Palladium mediated synthesis of N-heterocycles by iminoannulation of allenes.

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UvA-DARE (Digital Academic Repository)

Diederen, J.J.H.

Publication date

2001

Link to publication

Citation for published version (APA):

Diederen, J. J. H. (2001). Palladium mediated synthesis of N-heterocycles by iminoannulation

of allenes.

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Synthesis of Isoquinolines and Pyridines from

o-Halide-Substituted Aryl and Vinyl Imines via

Palladium-Catalyzed Iminoannulationm

Abstract

afferent bromo-bridged palladium complexes (2) derived from o-bromoacetophenone etimines (1) were prepared and used in stoichiometric amounts as starting materials for the igioselective synthesis of 4-isopropyl-l-methyl-isoquinolinium salts (4). The crystal structure f isoquinolinium salt 4d is described. Mono-substituted aliènes were converted into aromatic '-heterocycles in a Pd-catalyzed reaction from different o-halide-substituted aryl and vinyl nines. N-Dealkylation takes place by either debenzylation (R = Bn) or ß-elimination (R = tert-utyl) in a consecutive reaction. Because of the difficulty to remove the N-alkyl group, ropanenitrile was used as the protecting group on the imine nitrogen, which could be emoved in situ with formation of acrylonitrile. The regioselectivity strongly depends on the ibstituents on the imine and the aliène. The solvent also has a profound effect on the >gioselectivity of these iminoannulations, as is apparent from a comparison of the reactions

hich are stoichiometric and catalytic in palladium.

^ N .Ft

X Pd cat. X = Br, I

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via hninoannulation

3.1 Introduction

The discovery of the cyclometallation reaction of organic compounds[2] leading to the formation of both metal-carbon and metal-donor atom bonds (eq 1) has initiated a thorough study of cyclometallated compounds. Much work has been devoted to the preparation and characterization of these complexes and these aspects have been summarized in several reviews. [3-5]

C-H

+ H+ ₍₁₎

E = donor atom

The growing interest in these compounds is at least partly due to the fact that they appear to be promising starting materials for organic syntheses, in particular when palladium is used.[6, 7] However, the above mentioned reviews contain only a few examples of synthetic applications. The principal constraint of organic synthesis using cyclopalladated complexes is the cost of stoichiometric amounts of palladium. It was shown in all the applications reported in the literature until now, that reoxidation of the palladium is the main problem to close the catalytic cycle.

Synthetic procedures using catalytic amounts of palladium are in most cases based upon an oxidative addition step of aryl or vinyl halides to Pd(0) prior to insertion of unsaturated substrates and reductive elimination (Eq 2).

Pd(0) (2) X — P d Y X: Y: Cl, Br, I N , S 3.1.1 Alkynes

Synthetic applications of alkynes in organopalladium chemistry have received considerable attention in recent years. Most examples involve stoichiometric amounts of arylpalladium complexes, formed by orf/io-palladation, and insertion of more than one equivalent of alkyne, followed in many cases by annulation onto the preexisting aromatic

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ing. [8, 9] An interesting catalytic example is the synthesis of aporphine related heterocycles eq 3).[10, 11] The synthesis is based on iodo compound A, that can oxidatively add to Pd(0) forming the Pd-iodo bridged dimer B, which inserts one alkyne molecule. After reductive elimination, the heterocycle C is formed (eq 3).

02Et

P h +MeI (3)

NMe

Based on this methodology, a whole range of publications have appeared, involving the vnthesis of a variety of heterocycles like indoles[12], indenones[13], isocoumarins[14], enzofurans[14, 15], benzopyrans[14], l,2-dihydropyrans[14], azaindole^ló, 17], and cc-;yrones[18]. It was also possible, using the above mentioned strategy, to synthesize polycyclic

romatic hydrocarbons. [19] A few other articles based on the electrophilic activation of alkynes by palladium(II) intermediates, formed after oxidative addition of an organic halide (RX) to d(0), and subsequent intramolecular nucleophilic attack onto the palladium-intermediate, fading to 2-alkylidene-pyrrolidines or -piperidines[20], furans[21] and furanones[21, 22] were Hiblished.

Recently, an elegant synthesis of isoquinolines and pyridines based on alkynes and aryl-or vinylimines catalyzed by palladium was published by Roesch and Larock (eq 4).[23] The

egioselectivity was found to be analogous to their earlier alkyne annulation,[12-14, 19] viz. the more sterically demanding R-group (R2) ends up next to the nitrogen atom. A problem in these

syntheses is that multiple alkyne insertions may occur.[24, 25]

f-Bu

Rl = R2 cat. 5% Pd(OAc)2 / 10% PPh3

N a2C 03 / DMF / 100 °C

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Synthesis ofIsoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Mines via Iminoannulation

3.1.2 Aliènes

The use of aliènes as synthetic building blocks has received less attention than that of alkynes. For a long time it has been known that aliènes may insert into a Pd-halide bond of palladium salts leading to a mono-inserted product D (eq 5)[26], while the nucleophile has migrated to the central carbon atom of the aliène. The reaction is performed with a stoichiometric amount of palladium halide.

PdX2 (5)

Pd

/ X2

D

It should be noted that under catalytic conditions aliènes form complexes which are derived from migration of the halide to the outer carbon of the coordinated aliène leading to a Pd-a-intermediate (Scheme 1, step (ii)) which inserts a second aliène moiety to form complexes E (Scheme 1, step (iii)).[27, 28]

PdX2

\

A

(i)

* v * 5 ~ v~> ~

i

^

r 2

^

pd_

M

Scheme 1

Later it was shown that Pd(0) complexes can dimerize aliène to give a palladacycle which may be trapped by nucleophiles like a malonate anion (Scheme 2).[29]

/ HC

0

N COOEt COOEt 1% Pd(0)L4 Pd

^y^ cooEt

COOEt Scheme 2

The group of Cazes showed that aliènes can be used to provide a 7t-allylpalladium intermediate from aryl or vinyl halides and a catalytic amount of Pd, which may be trapped by

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-rious soft carbanions like a malonate anion (Scheme 3).[30-32] They found that nucleophilic tack predominantly takes place at the sterically favored position. This methodology was further applied to intramolecular reactions in which the nucleophile was tethered to the

ene. [33]

<?

Pd(dba)2 / 4 PPh3 [ - Pd(0) Nu

2 L i C l / D M S O

©PdL

2 Scheme 3

Besides carbanions, 7t-allyl palladium complexes react with oxygen nucleophiles. 6-I iydroxyallene G [34, 35] forms tetrahydrofuran H (eq 7) and 4,5-hexadienoic acid (6-I)[34] forms

iutyrolactone J (eq 8) in a Pd-catalyzed reaction. In all tetrahydro cases 5-membered ring rmation is favored over membered ring formation. Electrophile-mediated cyclizations of

7-droxyallenes[36, 37] or 6-aminoallenes[38] using stoichiometric amounts of silver salts were eribed as well. Ph ^ • ^ H O , _ + P hi Pd(PPh3)4 / K2CQ3 i ^ / O ^ ^ ^ ( 7) DMF / 100 °C G H Ph

\

H

y

+PW pd(pph3k/K2C

P

3 À v V ° (8)

^ — ' DMF / 100 °C ^ — '

A wide variety of N-heterocycles were synthesized according to the above described : inciple. Various bicyclic lactams were synthesized from allene-substituted lactams in a Pd-jtalyzed reaction[39] (eq 9). Note that nucleophilic attack of the amide nitrogen atom takes dace at the central carbon atom, a reactivity which had not been reported until then.

r I

Phi / Pd(PPh3)4

K2C03 / TBAC1

0 MeCN ° ^ ~ P h

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation

Carbapenems were synthesized catalytically in Pd from allene-substituted azetidones[40] (eq 10).

TBDMSO | TBDMSO

PdCl2 / Et3N

n \

ç f m CH2=CH-E

Palladium-catalyzed hetero- and carboannulations, employing aliènes as unsaturated substrates in an intermolecular process, have been studied recently. Tsuji published a method to synthesize allylamines from aliènes and vinyl or aryl halides (eq 11).[41]

Ph

r - A P h I

= « = / + r NH • r " \ v ~ ^

(11)

^ -

/ PdrOArl, / dnne ^-V Pd(OAc)2 / dppe

MeCN

Larock et a/[42-45] and others[46, 47] have shown that a wide variety of (hetero)cyclic products may be synthesized with aryl or vinyl halides by this method. As an example, (Z)-4-iodo-4-phenyl-3-buten-2-ol in reaction with methoxyallene gave an oxygen heterocycle in which nucleophilic attack of the alcohol took place at the electronically favored position (eq 12).[42]

Pd(OAc)2 / PPh3

OMe Na2C03 / TBAC1

DMF

Our interest in the iminoannulation of aliènes, as shown by the synthesis of N-heterocyclic products using stoichiometric Pd from cyclopalladated a-tetralone ketimines[48], prompted us to investigate the possibility of a Pd(0)-catalyzed version of this reaction. The results are presented here.

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3.2 R e s u l t s

In order to make the iminoannulation reaction with aliènes catalytic in palladium, we first tried the possibility to synthesize N-heterocycles, starting from Pd-complexes which could be active in the catalytic cycle.

3.2.1 Stoichiometric Reactions

.2.1.1 Synthesis of bromo bridged palladium dimers of o-bromoacetophenone ketimines ta-e)

Starting from o-bromoacetophenone, the corresponding o-bromoacetophenone ketimines ould be obtained in good yields via a simple condensation reaction with the appropriate amine : Scheme 4, step (i)). These imines were formed as two stereoisomers as shown by 'H-NMR, i.e. the anti and syn isomer (ratio 74-54 : 26-46) which could not be separated (see Fig. 1). It is Mown that syn-anti isomerism can occur in imines[49], with a preference for the anti-isomer due to steric hindrance between the aryl ring and the substituent on the imine.

syn le' Figure 1 Isomers of le

The synthesis of cyclopalladated complexes of o-bromobenzalimines was carried out by xidative addition of these imines with Pd(dba)2 , as shown by Clarke and Dyke.[50] When

.etimines la-e were treated with Pd(dba)2 in benzene at reflux temperatures, according to the

above mentioned method, bromo-bridged palladium dimers of o-bromoacetophenone ketimine ïa-e were obtained in reasonable to excellent yields (Scheme 4, step (ii) and experimental -ection). These dimeric palladium complexes were insoluble in organic solvents. To make these iimeric complexes soluble, complexes 2a-e were characterized as pyridine-d' monomers by Teaking the bromo bridge. Complexes 2a-e were also converted into the corresponding riphenylphosphine momomers 3a-e, by reaction with triphenylphosphine in dichloromethane at room temperature (Scheme 4, step (iii)). Complexes 3a-e were characterized by 'H-, C- and

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Mines via Iminoannulation

"P-NMR spectroscopy. In the 31P-NMR spectrum one singlet is observed at ca. 44 ppm for the

triphenylphosphine coordinated to the palladium, which is in agreement with a trans disposition of the phosphorus and nitrogen atom.[51-53] The signal of the carbon atom at phosphorus (around 132 ppm) is split by 49.5 ppm, which is in agreement with the results of Clarke and Dyke. [54]

R

y

i) RNH

2

^ J k / B r ii) Pd(dba)

2 toluene [I J benzene a) R = Ph b) R = p-Tol iii)PPh3 ^ L / r U \ c)R = p-An d) R = 3,5-Me2-Ph CH2C12 U J e)R = Bn 2 3 Scheme 4

3.2.1.2 Synthesis of isoquinolinium salts 4

Complexes 2a-e reacted with 1,1-dimethylallene (DMA) in a dichloromethane-methanol mixture at room temperature to give a purple-red clear solution. The mixture was heated to reflux for 15 min and after anion exchange with KPF6/ the N-heterocyclic products were

obtained as mixtures of products with a high degree of regioselectivity (Table 1 and Scheme 5). From Table 1 it can be seen that products 4 and 4' are produced in high regioselectivities. Extending the reaction time did not lead to substantial differences in regioselectivity. Product 4' is not isomerized toward 4 upon heating in the mixture with Pd black, obtained after annulation of the imine. Only with a soluble Pd(0) source, e.g. Pd(PPh,)4, 4' could be transformed into 4.

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Table 1. Product distribution in reaction of complexes 2 with DMA in a mixture of CH2CI2 and MeOH."

entry complex ratio 4 : 4' : 4"

2a 100 : 0 : 0

2b 84 : 8 : 8

2c 13 : 40 : 47

2d 100 : 0 : 0

2e 75 : 25 : 0

a: ratios of isomers were determined by NMR

a) R = Ph b) R = p-Tol c) R = p-An d) R = 3,5-Me2-Ph e) R = Bn Scheme 5

We were able to grow crystals from 4d which were suitable for an X-ray crystal structure .^termination. The crystal structure is presented in Fig. 2. See Table 2 and Table 3 for .formation about bond distances and bond angles (experimental section). The 3,5-dimethyl-Kenyl group is perpendicular with respect to the flat isoquinolinium ring system, as can be ;en from Figure 2.

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C21

Figure 2 Crystal structure of 4d

A similar reaction of 2a with DMA was performed in acetonitrile and led to the exclusive formation of 4", i.e., a completely different regioselectivity than in the mixture of dichloromethane and methanol. From Table 1 it can be seen that nucleophilic attack of the imine nitrogen atom predominantly takes place at the least hindered position of the Pd-Tt-allyl intermediate in a mixture of dichloromethane and methanol. This result is in contrast with our earlier found iminoannulation reactions with cyclopalladated oc-tetralone ketimines. [48, 55]

3.2.2 Catalytic Reactions

In order to facilitate the oxidative addition step of palladium in the catalytic reaction, o-bromoacetophenone was replaced by o-iodoacetophenone (5). The latter was synthesized from o-aminoacetophenone by a Sandmeyer reaction. This ketone reacted with p-toluidine in the presence of a catalytic amount of p-TsOH to give p-tolyl ketimine 6 with a sxjn to anti ratio of 32:68. A similar reaction of 5 with benzylamine gave the N-benzyl ketimine 7 with a syn to anti ratio of 23:77. When 6 was treated with DMA in the presence of 5 mol% Pd(OAc)2/ 10 mol%

PPh, and 7 equiv of KPF„ in DMF at 40 °C in a sealed tube, iminium salt 8 was produced regioselectively and almost quantitatively (eq 13). The reaction did not proceed at room temperature. Reactions at more elevated temperatures gave mixtures of regioisomers, similar to the earlier mentioned products of the stoichiometric reactions but with a preference for the electronically favored product 8.

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f^Y^

5 % Pd(OAc)2 / 10 % PPh3 I I I ^+ P F ó ^ v > \ DMF / KPF6 / 40 °C

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Reaction of N-benzyl-substituted ketimine 7 with DMA in the presence of 5 mol% i(OAc)2, 10 mol% PPh, and 3 equiv of KPF„ at 100 °C gave almost quantitatively iminium salt

(eq 14).

f ^ V ^ N ^ P h \

kA,

I 5 % Pd(OAc)2 / 10 % PPh3

DMF / KPF6 / 100 °C

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Iminium salts 8 and 9 are both produced after nucleophilic attack of the imine nitrogen c torn at the disubstituted end of the aliène, whereby the formation of an aromatic system is

evented. We therefore turned our attention to mono-substituted aliènes. Reaction of imine 7 ith several mono-substituted aliènes [56] in the presence of 5 mol% of Pd(OAc); and 10 mol% PPh, in acetonitrile at 100 °C produced isoquinolinium salts quantitatively (eq 15,16). ydrogenolysis of the N-benzyl group with a catalytic amount of P d / C or Pd/BaS04 [57] in

ethanol gave isoquinolines 11 - 1 3 in only very moderate yields (eq 15). We therefore vestigated other removable substituents on the imine nitrogen. Firstly we tried the methylsilyl imine of o-iodobenzaldehyde[58] but this substrate failed to give any heterocyclic roduct because of its instability during catalysis.

Roesch and Larock have shown that N-fert-butyl imines cyclize with alkynes to give ridines and isoquinolines in which the nitrogen of the intermediates is dealkylated in S!ti/.[23] aaction of N-tert-butyl imine 14 with several mono-substituted aliènes in the presence of 5 >.ol% Pd(OAc)2, 10 mol% PPh, and Na2C03 as base in a sealed tube gave isoquinolinium salts

j.antitatively, without dealkylation of the imine nitrogen (eq 16). Removal of the N-ferf-butyl >'oup was difficult and could only be achieved under rather severe conditions (5 equiv Na2C03

DMF, 140 CC, >2 days). Isoquinolines 16 -18 could be made in this way in moderate to good

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation (15) 14 5% Pd(OAc)2 10% PPh3 MeCN 100 °C 5% Pd(OAc)2 5% PPh3 MeCN 100 °C 11: R = cyclohexyl (10%) 12: R = phenyl (18%) 13: R = rz-butyl (55%) N+I" 10 equiv Na2C03 DMF, 140 °C, 2 d 16-18 (16) 16: R = «-butyl (40%) 17: R = phenyl (80%) 18: R = cyclohexyl (58%)

On applying the latter conditions to the vinylic N-fert-butyl imine 19, the pyrindinium salt was produced quantitatively but the terf-butyl group was difficult to remove, and only a low yield of the neutral pyrindine 21 was obtained (eq 17).

«s.

X

Br 19 Ph 5% Pd(dba)2 5% dppp MeCN 100 °C N+Br" 10Na2CO3 DMF, 140 °C 2 d (17) 21 (10%)

Vinylic N-ferf-butyl imine 20 was converted to pyridine 22 in a moderate yield (Scheme 6) using the same reaction conditions as in the synthesis of 21. During the de-alkylation step, as a result of the present Pd(0), 22 was partly dehydrogenated towards the fully aromatic 22', as shown by NMR and GC-MS. A similar result has been observed earlier during hydrogénation of iminium salts. [55]

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Br 20

V

Ph 5% Pd(dba)2 5% dppp MeCN 100 °C 1 0 Na2C03 ' DMF 140 °C / 2 d 22 22+22' (56%, 90:10) 22' Scheme 6

Encouraged by the promising results with the removal of the N-tert-buty\ substituent on I e pyridinium or isoquinolinium salts by ß-elimination, we decided to search for a substituent

\ th more acidic protons than those in the ferf-butyl group, to facilitate the de-alkylation step.

• e eventually found an easily removable Af-substituent, based upon condensation of various t lehydes with 3-aminopropionitrile. The latter group was also used to protect several azoles Horvâth et al. [59] The reaction of our imines with 1.5 equiv of a mono-substituted aliène in e presence of 5 mol % Pd(dba)2 and 5 mol% dppp and 1 equiv of Na2C03 in acetonitrile at

'0 °C in a sealed tube afforded the desired N-heterocycles in good to excellent yields (eq

18-From eq 19-21 it can be seen that in the case of rc-butylallene mixtures of regioisomers -:• produced in all cases. Phenylallene shows some regioselectivity (eq 20), but in other cases uimolar mixtures of regioisomers are found (eq 18 and 19). Cyclohexylallene and tert-'.tylallene gave in their reactions with imines 23-26 mostly regioisomer A, in which

cleophilic attack of the imine nitrogen has taken place at the least hindered position of the --ne.

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation 23 CN 5% Pd(dba)2 5% dppp 1 N a2C 03 MeCN 100 °C (18) B R=Ph : 20% A + 21% B (17+27) R=f-Bu : 27% A (28) Br 24 NC 5% Pd(dba)2 5% dppp 1 N a2C 03 MeCN 100 °C (19) A B R R=n-Bu : 85%a , 50 (A) : 50 (B) (29+30)b R=Cy : 70% A (31) R=Ph : 20% A + 21% B (22+32) R=f-Bu : 32% A (33) Br 25 CN 5% Pd(dba)2 5% dppp 1 N a2C 03 MeCN 100 °C (20) R=Ph:76%B(34) R=Cy : 83% A (35) R=n-Bu : 59%a, 41 (A) : 59 (B) (36+37) R=r-Bu :10% A (38) Br 26 CN 5% Pd(dba)2 5% dppp 1 N a2C 03 MeCN 100 °C (21) R=Cy : 33% A (39) R=n-Bu : 51%a, 50 (A) : 50 (B) (40+41)

All given percentages are isolated yields; a: Obtained as an unseparable mixture of isomers; 1 : Numbering between parentheses corresponds with Experimental Section

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The catalyst is formed in situ from Pd(dba)2 and dppp. Initial attempts with a catalytic

; -tern based on 5 mol% Pd(OAc)2 and 10 mol% PPh, gave lower yields of neutral pyridines

and isoquinolines. Phosphorus ligands are known to increase the electrophilic nature of n-ailylpalladium complexes.[60] Furthermore, the use of bidentate phosphorus ligands facilitates

formation of cationic n-allylpalladium species which are more electrophilic than neutral complexes and therefore highly reactive toward nucleophiles.[60]

All aliènes reacted easily to give N-heterocycles. However, in the case of a functionalized allene (eq 22 and Chapter 4) no reaction took place under the same reaction conditions.

N

**^1 + f Y ^ * ~ (22)**

I C N ^ ^ O T H P 5%Pd(dba)2

23 5% dppp MeCN 100 °C

After finding a way to synthesize pyridines and isoquinolines catalytically in palladium r n mono-substituted aliènes, we tried to introduce two substituents on the pyridine ring by r ction with 1,3-disubstituted aliènes. Reaction of imine 14 with l,3-dimethylallene[56] in the F sence of 5 mol% of Pd(OAc)2, 10 mol% of PPh3 and 1 equiv of Na2C03 in acetonitrile in a

sealed tube at 100 °C gave a mixture of stereoisomers (42 and 42'), with a preference for the Z-is ner 42 (eq 23). The stereochemZ-istry of the products, as shown in eq 23, was determined on the basis of 2D-NOESY experiments. Cross-peaks in the NOESY spectrum were observed for the vinylic proton H„ and H12, for H12 and the protons of the methyl group (H13), for H, and H12

a for H9 and H13. More importantly, vinylic proton 11 also showed cross-peaks with H, ,

indicating that the major product is the Z-isomer. It should be noted that in the NOESY S; :trum only the most abundant isomer can be observed (i.e. 42). When the mixture of oisomers was heated in CC14 in the presence of a catalytic amount of trifluoroacetic acid,

natization did not take place, not even at 120 °C. When the mixture was treated with : urn ferf-butoxide, decomposition of 42 and 42' was observed.

Reaction of imine 7 with 1,3-dimethylallene under similar conditions, gave an almost e imolar mixture of stereoisomers (43 and 43', eq 23). The methylene protons of the benzyl group of both stereoisomers are diastereotopic because of a chiral center created at C9 and are

found in the 'H-NMR spectrum at around 5.8 ppm (43) and 5.2 ppm (43') as double doublets e experimental section). Also in this case aromatization to the corresponding isoquinolinium t did not take place. Attempts to remove the benzyl group from the iminium nitrogen by

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Synthesis of' Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation (23) 7: R! = Bn 14: Rj = terf-Bu cat. Pd(OAc)2 PPh3 Z-isomer Z-isomer : Rx = tert-Bu : 42 (92%)a Rj = Bn : 43 (48%)a E-isomer : Ri = tert-Bu: 42' (8%) Rj = Bn: 43' (52%) a: ratio of isomers as determined by NMR

When imine 14 was treated with 1,3-diphenylallene under the same reaction conditions as to produce 42 and 43, except for the addition of base, the stereoisomers 44 and 44' w e « produced quantitatively in a 1 : 1 ratio. To the reaction mixture was added Na2C03 and tht

resulting mixture was heated to reflux for a few hours. 'H-NMR showed only one of the twc stereoisomers, i.e. one stereoisomer was converted into the thermodynamically more favored isomer. In the NOESY spectrum of this product, cross-peaks were found for H9 with protons of

the feri-butyl group. However, the vinylic proton (Hn) lies hidden in the aromatic region and

therefore it was impossible to determine which stereoisomer was formed. On the basis of th£ results of the reaction of imine 14 and 1,3-dimethylallene (regioisomers 42 and 42'), we assumt that the Z-isomer (44) was formed (eq 24).

f-Bu 14 Ph Ph cat. Pd(OAc)2 2 PPh3 l N a2C 03 (24)

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3.3 Product selectivities w i t h different allene substitution patterns

5.1 1,1-Disubstituted allene

Starting from bromo-bridged palladium dimers of o-bromoacetophenone imines 2, 1,1-dimethylallene inserts into the a-Pd-C bond to form a Pd-jt-allyl intermediate. Intramolecular n jcleophilic attack of the imine nitrogen on either of the two allyl carbon termini, produces N-! ïterocyclic products 4' and 4" (Scheme 5). The regioselectivity of iminoannulations with 1,1-methylallene seems to depend strongly on the solvent used. In acetonitrile without losphines present, nucleophilic attack predominantly takes place at the most substituted ] jsition, and if phosphines are present, exclusively takes place at the least substituted position I q 25). In a mixture of dichloromethane and methanol, conditions used in the stoichiometric reactions, nucleophilic attack occurs at the least substituted end of the n-allyl moiety (eq 25).

R2 - R i

> • =

Pd condition 1 condition 2 (25) condition 1 condition 1: MeCN condition 2: CH2Cl2/MeOH condition 2

Apparently, in controlling the regiochemistry, electronic factors play a more important !e in acetonitrile as compared to a mixture of dichloromethane and methanol. In principle, icleophilic attack can take place at both ends of the n-allyl termini. From the literature it is ».own that the regioselectivity is determined by several factors. Nucleophilic attack at the most bstituted position of the allyl moiety was found to proceed in the presence of phosphine ;,ands. Âkermark et al. studied the amination of 7t-allylpalladium complexes in the presence of iphenylphosphine and showed that 1,1-dimethylallylpalladium chloride reacted with

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< | - P /

C

X 2

Me 2NH m 4PPh3 THF L I Pd—CI NMe2

-A

(26)

Okuro and Alper showed that carbonylation of o-iodophenols in the presence of DMA catalyzed by Pd(OAc)2 and dppb in benzene, produced exo-methylene products, i.t

nucleophilic attack of the alcoholic oxygen took place at the disubstituted end of the allene, ii agreement with our results (eq 27). [47]

OH

R2

CO / Pd(OAc)2 / dppb

(i-Pr)2NEt

(27)

Nucleophilic attack at the least substituted position was found to proceed in the absencr of ligands in non-coordinating solvents. Pfeffer et al. found that in reactions of cyclopalladatet pyridines with DMA in dichloromethane, nucleophilic attack of the pyridine nitrogen occurrec at the least substituted position of the jr-allyl i n t e r m e d i a t e ^ ] , similar to our results for the iminoannulation reactions performed in dichloromethane (eq 28). In their cases of 6-memberec N-heterocycles, aromatization did not take place, probably because of the difficulty of palladium to coordinate to the formed exocyclic disubstituted alkene for steric or electronic reasons. PdCI/2

> •

CH2C12 ; A

-Pd°

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In all of these reactions, the structure of the Pd-allyl-complex has a profound effect o; the regioselectivity of the annulation reaction. The counterion plays a very important role ir allylic aminations. In the case of a BF4 anion, a cationic palladium complex is formed whicl

favors a rc-allyl structure, whereas in the case of chloride as anion, a neutral a-allyl complex i formed (as shown by Shaw et fl/.[63]), which is attacked at the most substituted position (electronic control, Scheme 7). In the presence of phosphine ligands or coordinating solvents, a

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Pd-o-allyl complex is formed which directs attack at the most substituted position of the allyl-t minus. In conallyl-trasallyl-t, wiallyl-thouallyl-t phosphine ligands or coordinaallyl-ting solvenallyl-ts presenallyl-t, a Jallyl-t- Jt-a ylpJt-allJt-adium species is formed, which directs Jt-attJt-ack Jt-at the leJt-ast substituted end of the Jt-allyl terminus (steric control, Scheme 7).

4L

tK?

AgBF4 IL I Me2NH Pd—CI " N M e2 BF4 Me2NH electronic control NMe2 steric control Scheme 7

The stoichiometric reactions are carried out in the absence of phosphine ligands. In a n xture of dichloromethane and methanol, a 7c-allylpalladium structure is predominantly formed, which as a result is attacked by nucleophiles at the least substituted end. In the case of acetonitrile as solvent, a a-allylpalladium intermediate is formed which leads to the formation oi heterocyclic products that are derived from nucleophilic attack at the most substituted i »ition. Acetonitrile may coordinate to the rc-allylpalladium bromide dimer, to form a

lonuclear complex which is attacked at the electronically most favored position (Scheme 8). I the case of extra phosphine ligands present, this formation is made irreversible and attack . dusively takes place at the disubstituted end of the a-allylpalladium intermediate (Scheme 8).

In the reaction of complex 2 with DMA (Scheme 8), 4 can only be formed if product 4' emains coordinated towards the formed Pd(0). A Pd-mediated hydrogen shift of 4' results in formation of 4, which is thermodynamically more stable than the former product. If the ovalent palladium precipitates before the 1,3-H shift occurs, product 4' is isolated. parently this 1,3-H shift took place in 4' whereas in the case of a-tetralone ketimines, a 1,3-H ft was not observed (Chapter 2).[48] This may be explained by the restricted flexibility of the rlohexane moiety of the a-tetralone ketimine, which prevents the formation of a flat aromatic

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation R' R / X" /

y

4a-e

j

X = Br, I R' X" _{+ //}

_{_ƒ}

_\\> R - N 8-9 Scheme 8 3.3.2 Mono-substituted aliènes

When mono-substituted aliènes are used in the catalytic reactions, the initial products may always undergo a 1,3-H shift towards an aromatized product. Indeed this is found for all mono-substituted aliènes (Scheme 6, eq 15-21). From these reactions we can conclude that the regioselectivity is governed either by electronic effects (leading to product B) or steric effects

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(leading to product A, see eq 18-21). In the case of N-tert-butyl substituted imines 14 and 19-20, nucleophilic displacement of palladium by the imine nitrogen exclusively takes place at the least substituted position of the aliène (Scheme 6 and eq 16-17). Apparently only steric effects control the regiochemistry of these reactions, as a result of the bulky terf-butyl group on the imine nitrogen atom. In the case of ß-cyanoethyl substituted imines 23-26, regioselectivity is subject to steric and electronic effects. The bulky cyclohexylallene and ferf-butylallene only show products that are derived from steric control, i.e. nucleophilic attack at the least substituted position, leading to products A (eq 18-21). Phenylallene is in principle able to stabilize a positive charge on the carbon atom of the allyl to which it is bonded by derealization over the phenyl ring. In the case of imine 25 in reaction with phenylallene only electronic effects are involved to produce pyrindine 34 (eq 20). In all other cases a combination of steric and electronic effects gives mixtures of regioisomers. n-Butylallene does not show any selectivity in all of the reactions studied. Low steric bulk of the n-butyl group and a stabilizing effect of a positive charge on the n-butyl substituted end of the allyl leads to both regioisomers.

Isoquinolines or pyridines derived from N-terf-butyl substituted imines are generated by an extra dealkylation step under extremely harsh conditions (DMF, 140 °C, > 2 days). In the reaction of Larock and coworkers[23] (eq 4), the N-tert-buty\ is spontaneously removed. This was explained by Heck[24] as being due to the relief of strain generated by the interaction between the tert-butyl group and the substituents in the 3-position of the pyridine or isoquinoline ring. In our reactions, there is not such an interaction for there are no substituents in the 3-position.

3.3.3 1,3-Disubstituted aliènes

Imine 14 reacted with 1,3-dimethylallene and 1,3-diphenylallene, under basic conditions, to give the Z-isomers 42 and 44 (eq 23 and 24). These isomers originate from Pd-n-allyl complexes with methyl group 12 in an anti-position. This result is in contrast with those of Larock et al. who found that similar reactions with amines[43] or malonates[42] gave products that were derived from syn-substituted Pd-7i-allyl complexes. After insertion of the aliène into the Pd-C bond a syn- and anti-Pd-7t-allyl complex is formed which may interconvert by a dynamic Jt-a-Jt (n^-n'-n3) equilibration. Imine 7 reacted with 1,3-dimethylallene to an equimolar

mixture of stereoisomers (43 and 43'). Apparently, in comparing imine 7 and 14 in the reaction with 1,3-dimethylallene (eq 23), the R,-substituent has a profound effect on the regioselectivity. In the case of a benzyl substituent (imine 7), the interaction with the vinylic methyl group is much less than in the case of a ferf-butyl group (imine 14) (eq 23). Interestingly, neither of all these iminium salts can be isomerized towards the corresponding aromatic products. On the

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basis of electronic effects, one would predict, however, the formation of the aromatized product. We do not have a clear explanation for this result.

3.4 C o n c l u s i o n s

Imines 2a-e were prepared via a simple condensation reaction of o-bromoacetophenone with different amines. Bromo-bridged palladium complexes 2a-e were synthesized successfully by an oxidative addition reaction of imines 2a-e with Pd(dba)2 in benzene. These complexes

have been characterized as their bridge-opened monomers by 'H- 13C- and "P-NMR.

Stoichiometric reactions of palladium complexes 2a-e with 1,1-dimethylallene in a mixture of dichloromethane and methanol at elevated temperatures led to the regioselective synthesis of isoquinolinium salts 4a-e. Nucleophilic attack of the imine nitrogen predominantly occurred at the least substituted end of the palladium- n-allyl terminus. In contrast to the stoichiometric iminoannulations with a-tetralone ketimines, these reactions are followed by an additional 1,3-H shift, probably catalyzed by palladium, leading to aromatic N-heterocycles. The fact that oc-tetralone ketimines do not show this behavior, is probably due to the rigid character of the unsaturated ring of the a-tetralone ketimine which makes it difficult to become planar. A similar reaction performed in acetonitrile shows a completely different regioselectivity; nucleophilic attack occurred at the most substituted position of the aliène.

Reactions of o-iodoacetophenone ketimines with 1,1-dimethylallene in DMF lead to iminoannulations at the most substituted carbon atom of the Pd-ir-allyl complex. As a result, no aromatic N-heterocyclic products can be obtained with 1,1-disubstitued aliènes under catalytic conditions. Mono-substituted aliènes on the other hand, are useful unsaturated substrates, that in reaction with o-iodo (or bromo) substituted aryl or vinyl imines, lead to isoquinolinium, pyrindinium or pyridinium salts. These products lose their N-substituent by ß-elimination (in the case of a tert-butyl or ß-cyanoethyl group) or a Pd-catalyzed debenzylation. We showed that the ß-cyanoethyl substituent is removed in situ from the nitrogen, whereas the (erf-butyl group needs an extra dealkylation step under harsh conditions that in some cases leads to lower yields and byproducts. No substituent is present on the 3-position of the pyridine ring produced, which may interact with the tert-butyl group on the nitrogen. Probably because of the latter, this leads to stable isoquinolinium, pyrindinium and pyridinium salts. In all cases studied,

tert-butyl and benzyl substituted imines lead to the regioselective formation of aromatic

N-heterocycles. When the less sterically demanding ß-cyanoethyl group was used as substituent on the imine, regioselectivities were lower. Only when mono-substituted aliènes with a sterically demanding group (e.g. cyclohexyl) were used, regioselective reactions were observed.

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The use of 1,3-disubstituted aliènes under the same conditions as described above, did not lead to the formation of 3,4-disubstituted aromatic N-heterocycles. Iminium salts were produced in which the exocyclic double bond could not be isomerized, probably due to steric reasons.

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3.5 Experimental Section

All manipulations were carried out in an atmosphere of purified, dry nitrogen by using standard Schlenk techniques. Solvents were dried according to literature procedures[64] and stored under nitrogen. KPF6 and KOH were purchased from Acros Chimica. Lithium chloride

and sodium borohydride were obtained from Aldrich, 1,1-dimethylallene from Fluka and p-toluene sulphonic acid monohydrate and sodium acetate from Merck. All of these compounds were used without further purification. Aniline and benzylamine were dried over calcium hydride and distilled. Propargyl alcohol was distilled from K2C03. Xylene (mixture of isomers)

and toluene were distilled from sodium. Sealed tubes were obtained from Aldrich. Heterocyclic products obtained by Pd-catalyzed annulation reactions were purified by flash chromatography on a 1 cm diameter/15 cm length column using silica gel as stationary phase. Elemental analyses were performed on a Vario EL in the Inorganic Laboratory of this university or by Kolbe Microanalytisches Laboratorium, Mülheim an der Ruhr, Germany. 'H and "CpHJ-APT NMR spectra were recorded on a Bruker AMX 300 spectrometer. 'H-COSY, HETCOR CH-13C)

and 'H-NOESY NMR were recorded on a Bruker DRX 300 spectrometer using standard COSY-45 (Gradient Selected), HETCOR [J(C-H) = 140 Hz] and 2D NOESY pulse sequences. C-H-HETCOR spectrum was used to calculate 'J,^. AU NMR spectra were recorded in CDC13 (unless

indicated otherwise). 'H-NMR spectra of complexes 3 were recorded in CDC13 with a drop of

pyridine-d5, except 3h which was measured in CDC13. Mass spectra and accurate mass

determinations were performed on a JEOL JMS SX/SX102A four-sector mass spectrometer, coupled to a JEOL MS-MP7000 data system.Aniline and benzylamine were dried over calcium hydride and distilled. Dibenzylideneacetone[65] and Pd(dba)2 [66] were synthesized according

to literature procedures.

Preparation of l a as general procedure A for the synthesis of o-bromoacetophenone ketimines (la-e)

Ph [l-(2-Bromo-phenyl)-ethylidene]-phenyl-amine (la). In a N 100 mL 2-necked Schlenk flask equipped with 4Â

molecular sieves, o-bromoacetophenone (2.03 g, 10.18 mmol), freshly distilled aniline (0.999 g, 10.74 mmol, 1.05 equiv) and a catalytic amount of p-toluene sulphonic acid were dissolved in toluene (20 mL). The mixture was heated to reflux until GC-MS did not detect o-bromoacetophenone anymore. After the mixture was cooled to room temperature the yellow solution was filtered to remove

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p-toluene sulphonic acid. The molsieves were washed with diethyl ether (2x10 mL). The volatile solvents in the combined extracts were removed in vacuo to give a yellow oil. After flash chromatography over silica gel (Et2Û / hexanes 50:50), an inseparable mixture of l a and l a ' (1.75 g, 6.38 mmol, 63%, ratio 60:40) was obtained as a yellow oil. ÏH-NMR (300 MHz): 7.63 (d, 1 H, J = 10.0 Hz, la), 7.5-7.35 (m, 5 H, la+la'), 7.22 (t, 1 H, la), 7.18-7.10 (m, 4 H, la+la'), 7.02 (t, 1 H, la'), 6.93 (m, 4 H, la+la'), 6.79 (d, 2 H, J = 10.0 Hz, la'), 2.54 (s, 3 H, CH3, la'), 2.21 (s, 3 H,

CH3, la). 13C-NMR (75 MHz): 169.3, 168.6, 150.3, 150.1, 142.9, 140.4, 132.9, 132.4, 129.8, 129.4,

128.9, 128.6, 128.4, 128.2, 127.4, 126.9, 123.6, 123.3, 120.00, 119.96, 119.6, 119.1, 27.9 (CH3, la'),

21.0 (CH3, la).

p-Tol [l-(2-Bromo-phenyl)-ethylidene]-p-tolyl-amine (lb) N According to general procedure A, starting from

o-bromoacetophenone (2.03 g, 10.18 mmol), p-toluidine l b '

(1.16 g, 10.80 mmol, 1.05 equiv) and a catalytic amount of TsOH, a mixture of l b and l b ' (2.78 g, 9.66 mmol, 89%, ratio 60:40) was obtained after flash chromatography over silica gel (Et2Ü / hexanes 50:50) as a yellow oil. 1H-NMR (300 MHz): 7.61

(dd, 1 H, J = 7.8 Hz, J = 0.9 Hz, lb), 7.48-7.36 (m, 3 H), 7.26 (dd, J = 7.7 Hz, J = 1.8 Hz), 7.21-7.13 (m, 5 H), 7.09-7.04 (m, 1 H), 6.93-6.89 (m, 3 H), 6.81 (d, 2 H, J = 8.2 Hz, lb), 6.66 (d, 2 H, J = 8.3 Hz, lb'), 2.52 (s, 3 H, PhCH3, lb'), 2.36 (s, 3 H, PhCH3, lb), 2.21 (s, 3 H, N=C-CH3, lb), 2.19 (s, 3

H, N=C-CH3, lb'). 13C-NMR (75 MHz): 169.2, 168.5, 147.7, 143.0, 140.6, 132.95, 132.86, 132.8,

132.4, 129.6, 129.4, 129.2, 128.7, 128.5, 128.4, 127.3, 126.9, 120.03, 119.96, 119.5, 119.1, 27.9, 20.9, 20.7,20.6. HRMS calcd. for Ci5Hi4NBr 288.0388, found 288.0369.

p-An [l-(2-Bromo-phenyl)-ethylidene]-(4-methoxy-N phenyD-amine (lc) According to general procedure • 1 • A, starting from o-bromoacetophenone (2.01 g, 10.11

mmol), p-anisidine (1.36 g, 10.62 mmol, 1.05 equiv) and a catalytic amount of TsOH, a mixture of lc and lc' (2.12 g, 6.97 mmol, 69%, ratio 54:46) was obtained as a brown oil and was used without further purification. 1H-NMR (300 MHz): 7.60 (d,

1 H), 7.6-7.35 (m, 3 H), 7.2-7.0 (m, 3 H), 6.92-6.85 (m, 5 H), 6.75-6.60 (m, 4 H), 3.81 (s, 3 H, OCH3,

lc), 3.67 (s, 3 H, OCH3, lc'), 2.50 (s, 3 H, CH3, lc'), 2.21 (s, 3 H, CH3, lc). 13C-NMR (75 MHz):

169.3, 138.1, 156.1, 155.8, 143.7, 143.2, 143.1, 140.8, 132.9, 132.4, 129.6, 129.1, 128.5, 128.4, 127.3, 127.0,121.5,120.5,120.0,119.6,114.1,113.4, 55.2 (OCH3, lc), 55.0 (OCH3, lc'), 28.0 (CH3, lc), 20.9

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[l-(2-Bromo-phenyl)-ethylidene]-(3,5-dimethyl-phenyU-amine (Id) According to general p r o c e d u r e A, starting from o-bromoacetophenone (2.00 g, 10.05 mmol), 3,5-dimethylaniline (1.23 g, 10.05 mmol) and a catalytic amount of TsOH, and after flash chromatography over activated silica gel (EtOAc / hexanes 25:75), an inseparable mixture of Id and Id' (2.25 g, 7.44 mmol, 74%, ratio 30:70) was obtained as an orange oil. aH-NMR (300 MHz):

7.64 (dd, 1 H, J = 8.3 Hz, 0.8 Hz), 7.51 (dd, 1 H, J = 7.7 Hz, 1.7 Hz), 7.45 (dd, 1 H, J = 7.9 Hz, 1.0 Hz), 7.40 (dt, 1 H, J = 7.7 Hz, 1.0 Hz), 7.26 (dd, 1 H, J = 7.9 Hz, 1.6 Hz), 7.19-7.15 (m, 1 H), 7.11 (dt, 1 H, J = 7.3 Hz, 1.0 Hz), 7.02 (dt, 1 H, J = 7.8 Hz, 1.8 Hz), 6.91-6.85 (m, 2 H), 6.741 (s, 1 H), 6.736 (s, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 2.54 (s, 3 H, N=C-CH3, Id), 2.24 (s, 3 H, N=C-CH3, Id'), 1.36 (s, 18 H, C-(CH3)3), Id'), 1.17 (s, 18 H, C-(CH3)3), Id). ^C-NMR (75 MHz): 168.5, 168.2, 151.3, 150.3, 149.5, 149.3, 143.2, 141.1, 132.9, 132.2, 129.6, 128.82,128.76, 128.3,127.3, 126.7, 120.1, 119.7, 117.4, 116.9, 115.1, 113.6, 34.7 (C-(CH3)3, Id'), 34.5 (C-(CH3)3, Id), 31.3 (C-(CH3)3, Id'),

31.1 (C-(CH3)3, Id), 27.7 (N=C-CH3, Id), 20.9 (N=C-CH3, Id'). HRMS calcd. for C i o H i / N B r

302.0544, found 302.0540.

-Ph Benzyl-[l-(2-bromo-phenyl)-ethylidene]-amine (le) ' ^ 11 ^-L N According to general procedure A, starting from

o-b r o m o a c e t o p h e n o n e (2.02 g, 10.17 m m o l ) , le' benzylamine (1.10 g, 10.17 mmol) and a catalytic amount of TsOH, and after flash chromatography over activated silica gel (EtOAc / hexanes 25:75), an inseparable mixture of l e and le' (2.60 g, 9.02 mmol, 89%, ratio 26:74) was obtained as an orange oil. iH-NMR (300 MHz): 7.65 (d, 1 H, J = 8.0 Hz, le'), 7.60 (d, 1 H, J = 8.0 Hz, le), 7.50 (d, 1 H, J = 7.5 Hz, le'), 7.43-7.15 (m, 11 H, le+le'), 7.10 (d, 4 H, le+le'), 4.76 (s, 2 H, PhCH2, le),

4.43 (d, 1 H, J = 15.0 Hz, PhCHH', le'), 4.26 (d, 1 H, J = 15.0 Hz, PhCHH', le'), 2.43 (s, 3 H, CH3,

le'), 2.35 (s, 3 H, CH3, le). 13C-NMR (75 MHz): 168.9, 167.5, 144.4, 140.6, 139.7, 139.6, 132.73,

132.70, 129.6, 129.4, 129.2, 128.3, 128.3, 127.9, 127.8, 127.6, 127.4, 127.2, 126.6, 120.1, 119.1, 57.3 (PhCH2, le'), 55.8 (PhCH2, le), 27.9 (CH3, le'), 19.7 (CH3, le). HRMS calcd. for C i5H i5N B r

288.0388, found 288.0364.

Preparation of 2a as general procedure B for the synthesis of the di-ji-bromo-bisUV-substituted-acetophenoneketimine-5,C,N)dipalladium(II) complexes (2a-e)

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Di-|i-bromo-bis(N-phenyl-acetophenoneketimine-5,C/N)dipalladium(II)

(2a) In a 100 mL 2-necked Schlenk,la (1.54 g, 5.62 mmol) and Pd(dba)2 (3.15

g, 5.48 mmol) were dissolved in benzene (10 mL) under nitrogen atmosphere. The deeply purple coloured mixture was heated to reflux until the colour changed to dark green. After cooling the mixture to room temperature, the solution was filtered over Celite to remove Pd(0). The resulting crude complex was washed several times with benzene. After removal of benzene in

vacuo, 2a (2.06 g, 2.71 mmol, 96%) was obtained as a brown solid. ÏH-NMR (300 MHz): 8.35 (b, 1

H), 7.30-7.26 (m, 2 H), 7.15-6.70 (m, 6 H), 2.15 (s, 3 H, CH3). " C - N M R (75 MHz): 183.9, 148.1,

131.3,128.6,128.1,127.7, 126.1,124.0,122.8,116.5,106.9,17.0 (CH3).

Di-^-bromo-bis(N-p-tolyl-acetophenoneketimine-5,C,N)dipalladium(II) (2b) According to general procedure B, starting from l b (144 mg, 0.500 mmol) and Pd(dba)2 (181 mg, 0.454 mmol), 2b (77.7 mg, 0.0985 mmol, 43%)

was obtained as a yellow solid. !H-NMR (300 MHz): 7.28 (m, 1 H), 7.10 (m, 2 H), 6.93 (b, 2 H), 6.76 (b, 2 H), 2.23 (s, 3 H, PhCH3), 2.13 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 184.0, 148.2, 135.8, 131.2, 129.1, 127.5, 124.0, 122.6, 20.7

(PhCH3), 16.9 (N=C-CH3).

Di-n-bromo-bis(A/-p-anisyl-acetophenoneketimine-5,C,N)dipalladium(II) (2c) According to general procedure B, starting from lc (3.18 g, 5.23 mmol) and Pd(dbab_ (3.01 g, 5.22 mmol), 2c (1.61 g, 1.96 mmol, 75%) was obtained as a brown solid. !H-NMR (300 MHz): 7.30-7.26 (m, 1 H), 7.10 (m, 3 H), 6.81 (b, 2 H), 6.07 (b, 2 H), 3.72 (s, 3 H, OCH3), 2.15 (s, 3 H, CH3). 13C-NMR (75

MHz): 184.4,157.5,148.1,131.2,127.6,124.0,113.7, 55.2 (OCH3), 16.9 (CH3).

Di-n-bromo-bis(N-3,5-dimethyl-phenyl-acetophenoneketimine-5,C,N)dipalladium(II) (2d) According to general procedure B, starting from Id (1.07 g, 3.54 mmol) and Pd(dba)2 (2.03 g, 3.54 mmol), 2d (0.721 g, 0.882 mmol, 50%) was obtained as a brown solid. !H-NMR (300 MHz): 7.72 (b, 1 H), 7.44 (d, 1 H, J = 7.1 Hz), 7.30 (s, 1 H), 7.18 (d, 1 H, J = 7.1 Hz), 7.11-6.99 (m, 2 H), 6.93 (s, 2 H), 2.12 (s, 3 H, N=C-CH3), 1.35 (s, 6 H, PhCH3). 1 3C

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20.8 (PhCH3), 16.9 (N=C-CH3).

Di-^-bromo-bis(N-benzyl-acetophenoneketimine-5,C,N)dipalladium(II) (2e) According to general procedure B, starting from l e (1.00 g, 3.48 mmol) and Pd(dba)2 (2.00 g, 3.48 mmol), 2e (0.792 g, 1.00 mmol, 58%) was obtained as a brown solid. !H-NMR (300 MHz): 7.54 (b, 2 H), 7.31 (d, 2 H, J = 7.1 Hz), 7.23-7.19 (m, 2 H), 7.07 (t, 1 H, J = 7.4 Hz), 6.96 (t, 1 H, J = 7.1 Hz), 6.06 (b, 1 H), 5.51 (s, 2 H, PhCH2), 2.28 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 184.9,

148.5,130.8, 128.3,127.5,126.9,126.8,124.1,117.8,117.3, 57.9 (PhCH2), 15.6 (N=C-CH3).

Preparation of 3a as general procedure C for the synthesis of bromo(N-substituted-acetophenoneketimine-5,C,N)triphenylphosphinepalladium(II) (3a-e)

Bromo(N-phenyl-acetophenoneketimine-5,C,N)triphenylphosphine-palladium(II) (3a) In a 50 mL 2-necked Schlenk flask, a mixture of 2a (102.5 mg, 0.135 mmol) and PPh3 (69.3 mg (0.263 mmol, 1.95 equiv) dissolved in

dichloromethane (10 mL) was stirred at room temperature for one day. The mixture was filtered over Celite to remove Pd(0). The yellow filtrate was concentrated and 3a was precipitated with pentane. After washing several times with pentane and drying in vacuo, 3a (123 mg, 0.191 mmol, 71%) was obtained as a light yellow powder. !H-NMR (300 MHz): 7.77 (m, 6 H), 7.36 (m, 12 H), 7.18 (t, 1 H, J = 7.6 Hz), 7.08 (d, 2 H, J = 7.6 Hz), 6.63 (t, 1 H, J = 7.6 Hz), 6.54 (d, 1 H, J = 7.6 Hz), 2.24 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 183.3,160.1, 149.4, 148.7,135.4, 135.2, 131.9 (d, MP-C = 49.5 Hz, C(aryl)-Pd),

130.5, 130.3, 128.1, 127.8, 127.6, 125.6, 123.5, 123.4, 17.8 (CH3). 31P-NMR (121 MHz): 43.8 (s).

HRMS calcd. for C32H27NPBrPd 562.0928, found 562.0883.

Bromo(N-p-tolyl-acetophenoneketimine-5,C,N)triphenylphosphine-palladium(II) (3b) According to general procedure C starting from 2b (104.3 mg, 0.132 mmol) and PPh3 (67.5 mg, 0.258 mmol, 1.95 equiv), 3b

(89.9 mg, 0.137 mmol, 72%) was obtained as a light yellow powder. 1 H-NMR (300 MHz): 7.77 (m, 6 H), 7.36 (m, 11 H), 7.17 (d, 2 H, J = 7.4 Hz), 6.97 (d, 2 H, J = 7.4 Hz), 6.63 (t, 1 H, J = 7.3 Hz), 6.53 (t, 1 H, J = 7.3 Hz), 2.34 (s, 3 H, PhCH3), 2.24 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 183.4,180.1,149.5,

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130.30,128.6, 127.8,127.6, 123.5,123.2, 20.9 (PhCH3), 17.8 (N=C-CH3). 31P-NMR (121 MHz): 43.7

(s). HRMS calcd. for C3 3H29NPPd (M - Br) 576.1085, found 576.1127.

OMe Bromo(N-p-anisyl-acetophenoneketimine-5,C,N)triphenylphosphine-palladium(II) (3c) According to general procedure C starting from 2c (99.6 mg, 0.117 mmol) and PPh3 (61.3 mg, 0.234 mmol, 2 equivï, 3c (122.4 mg,

0.182 mmol, 78%) was obtained as a yellow solid. ÎH-NMR (300 MHz):

N N /B r 7.80-7.70 (m, 6 H), 7.40-7.30 (m, 10 H), 7.01 (d, 2 H, J = 8.8 Hz), 6.95 (t, 1 H, J P d x = 6.9 Hz), 6.89 (d, 2 H, J = 8.8 Hz), 6.62 (t, 1 H, J = 6.9 Hz), 6.52 (t, 1 H, J = 6.9

P P h3 Hz), 3.80 (s, 3 H, OCH3), 2.24 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 183.9,

160.2, 157.1, 149.4, 142.2, 135.9, 135.2, 131.9 (d, % < = 49.5 Hz, C(aryl)-Pd), 130.30, 130.28, 127.7, 127.6, 124.5, 123.5, 113.1, 55.1 (OCH3), 15.05 (N=C-CH3). 3 1P-NMR (121

MHz): 43.5 (s). HRMS calcd. for C3 3H29NOPPd (M - Br) 592.1034, found 592.0995.

Bromo(N-3,5-dimethyl-phenyl-acetophenoneketimine-5,C,N)-triphenylphosphine-palladium(II) (3d) According to general procedure C starting from 2d (94.0 mg, 0.115 mmol) and PPh3 (58.3 mg, 0.224 mmol, 1.95

equiv), 3d (131.8 mg, 0.196 mmol, 85%) was obtained as a yellow solid. ^H-NMR (300 MHz): 7.78 (m, 6 H), 7.35 (m, 10 H), 6.95 (t, 1 H, J = 6.9 Hz), 6.80 (s, 1 H), 6.69 (s, 2 H), 6.61 (t, 1 H, J = 6.9 Hz), 6.53 (t, 1 H, J = 6.9 Hz), 2.30 (s, 6 H, PhCH3), 2.23 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 149.6, 148.5,

138.4, 138.3, 137.3, 135.5, 135.3, 131.9 (ÏJp.c = 49.5 Hz, C(aryl)-Pd), 130.3, 127.7, 127.6, 127.3, 123.5, 121.1, 21.2 (PhCH3), 17.8 (N=C-CH3). 31P-NMR (121 MHz): 44.2 (s).

HRMS calcd. for C3 4H3iNPPd (M - Br) 590.1242, found 590.1241.

Bromo(N-benzyl-acetophenoneketimine-5,C,N)triphenylphosphine-palladium(II) (3e) According to general procedure C starting from 2e (102.9 mg, 0.130 mmol) and PPh3 (66.7 mg, 0.254 mmol, 1.95 equiv), 3e (113.8 mg,

0.173 mmol, 67%) was obtained as a yellow solid. ÏH-NMR (300 MHz): 7.78 (m, 6 H), 7.52 (d, 2 H, J = 7.4 Hz), 7.4 - 7.2 (m, 13 H), 6.91 (t, 1 H, J = 7.4 Hz), 6.56 (t, 1 H, J = 7.1 Hz), 6.48 (d, 1 H, J = 7.1 Hz), 5.72 (s, 2 H, PhCH2-N), 2.33 (s, 3 H, N=C-CH3). 13C-NMR (75 MHz): 159.5,150.0,138.7,138.0,137.8,135.3,135.2,132.0 (ÏJp-C = 49.5 Hz, C(aryl)-Pd), 130.4, 130.0,128.2,127.9, 127.7,127.6,127.1,126.5,123.6, 56.3 (PhCH2-N), 16.2 (N=C-CH3). 31P-NMR (121 MHz): 43.0 (s). HRMS calcd. for C3 3H2 9NPPd (M - Br) 576.1085, found 576.1100.

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Synthesis of IsoquinoUnes and Pyridines from o-Halide-substituted Aryl and Vinyl Imines via Iminoannulation

Preparation of 4a as general procedure D for the synthesis of isoquinolinium salts (4a-e)

4-Isopropyl-l-methyl-2-phenyl-isoquinolinium, hexafluoro phosphate (4a) See step 1 in Scheme 2. To a suspension of 2a (101 mg, 0.132 mmol) in dichloromethane (10 mL) in a 50 mL Schlenk flask was added 1,1-dimethylallene (DMA, 33 |il, 0.330 mmol, 2.5 equiv). The mixture was allowed to stir at room temperature. During the reaction the pale yellow suspension turned into a red purple clear solution. After one day MeOH (40 mL) was added and the mixture was heated to reflux for 10 minutes. During this time the colour of the solution changed from purple to yellow green with formation of Pd(0). The resulting mixture was filtered over Celite to remove Pd(0) and to the resulting solution was added KPFç, (606 mg, 3.3 mmol, 10 equiv). After anion exchange for one day, the solvent was removed and 4a was extracted in CH2CI2 and filtered over Celite to remove inorganic salts. After concentration of the solution, 4a was precipitated by adding pentane. After filtration and washing several times with pentane, the volatile solvents were removed in vacuo . Isoquinolinium salt 4a (212 mg, 0.161 mmol, 61%) was obtained as a light brown solid. !H-NMR (300 MHz): 8.55 (d, 1 H, J = 8.6 Hz), 8.35 (d, 1 H, J = 8.5 Hz), 8.19 (t, 1 H, J = 8.5 Hz), 7.99 (t, 1 H, J = 7.8 Hz), 7.91 (s, 1 H, H9),

7.69 (m, 3 H), 7.60 (m, 2 H), 3.80 (sept, 1 H, J = 6.9 Hz, Hi 2) , 2.97 (s, 3 H, H n ) , 1.45 (d, 6 H, J = 6.9

Hz, H13). 13C-NMR (75 MHz): 159.7, 144.6, 143.6, 138.9, 138.1, 133.4, 133.2, 132.6, 131.2, 129.2,

127.1, 126.1, 29.7 (C12), 24.0 (C13), 20.2 (Cn). 31P-NMR (121 MHz): -144.3 (sept, Jp.F = 702 Hz).

HRMS calcd. for C19H21N (M + H - PF6) 263.1674, found 263.1693.

4-Isopropyl-l-methyl-2-p-tolyl-isoquinolinium, hexafluoro phosphate (4b) According to general procedure D starting from 2b (66.4 mg, 0.0841 mmol), DMA (21 [i\, 0.210 mmol) and KPF6 (155 mg, 0.841 mmol) 4b (39.7

mg, 0.0942 mmol, 56%) was obtained as a brown solid. 1H-COSY NMR

(300 MHz): 8.57 (d, 1 H, J2-3 = 8.5 Hz, H3), 8.36 (d, 1 H, h_6 = 8.5 Hz, H6), 8.19 (t, 1 H, J i .6 = J1-2 = 8.5 Hz, Hi), 8.00 (t, 1 H, Ji_2 = J2-3 = 8.5 Hz, H2), 7.90 (s, 1 H, H9), 7.45 (d, 2 H, J = 8.7 Hz), 7.47 (d, 2 H, J = 8.7 Hz), 3.80 (sept, 1 H, J12-13 = 6.9 Hz, H12), 3.00 (s, 3 H, H n ) , 2.51 (s, 3 H, Hi8), 1.45 (d, 6 H, J12-13 = 6.9 Hz, H13). 13C-NMR (75 MHz): 158.6 (C7), 142.5, 142.3, 140.0, 137.0 (Ci, Jc-H = 168 Hz), 136.5, 131.8 (C9, JC-H = 191 Hz), 131.6 (C2, Jc-H = 178 Hz), 131.5, ( Q 5 or Q6, Jc-H = 173 Hz), 130.0 (C3, Jc-H = 171 Hz), 127.9, 125.3 (C15 or Ci6, Jc-H = 173 Hz), 124.4 ( Q , Jc-H = 171 Hz), 107.5, 28.1 (C12), 22.7 (C13), 21.6 (Ci8), 18.7 (Cn). 31P-NMR (121 MHz): -144.2 (sept, JP_F =

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0Mei8

0Mei8 4-Isopropyl-2-(4-methoxy- phenyl)-l-methyl-i s o q u phenyl)-l-methyl-i n o l phenyl)-l-methyl-i n phenyl)-l-methyl-i u m , hexafluoro phosphate (4c) According to general procedure D starting from 2c (99.3 mg, 0.121 mmol), DMA (30 \d, 0.305 mmol) and KPF6 (222

mg, 1.21 mmol) a mixture of 4c, 4c' and 4c" (see Scheme 5) (51.3 ng, 0.175 mmol, 73%, ratio 13:42:47) was obtained as a brown solid. iH-NMR (300 MHz) (4c): 3.55 (d, 1 H, J = 8.5 Hz), 8.36 (d, 1 H, J = 8.5 Hz), 8.19 (t, 1 H, J = 8.5 Hz), 7.94 (s, 1 H, H9), 3.92 (s,

3 H, H i8) , 3.85 (sept, 1 H, J12-13 = 6.8 Hz, Hi 2) , 3.01 (s, 3 H, H11), 1.46 (d, 6 H, J12-13 = 6.8 Hz,

Î13). !H-NMR (300 MHz) (4c' + 4c"): 8.08 (d, 1 H, J = 8.0 Hz), 7.99 (d, 1 H, J = 8.0 Hz), 7.85 (t, 1 -i, J = 8.0 Hz), 7.75 (t, 1 H, J = 6.7 Hz), 7.6-7.45 (m, 4 H), 7.27 (m, 4 H), 7.13 (m, 4 H), 5.86 (s, 1 H, ll3, 4c"), 5.71 (s, 1 H, Hi3', 4c"), 4.83 (s, 2 H, H9, 4c'), 3.89 (s, 3 H, His), 3.88 (s, 3 H, His), 2.69 (s,

H, H u , 4c"), 2.63 (s, 3 H, H n , 4c'), 2.11 (s, 3 H, H13, 4c'), 2.02 (s, 3 H, H13', 4c'), 1.51 (s, 6 H, H9, c"). 13C-NMR (75 MHz): 142.0, 141.9, 136.5, 136.1, 134.6, 131.7, 131.1, 130.2, 129.5, 127.5, 126.7,

26.6, 123.9, 115.6, 55.7 (Cis), 55.6 ( Q s ) , 27.7, 25.4, 22.5, 22.3, 18.3. 31P-NMR (121 MHz): -144.0

sept, Jp.p = 708 Hz). HRMS calcd. for C20H23NO (M + H - PF6) 293.1780, found 293.1779.

2-(3,5-Dimethyl-phenyl)-4-isopropyl-l-methyl-isoquinolinium, hexafluoro phosphate (4d) According to general procedure D starting from 2d (99.8 mg, 0.126 mmol), DMA (31 \û, 0.315 mmol) and KPF6 (232

mg, 1.26 mmol) 4d (39.1 mg, 0.141 mmol, 56%) was obtained as a light brown solid. ÏH-NMR (300 MHz): 8.59 (d, 1 H, J2-3 = 8.6 Hz, H3), 8.36 (d, 1

H, Ji_6 = 8.6 Hz, H6), 8.20 (t, 1 H, Ji_6 = Ji-2 = 8.6 Hz, Hi), 8.02 (t, 1 H, h-2

= J2-3 = 8.6 Hz, H2), 7.90 (s, 1 H, H9), 7.31 (s, 1 H, H17), 7.18 (s, 2 H, H15),

3.81 (sept, 1 H, H12, J12-I3 = 6.8 Hz), 3.03 (s, 3 H, H n ) , 2.47 (s, 6 H, H i6) ,

48 (d, 6 H, J12-13 = 6.8 Hz, H13). 13C-NMR (75 MHz): 158.0 (C7), 142.0, 141.9, 141.0, 136.4,

36.0, 132.7, 131.2, 131.1, 129.5, 127.4, 123.8, 122.7, 27.7 ( Q2) , 22.3 (C13), 20.9 (Ci6), 18.3 ( C n ) .

'P-NMR (121 MHz): -144.3 (sept, JP.F = 706 Hz). HRMS calcd. for C21H25N (M + H - PF6)

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Synthesis of Isoquinolines and Pyridines from o-Halide-substituted Aryl and Vinyl lmines via Iminoannulation

Table 2. Selected bond distances (Â) for 4d (with ESD in parentheses)

N-C(l) 1.340(3) C(l)-C(10) 1.486(3) C(4)-C(5) 1.411(3) C(7)-C(8) 1.371(4) C(14)-C(15) 1.375(4) C(16)-C(20) 1.506(4) N-C(14) 1.468(3) C(3)-C(4) 1.437(3) C(5)-C(6) 1.375(4) C(ll)-C(12) 1.526(4) C(15)-C(16) 1.394(4) C(18)-C(19) 1.394(4) N-C(2) 1.387(3) C(2)-C(3) 1.353(3) C(4)-C(9) 1.418(3) C(8)-C(9) 1.413(3) C(14)-C(19) 1.386(4) C(17)-C(18) 1.393(4) C(l)-C(9) 1.431(3) C(3)-C(ll) 1.516(3) C(6)-C(7) 1.392(4) C(ll)-C(13) 1.529(4) C(16)-C(17) 1.385(4) C(18)-C(21) 1.499(4)

Table 3. Selected bond angles (°) for 4d (with ESD in parentheses)

C(l)-N-C(2) 122.7(2) N-C(l)-C(9) 117.36(19) N-C(2)-C(3) 122.7(2) C(4)-C(3)-C(ll) 121.55(19) C(5)-C(4)-C(9) 118.64(19) C(6)-C(7)-C(8) 120.5(2) C(l)-C(9)-C(8) 119.9(2) C(3)-C(ll)-C(13) 113.7(2) N-C(14)-C(19) 118.0(2) C(15)-C(16)-C(17) 118.1(2) C(16)-C(17)-C(18) 123.2(2) C(2)-N-C(14) 115.47(18) C(9)-C(I)-C(10) 122.27(19) C(2)-C(3)-C(ll) 120.9(2) C(3)-C(4)-C(9) 119.11(18) C(5)-C(6)-C(7) 120.8(2) C(l)-C(9)-C(4) 120.51(17) C(3)-C(ll)-C(12) 109.8(2) P l K

Ph.

X

l l \ N+ P F6 " 11- \ / < P F6 -\*^ M 9 T ^ T9 7 r

^ ^ ^ \ ^

1 3 X ^ > ^ ^ ^

3f| J JÏ2

3

[

T r

2 2

k ^ 6

[

3

2^

\ ^ 6 13 C(l)-N-C(14) 121.79(18) N-C(l)-C<10) 120.37(19) C(2)-C(3)-C(4) 117.4(2) C(3)-C(4)-C(5) 122.2(2) C(4)-C(5)-C(6) 120.4(2) C(7)-C(8)-C(9) 120.1(2) C(4)-C(9)-C(8) 119.57(19) C(12)-C(ll)-C(13) 110.9(2) C(15)-C(14)-C(19) 122.9(2) C(15)-C(16)-C(20) 121.0(3) C(17)-C(18)-C(19) 118.0(2) N-C(14)-C(15) 119.0(2) C(14)-C(15)-C(16) 119.1(2) C(17)-C(16)-C(20) 120.9(2) C(17)-C(18)-C(21) 121.2(2) C(19)-C(18)-C(21) 120.8(3) C(14)-C(19)-C(18) 188.8(2) 13' 2-Benzyl-4-isopropyl-l-methyl-isoquinolinium, hexafluoro phosphate (4e) According to genera

procedure D starting from 2e (203 mg, 0.25/ mmol), DMA (64 jil, 0.771 mmol) and KPF6 (47:

mg, 2.57 mmol) a mixture of 4e and 4e' (112 mg

1 4e l 4e' 0.406 mmol, 79%, ratio 75:25) was obtained as .'

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Hz, H6, 4e), 8.15 (t, 1 H, Ji.6 = h-2 = 8.6 Hz, Hi, 4e), 8.15 (s, 1 H, H9, 4e), 7.97 (t, 1 H, Ji_2 = h-3 =

8.6 Hz, H2, 4e), 7.51-7.39 (m, 3 H, 4e), 7.02 (m, 2 H, 4e), 6.04 (s, 2 H, H14, 4e), 5.33 (s, 2 H, Hu, 4e'), 4.54 (s, 2 H, H9, 4e'), 3.77 (sept, 1 H, Ji2-13 = 6.8 Hz, H13, 4e), 3.21 (s, 3 H, H n , 4e), 2.99 (s, 3

H, H n , 4e'), 2.00 (s, 3 H, H13, 4e'), 1.56 (s, 3 H, H13', 4e'), 1.48 (d, 6 H, H13, 4e). 13C-NMR (75

MHz): 135.9, 132.4, 130.7, 129.5, 129.1, 128.8, 128.0, 127.9, 127.3, 126.7, 123.9, 117.8, 117.5, 117.1, >2.6 (C14), 27.8 (C12), 22.2 (C13), 16.8 ( C n ) . 31P-NMR (121 MHz): -144.0 (sept, Jp.F = 711 Hz).

HRMS calcd. for C20H22N (M + H - PF6) 276.1752, found 276.1758.

o-Iodoacetophenone (5) To a 500 mL round bottom flask equipped ith

0->Q aminoacetophenone (13.5 g, 0.10 mol) was added a solution of 2N HCl (125 mL)

and the mixture was heated until o-aminoacetophenone was dissolved completely. The solution was cooled to 0 °C and purged with nitrogen to emove the air. A solution of NaNÜ2 (7.1 g, 0.10 mol) in water (25 mL) was added slowly with xtensive stirring. After stirring for 15 minutes at 0 °C, a solution of KI (17 g, 0.10 mol) in water

15 mL) was added. The mixture was allowed to warm to room temerature and heated to 40 °C

3r 30 minutes. The reaction mixture was extracted (Et20, 2x) and the combined organic layers ,/ere washed (NaHCÜ3 sat., 2x). The combined water layers were washed (Et20, 2x) and the jmbined organic layers were dried (MgSC>4) and concentrated in vacuo, giving a dark brown )il which was used without further purification. XH-NMR (300 MHz): 7.94 (dd, 1 H, J = 7.9 Hz,

0.8 Hz), 7.47 (dd, 1 H, J = 7.7 Hz, 1.8 Hz), 7.41 (dt, 1 H, J = 7.7 Hz, 0.9 Hz), 7.13 (dt, 1 H, J = 7.6 iz, 1.9 Hz), 2.62 (s, 3 H, CH3). 13C-NMR (75 MHz): 201.6 (C=0), 143.8,131.6, 128.1, 127.9, 90.7,

).3 (CH3).

[l-(2-Iodo-phenyl)-ethylidene]-p-tolyl-amine (6) According to general procedure A, starting from 5 (2.46 g, 10.0 mmol), p-toluidine (1.07 g, 10.0 mmol) and a catalytic amount of TsOH, a mixture of 6 and 6' (3.00 g, 8.96 mmol, 90%, ratio 68:32) was obtained as a yellow oil and was used without further purification (< 4% 0-)doacetophenone). !H-NMR (300 MHz): 7.93 (dd, 1 H, J = 7.8 Hz, 0.7 Hz, 6), 7.71 (d, 1 H, J = 7.8 Hz, 6'), 7.41-7.36 (m, 2 H), 7.19 (m, 1 H, 6'), 7.19 (d, 2 H, J = 8.1 Hz, 6), 7.07 (m, 1 H, 6),

6.92-.89 (m, 2 H), 6.84 (d, 2 H, J = 8.1 H, 6), 6.69 (d, 2 H, J = 8.3 Hz), 2.51 (s, 3 H, PhCH3, 6'), 2.37 (s, 3

i PhCH3, 6), 2.19 (s, 6 H, N=C-CH3, 6+6').

Benzyl-[l-(2-iodo-phenyl)-ethylidene]-amine (7) According to general M-^^pu procedure A, starting from 5 (18.58 g, 75.5 mmol), benzylamine (16.2 g,

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7' (19.09 g, 57.0 mmol, 75%, ratio 23:77) was obtained after flash chromatography over silica gel

(EtOAc / hexanes 10:90) as a yellow oil. The purified product contained less than 5% o-iodoacetophenone. iH-NMR (300 MHz): 7.89 (d, 1 H, J = 8.1 Hz, 7), 7.83 (dd, 1 H, J = 7.8 Hz, 0.9 Hz, 7'), 7.45-7.21 (m, 13 H), 7.10-7.02 (m, 3 H, 7+7'), 4.71 (s, 2 H, 7'), 4.40 (d, 1 H, J = 14.6 Hz, PhCHH-N, 7'), 4.15 (d, 1 H, J = 14.6 Hz, PhCHH-N,7'), 2.36 (s, 3 H, N=C-CH3, 7'.

l,3,3-Trimethyl-4-methylene-2-p-tolyl-3,4,4a,8a-tetrahydro-isoquinolinium, hexafluoro phosphate (8) A sealed tube (15 mL) was charged with Pd(OAc)2 (6.75 mg, 0.0301 mmol, 5 mol%), PPh3 (7.88 mg, 0.0301 mmol, 5 mol%) and K P F ô (0.78 g, 4.21 mmol, 7 equiv). Imine 6 (201 mg, 0.601 mmol) and DMA (180 \A mL, 1.80 mmol, 3 equiv) in DMF (1.5 mL) were added to the mixture after the tube was flushed with nitrogen. The tube was sealed and heated to 40 °C for 16 hours. The reaction mixture was then cooled to room temperature. The solvent was evaporated under reduced pressure and the the mixture was washed with Et20 to give 8 (142 mg, 0.338 mmol, 56%) as a yellow powder. aH-NMR (300 MHz): 8.23 (d, 1 H, J = 7.8 Hz), 7.84 (t,

1 H, J = 7.8 Hz), 7.73 (d, 1 H, J = 7.8 Hz), 7.73 (t, 1 H, J = 7.8 Hz), 5.87 (s, 1 H, H n ) , 5.71 (s, 1 H, H i r ) , 2.80 (s, 3 H, Hi3), 2.46 (s, 3 H, Hi4), 1.55 (s, 6 H, Hi 2) . 31P-NMR (121 MHz): -143.9 (sept,

Jp_F = 711Hz).

2-Benzyl-l,3,3-trimethyl-4-methylene-3,4,4a,8a-tetrahydro-isoquinolinium, hexafluoro phosphate (9) A sealed tube (15 mL) was charged with Pd(OAc)2 (11 mg, 0.050 mmol, 5 mol%), PPhi3 (26 mg, 0.100 mmol, 10 mol%) and K P F ó (552 mg, 3.00 mmol, 3 equiv). Imine 7 (335 mg, 1.00 mmol) and DMA (300 \d, 3.00 mmol, 3 equiv) in MeCN (5 mL) were added to the mixture after the tube was flushed with nitrogen. The tube was heated to 100 °C for 16 hours. The reaction mixture was then cooled to room temperature. The solvent was evaporated under reduced pressure and the product was dissolved in MeOH and washed several times with pentane. MeOH was removed in vacuo and 9 was dissolved in CH2CI2 and filtered over Celite. After precipitation by pentane and removal of the volatile solvents in vacuo, 9 (231 mg, 0.55 mmol, 55%) was obtained as a yellow solid. !H-NMR (300 MHz): 8.11 (d, 1 H, J = 8.0 Hz), 7.84 (t, 1 H, J = 7.5 Hz), 7.71-7.65 (m, 2 H), 7.40-7.30 (m, 3 H), 7.20 (d, 2 H, J = 7.5 Hz), 5.82 (s, 1 H, H n ) , 5.71 (s, 2 H, H14), 5.69 (s, 1 H, H i r ) , 3.16 (s, 3 H, H13), 1.72 (s, 6 H, H12). 13C-NMR (75 MHz): 184.8 (C7), 146.9, 142.8, 140.6, 137.6, 135.8, 135.1, 134.4, 133.4,

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2-BenzyI-4-cyclohexylmethyl-l-methyl-isoquinolinium, hexafluoro phosphate (10) The synthesis was carried out similar to 9. Starting from 7 (335 mg, 1.00 mmol), cyclohexylallene[56] (244 mg, 2.00 mmol, 2 equiv), KPF6 (552 mg, 3.00 mmol, 3 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 5 mol%) and PPh3 (26.2 mg, 0.100 mmol, 10 mol%), 10 (265 mg, 0.0656 mmol, 66%)

was obtained as an orange/brown solid. !H-NMR (300 MHz, CD3CN): 8.55 (s, 1 H, H 9), 8.53 (d, 1 H, J = 8.3 Hz), 8.21 (d, 1 H, J = 8.3 Hz), 8.13 (t, 1 H, J = 8.3 Hz), 7.96 (t, 1 H, J = 8.3 Hz), 7.6-7.1 (m, 5 H), 6.28 (s, 2 H, H14), 3.34 (s, 3 H, H13), 3.04 (d, 1 H, J = 6.8 Hz), 1.69 (m, 6 H), 1.15 (m, 5 H). 13C-NMR (75 MHz, CD3CN):

163.1, 141.8, 141.2, 140.9, 138.3, 137.4, 136.0, 134.4, 134.3, 134.1, 132.4, 130.1, 66.5, 43.3, 41.9, 37.8, 31.0, 30.9, 21.7. HRMS calcd. for C24H28N 330.2222, found 330.2231.

4-Cyclohexylmethyl-l-methyl-isoquinoline (11) A mixture of 10 (624 mg, 1.32 mmol), P d / C (10%, 200 mg) and NaHCC>3 (0.56 g, 6,67 mmol, 5 equiv) was suspended in MeOH (50 mL). The resulting mixture was stirred at room temperature under an atmosphere of H2 for 1 day. The solvent was removed under reduced pressure and the mixture was poured into Et2Ü (50 mL) and washed with saturated NH4CI (50 mL), dried (MgSC>4) and filtered. The solvent was removed under reduced pressure, and 11 (30 mg, 0.125 mmol, 10%) was obtaind as a light-yellow oil after flash chromatography (EtOAc / hexanes 25:75). ÏH-COSY NMR (300 MHz): 8.19 (s, 1 H, H9), 8.12 (d, 1 H, Ji_2 = 8.3 Hz, Hi), 7.98 (d, 1 H, J3.4 = 8.4 Hz, H4), 7.70 (ddd,

1 H, J3.4 = 8.3 Hz, J2-3 = 7.0 Hz, J .3 = 1.3 Hz, H3), 7.58 (ddd, 1 H, h-2 = 8.3 Hz, J2-3 = 7.0 Hz, J2-4

= 1.2 Hz, H2), 2.93 (s, 3 H, H13), 2.83 (d, 2 H, J n _ i2 = 6.8 Hz, Hn) , 1.69 (m, 6 H), 1.15 (m, 5 H). 13C-NMR (75 MHz): 156.5, 142.0 (C9), 134.9, 129.3, 128.3, 127.1, 126.1, 126.0, 123.7, 38.6 (Ci2),

37.7 (Cu), 33.3, 26.3, 26.0, 22.1 (C13). HRMS calcd. for C17H21N 239.1674, found 239.1685.

4-Benzyl-l-methyl-isoquinoline (12) The synthesis of 2,4-dibenzyl-l-methyl-isoquinolinium hexafluorophosphate was carried out similar to 9, starting from 7 (335 mg, 1.00 mmol), phenylallene[55] (232 mg, 2.00 mmol, 2 equiv), KPF6 (550 mg, 2.99 mmol, 3 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,

5 mol%) and PPh3 (26.2 mg, 0.100 mmol, 10 mol%). The isoquinolinium salt

was used for the following step without further purification. ÏH-NMR (300 MHz): 8.54 (d, 1 H, J = 8.5 Hz), 8.50 (s, 1 H, H9), 8.22 (d, 1 H, J = 8.2 Hz), 8.07 (t, 1 H, J = 8.2 Hz),

7.95 (t, 1 H, J = 8.5 Hz), 7.37-7.20 (m, 5 H), 6.29 (s, 2 H, NCH2Ph), 4.57 (s, 2 H, H n ) , 3.41 (s, 3 H,

H13). The isoquinolinium salt, NaHCC>3 (0.42 g, 5.0 mmol, 5 equiv) and P d / C (10%, 350 mg) were dissolved in MeOH (100 mL). The resulting mixture was allowed to stir at room