The absolute configuration R
was determined by comparison of the optical rotation val-
ues for adducts 8d22 and 8i23 with that previously reported
in the literature for the same product. We assume the same
TS and therefore the same configurational assignment for
the rest of products 8a–l. The stereochemistry on chiral
center in position C2 on the catalyst seems to drive the ab-
solute configuration in the final products.
Calculations also predict low values of enantioselectivi-
ties with a difference of 0.3 kcal/mol between TS1 and the
nearest transition structure leading to the S-isomer with
catalyst 4. Similarly, a difference of 0.6 kcal/mol between
TS3 and the nearest transition structure leading to the R-
isomer is obtained for catalyst 5. In this respect, it is worth
of note that calculations quantitatively predict the higher
enantioselectivity observed for 5 with respect to 4.
In summary, we have reported by the first time the use of
(2R,3aS,7aS)-octahydroindole-2-carboxylic acid 5 as a
suitable organocatalyst for the less studied addition of ac-
etone to diverse nitroolefins. The obtained results, al-
though better than proline, are still only modest (up to
58% ee); however, this example represents an unexplored
case on the variation on the pyrrolidine ring structure at
positions 4 and 5. The substituents in the proline ring
Synlett 2011, No. 2, 249–253 © Thieme Stuttgart · New York

252
D. Roca-López et al.
LETTER
Badía, D.; Carrillo, L. Synthesis 2007, 2065. (d) Sulzer-
Mossé, S.; Alexakis, A. Chem. Commun. 2007, 3123.
(e) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009,
15, 11058.
(4) For a recent review concerning the organocatalytic addition
of ketones to nitroalkenes, see: Roca-López, D.; Sádaba, D.;
Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron:
Asymmetry 2010, 21, 2561.
(5) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001. (b) Ballini, R.; Petrini, M.
Tetrahedron 2004, 60, 1017.
(6) For pioneering examples, see: (a) List, B.; Pojarliev, P. H.;
Martin, H. J. Org. Lett. 2001, 3, 2423. (b) Betancort, J. M.;
Barbas, C. F. III Org. Lett. 2001, 3, 3737. (c) Enders, D.;
Seki, A. Synlett 2002, 26.
(7) For selected examples, see: (a) Huang, H.; Jacobsen, E. N.
J. Am. Chem. Soc. 2006, 128, 7170. (b) Yalalov, D. A.;
Tsogoeva, S. B.; Schmatz, S. Adv. Synth. Catal. 2006, 348,
826. (c) Gun, Q.; Guo, X.-T.; Wu, X.-Y. Tetrahedron 2009,
65, 5265. (d) Peng, L.; Xu, X.-Y.; Wang, L.-L.; Huang, J.;
Bai, J.-F.; Huang, Q.-C.; Wang, L.-X. Eur. J. Org. Chem.
2010, 2978.
(8) Sayago, F. J.; Jiménez, A. I.; Cativiela, C. Tetrahedron:
Asymmetry 2007, 18, 2358.
(9) Sayago, F. J.; Calaza, M. I.; Jiménez, A. I.; Cativiela, C.
Tetrahedron 2008, 64, 84.
Figure 2 Optimized geometries [PCMDMSO/B3LYP/6-31+G(d,p)]
for transition structures TS1–TS4; some hydrogen atoms have been
omitted for clarity
(10) For selected examples, see: (a) Hurst, M.; Jarvis, B. Drugs
2001, 61, 867. (b) Reissmann, S.; Imhof, D. Curr. Med.
Chem. 2004, 11, 2823. (c) Gass, J.; Khosla, C. Cell. Mol.
Life Sci. 2007, 64, 345.
(11) For selected examples, see: (a) Bellemère, G.; Vaudry, H.;
Morain, P.; Jégou, S. J. Neuroendocrinol. 2005, 17, 306.
(b) Curran, M. P.; McCormack, P. L.; Simpson, D. Drugs
2006, 66, 235. (c) Bas, M.; Bier, H.; Greve, J.; Kojda, G.;
Hoffmann, T. K. Allergy 2006, 61, 1490. (d) Sorbera, L. A.;
Fernández-Forner, D.; Bayes, M. Drug Future 2006, 31,
101.
seem to play a very important role both in the yield and in
the enantioselectivity. Further modifications in the skele-
ton are being performed to pursue higher enantioselectiv-
ities and they will be published in due course.
Acknowledgment
We thank the Spanish National Research Council (CSIC. Project
PIE-200880I260), the Ministry of Science and Innovation (MI-
CINN, Madrid; Projects CTQ2009-09028, CTQ2010-19606, and
CTQ2010-17436) and the Government of Aragón (Zaragoza; Pro-
ject PI064/09 and Research Groups E-10 and E-40) for financial
support of our research. R.P.H. thanks the Aragón I + D Foundation
for her permanent contract.
(12) For reviews on enamine catalysis, see: (a) List, B. Synlett
2001, 1675. (b) List, B. Tetrahedron 2002, 58, 5573.
(c) List, B. Chem. Commun. 2006, 819. (d) Marigo, M.;
Jørgensen, K. A. Chem. Commun. 2006, 2001.
(e) Mukherjee, S.; Yang, J.-W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (f) Pihko, P. M.; Majander, I.;
Erkilä, A. Top. Curr. Chem. 2010, 291, 29.
(13) During the development of our project, a novel application
of structure 4 analogue as organocatalyst has been reported:
Luo, R.-S.; Weng, J.; Ai, H.-B.; Lu, G.; Chan, A. S. C. Adv.
Synth. Catal. 2009, 351, 2449.
(14) For the single reported example of 4 as suitable
organocatalyst, see: Tang, X.; Liégault, B.; Renaud, J.-L.;
Bruneau, C. Tetrahedron: Asymmetry 2006, 17, 2187.
(15) Typical Experimental Procedure
References and Notes
(1) (a) Berkessel, A.; Gröger, H. In Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2004.
(b) Enantioselective Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, 2007. (c) Organocatalysis; Reetz,
M. T.; List, B.; Jaroch, S.; Weinmann, H., Eds.; Springer:
Berlin, Heidelberg, 2008.
To a suspension of catalyst (10 mol%) and nitroalkene (0.5
mmol) in DMF (4 mL), acetone (13.5 mmol, 1 mL) was
added, and the resulting mixture was stirred at 25 °C for the
time indicated in Table 3. After that time the reaction was
quenched with sat. NH4Cl (2 × 20 mL), the layers were
separated and the aqueous layer extracted with EtOAc
(3 × 25 mL). The combined organic layers were washed with
brine (2 × 20 mL), dried (MgSO4), filtered, and rotatory
evaporated to give a residue which was purified by flash
chromatography using hexane–EtOAc (7:3) as an eluent.
Selected Spectral Data
(2) For reviews on asymmetric Michael addition reactions, see:
(a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(b) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171.
(c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877. (d) Christoffers, A.; Baro, A. Angew.
Chem. Int. Ed. 2003, 42, 1688. (e) Christoffers, J.;
Koripelly, G.; Rosiak, A.; Rössle, M. Synthesis 2007, 1279.
(f) Enders, D.; Saint-Dizier, A.; Lannou, M. I.; Lenzen, A.
Eur. J. Org. Chem. 2006, 29. (g) Enders, D.; Luttgen, K.;
Narine, A. A. Synthesis 2007, 959.
(3) For reviews on 1,4-addition reactions catalyzed by
organocatalysts, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701. (b) Almaşi, D.; Alonso, D. A.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 299. (c) Vicario, J. L.;
Compound 8j: Following the general procedure, compound
8j was obtained after 10 d at r.t. as a white solid in 68% yield;
mp 135–136 °C. 1H NMR (400 MHz, CD3OD): d = 2.05 (s,
3 H), 2.88 (dd, J = 2.6, 7.2 Hz, 2 H), 3.82–3.89 (m, 1 H), 4.57
Synlett 2011, No. 2, 249–253 © Thieme Stuttgart · New York

LETTER
Organocatalyzed Michael Addition Reaction by a New Fused Proline
253
(dd, J = 9.2, 12.4 Hz, 1 H), 4.70 (dd, J = 6.3, 12.4 Hz, 1 H),
3772. (d) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G.
Org. Lett. 2009, 11, 1927.
6.70–6.74 (m, 2 H), 7.06–7.10 (m, 2 H). 13C NMR (100
MHz, CD3OD): d = 30.4, 40.0, 47.2, 80.9, 116.5, 129.8,
131.5, 157.9, 208.8. The ee of the product was determined
by HPLC using a Daicel Chiralpak IA column (n-hexane–i-
PrOH = 90:10, flow rate 1 mL/min, l = 230 nm):
(20) (a) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W.
Chem. Eur. J. 2006, 12, 4321. (b) Arno, M.; Zaragoza, R. J.;
Domingo, L. R. Tetrahedron: Asymmetry 2007, 18, 157.
(c) Okuyama, Y.; Nakano, H.; Watanabe, Y.; Makabe, M.;
Takeshita, M.; Uwai, K.; Kabuto, C.; Kwon, E. Tetrahedron
Lett. 2009, 50, 193.
tR(major) = 29.1 min; tR(minor) = 26.9 min. HRMS: m/z
calcd for C11H13NNaO4: 246.0737; found: 246.0728 [M+ +
Na]. [a]D22 7.3 (c 1.0, MeOH, 33% ee).
(21) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am.
Compound 8k: Following the general procedure, compound
8k was obtained after 10 d at r.t. as a yellow oil in 74% yield;
mp 131–133 °C. 1H NMR (400 MHz, CDCl3): d = 2.11 (s, 3
H), 2.88 (d, J = 7.1 Hz, 2 H), 3.96 (q, J = 7.1 Hz, 1 H), 4.55
(dd, J = 7.8, 12.2 Hz, 1 H), 4.65 (dd, J = 6.8, 12.2 Hz, 1 H),
5.02 (s, 1 H), 6.91–6.95 (m, 2 H), 7.12–7.15 (m, 2 H), 7.31–
7.44 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 30.3, 38.3,
46.2, 70.0, 79.6, 115.2, 127.4, 128.0, 128.4, 128.5, 130.9,
136.7, 158.3, 205.5. The ee of the product was determined
by HPLC using a Daicel Chiralpak IA column (n-hexane–i-
PrOH = 97:3, flow rate 1 mL/min, l = 230 nm):
Chem. Soc. 2010, 132, 6.
(22) Xue, F.; Zhang, S.; Duan, W.; Wang, W. Adv. Synth. Catal.
2008, 250, 2194.
(23) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958.
(24) All calculations were carried out with the Gaussian 09 suite
of programs: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani,
G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.;
Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A. Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark,
M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.
N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Dapprich, S.; Daniels, A. D.; Farkas, ; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision
A.1; Gaussian, Inc.: Wallingford CT, 2009.
(25) Calculations were carried out by fully optimizing transition
structures at the B3LYP/6-31+G(d,p) level and then
performing single-point calculations at M062X/6-
311+G(d,p) level with correction for solvent using Tomasi’s
polarizable continuum model (PCM) for DMSO level. The
use of M062X functional was chosen following recent
studies carried out by Houk and Papai. See: (a) Rokob,
T. A.; Hamza, A.; Papai, I. Org. Lett. 2007, 9, 4279.
(b) Wheeler, S. E.; Moran, A.; Pieniazek, S. Z.; Houk, K. N.
J. Phys. Chem. 2009, 113, 10376.
tR(major) = 44.5 min; tR(minor) = 41.1 min. HRMS: m/z
calcd for C18H19NNaO4: 336.1206; found: 336.1215 [M+ +
Na].
Compound 8l: Following the general procedure, compound
8l was obtained after 2 d at r.t. as a yellow oil in 67% yield.
1H NMR (300 MHz, CDCl3): d = 2.13 (s, 3 H), 2.88 (d,
J = 6.9 Hz, 2 H), 3.97 (q, J = 6.9 Hz, 1 H), 4.56 (dd, J = 8.1,
12.6 Hz, 1 H), 4.67 (dd, J = 6.3, 12.6 Hz, 1 H), 7.07 (dd,
J = 2.1, 8.4 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.39 (d,
J = 8.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 30.2, 38.0,
45.7, 78.8, 126.9, 129.4, 130.9, 132.0, 133.0, 139.1, 204.6.
The ee of the product was determined by HPLC using a
Daicel Chiralpak IA column (n-hexane–i-PrOH = 97:3, flow
rate 1 mL/min, l = 230 nm): tR(major) = 29.1 min;
tR(minor) = 26.1 min. HRMS: m/z calcd for
C11H11Cl2NNaO3: 298.0008; found: 298.0007 [M+ + Na].
[a]D22 –1.53 (c 1.0, CHCl3, 44% ee).
(16) For the single reported example of 2 as suitable
organocatalyst, see: Vignola, N.; List, B. J. Am. Chem. Soc.
2004, 126, 450.
(17) Flores-Ortega, A.; Jiménez, A. I.; Cativiela, C.; Nussinov,
R.; Alemán, C.; Casanovas, J. J. Org. Chem. 2008, 73, 3418.
(18) For scarce reported examples of 3 as suitable organocatalyst,
see: (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 3240. (b) Hartikka, A.; Arvidsson, P. I. J. Org.
Chem. 2007, 72, 5874.
(19) (a) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005,
611. (b) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006,
128, 7170. (c) Laars, M.; Ausmess, K.; Uudesmaa, M.;
Tamm, T.; Kanger, T.; Lopp, M. J. Org. Chem. 2009, 74,
(26) See ref. 25b. Whereas the mean error is estimated of about
2.0 kcal/mol for M062X functional, for B3LYP deviations
up to more than 10 kcal/mol could be observed. For this
reason, although B3LYP correctly predict the observed
enantioselectivity for 4, it cannot be considered
representative.
Synlett 2011, No. 2, 249–253 © Thieme Stuttgart · New York

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