Phase-transfer-catalyzed enantioselective Mannich reaction of malonates with α-amido sulfones

Article abstract of DOI:10.1002/adsc.200600250

The highly enantioselective reaction between in situ generated, Cbz-protected azomethines and malonates in the presence of 150 mol% of potassium carbonate (50% w/w) and 1 mol% of quinine-derived quaternary ammonium bromides as phase-transfer organocatalys

Full text of DOI:10.1002/adsc.200600250

COMMUNICATIONS
DOI: 10.1002/adsc.200600250
Phase-Transfer-Catalyzed Enantioselective Mannich Reaction of
Malonates with a-Amido Sulfones
Francesco Fini,a Luca Bernardi,a Raquel P. Herrera,a Daniel Pettersen,a
Alfredo Ricci,a,* and Valentina Sgarzania
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, V. Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; e-mail: ricci@ms.fci.unibo.it
Received: May 29, 2006; Accepted: August 8, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The highly enantioselective reaction be-
tween in situ generated, Cbz-protected azomethines
and malonates in the presence of 150 mol% of po-
tassium carbonate (50% w/w) and 1 mol% of qui-
nine-derived quaternary ammonium bromides as
phase-transfer organocatalysts has been developed.
This study reports a novel approach for the asym-
metric Mannich-type reaction and a wide range of
azomethines, including those derived from enoliza-
ble aldehydes, is tolerated by the present system.
The adducts, obtained in excellent yields with ee up
to 98%, are suitable precursors of optically pure b-
amino acids.
catalysis (PTC) as a tool for the catalytic asymmetric
Mannich reaction is still relatively undeveloped,[9] al-
though this approach appears highly attractive consid-
ering the mild reaction conditions and the operational
simplicity typical of PTC.[10] Furthermore, we and
others have recently demonstrated that by exploiting
PTC it is possible to generate N-carbamoyl (Boc and
Cbz) imines in situ from the corresponding a-amido
sulfones, activating at the same time a nucleophile,
namely nitromethane, for the asymmetric addition.[11]
This strategy allows the use of enolizable N-carb-
amoylimines derived from aliphatic aldehydes, whose
isolation has only seldom been reported as they are
unstable and moisture-sensitive and readily tautomer-
ize to the more stable ene-carbamate form.[12] On this
basis we decided to explore the direct Mannich reac-
tion of malonates with N-carbamoylimines generated
in situ from a-amido sulfones,[13] using inexpensive
and readily available quaternary ammonium salts de-
rived from Cinchona alkaloids as phase-transfer cata-
lysts.[14] The products of this transformation are direct
Keywords: a-amido sulfones; asymmetric synthesis;
Mannich reaction; nucleophilic addition; phase-
transfer catalysis
The Mannich reaction is a fundamental transforma- precursors of optically active b-amino acids bearing
tion in synthetic organic chemistry.[1] Due to the im- synthetically useful and readily removable N-carba-
portance of the products in their enantioenriched moyl protecting groups such as Boc and Cbz.[15]
form, tremendous efforts have been made in the last
The initial screening of several chiral quaternary
years towards the development of an asymmetric ver- ammonium salts in the PTC Mannich reaction be-
sion of this reaction.[2] After several chiral auxiliary tween dimethyl malonate and a-amido sulfone 1a,
and reagent-based approaches,[3] the first reports of was informative in that only quinine derivatives ex-
catalytic asymmetric Mannich reactions involved the hibited a significant though modest enantioselectivity
use of chiral Lewis acids for the activation of the (see Supporting Information). Additional observa-
imine moiety in combination with preformed enolates, tions gave further insight into the requirements of the
such as silylenol ethers.[4] Shortly after, a few direct catalyst, indicating the crucial importance of the hy-
Mannich reactions were reported, wherein the chiral droxy function since the catalyst, whose alcohol group
Lewis acids were also able to trigger the enolization has been protected in the form of allyl ether, did not
process, thus allowing the use of unmodified carbonyl show any significant asymmetric induction. Toluene
donors as nucleophiles.[5] More recently several orga- and potassium carbonate were determined to be the
nocatalytic protocols have been developed, especially best solvent and base, respectively, and running the
using as catalysts secondary amines,[6] tertiary nitro- reaction under dilute conditions (0.05M) afforded
gen bases derived from Cinchona alkaloids,[7] or chiral better enantioselectivities, probably due to a polarity
Brønsted acids.[8] However, the use of phase-transfer change of the reaction medium.[16] To examine the
Adv. Synth. Catal. 2006, 348, 2043 – 2046
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2043

Francesco Fini et al.
COMMUNICATIONS
role of the electronic and steric factors present in the vided a further beneficial effect (compare entries 1, 3
quinuclidinic nitrogen substituent, various N-benzyl- and entries 2, 4).
quininium derivatives were prepared from quinine
Next we attempted the Mannich reaction using
and benzyl bromides bearing various functional 50% (w/w) aqueous K2CO3 (entries 5–10). Under
groups at the ortho- and para-positions. A significant these conditions the rate was markedly enhanced and
difference in asymmetric induction was noticed be- gratifyingly the enantioselectivity was substantially
tween para- and ortho-substituted derivatives and no- improved with respect to the anhydrous conditions[17]
tably among the latter were those with electron-with- when using the NH-Cbz protected a-amido sulfone 2a
drawing functional groups, like CN and CF3, which (compare entries 3, 7 and 4, 8 in Table 1), though the
gave higher enantioselectivity. In general, the size of enantioinduction in the case of the NH-Boc protected
the ester moiety of the malonates did not affect to a a-amido sulfone 1a remained unaffected (compare
substantial extent the chemical and stereochemical entries 1, 5 and 2, 6). Bearing in mind the possibility
outcomes. Conversely aryl malonates and especially to synthesize the opposite enantiomer, we performed
the p-methoxyphenyl derivative 3 afforded an in- the reaction with N-(o-cyanobenzyl)quinidinium bro-
crease in stereoselectivity up to 76% ee (see Support- mide as catalyst and the resulting product was ob-
ing Information).
tained in high yield but with slightly lower enantiose-
These observations encouraged us to pursue a lectivity (entry 9, Table 1).[18]
study to find the optimized conditions. As shown in
Finally, an enantioselectivity/temperature profile
Table 1, variously N-protected a-amido sulfones were documented that the optimal enantiocontrol was
screened using catalysts 6 and 7, and although excel- available by lowering the temperature: cooling the re-
lent conversion yields and fairly good enantioselectiv- action had a remarkably positive effect as the enan-
ities were uniformly attained, the Cbz protection pro- tioselectivity rose to 98% (entry 9) at À208C. It is
Table 1. Optimization of the catalyst, base and protecting group at nitrogen in the reaction of p-anisyl malonate 3 with a-
amido p-tolyl sulfones 1a and 2a.[a]
Entry
Catalyst
Base
Protecting Group
Boc
Product
Time [h]
21
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
6
7
6
7
6
7
6
7
K2CO3 (s)
4a
4a
5a
5a
4a
4a
5a
5a
5a
5a
60
70
85
80
>95
>95
>95
>95
>95
>95
76
67
84
83
72
64
93
Cbz
Boc
Cbz
K2CO3 (aq)[d]
5
93
QD-6
6
7
48
87[e]
98[f]
10
[a]
Reactions conducted on a 0.1 mmol scale.
Determined by H NMR analysis.
Determined by chiral HPLC analysis.
Aqueous K2CO3 (50% w/w) was used.
The reaction performed with catalyst QD-6 gave the opposite enantiomer of 5a
Reaction conducted at À208C with 1 mol% catalyst.
[b]
[c]
[d]
[e]
[f]
1
2044
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2043 – 2046

Enantioselective Mannich Reaction of Malonates with a-Amido Sulfones
COMMUNICATIONS
noteworthy that this superior level of asymmetric in- this catalytic process to construct b-amino acid moiet-
duction and efficiency was maintained even with a ies bearing synthetically useful protecting groups at
catalyst loading reduced to 1 mol% (entry 10). The nitrogen such as Cbz, allowing at the same time the
optimized conditions outlined in Table 1 were select- determination of the absolute configuration of the ad-
ed for exploring the substrate scope of this Mannich ducts.
reaction (Table 2).
In summary, a novel organocatalytic, highly enan-
As listed in Table 2 the adducts were generally ob- tioselective Mannich reaction is described which
tained in very good chemical yields using 6 as the cat- holds distinct practical advantages and requires only a
alyst (1 mol%). With the aryl-substituted a-amido low catalytic loading. With respect to the direct cata-
sulfones 1a, b and 2a–e the reaction proceeded lytic, asymmetric reaction,[4–9] our approach displays a
smoothly with excellent enantioselectivity irrespective considerably broader scope[19] since it also gives a
of the electronic nature of the aromatic ring (en- straightforward access to optically active b-alkyl N-
tries 1–7). Most remarkably also alkyl a-amido sul- carbamoyl b-amino acids, starting from readily avail-
fones 1c and 2f–j, precursors of enolizable azome- able and stable a-amido sulfones.
thines, gave the corresponding adducts 4c and 5f–j
with enantiomeric excesses in the 76–96% range (en-
tries 8–13).
Experimental Section
Finally,
a decarboxylation/transesterification se-
quence (Scheme 1) delineated the synthetic utility of
Preparation of Catalyst 6
A mixture of (À)-quinine (648 mg, 2 mmol) and o-cyano-
benzyl bromide (431 mg, 2.2 mmol) in a mixture of THF
(1.8 mL), ethanol (1.5 mL), and chloroform (0.6 mL), was
stirred at 1008C for 3 h. After cooling to room temperature,
the crude material was evaporated under reduced pressure
and the product was purified by chromatography on silica
gel (CH2Cl2/MeOH 90:10) to afford 6 as a pale yellow solid;
yield: 925 mg (89%).
Scheme 1. Determination of absolute configuration by trans-
esterification/decarboxylation sequence.
Table 2. Scope of the organocatalyzed Mannich reaction of malonate 3 with azomethines generated in situ from a-amido sul-
fones 1 and 2 under PTC.[a]
Entry
a-Amido Sulfone
R
Protecting Group
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
2a
1b
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Boc
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Cbz
4a
5a
4b
5b
5c
5d
5e
5f
5g
5h
5i
92
81
90
94
85
95
90
93
90
90
80
50
80
90
98
84
95
98
98
96
86
86
96
86[d]
76
95
2-Naphthyl
1-Naphthyl
p-MeO-C6H4
o-Br-C6H4
p-Cl-C6H4
Me
9
Et
10
11
12
13
PhCH2CH2
i-Pr
Cy
1c
2j
4c
5j
Cy
[a]
Reactions conducted on a 0.1 mmol scale at À208C for 48 h, using 1 or 2:3:6:aqueous K2CO3 in a 1:1.2:0.01:1.5 molar
ratio.
[b]
[c]
[d]
Isolated yields after column chromatography.
Determined by chiral HPLC analysis.
Determined by chemical correlation with compound 8i.
Adv. Synth. Catal. 2006, 348, 2043 – 2046
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2045

Francesco Fini et al.
COMMUNICATIONS
[7] S. B. Lou, M. Taoka, A. Ting, S. E. Schaus, J. Am.
Chem. Soc. 2005, 127, 11256–11257, and reference
cited therein.
[8] a) A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc.
2002, 124, 12964–12965; D. Uraguchi, M. Terada, J.
Am. Chem. Soc. 2004, 126, 5356–5357, and references
cited therein.
[9] a) A. Okada, T. Shibuguchi, T. Ohshima, H. Masu, K.
Yamaguchi, M. Shibasaki, Angew. Chem. 2005, 117,
4640–4643; Angew. Chem. Int. Ed. 2005, 44, 4564–
4567; b) T. Ooi, M. Kameda, J.-i. Fujii, K. Maruoka,
Org. Lett. 2004, 6, 2397–2399.
[10] For recent reviews, see: a) K. Maruoka, T. Ooi, Chem.
Rev. 2003, 103, 3013–3028; b) B. Lygo, B. I. Andrews,
Acc. Chem. Res. 2004, 37, 518–525; c) M. J. OꢁDonnell,
Acc. Chem. Res. 2004, 37, 506–517.
General Procedure for the Catalytic Enantioselective
Reaction of Malonate 3 with a-Amido Sulfones 1a–c,
2a–j
A solution of N-(o-cyanobenzyl)quininium bromide 6 in tol-
uene (2 mL, 5.0”10À4 M, 1.0 mmol) was added to a test tube
containing a mixture of the a-amido sulfone 1a–c, 2a–j
(0.1 mmol) and malonic acid bis-(4-methoxyphenyl) ester 3
(38 mg, 0.12 mmol). After the resulting solution had been
cooled to À208C, 50% aqueous K2CO3 (w/w, 28 mL,
0.15 mmol) was added in one portion. The reaction mixture
was then vigorously stirred at the same temperature without
any precaution to exclude moisture or air. After 48 h, the re-
action product was directly purified by chromatography on
silica gel (CH2Cl2).
[11] a) F. Fini, V. Sgarzani, D. Pettersen, R. P. Herrera, L.
Bernardi, A. Ricci, Angew. Chem. 2005, 117, 8189–
8192; Angew. Chem. Int. Ed. 2005, 44, 7975–7978;
b) C. Palomo, M. Oiarbide, A. Laso, R. López, J. Am.
Chem. Soc. 2005, 127, 17622–17623; non-asymmetric
PTC transformations on a-amido sulfones: c) R.
Kimura, T. Nagano, H. Kinoshita, Bull. Chem. Soc.
Jpn. 2002, 75, 2517–2525; d) V. Banphavichit, S. Cha-
leawlertumpton, W. Bhanthumnavin, T. Vilaivan,
Synth. Commun. 2004, 34, 3147–3160.
Acknowledgements
We acknowledge financial support by the “Consorzio CINM-
PIS”, by the MIUR-National Project 2005, and by the EC-
RTN ꢀDACCORDꢁ project, which also provided post-doctor-
al fellowships to R.P.H. and D.P.
References
[12] T. Mecozzi, M. Petrini, Synlett 2000, 73–74.
[13] For a comprehensive review on a-amido sulfones as
precursors of N-acylimines, see: M. Petrini, Chem. Rev.
2005, 105, 3949–3977.
[1] E. F. Kleinmann, in: Comprehensive Organic Synthesis,
Vol. 2, (Eds.: B. M. Trost, I. Fleming), Pergamon, New
York, 1991, pp. 893–951.
[14] a) H. Wynberg, Top. Stereochem. 1986, 16, 87–129;
b) K. Kaprczak, J. Gawronski, Synthesis 2001, 961–998.
[15] For the importance and usefulness of b-amino acids in
organic and pharmaceutical chemistry, see a) E. F.
Kleinmann, in; Enantioselective Synthesis of b-Amino
Acids, (Ed.: E. Juaristi), Wiley-VCH, New York, 1997;
b) T. Hintermann, D. Seebach, Chimia 1997, 50, 244–
247; c) J.-A. Ma, Angew. Chem. 2003, 115, 4426–4435;
Angew. Chem. Int. Ed. 2003, 42, 4290–4299.
[2] a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99,
1069–1094; b) S. Denmark, O. J.-C. Nicaise, in: Com-
prehensive Asymmetric Catalysis, Vol. 2, (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin,
1999, pp. 923–964; c) A. Córdova, Acc. Chem. Res.
2004, 37, 102–112.
[3] See for example: a) P. G. Cozzi, B. Di Simone, A.
Umani-Ronchi, Tetrahedron Lett. 1996, 37, 1691–1694;
b) D. Enders, S. Oberbçrsch, Synlett 2002, 471–473;
c) C. Palomo, M. Oiarbide, A. Landa, M. C. Gonzales-
Rego, J. M. Garcia, A. Gozales, J. M. Odriozola, M.
Martin-Pastor, A. Linden, J. Am. Chem. Soc. 2002, 124,
8637–8643, and references cited therein.
[4] See for example: a) H. Ishitani, M. Ueno, S. Kobayashi,
J. Am. Chem. Soc. 1997, 119, 7153–7154; b) E. Hagi-
wara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998,
120, 2474–2475; c) D. Ferraris, B. Young, T. Dudding,
T. Lectka, J. Am. Chem. Soc. 1998, 120, 4548–4549.
[5] a) S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron Lett.
1999, 40, 307–310; b) K. Juhl, N. Gathergood, K. A.
Jørgensen, Angew. Chem. 2001, 113, 3083–3085;
Angew. Chem. Int. Ed. 2001, 40, 2995–2997; c) Y. Ha-
mashima, N. Sasamoto, D. Hotta, H. Somei, N. Ume-
bayashi, M. Sodeoka, Angew. Chem. 2005, 117, 1549–
1553; Angew. Chem. Int. Ed. 2005, 44, 1525–1529, and
references cited therein.
[16] U.-H. Dolling, P. Davis, E. J. J. Grabowski, J. Am.
Chem. Soc. 1984, 106, 446–447.
[17] Regarding this cooperative effect of water, along with
the hypothesis of an internal hydrogen bonding of
water with the ortho-substituents and the OH group in
6 and 7 which might contribute to maintain a more
rigid catalyst conformation (M.-S. Yoo, B.-S. Jeong, J.-
H. Lee, H.-g. Park, S.-s. Jew, Org. Lett. 2005, 7, 1129–
1131, and references cited therein), also an interaction
of water with the imine moiety and with the OH func-
tion of the catalyst cannot be ruled out at this stage.
[18] Usually the catalyst derived from the Cinchona alka-
loids that has the opposite absolute configuration at C-
9 and C-10 furnishes an inverse catalysis, giving the op-
posed enantiomer. For more recent example see
refs.[7,][11b]
[19] In a very recent paper a Zn-catalyzed direct asymmet-
ric Mannich reaction using a-enolizable N-Boc imines
(2 examples) has been reported: B. M. Trost, J. Jaratjar-
oonphong, V. Reutrakul, J. Am. Chem. Soc. 2006, 128,
2778–2779.
[6] a) B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am.
Chem. Soc. 2002, 124, 827–833; b) A. Córdova, W.
Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J.
Am. Chem. Soc. 2002, 124, 1842–1843, and references
cited therein.
2046
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2043 – 2046