Synthesis of novel tetrahydroindeno[1,2-b ]pyrrolidines via Ugi multicomponent and palladium-catalyzed aerobic oxidative cyclization

Article abstract of DOI:10.1080/00397911.2016.1152372

Novel tetrahydroindeno[1,2-b]pyrrolidines were conveniently prepared in moderate to good yields via a sequential Ugi multicomponent reaction or Staudinger/aza-Wittig/Ugi combination, followed by the palladium-catalyzed aerobic oxidative cyclization of the

Full text of DOI:10.1080/00397911.2016.1152372

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Novel Tetrahydroindeno[1,2-
b]pyrrolidines via Ugi MCR and Palladium-
Catalyzed Aerobic Oxidative Cyclization
Tannya R. Ibarra-Rivera, Manuel Alejandro Rentería-Gómez, Eduardo Nieto-
Sepúlveda, Rocío Gámez-Montaño, Verónica M. Rivas-Galindo & Eugenio
Hernandez-Fernandez
To cite this article: Tannya R. Ibarra-Rivera, Manuel Alejandro Rentería-Gómez, Eduardo
Nieto-Sepúlveda, Rocío Gámez-Montaño, Verónica M. Rivas-Galindo & Eugenio Hernandez-
Fernandez (2016): Synthesis of Novel Tetrahydroindeno[1,2-b]pyrrolidines via Ugi MCR
and Palladium-Catalyzed Aerobic Oxidative Cyclization, Synthetic Communications, DOI:
10.1080/00397911.2016.1152372
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1152372
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Date: 22 February 2016, At: 20:27

Synthesis of Novel Tetrahydroindeno[1,2-b]pyrrolidines via Ugi MCR and
Palladium-Catalyzed Aerobic Oxidative Cyclization
Tannya R. Ibarra-Rivera1,, Manuel Alejandro Rentería-Gómez2, Eduardo Nieto-
Sepúlveda1, Rocío Gámez-Montaño2, Verónica M. Rivas Galindo1, Eugenio Hernandez-
Fernandez3
1Departamento de Quimica Analitica, Universidad Autónoma de Nuevo León, Facultad
de Medicina, Monterrey, Nuevo León (México), 2Departamento de Química, División de
Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, Guanajuato
(México), 3Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, San
Nicolas de los Garza, Nuevo León (México)
Address correspondence to Tannya R. Ibarra-Rivera, Universidad Autonoma de Nuevo
Leon, Facultad de Medicina, Departamento de Quimica Analitica. Fco. I. Madero s/n,
Col. Mitras Centro, Monterrey, Nuevo Leon, 64460 México. E-mail:
tannya.ibarrarv@unal.edu.mx
Abstract
Novel tetrahydroindeno[1,2-b]pyrrolidineswereconveniently prepared in moderate to
good yields via a sequential Ugi multicomponent reaction or Staudinger/aza-Wittig/Ugi
combination, followed by the palladium-catalyzed aerobic oxidative cyclization of the
resulting Ugi adducts.
KEYWORDS: Tetrahydroindeno[1,2-b]pyrrolidines, Ugi reaction, oxidative cyclization.
INTRODUCTION

Synthetic Multi-Component Reactions (MCR´s) have emerged as an efficient and
powerful tool in modern synthetic organic chemistry.1 They are well known to be
selective, efficient, atom economic, time and energy saving and easy to perform. MCR´s
are extremely powerful to prepare structurally diverse complex molecules in a single
chemical step and in combination with a second chemical transformation or post-
condensation process ifimproves its chances to obtain more elaborated cyclic structures.2–
4 Among others MCRs, isocyanide-based MCRs (Ugi and Passerini) in combination with
any intramolecular reaction, are the most used strategy to construct highly diverse
heterocycles. Depending on the functional groups introduced during the MCR, several
MCRs/post-condensation strategies have been described.5–7
Indeno[1,2-b]pyrrolidines are an interesting class of polycyclic heterocycles, which
exhibit important biological effects. They have been reported to have hypoglycemic
activity (1)8 and recently, 2 has demonstrated high affinity and selectivity for the NMDA
receptor.9 To date, there are some synthetic methods for the preparation of
tetrahydroindeno[1,2-b]pyrrolidines. In general they consist in multistep synthesis from
unusual starting materials which incorporate one of two indeno[1,2-b]pyrrolidines
cycles.9,10–12 Recently, we have reported on palladium-catalyzed oxidative cyclization of
N-arylpeptides which afforded some hydroindeno[1,2-b]pyrrolidines.13 As an extension
of this work we describe here the palladium-catalyzed oxidative cyclization of Ugi
adducts to prepare new indeno[1,2-b]pyrrolidines which can be further transformed to
more complex and constrained polyheterocyles.

RESULTS AND DISCUSSION
Ugi adducts7a-g were easily prepared in good yields (90-99%)by the reaction
homoallylamine 3 with various aromatic aldehydes 4, aromatic acids5 and alkyl
isocyanides 6, in methanol with catalytic indium trichloride at room temperature.14–17
Compounds 7band 7e-hwere obtained via a Staudinger/aza-Wittig/Ugi18 sequencefrom
homoallyl bromide8. It is well documented that imines, the first Ugi intermediate, can be
obtained from Staudinger iminophosphoranes and carbonyl compounds like
benzaldehydes in good yields.19The Staudinger/aza-Wittig/Ugi combination has been
used commonly to prepare Ugi derivatives from azides. In addition, the nucleophillic
substitutionof sodium azide on alkyl halides is fully compatible with the Staudinger
reaction in order to obtainany imine. Therefore, bromide was mixed with sodium azide
in DMSO at 60 °C, and then were added successively PPh3 and benzaldehydes4in order
to get imine 9. Assumingthe imine was formed,benzoic acid 5 and isocyanide 6were
added to the mixture to complete this route.Without further optimization, this
combination affords the desired products in moderate yield (44-54%). In some cases the
Passerini product 8was obtained, which could explain the lower yields compared to
original route (Ugi). Nevertheless, it turned out to be a general methodology to
preparethe homoallyl Ugi derivatives from a cheaper and less volatile raw material than
homoallyl amine.
Palladium cyclization was initially proved with compound 7e using 5 mol% of palladium,
2 equivalents of K2CO3 and air as oxidant (Table 2, entry 1). Indeno[1,2-b]pyrrolidine 9e

was recovered in 30% yield as single product and no starting material was
detected.Comparing with the oxidative palladium cyclization of N-aryl amides (Ugi-
Smiles), the N-acyl-amides (Ugi) gave lower yield. An attempt to improve this yield was
performed by variations in the base and oxidant.However our initial conditions were the
best in this process. Other bases such as 1,8-diazabicycloundec-7-ene (DBU) and NaH
did not benefitthe reaction (Table 2, entry 2 and 3); the desired product 9e was not
detected. Some starting material was recovered in the case of DBU. When p-
benzoquinone was used as the only oxidant the yield dropped to 10% and reaction time
increased to 8 h (Table 2, entry 4). Finally, the yield using the combination of p-
benzoquinone with oxygen (air) was slightly better than prior example but lower than
only oxygen from air.20
With the best conditions in hand, oxidative palladium cyclization was performed with
Ugi derivatives 7a-h and six different indeno[1,2-b]pyrrolidines 9a, 9b, 9c, 9e, 9f and
9hwere obtained. Higher-yield was achieved for compound 9f. The presence of electron-
withdrawing groups in both aromatic rings slightly enhances this cyclization process,
where p-chloro derivatives 9c and 9f gave 5 to 10% more than corresponding benzene
tetrahydroindeno[1,2-b]pyrrolidines9b and 9e.It was not possible to evaluate the direct
electron-donating effect of electron rich groups in both aromatics. However, the reaction
did not proceeed with Ugi 7d, which contains one methoxy group in para position at the
nitro aromatic ring, indicating a negative effect.Finally, compounds 9gwere not found in
crude reaction mixture.

This oxidative cyclizationprocess complements our mechanism proposed in 2007 (Figure
2), where the acidic proton removal in 7e is associated withPd-enolateIcreation and
capture by the olefin to formPd-alkyl intermediate IIwhich further cyclizes onto the
aromatic ring. In agreement to our resultsthe Pd-enolate I is better stabilized by electron-
withdrawing groups as nitro or chloro.13The higher yields observed with N-aryl amides
(Ugi-Smiles) can be explained in the first step, where Pd-enolate I seems to be better
stabilized byp-nitrophenyl group or it could be the N-acyl group destabilizes the enolate
formation because of the complexation of Pd with a second carbonyl group. The use of
benzoquinone as single oxidant is reported in similar palladium-catalyzed
reactions.However, according to our results, the Pd (0) generated is oxidized back to
Pd(II) more efficiently by air oxygen than benzoquinone.
CONCLUSIONS
In summary, we have prepared six new indeno[1,2-b]pyrrolidinesusing a two step
Ugi/Palladium-Catalyzed Aerobic Oxidative Cyclizationin moderate yields. Electron-
withdrawing groups are important to produce the oxidative palladium cyclization in N-
acyl amides (Ugi). Further work is necessary to improve palladium oxidative process
with this type of Ugi products. In addition,this method would be useful for rapid access to
this new type of bioactive polyheterocycles.We believe this method hasa significant
synthetic value due conformationally constrainedL-proline derivatives can be prepared
and therefore we are working to extend it.
EXPERIMENTAL

Typical Procedure For The Synthesis of Ugi Compounds
Acid (1 mmol) and isocyanide (1 mmol) were added successively to a mixture of
homoallyl amine (1 mmol) and benzaldehyde (1 mmol)and 5% mol of InCl3 in methanol
(0.5 M). The resulting mixture was stirred at room temperature during 18 h before being
concentrated under reduced pressure. The crude product was chromatographed using a
mixture of hexane and ethyl acetate as the eluents, affording the pure Ugis 7a-f in 90-
99% yields.
N-(But-3-En-1-Yl)-N-(2-(Tert-Butylamino)-2-Oxo-1-Phenylethyl)-4-Nitrobenzamide
(7e).
A Colorless Viscous Liquid. 1H NMR (400 Mhz, Cdcl3)( , Ppm):8.22 (D, 1H, J=8.2 Hz,
Ar-H), 7.73 (Dd, 1H, J1=7.5 Hz, J2=0.9 Hz, Ar-H), 7.61-7.52 (M, 2H, Ar-H), 7.45-7.36
(M, 5H, Ar-H), 6.06 (Sb, 1H, NH), 5.84 (S, 1H, CH-CO), 5.30-5.19 (M, 1H, CH=), 4.77-
4.75 (D, J=9.9 Hz, 1H, CH2=), 4.63-4.59 (D, 1H, J=17.1 Hz, CH2=), 3.84-3.16 (M, 2H,
CH2), 2.42-1.97 (M, 1H, CH2), 1.40 (S, 9H, CH3-C). 13C NMR (100 Mhz, Cdcl3)( ,
Ppm): 168.5, 144.9, 135.0, 134.3, 133.9, 132.8, 130.1, 129.9, 129.8, 129.5, 129.1, 128.8,
128.5, 124.8, 116.8, 63.5, 51.7, 47.9, 33.2, 28.5. HRMS (FAB):Calculated For
C23H27N3O4 409.4781 [M]+; Found 410.2079.
Typical Procedure For The Synthesis Of Palladium Catalyzed Oxidative Cyclization
To a 0.2 M solution of Ugi adduct (1 mmol) in DMF were added successively 2 equiv. of
K2CO3 and 5% mol of Pd (OAc)2. The resulting mixture was stirred at 110 C for 3 h
under constant airflow suministrated by a ballon full or air. The reaction mixture was

diluted with water, and extracted with AcOEt. Organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was chromatographed product
was chromatographed using a mixture of hexane and ethyl acetate as the eluents,
affording the pure indeno[1,2-b]pyrrolidine 9a-h in 15-40% yields.
N-(Tert-Butyl)-1-(4-Nitrobenzoyl)-2,3,3a,4-Tetrahydroindeno[1,2-B]Pyrrole-8b(1H)-
Carboxamide (9e).
A colorless viscous liquid. 1H NMR (400 MHz, CDCl3)( , ppm): 8.24 (dd, 2H, J1=6.9
Hz, J2=1.8 Hz), 8.12 (d, 1H, J1=7.0 Hz), 7.67 (dd, 2H, J1=7.0 Hz, J2=1.9 Hz), 7.38-7.29
(m, 3H), 5.41 (sb, 1H, NH), 3.70-3.63 (m, 1H), 3.47-3.41 (m, 1H), 3.27-3.17 (m, 2H),
2.84-8.80 (m, 1H), 2.29-2.22 (m, 1H), 1.71-1.62 (m, 1H), 1.29 (s, 9H). 13C NMR (100
MHz, CDCl3)( , ppm): 170.5, 167.6, 148.2, 143.6, 143.4, 141.5, 129.7, 128.1, 127.9,
127.7, 125.9, 123.7, 82.1, 51.6, 51.3, 50.1, 35.1, 31.1, 28.6. HRMS (FAB):calculated for
C23H25N3O4 407.4623 [M]+; found 408.1905.
Supporting Information
Full experimental detail, 1H and 13C NMR spectracan be found via the “Supplementary
Content” section of this article’s webpage.
ACKNOWLEDGMENTS
We thank Secretaría de Educación Pública-Programa de Mejoramiento del Profesorado
(SEP-PROMEP, Project: PROMEP/103.5/12/3585) and Dirección de Investigación de la
Universidad Autonoma de Nuevo Leon (PAICYT 2012) for the financial support and also

professor Mario Ordoñez from Centro de Investigaciones Quimica-Universidad
Autónoma de Morelos (UAEM) for technical support with respect to HRMS.
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Table 1. Synthesis of Ugi adducts 7b and 7e-hvia Staundinger/aza-Wittig/Ugi.a
Entry Product
R1
R2
R3
R4
H
Yield/%b
7
8
1
2
3
4
H
NO2 Tert-Butyl
57
10
15
11
10
b
e
f
H
H
H
Tert-Butyl
Tert-Butyl
NO2 53
NO2 54
Cl
Cl
NO2 Cyclohexyl Cl
52
h
a Reaction conditions: i. NaN3(1 mmol), DMSO (1 mL) 60 °C, ii. Benzaldehyde 4 (1
mmol)
and PPh3 (1 mmol). iii. Benzoic acid 5 (1 mmol), Isocyanide 6 (1 mmol), MeOH (1 mL),
60 °C.

Table 2. Optimization of palladium-catalyzed oxidative cyclization.
Entry Base
Oxidant
Time/h
Yield/%
1
2
3
4
5
K2CO3
O2 (Air)
4
30
0
DBU
O2 (Air)
15
3
NaH
O2 (Air)
0
K2CO3
K2CO3
p-benzoquinonea
O2(air)/p-benzoquinonea
8
10
20
3
a Benzoquinone (2 mmol).

Figure 1. Bioactive Indeno[1,2-b]pyrrolidines

Figure 2. Palladium-catalyzed oxidative cyclization-proposed mechanism.

Scheme 1. Synthesis of Ugi adducts 7a-7g.

Scheme 2. Tetrahydroindeno[1,2-b]pyrrolidines 9a-c, 9e-f and 9h..