Christian Laugier
email: christian.laugier@inria.frjulia.chartre@inria.fr

Julia Chartre

Procópio Mathias Perrollaz

Silveira Stein

Christopher Tay

Meng Keat

Stephanie Lefevre

Javier-Ibanez Guzman

Amaury Negre

Lukas Rummelhard

Nicolas Turro

Jean-Alix David

Jérôme Lussereau

Jetson Tk1

Jetson Tx1

Renault Zoé

J Machan

Intelligent Perception and Situation Awareness for Automated vehicles

Keywords: Intelligent Perception and Situation Awareness for Automated vehicles Christian Laugier, Julia Chartre Embedded Bayesian Perception  Main challenges Basic idea  Multi-Sensors Observations Lidar, Radar, Stereo camera, IMU …  Probabilistic Environment Model  Sensor Fusion Uncertainty, Partial Knowledge, World changes

published or not. The documents may come   L'archive ouverte pluridisciplinaire

Solving for each cell

Joint Probability decomposition:

P(C A O O -1 V V -1 Z) = P(A) P(O -1 V -1 | A) P(O V | O -1 V -1 ) P(C | A V) P(Z | O C)
Bayesian Filtering



  Approach: Embedded Bayesian Perception  Reasoning about Uncertainty & Time window (Past & Future events)  Improving robustness using Bayesian Sensors Fusion  Interpreting the dynamic scene using Contextual & Semantic information  Software & Hardware integration using GPU, Multicore, Microcontrollers… Bayesian Occupancy Filter (BOF) => Patented by Inria & Probayes => Commercialized by Probayes => Robust to sensing errors & occultation  Used by: Toyota, Denso, Probayes, IRT Nanoelec / CEA  Free academic license available  Industrial license conditions under negotiation with Toyota[Coué & Laugier IJRR 05] [Laugier et al ITSM 2011] [Laugier, Vasquez, Martinelli Mooc uTOP 2015]

(

  Grid update at each time step) C. LAUGIER & J. CHARTRE -"Intelligent Perception & Situation Awareness for Automated vehicles" GTC Europe 2016, Amsterdam , September 28Spatial occupancy for each cell of the grid P (O | Z ) • Grid update is performed in each cell in parallel (using BOF equations) • Extract Motion Field (using Bayesian filtering & Fused Sensor data) • Reason at the Grid level (i.e. no object segmentation at this reasoning level) Exploiting Dynamic information ! => Drastic memory size reduction (factor 100) + Increased efficiency (complex scenes) + More accurate Velocity estimation (using Particles & Motion data from ego-vehicle )  Conditional Monte-Carlo Dense Occupancy Tracker (CMCDOT, 2015) => Increased efficiency using "state data" (Static, Dynamic, Empty, Unknown) + Integration of a "Dense Occupancy Tracker" (Object level, Using particles propagation & ID) [Negre et al 14] [Rummelhard et al 14] [Rummelhard et al 15] Several implementations (models & algorithms) more and more adapted to Embedded constraints & Scene complexity Jetson TK1 Tracking & Classification => See experimental results at the end of the talk (video) Tracked Objects Classification (using Deep Learning) Grid & Pseudo-objects Short-term collision risk -Main features => Grid level & Conservative motion hypotheses (proximity perception) o Detect "Risky Situations" a few seconds ahead (0.5 to 3s) o Risky situations are localized in Space & Time  Conservative Motion Prediction in the grid (Particles & Occupancy)  Collision checking with Car model (shape & velocity) for every future time steps (horizon h) o Resulting information can be used for choosing Avoidance Maneuvers Proximity perception: d <100m and t <5s d= 0.5 s => Precrash d= 1 s => Collision mitigation d > 1.5s => Warning / Emergency Braking Understand the current traffic situation & its likely evolution  Evaluate the Risk of future collision by reasoning on traffic participants Behaviors  Takes into account Context & & J. CHARTRE -"Intelligent Perception & Situation Awareness for Automated vehicles" GTC Europe 2016, Amsterdam , September 28-29 2016 19 © Inria. All rights reserved  Highly parallelizable framework, 27 kernels over cells and particles. (Resampling, sorting, predict, occupancy, speed estimation)  Real-time implementation (processing 20 Hz sensor output), optimized using Nvidia profiling tools.  700 x 300 Grids  32768 velocity samples  Configuration with 8 to 12 Lidar layers (2x4 to 3 x 4),  Pushing the limits of the algorithm :


Mohamed Othman

Pascal Pigeon

Bernard Decroix

,2-d] [2,4]benzodiazocine and Isoindolo[1,2-d]pyrrolo[1,2-a][1,5]benzodiazocine

Keywords:

The synthesis of isoindolo[2,1-b]pyrrolo [l,2-d][2,4]benzodiazocine 7 and isoindolo[l,2-d]pyrrolo[l,2-a][1,5]benzodiazocine 13 are described starting from 2-

(2-methoxycarbonyl)benzylphthalimide 1a and ethyl α-bromohomophthalate 9 respectively.

Over the last ten years many synthetic efforts have been directed toward synthesis of polycyclic compounds containing an isoindole, pyrrole, benzazepine, benzazocine, or benzodiazepine systems because a number of natural products as chilenine [1,2] or magallanesine [2,4] have these moieties and present potential biological activities. Recently we described [5] some thienothiazocinoisoindolediones from mercaptothiophenes and chloromethylphthalimide. With our interest in the synthesis of diversely substituted polycyclic systems [5][6][7][8][9] we wish to report herein an interesting approach to [1,3] or [1,5] diazocines annelated to isoindole and pyrrole moieties and either a benzene ring or a thiophene ring.

The [l,3]diazocines were prepared as indicated in Scheme 1. Reduction of imide 1a by sodium borohydride in the presence of acid [10] gave the hydroxylactam 2a (X = OH). The latter was treated with thionyl chloride in dichloromethane and the resulting chlorolactam 3 (X = Cl) submitted to the action of ammonia in dichloromethane [11] led to the 3-amino derivative 4a (X = NH2) [12] in an overall yield of 74%. Reaction of the amino group with 2,5dimethoxytetrahydrofuran in acetic acid, according to the Clauson-Kaas procedure [13], provided the pyrrole derivative 5 (58%). Saponification of 5 with potassium carbonate furnished the corresponding acid 6a (99%). Treated with thionyl chloride in dichloromethane 6a gave the acid chloride which under Friedel-Crafts cyclization conditions using boron trifluoride as a catalyst afforded the expected ketone 7 in 48% yield. The ketone 7 exhibits a N-CH2 methylene 1 H nmr signal as two doublets with chemical shifts of 4.12 and 5.21 ppm with a coupling constant of J = 14 Hz. The N-CH-N proton appears as a singlet with a chemical shift of 6.35 ppm and the pyrrole presents a AMX system characteristic of a 1,2 disubstituted pyrrole.

A generalization of this procedure could be given starting from the known methyl 3phthalimidomethylthiophene-2-carboxylate 1b [14], According to Scheme 1 in five steps the ester 1b gave the expected thieno[2',3':6,7][l,3]diazocino[2,l-a]isoindoledione 8 in an overall yield of 26%.

The isoindolo [1,2-d]pyrrolo[1,2-a][1,5]benzodiazocine 13 isomer of 7 has been synthesized as shown in Scheme 2. Reaction of o-(pyrrol-1-yl)benzylamine [15] with diethyl bromohomophthalate 9 [9] in acetonitrile at room temperature led to the phthalimidine 10 (72%). This reaction was similar to that used in our previous work [9] describing a new access to ethyl phthalimidine-3-carboxylate. Saponification of the ester 10 by sodium hydroxide at room temperature furnished the acid 11 accompanied with a small amount of 12. Actually, as previously mentioned [16] we have observed that N-substituted phthamidine-3-carboxylic acids were very sensitive to decarboxylation. A light heating or even on standing at room temperature decarboxylation occurred. These acids might be conserved in a cold storage (-18°). Compounds 11 and 12 were separated by chromatography (silica gel, dichloromethane-acetone) to get analytical samples. Nevertheless, the mixture 11 + 12 was sufficiently pure to react in the next step. Submitted to oxalyl chloride at 0°, 11 gave the acid chloride which was cyclized in a Friedel-Crafts procedure using aluminium trichloride (99.99%) as a catalyst. The unreactive compound 12 was separated from 13 by chromatography (silica gel, dichloromethane). The benzodiazocine 13 was obtained in a 80% yield.

A similar reaction conducted with thionyl chloride, followed by the action of aluminiun trichloride gave poor yield. The structure of 13 was supported by spectroscopic measurements as well as by microanalysis. Details are reported in the Experimental. In view of the 1 H nmr spectra the distinguish between 7 and 13 was particularly evident with respect to the chemical shift of N-CH-CO proton in 13 ( = 4.83 ppm), compared to the corresponding N-CH-N proton in 7 ( = 6.35 ppm). The chemical shifts of the other protons are similar.

In summary, we have described the synthesis of isoindolopyrrolo [2,4] or [l,5]benzodiazocine from ready available N-substituted 3-(pyrrol-l-yl)phthalimide or phthalimidine-3-carboxylic acid derivatives. Further studies of these polycyclic systems and biological screening are under investigations and will be published soon.

EXPERIMENTAL

Melting points are uncorrected. The infrared spectra of solids (potassium bromide) were recorded on a Perkin Elmer FTIR paragon 1000 spectrometer. The 1 H and l3 C nmr spectra were recorded on a Bruker AC-200 (200 MHz) instrument in deuteriochloroform solution and the chemical shifts () are expressed in ppm relative to internal tetramethylsilane. Ascending thin layer chromatography was performed on precoated plates of silica gel 60 F 254 (Merck) and the spots visualized using an ultraviolet lamp or iodine vapor. E. Merck silica gel 60 F (70-300 mesh) was used for column chromatography. The elemental analyses were carried out by the microanalysis laboratory of INSA at Rouen, F 76130 M t . S t . Aignan, France. The amines 4a,b were synthesized as previously described [12].

2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-methoxycarbonylarylmethyl)-1H-isoindol-1-ones 5a,b.
General Procedure.

A solution of aminolactams 4a,b (10 mmoles), dimethoxytetrahydrofuran (0.65 ml) in acetic acid was refluxed for 4 hours. The solution was concentrated under reduced pressure then the residue was dissolved in dichloromethane. The organic layer was washed with a solution of sodium hydrogen carbonate, dried and concentrated under reduced pressure. The residue was chromatographed (silica gel, dichloromethane). Recrystallization from ethanol afforded pure compounds 5a,b.

2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-methoxycarbonylbenzyl)-1H-isoindol-1-one (5a).
This compound was obtained in a yield of 58%, mp 110°; ir: (C=O), 1694 (C=O) cm A mixture of esters 5a,b (3 mmoles), potassium carbonate (0.8 g), water (2 ml) and methanol (8 ml) was stirred under reflux for 2 hours. After cooling, the solution was concentrated under reduced pressure. Water and dichloromethane were added and the organic layer was discarded.

The aqueous layer was washed with dichloromethane and acidified with hydrochloric acid (10%) to pH = 2. Compounds 6a,b were extracted with dichloromethane several times. After removal of the solvent, the residue was recrystallized from acetone to give pure 6a,b.

2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-carboxybenzyl)-1H-isoindol-1-one (6a).
This compound was obtained in a yield of 99%, mp 191°; ir: 3023 (OH), 1706 (C=O), 1691 (C=O) cm -1 ; 1 H nmr: A mixture of acid 6a,b (3.5 mmoles), dry dichloromethane (20 ml) and thionyl chloride (0.3 ml) was stirred under reflux until all solid has disappeared. Reflux was continued for 30 minutes. After cooling, the solution was evaporated. The residue was dissolved in dry dichloromethane (50 ml). To this solution of acid chloride was added a solution of borontrifluoride-etherate complex (1.4 ml, 48% in ether). Stirring was continued for 2 days, then the solution was poured in cold water and the mixture was decanted. The aqueous layer was extracted with dichloromethane (20 ml). The combination of organic layers was washed with water, dried and evaporated. The solid was recrystallized from chloroform to give 7 or 8.

5,11b-Dihydroisoindolo

[2,1-b]pyrrolo[1,2-d][2,4]benzodiazocine-7,16-dione (7).
This compound was obtained in a yield of 48%, mp >270°; ir: 1699 (2C=O) cm -1 ; 1 H nmr:  4.12 (d, J = 14 Hz, 1H, H5), 5.21 (d, J = 14 Hz, 1H, H5), 6.23-6.27 (m, 1H, H14), 6.35 (s, 1H, H11b). 6.48-6.50 (m, 1H, Hpyrrole), 7.32-7.66 (m, 8H, 7Harom + 1Hpyrrole), 7-86-7.97 (m, 1H, H8); This compound was obtained in a yield of 56%, mp >270°; ir: 1704 (C=O), 1696 (C=O) cm - 1 ; 1 H nmr:  3.91 (d, J = 14 Hz, 1H, H4), 5.33 (d, J = 14 Hz, 1H, H4), 6.26 (t, J = 3 Hz, 1H, H13), To the ester 10 (3.6 g, 10 mmoles) in 20 ml of ethanol was added sodium hydroxide (0.8 g, 20 mmoles) in 5 ml of water. The reaction mixture was stirred at room temperature for 12 hours, concentrated in vacuo, diluted with water and washed with dichloromethane and decanted.

2,3-Dihydro-2-[2-(pyrrol-1-yl)-benzyl]-1H-isoindol-1-one (12).

The above organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to furnish pure 12 (0.6 g, 10%), mp 109°; ir: 1683 (C=O) cm -1 ; A mixture of acid 11 (1 g, 3 mmoles) in dry dichloromethane (20 ml), oxalyl chloride (0.3 ml) and 3 drops of N,N-dimethylformamide was stirred for 4 hours. The solution was evaporated under reduced pressure and the residue was dissolved into dry dichloromethane (20 ml) to furnish a solution of the corresponding acyl chloride. This solution was added dropwise to a stirred mixture of aluminium trichloride (99.99%, 1.5 g, 11 mmoles) and dry dichloromethane (40 ml). Stirring was continued for 1 hour. The solution was poured into cold water and decanted. The aqueous layer was extracted once with dichloromethane (20 ml). The combination of organic layers was dried over magnesium sulfate and concentrated.

Recrystallization from ethanol gave pure 13 (0.7 g, 80%), mp 261°; ir: 1702 (C=O), 1645 (C=O) cm -1 ; 1 H nmr:  4.17 (d, J = 13 Hz, 1H, H16), 4.83 (s, 1H, H9a), 5.40 (d, J = 13 Hz, 1H, H16), 6.46-6.49 (m, 1H, Hpyrrole), 7.05 (t, J = 2 Hz, 1H, Hpyrrole), 7.37-7.57 (m, 8H, 1Hpyrrole + 7Harom), 7.82 (d, J = 7 Hz, 1H, H13); 13

  -1 ; 1 H nmr:  3.77 (s, 3H, CH3), 4.40 (d, J = 14 Hz, 1H, NCH2), 5.31 (d, J = 14 Hz, 1H, NCH2), (t, J = 2 Hz, 2H, Hpyrrole), 6.13 (s, 1H, CH), 6.40 (t, J = 2 Hz, 2H, Hpyrrole), 7.12-7.41 (m, 4H, Harom), 7.44-7.55 (m, 2H, Harom), 7.79-7.92 (m, 2H, Harom). Anal. Calcd. for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.60; H, 5.29; N, 8.05. 2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-methoxycarbonylthien-3-yl-methyl)-1H-isoindol-1-one (5b). This compound was obtained in a yield of 62%, mp 125°; ir: (C=O), 1702 (C=O) cm -1 ; 1 H nmr:  3.80 (s, 3H, CH3), 4.72 (d, J = 16 Hz, 1H, NCH2), 5.12 (d, J = 16 Hz, 1H, NCH2), 6.08 (t, J = 2 Hz, 2H, Hpyrrole), 6.26 (s, 1H, CH), 6.49 (t, J = 2 Hz, 2H, Hpyrrole), 6.99 (d, J = 5 Hz, 1H, Hthiophene), 7.20-7.30 (m, 1H, Harom), 7.33 (d, J = 5 Hz, 1H, Hthiophene), 7.45-7.55 (m, 2H, Harom). 7.85-7.95 (m, 1H, Harom). Anal. Calcd. for C19H16N2O3S: C, 64.76; H, 4.58; N, 7.95. Found: C, 64.67; H, 4.51; N, 7.92. 2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-carboxyarylmethyl)-lH-isoindol-1-one 6a,b. General Procedure.

   4.60 (d, J = Hz, 1H, NCH2), 5.35 (d, J = 16 Hz, 1H, NCH2), 6.01 (t, J = 2 Hz, 2H, Hpyrrole), 6.23 (s, 1H, CH), 6.47 (t, J = 2 Hz, 2H, Hpyrrole), 7.14-7.18 (m, 1H, Harom), 7.26-7.45 (m, 3H, Harom), 7.49-7.60 (m, 2H, Harom), 7.91-8.02 (m, 2H, Harom). Anal. Calcd. for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43. Found: C, 71.95; H, 4.84; N, 8.44. 2,3-Dihydro-3-(pyrrol-1-yl)-2-(2-carboxythien-3-ylmethyl)-1H-isoindol-1-one (6b). This compound was obtained in a yield of 97%, mp 240°; ir: 2942 (OH), 1698 (C=O), 1664 (C=O) cm -1 ; 1 H nmr:  4.57 (d, J = Hz, 1H, NCH2), 4.97 (d, J = 17 Hz, 1H, NCH2), 6.01 (t, J = 2 Hz, 2H, Hpyrrole), 6.65 (t, J = 2 Hz, 2H, Hpyrrole), 6.74 (s, 1H, CH), 6.80 (d, J = 5 Hz, 1H, Hthiophene), 7.29-7.42 (m, 1H, Harom), 7.57-7.71 (m, 3H, Harom + Hthiophene), 7.76-7.88 (m, 1H, Harom). Anal. Calcd. for C18H14N2O3S: C, 63.89; H, 4.17; N, 8.28. Found: C, 63.98; H, 3.93; N, 8.25. Cyclization of Acids 6a,b into Diazocines 7 and 8. General Procedure.

13 C

 13 nmr:  41.7 (CH2), 67.6 (CH), 110.9 (CH), 122.1 (CH), 124.2 (CH), 124.3 (CH), 124.7 (CH), 129.3 (CH), 130.4 (CH), 130.8 (CH), 131.2 (CH), 132.2 (C), 132.3 (CH), 133.1 (CH), 133.4 (C), 136.1 (C), 138.0 (C), 140.2 (C), 164.0 (CO), 182.5 (CO). Anal. Calcd. for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91. Found: C, 75.98; H, 4.36; N, 8.82. 4,10b-Dihydropyrrolo[l',2':3,4]thieno[2',3':6,7][l,3]diazocino[1,2-a]isoindole-6,15-dione (8).

6 . 2 (

 62 38-6.43 (m, 1H, Hpyrrole), 6.64 (s, 1H, H10b), 7.10 (d, J = 5 Hz, 1H, H3), 7.15-7.25 (m, 1H, Harom), 7.45-7.55 (m, 1H, Hpyrrole), 7.58-7.65 (m, 2H, Harom), 7.66 (d, J = 5 Hz, 1H, H2), 7.85-7.95 (m, 1H, H7); 13 C nmr:  36.3 (CH2), 68.2 (CH), 111.1 (CH), 120.4 (CH), 123.5 (CH), 124.CH), 124.5 (CH), 130.8 (CH), 130.9 (CH), 132.6 (CH), 133.4 (C), 134.3 (CH), 134.7 (C), 136.4 (C), 138.5 (C), 144.5 (C), 164.4 (CO), 175.4 (CO). Anal. Calcd. for C18H12N2O2S: C, 67.48; H, 3.78; N, 8.74. Found: C, 67.10; H, 3.78; N, 8.68. 2,3-Dihydro-3-ethoxycarbonyl-2-[2-(pyrrol-1-yl)benzyl]-1H-isoindol-l-one (10). To a solution of diethyl α-bromohomophthalate 9 (3.15 g, 10 mmoles) in dry acetonitrile was added under an atmosphere of argon the o-(pyrrol-l-yl)benzylamine (3.5 g, 20 mmoles), and the resulting mixture was stirred at room temperature for 8 hours. The salt that formed was removed by filtration, and the filtrate was concentrated. The oily residue was purified by column chromatography (silica gel-dichloromethane) to give the ester 10 (2.6 g, 72%); ir: 1746 (C=O), 1702 (C=O) cm -1 ; 1 H nmr:  1.16 (t, J = 7 Hz, 3H, CH3), 3.98-4.09 (m, 2H, CH2), 4.26 (d, J = 15 Hz, 1H, CH2-N), 4.66 (s, 1H, CH), 5.23 (d, J = 15 Hz, 1H, CH2-N), 6.29 (t, J = 2 Hz, 2H, Hpyrrole), 6.75 (t, J = 2 Hz, 2H, Hpyrrole), 7.27-7.33 (m, 4H, Harom), 7.47-7.50 (m, 3H, Harom), 7.81-7.90 (m, 1H, Harom). Anal. Calcd. for C22H20N2O3: C, 73.31; H, 5.59; N, 7.77. Found: C, 73.02; H, 5.52; N, 7.79. Saponification of Ester 10 to Acid 11.

2, 3 -

 3 Dihydro-3-carboxy-2-[2-(pyrrol-1-yl)benzyl]-1H-isoindol-1-one(11).The previous aqueous layer was acidified with (10%) hydrochloric acid solution to pH = 2 and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give acid 1 (2 g, 62%). An analytical sample was obtained from a chromatography (silica gel-dichloromethane/acetone 9/1), mp 80° dec; ir: 2885 (OH), 1742 (C=O), 1700 (C=O) cm -1 ; 1 H nmr:  4.36 (d, J = 15 Hz, 1H, CH2N), 4.72 (s, 1H, CH), 5.27 (d, J = 15 Hz, 1H, CH2N,), 6.19 (t, J = 2 Hz, 2H, Hpyrrole), 6.73 (t, J = 2 Hz, 2H, Hpyrrole), 7.26-7.60 (m, 7H, Harom), 7.81 (d, J = 7 Hz, 1H, Harom). 10b,16-Dihydroisoindolo[l,2-d]pyrrolo[l ,2-a][l,5]benzodiazocine-9,14-dione (13).

2 (

 2 C nmr:  42.0 (CH2), 62.8 (CH), 111.7 (CH), 121.6 (CH), 123.8 (CH), 125.5 (CH), 126.3 (CH), 128.7 (CH), 129.7 (CH), 130.3 (CH), 130.9 (CH), 131.0 (C), 131.4 (CH), 131.6 (CH), 132.1 (CH), 135.3 (C). 139.7 (C), 140.2 (C), 166.8 (CO), 180.CO).

  Anal. Calcd. for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91. Found: C, 76.35; H, 4.41; N, 8.93.

  1 H nmr:  4.08 (s, 2H, CH2-N), 4.67 (s, 2H, CH2-N), 6.34 (t, J = 2 Hz, 2H, pyrrole), 6.83 (t, J = 2 Hz, 2H, pyrrole), 7.31-7.36 (m, 5H, Harom), 7.43-7.49 (m, 2H, Harom), 7.86 (d, J = 7 Hz, 1H, Harom). . Calcd. for C19H16N2O: C. 79.14; H, 5.59; N, 9.72. Found: C, 78.86; H, 5.54; N, 9.73.

	Anal


Pascal Pigeon

Mohamed Othman

Pierre Netchitaïlo

Bernard Decroix

Acyliminium Ion-Olefin Cyclization Leading to Isoindolo[2, l-a]quinoline Derivatives

Isoindolo[2,1-a]quinolines 10, 11, 12 were synthesized from hydroxylactams 8 or 9 via an Nacyliminium ion-π-olefin nucleophile cyclization reaction.

Previous reports from our laboratory have described the synthesis of

. Some isoindolo[2,1a]quinolines [6-8] have been already synthesized but to our knowledge none has used an Nacyliminium ion generated from an isoindole moiety.

The requisite phthalimides 3 and 6 were prepared as in Schemes I and II. Ethyl oaminobenzoate subjected to ethylmagnesium iodide gave the expected alcohol 1. Dehydration of 1 using p-toluenesulfonic acid as a catalyst in refluxing toluene furnished the vinyl derivatives 2 as a mixture of Z/E isomers. Condensation of 2 with phthalic anhydride led to the phthalimides 3 Z,E isomers (40/60). On the other hand, o-aminoacetophenone (Scheme II) treated with ethylmagnesium iodide gave alcohol 4. Dehydration of 4 led to three compounds: 5a, 5b Z and 5b E. Submitted to phthalic anhydride this mixture gave the corresponding phthalimides 6 Z (9%), 6 E (64%), 7 (27%). Interestingly, this mixture 6 + 7 treated with ptoluenesulfonic acid in refluxing toluene led to 6 Z (35%) and 6 E (65%). Indeed, the expected isomerization of 7 occurred and an equilibrium between 6 Z and 6 E was obtained after 48 hours of heating. In similar conditions, the mixture 3 Z + E (40/60) isomerized to furnish a mixture of 3 Z (71%) and 3 E (29%). The structures of 3 and 6 were supported by nmr ( 1 H, 13 C) spectroscopic analyses. NOE difference experiments were performed on 3 and 6 to determine the stereochemistry of the olefin part.

The phthalimides 3 and 6 were then reduced, by the action of sodium borohydride in methanol, into the hydroxylactams 9 (Z,E) and 8 (Z,E) with unchanged Z/E ratio. Under acidic conditions these hydroxylactams are precursors of N-acyliminium ions and an intramolecular cyclization could occur with the non aromatic π-nucleophile (olefin part). When 6 (Z + E) was treated for 40 minutes with a catalytic amount of p-toluenesulfonic acid in refluxing toluene, three cyclic products were obtained, 10a (33%), 10b (33%), 10d (34%) (Scheme III). After 3 hours of reaction the percentages were 27%, 27%, 46% respectively and after 24 hours 10d was the only product observed. In the latter case, degradation occurred and 10d was obtained in a 48% yield. If the reaction was carried out with one equivalent of acid during 30 minutes 10d was obtained in a 75% yield as the lone product. Evolution of the reaction could be rationalized as depicted in Scheme III. The π-nucleophile attack upon the N-acyliminium ion, generated in situ, led to the intermediate carbocation A. Stabilization of A with loss of a proton gave the exocyclic olefins 10a (racemic form of 6R*,6aS* relative configuration) and 10b (racemic form of 6S*,6aS* relative configuration), which were probably in equilibrium via the common isomer 10c (not detected). Izomerization of 10c furnished the stable enamide 10d.

One can note that we have already observed a similar isomerization in thienoazepinoisoindolone [9]. In contrast to the reactivity of other olefins [START_REF] Hiemstra | Comprehensive Organic Synthesis[END_REF] the stereochemistry of the cyclization was not respected since the starting Z,E mixture (35/65) should give an equal trans/cis (35/65) mixture but gave a 50/50 mixture of 10a and 10b which turned in time to 10d. Intermediates compounds 10a and 10b could not be separated (fractional recrystallizations and column chromatographies where attempted) but their structures were well assigned from nmr studies ( 1 H and COSY experiments). Compound 10a exhibited a trans coupling constant JH6-H6a = 11 Hz and 10b revealed a cis coupling JH6-H6a = 3 Hz. The spectrum of 10d revealed the absence of the H6a proton, but the H5 proton appeared as a quadruplet (JH5-Me = 7 Hz) with a chemical shift of  = 3.52 ppm.

From these results it was interesting to study the reactivity of 9 (Z,E) under similar conditions (Scheme IV). Thus, when hydroxylactams 9 (Z/E, 71/29) were submitted to p-toluenesulfonic acid (catalytic amount) a mixture of 12 (Z/E, 14%/14%, racemic form of 6R*,6aS* relative configuration), 11 (E, 72%, racemic form of 6S*,6aS* relative configuration) was obtained in 90% yield after 40 minutes of reaction. A trace of compound 14 was observed but its quantity increased with a longer time reaction. When the reaction was carried out during 10 days the mixture consisted in 14 (21%), 11 E (57%), 12 E (11%), 12 Z (11%) and after 25 days in 14 (42%), 11 E (48%), 12 E (5%), 12 Z (5%). The slow isomerization of 11 and 12 was probably due to the higher stability of the substituted exocyclic double bond compared to the unsubstituted one in compounds 10a,b (Scheme III). When the reaction was carried out with one equivalent of acid a mixture of 14 (22%), 11 E (68%), 12 E (5%), 12 Z (5%) was obtained after 1 hour but degradation products were also obtained and their amount was increasing with the reaction time. As intermediate 10c, the possible intermediate 13 has never been observed.

As described above for 8 (Z + E), the cyclization was not selective and the intermediate carbocation B stabilized with loss of a proton to furnish exocyclic olefins 11 and 12 and a small amount of 14. The structures of these compounds were assigned on the basis of their nmr Isomerization of phthalimides 6 Z, 6 E, 7 (9/64/27) into the mixture of 6 Z/E (35/65) was performed in refluxing toluene for 2 days with a catalytic amount of p-toluenesulfonic acid.

The solution was cooled, washed with an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, then was concentrated under reduced pressure to afford the 35/65 mixture of isomers 6 Z/E.

Mixture of isomers 3 Z/E (40/60) could be partially isomerized to afford a 71/29 ratio by the above procedure.

N-[2-(l-Ethylprop-1-enyl)phenyl]phthalimides (3 Z,E).

The mixture of Z (71%) and E (29%) isomers recrystallized from ethanol was obtained in a yield of 96%.

Isomer Z had 1 H nmr:  0.89 (t, J = 7 Hz, 3H,CH3), 1.41 (d, J = 7 Hz, 3H, =C-CH3), 2.22 (q, J = 7 Hz, 2H, CH2), 5.43 (q, J = 7 Hz, 1H, =CH), General Procedure.

To a mixture of phthalimide 6 Z,E or 3 Z,E (4 mmoles) in dry methanol (40 ml) at 10° was added sodium borohydride by portions and 5 drops of ethanolic hydrochloric acid solution (prepared from 9 drops of concentrated hydrochloric acid in 15 ml of ethanol) at regular intervals (10 minutes) until the reaction was complete (monitored by tlc). The excess of sodium borohydride was decomposed by careful addition of diluted hydrochloric acid. Sodium hydrogen carbonate was added and the solvent was evaporated. The residue was triturated with water and the hydroxylactams 8 Z,E or 9 Z,E were separated by filtration, washed with water, dried and recrystallized from ethanol.

2,3-Dihydro-3-hydroxy-2-[2-(1-methylprop-1-enyl)phenyl]-lH-isoindol-1-one (8 Z,E).
A mixture of Z (35%) and E (65%) isomers was obtained in a yield of 92%.

Isomer Z had 1 H nmr:  1.44 (d, J = 7 Hz, 3H, CH3), 1.86 (s, 3H, CH3), 3.27 (s broad, 1H, OH), 5.52 (q, J = 7 Hz, 1H, =CH), 6.17 (s, 1H, CH), 7.03-7.65 (m, 7H, Harom), 7.72 (d, J = 7

Hz, 1H, Harom).

Isomer E had 1 H nmr:  1.59 (d, J = 7 Hz, 3H, CH3), 1.79 (s, 3H, CH3), 3.27 (s broad, 1H, OH), 5.52 (q, J = 7 Hz, 1H, =CH), 6.06 (s, 1H, CH), 7.03-7.65 (m, 7H, Harom), 7.72 (d, J = 7

Hz, 1H, Harom).

Anal. Calcd. for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.31; H, 6.09; N, 5.06.

2,3-Dihydro-2-[2-(1-ethylprop-l-enyl)pheny l]-3-hydroxy-1H-isoindol-l-one (9 Z,E).
A mixture of Z (71%) and E (29%) isomers was obtained in a yield of 88%.

Isomer Z 1 H nmr:  0.85 (t, J = 7 Hz, 3H, CH3), 1.64 (d, J = 7 Hz, 3H, =C-CH3),

REFERENCES AND NOTES

( 1 HPhthalimides 3 , 6 .

 136 and 13 C) spectra. The configuration of 12 was supported by a coupling constant of 11 Hz characteristic of a trans relationship between H6 and H6a. Unfortunately it has not been possible to determine the geometry (Z or E) of the exocyclic double bond. The isoindoloquinoline 11 exhibits a cis coupling constant of 3 Hz (H6-H6a) and a E configuration (determined by NOE difference experiments). The oily mixture of 11, 12 and 14 could not be separated by column chromatography. In summary, we have demonstrated that disubstituted vinylbenzenes connected to hydroxylactam gave C5 and C6 substituted isoindolo[2,1-a]quinolines. The intramolecular cyclization was not selective and furnished a conjugate enamide 10d in the case of vicinal dimethyl substituted vinyl derivatives 8 and an exocyclic double bond in the major isoindoloquinoline 11 with vicinal methylethylvinyl derivatives 9. Further investigations are in progress particularly in order to obtain a selectivity during the cyclization step between the Nacyliminium ion and the π-olefin nucleophile. EXPERIMENTAL Melting points are uncorrected. The infrared spectra of solids (potassium bromide) were recorded on a Perkin Elmer FTIR paragon 1000 spectrometer. The 1 H and 13 C nmr spectra were recorded on a Bruker AC-200 (200 MHz) instrument in deuteriochloroform solution and the chemical shifts () are expressed in ppm relative to internal tetramethylsilane. Ascending thin layer chromatography was performed on precoated plates of silica gel 60 F 254 (Merck) and the spots visualized using an ultraviolet lamp or iodine vapor. E. Merck silica gel 60 F (70-300 mesh) was used for column chromatography. The elemental analyses were carried out by the microanalysis laboratory of INSA at Rouen, F 76130 M t . S t . Aignan, France.To a 0.5M solution of ethylmagnesium iodide (120 ml for 3, 80 ml for 6) was added dropwise, with stirring, a solution of 10 mmoles of the corresponding amine (1.65 g of ethyl oaminobenzoate for 3, 1.35 g of o-aminoacetophenone for 6) in 10 ml of dry ether. Stirring was continued overnight then the solution was carefully poured into 200 ml of 1M ammonium chloride solution. The organic layer was decanted and the aqueous layer was extracted with dichloromethane. The combination of the organic layers was evaporated, then toluene and a catalytic amount of p-toluenesulfonic acid were added. The flask was fitted with a Dean-Stark apparatus and the solution was refluxed for approximately 45 minutes (monitored by tlc). After cooling, triethylamine (2 ml) and phthalic anhydride (1.48 g, 10 mmoles) were added, then the solution was refluxed (Dean-Stark apparatus) for 2 days. The solution was cooled, then was concentrated under reduced pressure to give 3 or a mixture of 6 + 7.

This compound had 1 H 8 (

 18 nmr:  0.50 (d, J = 7 Hz, 3H, CH3), 1.91 (d, J = 7 Hz, 3H, =C-CH3),3.54 (qd, J = 7 and 3 Hz, 1H, H6), 4.82 (d, J = 3 Hz, 1H, H6a), 6.25 (q, J = 7 Hz, 1H, =CH), 6.81-8.04 (m, 7H, Harom), 8.60 (d, J = 8 Hz, 1H, Harom); 13 C nmr:  11.1 (CH3), 13.1 (CH3), 31.CH), 61.6 (CH), 119.1 (CH), 119.8 (CH), 121.6 (CH), 123.9 (CH), 123.9 (CH), 124.1 (CH), 127.6 (CH), 127.8 (C), 128.4 (CH), 131.9 (CH), 133.3 (C), 134.0 (C), 135.4 (C), 142.6 (C), 166.4 (CO). 5-Ethylidene-6-methylisoindolo[2,1-a]quinolin-11(6aH)-one (12 Z/E). Compound 12 Z had 1 H nmr:  1.52 (d, J = 7 Hz, 3H, CH3), 1.91 (d, J = 7 Hz, 3H, =C-CH3), 2.93-3.17 (m, 1H, H6), 4.36 (d, J = 9 Hz, 1H, H6a), 6.25 (q, J = 7 Hz, 1H, =CH), 6.80-8.05 (m, 8H, Harom). Compound 12 E had 1 H nmr;  1.50 (d, J = 7 Hz, 3H, CH3), 1.91 (d, J = 7 Hz, 3H, =C-CH3), 2.30-2.48 (m, 1H, H6), 4.46 (d, J = 10 Hz, 1H, H6a), 6.25 (q, J = 7 Hz, 1H, =CH), 6.80-8.05 (m, 8H, Harom). 5-Ethyl-6-methylisoindolo[2,1-a]quinolin-11(6aH)-one (14). This compound had 1 H nmr:  0.60 (d, J = 7 Hz, 3H, CH3), 1.68-1.85 (m, 2H, CH2), 2.32 (s, 3H, =C-CH3), 3.60 (t, 1H, J = 5 Hz, Hs), 6.81-8.04 (m, 7H, Harom), 8.96 (d, J = 8 Hz, 1H, H10); 13 C nmr:  8.4 (CH3), 17.5 (CH3), 28.8 (CH2), 45.7 (CH), 117.0 (CH), 120.4 (C), 122.5 (CH), 123.3 (CH), 124.4 (CH), 126.3 (C), 127.0 (CH), 127.8 (CH), 127.9 (CH), 129.1 (C), 130.5 (C), 131.9 (CH), 133.4 (C), 134.8 (C), 164.8 (CO).