Gandolfi Donadío, Lucía;† Galetti, Mariana A.;† Giorgi, Gianluca;‡ Comin, Maria J.*,†
•†Centro de Investigación y Desarrollo en Química, Instituto Nacional de Tecnología Industrial (INTI), San Martín, B1650WAB, Argentina. ‡Dipartimento di Biotecnologie, Chimica & Farmacia, Università di Siena, Italy
*e-mail: [email protected]
Organocatalytic Michael reaction study between phenyl acetaldehyde and nitrostyrene
INTRODUCTIONINTRODUCTIONOrganocatalytic Michael addittion has been intensively studied in recent years and provides Michael adducts in a highly stereoselective way. We were interested in developing a simple and stereo-controlled route to
3,4-diphenyl substituted pyrrolidines, that are structural motifs found in many biologically active compounds, using a Michael reaction between nitrostyrenes and benzylic aldehydes as the key step.Extensive studies on the organocatalyzed Michael reaction between nitroalkenes and aliphatic aldehydes were conducted showing a high syn diastereselection according to Seebach’s model.1 However, only four examples using α-unsubstituted benzylic aldehydes have been reported showing a relative low syn diasteroselectivity.2 Since the higher acidity of the α protons of benzylic aldehydes relative to aliphatic ones could affect the reaction mechanism, we decided to examine and optimize the diastereochemical outcome of this process. Herein we report our results concerning the diastereoselective Michael reaction between phenylacetaldehyde and nitrostyrene.
RESULTS AND DISCUSSIONRESULTS AND DISCUSSION
Primarily, a variety of solvents, secondary amines and catalyst concentrations were screened. The best result was obtained using toluene as solvent in presence of 20% mol of pyrrolidine and a 0.5 fold excess of aldehyde (Scheme 1).The reaction yielded a clean product with high conversion and diastereselection. 1H NMR data of the major diastereomer obtained was in accordance with the already described for the syn adduct2 (Table 1). The relative configuration of the major isomer of 3 was unambiguously determined by X-ray diffraction and surprisingly revealed to be anti (Figure 1).In order to understand this result, we monitored the Michael stoichiometric reaction by 1H NMR under anhydrous conditions (Figure 2 B and C). The major species observed was the product enamine with only a maximum ca. 20 % of cyclobutane that is typically observed as a major intermediate with aliphatic aldehydes3 (Scheme 2). Moreover, when we made the same experiment in presence of water (without molecular sieves) we observed a much rapid formation of the conjugated product enamine in comparison with the Michael product. In addition, when we tried the reaction using triethylamine instead of pyrrolidine as catalyst, we obtained 3 with the same diastereomeric ratio, suggesting a coexisting mechanism via the enolate. On the other hand, when we run the same experiments using an aliphatic aldehyde (hexanal) the predictable behavior was observed.3
• The organocatalized Michael addition of phenyl acetaldehyde to nitrostyrene was studied. The anti-adduct was obtained in high diastereoselectivity contrary to Seebach’s topological rule.
• Two types of mechanisms could be active, one involving an enolate, and other an enamine as reactive nucleophiles.
• We observed a very rapid formation of the conjugated product enamine’s. The anti diastereoselection must be governed by the hydrolysis of this intermediate toward the most stable anti adduct.
CONCLUSIONCONCLUSION
1 Seebach, D.; Golínski, J. HCA, 1981, 64, 1413–1423.2 (a) Laars, M.; Ausmees, K.; Uudsemaa, M.; Tamm, T.; Kanger, T.; Lopp, M. J. Org. Chem. 2009, 74, 3772–3775. (b) Zhao, G.-L.; Xu, Y.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Chem. Commun. 2009, 734–735.(c) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004, 346, 1147–1168. (d) Alza, E.; Pericãs, M. Adv. Synth. Catal. 2009, 351, 3051–3056. 3 (a) Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2011, 133, 8822–8825. (b) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. HCA, 2011, 94, 719–745. (c) Sahoo, G.; Rahaman, H.; Madarász, A.; Pápai, I.; Melarto, M.; Valkonen, A.; Pihko, P. M. Angew. Chem. Int. Ed. 2012, 51, 13144–13148.
REFERENCESREFERENCES
Scheme 1. Model Reaction.
Toluene, rt
NO2
PhH
O
Ph +
NH
(20 mol%)
31 (0.45 mmol) 2 (0.3 mmol)
H
O
Ph
Ph
NO2
dr= 98:2
Figure 1. X-ray crystal structure of 3
3
H
O
Ph
Ph
NO2
1H-NMR (CDCl3)
3 (major isomer)
δ [ppm, m, J (Hz), nH]
1H-NMR (CDCl3)
Compound 7d2a
1H-NMR (CDCl3)
Compound 4k2b
1H-NMR (CDCl3)
Compound 12e2c
4.07 (dd, J = 2.0, 10.2 Hz, 1H) 4.03 (dd, J = 2.0, 10.5 Hz, 1H) 4.08-4.05 (m, 1H, CH) 4.09 (dd, J = 2.0, 10.6 Hz, 1H)
4.30 (dt, 1H, J = 4.4, 10.3 Hz) 4.30-4.18 (m, 1H) 4.37-4.29 (m, 1H, CH 4.32 (dt, J = 4.3, 10.4 Hz, 1H)
4.39 (dd, 1H, J = 4.4, 12.8 Hz) 4.34 (dd, J = 4.3, 12.7 Hz, 1H) 4.49-4.40 (m, 2H, CH2), 4.41 (dd, J = 4.3, 12.6 Hz, 1H)
4.49 (dd, 1H, J = 10.3, 12.8 Hz) 4.44 (dd, J = 10.4, 12.7 Hz, 1H) 4.50 (dd, J = 10.4, 12.6 Hz, 1H)
7.45-7.25 (m, 10H) 7.42-6.88 (m, 10H) 7.55-7.24 (m, 10H, Ar-H) 7.48-7.27 (m, 10H)
9.56 (d, J = 2.2 Hz, 1H) 9.50 (d, J = 2.1 Hz, 1H) 9.53 (d, J = 1.6 Hz, 1H, CHO) 9.57 (d, J = 2.0 Hz, 1H)
Table 1: Comparison with published 1H NMR data of major isomer of 3
Scheme 2. Suggested mechanism for Amine-Catalyzed Michael Addition of Aldehydes to Nitro Olefins.3
NH
R H
O
R1
N R
R1
H
R2
NO2N R
R1 H
NOO
R2
R2
R1 NO2
N R
N R
R1 H
NO2
R2
X
N R
R1 H
NO2
R2
O
R1 H
NO2
R2
O
R1 H
NO2
R2
HX
epimerization in presence of catalyst
aldehyde´s enamine
cyclobutane
product´s enamine iminium ion
zwitterionic intermediate
Michael product
H2OH2O
N
Ph
H
(1 eq)
12
Ph
NO2
(1 eq)3
4
t = 1 h
t = 15 min
t = 2 h
t = 120 h
t = 168 h
Ph
Ph NO2
N1'
2'
3'4'
N
PhH
NO2
Ph
1''
2''
3''4''
4’
4’
4’
1’’
1’’
1’’
1’’
1
1
1
1
1
N
PhH
NO2
Ph
Ph
Ph NO2
N
N
Ph
H
O
PhH
NO2
PhO
PhH
NO2
Ph
Ph
Ph NO2
N
N
Ph
H
N
PhH
NO2
Ph
Figure 2. Temporal profiles : A-Formation cyclobutane. The reaction was carried out in an NMR tube: an equimolar amount of 2 was added to a suspension of preformed enamine, 4 Å molecular sieves in toluene-d8; B-Michael product formation. Michael addition of 1 to 2 in the presence of an equimolar amount of pyrrolidine (ratio 1 : 1 : 1). The reaction was carried out in an NMR tube in toluene-d8 without 4 Ǻ molecular sieves. C-1.Preformed phenylacetaldehyde’s enamine 1H NMR (toluene-d8); 2-6. Variable-time 1H NMR spectra of preformed phenylacetaldehyde´s enamine (1 eq.), 2 (1 eq) in toluene-d8
B
CA