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: jcomin@inti.gob.ar

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