Synthesis of carbo- and heterocycles via palladium catalysed cascade allene insertion-nucleophile incorporation-Michael addition processes

Tetrahedron 63 (2007) 6152–6169

Synthesis of carbo- and heterocycles via palladium catalysed

cascade allene insertion–nucleophile incorporation–Michael

addition processes^*

a

Ronald Grigg,^a,Martyn Inman, Colin Kilner, Ines Koppen, John Marchbank,

*

€

Peter Selby^band Visuvanathar Sridharan^a

^aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry,

Leeds University, Leeds LS2 9JT, United Kingdom

^bSt James’s University Hospital, Leeds LS9 7TF, United Kingdom

Received 15 January 2007; revised 5 March 2007; accepted 6 March 2007

Available online 12 March 2007

Abstract—Novel palladium catalysed two- and three-component thermal (conventional heating and microwave) cascade processes are

described involving allenylation of an aryl iodide to generate a (p-allyl)palladium species, which are intercepted (inter- or intramolecularly)

by a carbon or nitrogen nucleophile followed by intramolecular Michael addition to afford carbo- and heterocycles in good yields.

1. Introduction

In this paper we explore the tactical combinations of palla-

dium catalysed allenylation cascades with Michael addition

processes as the key step.¹Such processes can be classiﬁed

into eight distinct classes depending on whether the forma-

tion of p-allyl species (from aryl iodide and allene), nucleo-

philic capture, and the Michael addition step are inter- or

intramolecular (Table 1). Thus the immense synthetic power

of the Michael addition¹¹undergoes startling multiplication

when linked to palladium catalysed multi-component pro-

cesses.¹²In this paper we report palladium catalysed two-

and three-component cascades.

In recent years allenes have become useful building blocks

in palladium catalysed processes.²We have demonstrated

that they are powerful relay switches in our palladium cata-

lysed cyclisation-anion capture cascades.³Reactions of aryl/

vinyl palladium(II) intermediates with allenes lead to the

formation of (p-allyl)palladium species, which undergo

a wide range of transformations, including transmetalla-

tion,⁶or attack by nucleophiles⁴or electrophiles.⁵The versa-

tility and power of relay switch components can be

substantially enhanced by interfacing their palladium cata-

lysed processes with 100% atom economic core organic re-

actions such as cycloadditions (1,3-dipolar and Diels–Alder

reactions), aldol reactions and Michael addition reactions.

We have developed a number of one-pot cascade protocols,

which employ several types of 1,3-dipoles and palladium

catalysed allenylation processes, including combinations

with azomethine ylide/azomethine imine/azide/nitrone cy-

cloaddition cascades^7,8and cascade palladium catalysed tet-

ramolecular queuing processes involving carbon monoxide

and/or allene as relay switches followed by 1,3-dipolar cy-

cloaddition, Diels–Alder reaction or Michael addition.^9,10

The above processes result in rapid access to molecules pos-

sessing a high degree of complexity, which would otherwise

require tedious and/or technically demanding multi-step

syntheses.

Initially we explored a process in which a Michael acceptor

is incorporated into the aryl iodide (Scheme 1), which might

proceed via a class 2 (path a) or class 3 (path b) mechanism.

The key distinction between path a and path b is whether

Michael addition precedes (path b) or follows (path a) the

Table 1. Synthetic strategies for allenylation/nucleophilic capture/Michael

addition cascade

Class p-Allyl formation Nucleophilic capture Michael addition

1

2

3

4

5

6

7

8

Intermolecular

Intramolecular

Intermolecular

Intramolecular

Intermolecular

Intramolecular

Intermolecular

Intramolecular

Intermolecular

Intramolecular

Intermolecular

Intramolecular

Intermolecular

Intramolecular

*

See Ref. 1.

* Corresponding author. Tel./fax: +44 113 343 6501; e-mail: r.grigg@leeds.

ac.uk

doi:10.1016/j.tet.2007.03.044

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6153

Table 3. Three component cascade of 4-methylenetetrahydroisoquinolines^a

EWG

YH

Entry Aryl

iodide

Nucleophile

Product

Yield^b(%)

Ar

path a

EWG

6a 76 (82)^e

6b 60 (78)^e

6c 66^c

EWG

N

EWG

Y

2

NH₂

1

2

3

4

5

6

5

Pd(0), allene, YH₂

EWG

Ar

6d 73 (69)^e

6e 60

Ar

X

1

4

path b

EWG

N

YH

Ar

7a 90

7b 58

7c 69^c

7d 87

7e 54

X = I, Br, OTf etc; Y = NR, CR¹R²

Scheme 1.

S

X

3

NH₂

S

5

8a 80 (71)^e

8b 49 (74)^e

8c 68^c

EWG

allenylation step. A series of dual aryl iodide/Michael accep-

tors 5a–e were prepared in excellent yields from the com-

mercially available 2-iodobenzaldehyde.

NH₂

N

5

8d 80 (70)^e

8e 69

EWG

N

NH₂

5a

9a 62

I

a. EWG = COPh (trans)

5

b. EWG = CN (2:1 cis:trans)

c. EWG = NO₂(trans)

EWG

N

d. EWG = CO₂Me (1:5 cis:trans)

e. EWG = SO₂Ph (trans)

10a 72^d

10d 74^d

10e 72^d

5a,d,e

NH₂

An initial solvent, base, catalyst screening was carried out

using substrate 5a, allene (1 bar) and benzylamine (2.00 mol

equiv) (Table 2). The appearance of characteristic exo-

EWG

1

H₂N

N

methylene signals at d 4.93 and 5.69 ppm in the H NMR

N

5d

11d 71^d

spectrum of 6a indicated that allene had been successfully

incorporated. The highest yield of product 6a (Table 2, entry

1), was obtained in toluene. Varying the catalyst and base

had little effect (entries 6–8) on the yield of 6a. Substrates

5b–e were then reacted with Pd(OAc)₂(0.10 mol equiv),

PPh₃(0.20 mol equiv), amine (2.00 mol equiv) and allene

(1 bar) in toluene at 80 ^ꢀC for 18–36 h (Table 3) to afford

tetrahydroisoquinolines in moderate to excellent yields.

OMe

EWG

12a (78)^e

12b (68)^e

12d (87)^e

O

S

O

Ts

N

7

5a,b,d

NH₂

a

Pd(OAc)₂

(2.00 mol equiv), amine (2.00 mol equiv) and allene (1 bar) in toluene

(0.10 mol equiv),

PPh₃

(0.20 mol equiv),

K₂CO₃

The range of electron withdrawing groups examined, dem-

onstrates the robustness of this process with respect to vari-

ations of the Michael acceptor. However 5c (EWG¼NO₂)

requires a phosphine free catalyst system and palladacycle

13¹³was found to be an excellent substitute. A possible

explanation for this observation, is that PPh₃undergoes

at 80 ^ꢀC for 36 h.

Isolated yield.

b

c

Palladacycle 13 (0.05 mol equiv) was used instead of Pd(OAc)₂and PPh₃

(18 h).

d

e

Ratio of diastereoisomers (1:1).

Pd₂dba₃

(0.025 mol equiv),

TFP

(0.10 mol equiv),

K₂CO₃

(2.00 mol equiv), amine (1.20 mol equiv) and allene (0.2 bar) in toluene

under microwave irradiation at 100 ^ꢀC for 20 min.

Table 2. Optimisation of the palladium catalysed allene insertion–nucleo-

philic capture–Michael addition cascade^a,b

Entry

Solvent

Catalyst

Time (h)

Yield^c(%)

conjugate addition to the a,b-unsaturated nitro group. The

diastereoselectivity of the Michael addition has been brieﬂy

investigated. Thus using R-(+)-a-methylbenzylamine

afforded 10 as a 1:1 mixture of diastereoisomers (Table 3,

entry 5), whereas SAMP afforded 11 as a 2:1 diastereomeric

mixture. Recently Desmaele have reported related processes

in which p-allylpalladium(II) species are generated from

allylic acetates.¹⁴

1

2

3

4

5

6

7

8^d

Toluene

1,4-Dioxane

DMF

THF

MeCN

Toluene

Pd(OAc)₂

Pd(PPh₃)₄

Pd₂dba₃

36

18

36

76

32

65

36

53

67

71

75

Pd(OAc)₂

a

Catalyst (0.10 mol equiv), PPh₃(0.20 mol equiv), allene (1 bar), benzyl-

amine (2.00 mol equiv) and K₂CO₃(2.00 mol equiv).

Reactions were carried out in a Schlenk tube at 80 ^ꢀC.

Isolated yield.

Microwave acceleration was brieﬂy explored. A selection of

compounds were synthesised under modiﬁed conditions, us-

ing microwave irradiation with the reaction time reduced to

b

c

d

Cs₂CO₃(2.00 mol equiv) used as base.

6154

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

20 min, in comparable yield (Table 3, entries 1 and 3) to ther-

mal conditions. p-Toluenesulfonamide was also used as a

nucleophile under microwave conditions to yield 12a,b and

d (Table 3, entry 7).

show that the choice of path a or path b is, perhaps, inti-

mately connected with the type of Michael acceptor and sug-

gests that when benzylamine is used, the least reactive

Michael acceptors SO₂Ph, CN and CO₂Me react via path

a (class 2) whilst the more reactive Michael acceptors NO₂

and COPh react via path b (class 3). Caution must be applied

to this interpretation as the Michael addition is probably re-

versible and the relative rates of the Scheme 1 steps are not

known. In all cases 6a–6e were obtained when allene was

added to the crude material and the mixture recycled through

the standard cascade reaction conditions.

Successful utilisation of amines led us to investigate whether

carbon pronucleophiles could be incorporated into the cas-

cade. Thus exposure of 5a to Pd(OAc)₂(0.10 mol equiv),

PPh₃(0.20 mol equiv), dimethyl malonate (2.00 mol equiv),

allene (1 bar) and Cs₂CO₃(2.00 mol equiv) in MeCN at

50 ^ꢀC furnished the carbocycle 14a with a tetra-substituted

carbon centre in 62% yield (Table 4, entry 1). This method-

ology was then extended to diethyl malonate, malononitrile

and bisbenzenesulfonyl methane as pronucleophiles (Table

4, entries 1–3). Finally, on the carbocyclic theme, we

employed dimedone as the pronucleophile to synthesise

spirocyclic compounds 17a and 17d in 56–64% yields

(Table 4, entry 4).

EWG

NHPh

F

S

N

AcO

I

Pd

a. EWG = COPh

c. EWG = NO₂

18

2

13

Next we brieﬂy explored examples of Scheme 2 processes,

which potentially could proceed via a class 4 process (path

a) or class 7 process (path b) (Table 5). To study this we teth-

ered the amine and allene in one component and aryl iodide

and Michael acceptor in another component. Tethering two

of the compounds used in the cascade reactions offsets diver-

sity for a rapid increase in the molecular complexity of the

product, through the formation of additional rings and ster-

eocentres. Thus dual aryl iodide/Michael acceptor 1 reacts

with dual allene–amine 19 in the presence of palladium(0)

to afford tricyclic heterocycles 22 either via path a (class

4) or path b (class 7) (Scheme 2).

Table 4. Three component cascade synthesis of 4-methylenetetrahydro-

naphthalenes^a

Entry Aryl iodide Nucleophile

Product

Yield^b(%)

EWG

CO₂Me

14a 62

14d 49^d

14e 47

CO₂Me

1

2

5a,d,e

CO₂Me

EWG

CN

5d

15d 42

EWG

SO₂Ph

16a 52^c

16d 60^d

SO₂Ph

HN

3

5a,d

H₂N

Ar

path a

EWG

20

Pd

EWG

N

17a 56

EWG

O

17d 64^d

O

Pd(0)

Ar

+

NH₂

Ar

4

X

1

19

22

EWG

O

EWG

H

N

H

N

path b

a

Pd(OAc)₂(0.10 mol equiv), PPh₃(0.20 mol equiv), pronucleophile

(2.00 mol equiv), allene (1 bar), Cs₂CO₃(2.00 mol equiv) and MeCN at

50 ^ꢀC for 18 h.

Ar

I

b

c

d

Pd

Isolated yield.

Experiment performed at 60 ^ꢀC.

Experiment performed at 110 ^ꢀC in toluene.

21

Scheme 2.

2. Mechanism

The aminoallene 27 was synthesised in four steps from the

acetal 23 (Scheme 3).^15,16

To distinguish between path a (class 2) and path b (class 3)

(Scheme 1), the cascade was repeated in the absence of

allene using benzylamine as the representative nucleophile.

Importantly, the inclusion of Pd(OAc)₂and PPh₃was main-

tained due to the possibility of a Pd(II) species acting as

a Lewis acid, potentially activating the Michael acceptor to-

wards addition. Aryl iodides 5a and 5c afforded the Michael

addition intermediates 18a and 18c. With less reactive

Michael acceptors 5b, 5d and 5e only starting material was

observed in the ¹H NMR spectrum. These observations

The key step was the use of Crabbe reaction to synthesise the

allene 24.¹⁵Reaction of 27 (2.00 mol equiv) with aryl iodide

5b in the presence of Pd(OAc)₂(0.10 mol equiv), PPh₃

(0.20 mol equiv) and K₂CO₃(4.00 mol equiv) in toluene at

80 ^ꢀC over 18 h afforded the desired tricyclic product 29

in 67% yield as a 1:2 mixture of syn/anti diastereoisomers

(Table 5, entry 1). The stereochemistry of the major isomer of

29 was unequivocally established by an X-ray crystal struc-

ture (Fig. 1).¹⁷Utilisation of 27 as a key reactant militates

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

Table 5. Palladium catalysed synthesis of tetrahydroisoquinolines using 27^a

6155

Entry Aryl Allene/

iodide nucleophile

Product

Yield^b(%)

COPh

1

2

3

5a

5b

5e

27

N

44 anti only

NTs

28

CN

N

67 anti/syn 2:1

52 anti/syn 1:1

NTs

29

SO₂Ph

N

Figure 1. X-ray crystal structure of 29 (major isomer).

NTs

30

O

NH₂.TFA salt

NHBOC

TFA, 0 °C-rt, 0.5 h

OH

a

Pd(OAc)₂(0.1 mol equiv), PPh₃(0.2 mol equiv), 27 (2 mol equiv) and

K₂CO₃(4.0 mol equiv) in toluene at 80 ^ꢀC over 36 h.

Isolated yield.

3 steps

b

HO

CO₂Me

98%

O

CO₂Me

against path b as it involves formation of a nine-membered

ring in 21 (Scheme 2). Two other aryl iodides 5a and 5e

were also investigated in this cascade (Table 4, entries 1 and

3). When dual aryl iodide/Michael acceptor 5a was employed

in the cascade, only anti-isomer 28 was observed (Table 5,

entry 1). This may be due to a retro Michael–Michael

addition equilibration sequence to give the anti-isomer 28.

32

98%

31

Scheme 4.

and allene (1 bar) in acetonitrile at 50 ^ꢀC for 18 h, afforded

the desired product 33 in 47% yield as a 4.7:1 mixture of dia-

stereoisomers (Scheme 5). The stereochemistry of the major

isomer was established from NOE studies. A positive

enhancement of only H-(2) after irradiation of H-(12) was

indicative of the stereochemistry shown in Scheme 5.

An alternative three-component tethering strategy, which in-

corporates a further Michael addition reaction and employs

a dual nucleophile–Michael acceptor 32, shown in Scheme

5, which was synthesised in ﬁve steps from commercially

available trans-b-muconic acid 31 (Scheme 4).¹⁶The addi-

tional Michael acceptor can in theory be attached to any

one of the components utilised in the cascade (i.e., aryl

iodide, allene or nucleophile).

In summary, a novel 3-component palladium catalysed al-

lene insertion–nucleophile incorporation–Michael addition

cascade has been developed. This methodology is a powerful

tool for the synthesis of novel tetrahydroisoquinolines and

tetrahydronaphthalenes. The mechanism of this process is

strongly inﬂuenced by the choice of Michael acceptor.

When the amine and allene components are tethered, novel

Exposure of aryl iodide 5c and amine salt 32 (3.00 mol equiv)

to palladacycle 13 (0.05 mol equiv), K₂CO₃(6.00 mol equiv)

ⁱPr₂NH, HCHO, CuI

1,4 dioxand reflux, 18 h

1:2:1 TFA/CHCl₃/H₂O

NTs

40 °C, 2 h

NTs

O

24

O

23

68%

63%

O

25

NH₂OH.HCl,

MeOH, 80 °C

LiAlH₄, Et₂O, 0 °C-rt

NTs

47%

68%

NH₂

N

HO

27

26

Scheme 3.

6156

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

MeO₂C

O₂N

methyl(triphenylphosporanylidene)cyanide (3.01 g, 10.00

mmol) in benzene (20 ml) was heated at 80 ^ꢀC for 36 h.

The solvent was then evaporated under reduced pressure

and the residue partitioned between ether (20 ml) and water

(20 ml). The two layers were separated and the aqueous layer

was extracted with ether (2ꢁ10 ml). The combined organic

extracts were washed with brine (10 ml), dried (MgSO₄)

and the solvent evaporated under reduced pressure. The crude

product was puriﬁed by column chromatography eluting with

2:3 v/vether/petrol to afford theproduct (5b) (2.09 g, 82%)as

a colourless oil, which comprised of a 2:1 mixture of Z/E-

isomers. (Found: C, 42.50; H, 2.35; N, 5.40; I, 50.10;

C₉H₆NI requires C, 42.40; H, 2.40; N, 5.40; I, 49.80%);

NO₂

+

NH₂.TFA salt

palladacycle 13, K₂CO₃

MeCN, 40 °C

-

+

N

I

5c

CO₂Me

10.5%

H

2

H

O₂N

H

CO₂Me

12

N

n/max (ﬁlm) 3056, 2218, 1611, 1581, 1462 and 1432 cm^ꢂ1

m/z (%) (ES) 279 (MNa⁺, 40), 219 (22) and 213 (18).

;

33

4.7:1 mixture of diastereoisomers

(major isomer shown)

E-(5b): d_H(250 MHz, CDCl₃), 7.92 (1H, dd, J 8.2 and

0.9 Hz, ArH), 7.68 (1H, d, J 16.4 Hz, ArCH]CH), 7.49

(1H, dd, J 7.9 and 1.6 Hz, ArH), 7.39 (1H, d, J 7.9 and

0.9 Hz, ArH), 7.11 (1H, td, J 8.2 and 1.6 Hz, ArH), 5.79

(1H, d, J 16.4 Hz, ArCH]CH).

Scheme 5.

tricyclic tetrahydroisoquinolines are afforded in moderate

yields. Furthermore, an additional Michael addition reaction

has been successfully incorporated into the cascade se-

quence, forming four bonds, three stereocentres and two

rings in moderate yield. The importance, in certain cases,

of phosphine free catalyst systems employing palladacycles

as precursors of Pd(0) nanoparticles is described.

Z-(5b): d_H(250 MHz, CDCl₃), 7.96–7.92 (2H, m, 2ꢁArH),

7.46 (1H, t, J 8.2 Hz, ArH), 7.34 (1H, d, J 11.9 Hz, CH¹),

7.12 (1H, td, J 8.2 and 1.6 Hz, ArH), 5.57 (1H, d,

J 11.9 Hz, CH²).

3.1.2. 1-Iodo-2-[(E)-2-nitrovinyl]benzene (5c). A stirred

mixture of 2-iodobenzaldehyde (1.00 g, 4.3 mmol, 1.0

mol equiv), nitromethane(0.23 ml,4.30 mmol,1.0 mol equiv)

and anhydrous ammonium acetate (0.40 g, 5.20 mmol,

1.20 mol equiv) in glacial acetic acid (4 ml) was heated under

reﬂux for 30 min. The solvent was then evaporated under

reduced pressure. The crude product was puriﬁed by crystalli-

sation from methanol to afford the product (5c) (0.72 g, 61%)

as yellow prisms, mp 105–107 ^ꢀC. (Found: C, 34.90; H, 2.15;

N, 5.20; I, 46.20; C₈H₆NO₂I requires C, 34.90; H, 2.20; N,

5.10; I, 46.10%); n/max (Nujol mull) 1630, 1576, 1556, 1336

and1284 cm^ꢂ1;d_H(250 MHz, CDCl₃),8.29(1H,d,J13.5 Hz,

ArCH]CH), 7.97 (1H, dd, J 8.0 and 6.9 Hz, ArH), 7.54 (1H,

dd, J 7.8 and 1.6 Hz, ArH), 7.49–7.40 (2H, m, 1ꢁArH+

ArCH]CH), 7.17 (1H, td, J 7.8 and 1.6 Hz, ArH); m/z (%)

275 (M⁺, 13), 229 (86), 148 (48), 102 (100) and 75 (36).

3. Experimental

3.1. General

Microwave reactions were carried out in a CEM Discover

microwave reactor operating at 300 W. Melting points

were determined on a Reichert hot-stage apparatus and are

uncorrected. Mass spectral data were obtained from a VG

Autospec instrument operating at 70 eV (EI and FAB) or

ZD 2000 electrospray instrument (ES). Accurate molecular

masses were obtained from the EPSRC Swansea Mass Spec-

troscopy service using perﬂuorotributylamine or polyethyl-

enimine as an internal standard. Microanalyses were obtained

using a Carbo Erba MOD11016 instrument. IR spectra were

determined on a Nicolet Magna FT-IR 560 spectrometer.

The IR samples were prepared as thin ﬁlms by evaporation

of a solution of the compound in DCM onto a germanium

plate. Nuclear magnetic resonance spectra were recorded

on Bruker DPX250, DPX300 and DPX500 instruments op-

erating at 250, 300 and 500 MHz, respectively. The follow-

ing abbreviations are used: s¼singlet, d¼doublet, t¼triplet,

q¼quartet, q_i¼quintet, m¼multiplet, dd¼doublet of dou-

blets, ddd¼double doublet of doublets, ddt¼double doublet

of triplets, br¼broad. Solvents were dried according to

established methods, unless purchased dry from Aldrich in

sure-seal bottles. The term ether refers to diethyl ether and

the term petrol refers to the 40–60 ^ꢀC boiling point fraction

of petroleum ether. All the compounds are named according

to the IUPAC system and names were obtained using the

ACD/i-Lab software version 4.5. Compound 5a was pre-

pared by the literature method.¹⁹

3.1.3. Methyl 2-iodocinnamate (5d). A solution of 2-iodo-

benzaldehyde (2.11 g, 9.10 mmol) in dry dichloromethane

(25 ml) was added in one portion to a stirred solution of

carbomethoxymethylene triphenylphosphorane (3.56 g,

10.60 mmol) in dry dichloromethane (50 ml) at rt. The

resulting mixture was stirred for 16 h and concentration in

vacuo gave the crude product. Column chromatography elut-

ing with 9:1 v/v petroleum ether/ether afforded the product

(93%, 1:5 mixture of cis and trans isomers) as a light yellow

oil. The ¹H NMR spectra of both isomers were assigned from

the mixture of diastereoisomers.

trans-isomer: d_H(250 MHz, CDCl₃), 7.92–6.96 (m, 5H,

4ꢁArH and ArCH]), 6.31 (d, 1H, J 15.9 Hz, ]CHCO)

and 3.82 (s, 3H, OMe).

cis-isomer: d_H(250 MHz, CDCl₃), 7.92–6.96 (m, 5H,

4ꢁArH and ArCH]), 6.02 (d, 1H, J 11.8 Hz, ]CHCO)

and 3.64 (s, 3H, OMe).

3.1.1. 3-(2-Iodophenyl)acrylonitrile (5b). A stirred

mixture of 2-iodobenzaldehyde (2.32 g, 10.00 mmol) and

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6157

3.1.4. (E)-2-(2-Iodophenyl)vinyl phenyl sulfone (5e).

n-Butyllithium (3.44 ml, 5.50 mmol, 1.6 M solution in

hexanes, 1.10 mol equiv) was added dropwise over 30 min,

to a stirred solution of (phenylsulfonylmethyl)trimethylsil-

ane (1.14 g, 5.00 mmol, 1.00 mol equiv) in ethylene glycol

dimethyl ether (25 ml) under nitrogen at ꢂ78 ^ꢀC. After

20 min at ꢂ78 ^ꢀC, 2-iodobenzaldehyde (1.16 g, 5.00 mmol,

1.00 mol equiv) in ethylene glycol dimethyl ether (5.0 ml)

was added dropwise over 10 min and the mixture allowed

to reach rt. After 4 h at rt the mixture was quenched with

saturated aqueous ammonium chloride (5 ml). The solvent

was evaporated under reduced pressure and the residue par-

titioned between ether (20 ml) and water (20 ml). The two

layers were separated and the aqueous layer was extracted

with ether (2ꢁ10 ml). The combined organic extracts were

washed with brine (20 ml), dried (MgSO₄) and the solvent

evaporated under reduced pressure. The residue was puriﬁed

by column chromatography eluting with 2:3 v/v ether/petrol,

to afford the E-product (5e) (1.13 g, 61%) as a pale yellow

amorphous solid, mp 62–64 ^ꢀC. (Found: C, 45.40; H,

3.05; I, 34.10; C₁₂H₁₁SO₂I requires C, 45.40; H, 3.00; I,

34.30%); n/max (Nujol mull) 1608, 1580, 1209 1145 and

1083 cm^ꢂ1; d_H(250 MHz, CDCl₃), 8.01–7.89 (4H, m,

3ꢁArH+ArCH]CH), 7.69–7.54 (3H, m, 3ꢁArH), 7.46

(1H, dd, J 7.8 and 1.7 Hz, ArH), 7.35 (1H, t, 7.6 Hz, ArH),

7.08 (1H, td, J 7.8 and 1.7 Hz, ArH), 6.75 (1H, d, J

15.3 Hz, ArCH]CH); m/z (%) (ES) 371 (MH⁺, 22), 340

(18), 308 (48) and 243 (20).

to the tube via a needle, and the mixture was heated to

100 ^ꢀC for 20 min. Upon cooling, CHCl₃(2 ml) was added

and the mixture was ﬁltered, concentrated and puriﬁed by

column chromatography to afford the product.

3.4.1. 2-(2-Benzyl-4-methylene-1,2,3,4-tetrahydroisoqui-

nolin-1-yl)-1-phenyl-ethanone (6a).

6'

5'

4'

3'

1'

O

1

1''

8

8a

4a

2''

7

6

N

3

5

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and benzylamine (214 mg, 2.00 mmol) gives

the product (6a) (268 mg, 76%) as a yellow oil. (Found: C,

84.70; H, 6.60; N, 4.00; C₂₅H₂₃NO requires C, 84.90; H,

6.55; N, 4.00%); n/max (ﬁlm) 3061, 1682, 1629, 1597 and

1448 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.95–7.91 (2H, m,

0

2ꢁH⁴), 7.69 (1H, dt, J 9.3 a₀nd 3.6 Hz, 2ꢁArH⁵), 7.53

0

(1H, tt, J 7.4 and 1.3 Hz, ArH⁶), 7.45–7.4 (2H, m, ArH⁵),

7.25–7.11 (8H, m, 8ꢁArH), 5.69 (1H, t, J 1.0 Hz, ]CH),

4.93 (1H, t, J 1.0 Hz, ]CH), 4.57 (1H, dd, J 8.6 and

5.5 Hz, CH¹), 3.91 (1H, dt, J 15.5 and 1.8 Hz, CH³), 3.64

00

(1H, d, J 13.1 Hz, CH¹), 3.63 (1H, dd, J 15.5 and 8.6 Hz,

0

00

CH¹), 3.56 (1H, d, J 13.1 Hz, CH¹), 3.25 (1H, ₀d, J

15.5 Hz, CH³), 3.17 (1H, dd, J 15.5 and 5.5 Hz, CH¹); d_C

3.2. General procedure for the three-component

allenylation/amination/Michael addition cascade using

(5a, 5b, 5d and 5e)

0

00

0

(126 MHz, CDCl₃), 198.5 (C²), 138.8 (C²), 137.4 (C³),

0

136.8 (C]), 136.2 (C^8a), 132.9 (C⁶), 132.3 (C^4a), 129.0,

128.6, 128.3, 128.2, 128.0, 127.8, 126.9, 126.8, 123.6 (C⁵₀),

00

109.7 (]CH₂), 59.5 (C¹), 58.0 (C¹), 49.5 (C³), 45.3 (C¹);

m/z (%) (FAB) 353 (M⁺, 11), 262 (16) and 234 (100).

A mixture of aryl iodide (1.00 mmol, 1.00 mol equiv), amine

(2.00 mmol, 2.00 mol equiv), potassium carbonate (276 mg,

2.00 mmol, 2.00 mol equiv), palladium acetate (22 mg,

0.10 mmol, 0.10 mol equiv), triphenylphosphine (52 mg,

0.20 mmol, 0.20 mol equiv) and toluene (10 ml) in a Schlenk

tube was subjected to two freeze-pump-thaw cycles. Allene

gas was then added (1 bar) and the reaction mixture was then

heated at 80 ^ꢀC for 36 h. After cooling to rt, excess allene gas

was carefully vented, the reaction mixture ﬁltered and the

solids washed with ether (3ꢁ50 ml). The combined organic

ﬁltrates were dried (MgSO₄) ﬁltered and the ﬁltrate evapo-

rated under reduced pressure. The residue was puriﬁed by

column chromatography eluting with 2:3 v/v ether/petrol.

3.4.2. (2-Benzyl-4-methylene-1,2,3,4-tetrahydroisoqui-

nolin-1-yl)-acetonitrile (6b).

2'

NC

1'

8

1''

¹N

3

8a

2''

7

6

4a

5

Prepared by the general procedure from (5b) (255 mg,

1.00 mmol) and benzylamine (214 mg, 2.00 mmol). Column

chromatography afforded the product (6b) (165 mg, 60%) as

a pale yellow oil. (Found: C, 83.00; H, 6.70; N, 10.40;

C₁₉H₁₉N₂requires C, 82.90; H, 6.95; N, 10.20%); n/max

(ﬁlm) 3062, 2248, 1697, 1672, 1631 and 1598 cm^ꢂ1; d_H

(500 MHz, CDCl₃), 7.72–7.69 (1H, m, CH⁵), 7.39–7.37

(2H, m, 2ꢁArH), 7.35–7.31 (2H, m, 2ꢁArH), 7.30–7.26 (3H,

m, 3ꢁArH), 7.10–7.07 (1H, m, ArH⁸), 5.71 (1H, d, J 1.6 Hz,

]CH), 5.02 (1H, d, J 1.6 Hz, ]CH), 4.08 (1H, dd, J 9.2 and

5.6 Hz, CH¹), 3.86 (1H, dt, J 15.7 and 1.8 Hz, CH³), 3.75 (1H,

3.3. General procedure for the three-component all-

enylation/amination/Michael addition cascade using (5c)

As above but the reaction was run for 18 h at 80 ^ꢀC.

3.4. General procedure for microwave-accelerated

three-component allenylation/amination/Michael

addition cascade

00

Aryl iodide (0.50 mmol, 1 equiv), nucleophile (0.60 mmol,

1.2 equiv), Pd₂dba₃(0.0125 mmol, 2.50 mol %), tri-2-furyl-

phosphine (0.05 mmol, 0.10 equiv, K₂CO₃(1.0 mmol,

2.00 equiv) and toluene (2 ml) were combined in a 5 ml

microwave tube with a magnetic stirrer bar. The tube was

sealed with a septum and degassed via a needle through

two freeze-pump-thaw cycles. Allene (0.2 bar) was charged

d, J 13.3 Hz, CH¹), 3.64 (1H, d, J 13.3 Hz, CH¹), 3.40 (1H,

0

d, J 15.7, CH³), 2.88 (1H, dd, J 16.9 and 9.2 Hz, CH¹), 2.67

0

(1H, dd, J 16.9 and 5.6 Hz, CH¹); d_C(126 MHz, CDCl₃),

00

138.2 (C²), 136.0 (C⁴), 133.1 (C^8a), 132.4 (C^4a), 129.₀0,

128.6 (C⁸), 128.4, 127.8, 127.4, 124.0 (C⁵), 118.2 (C²),

00

0

110.5 (]CH₂), 58.3 (C¹), 58.0 (C¹), 50.0 (C³), 24.7 (C¹);

m/z (%) (ES) 297 (MNa⁺, 100).

6158

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

3.4.3. 2-Benzyl-4-methylene-1-(nitromethyl)-1,2,3,4-tet-

rahydroisoquinoline (6c).

Prepared by the general procedure from (5e) (370 mg,

1.00 mmol) and benzylamine (214 mg, 2.00 mmol). Column

chromatography afforded the product (6e) (212 mg, 60%) as

a colourless oil. (Found: C, 74.10; H, 6.20; N, 3.80;

C₂₄H₂₃NO₂S requires C, 74.00; H, 5.95; N, 3.60%); n/max

O₂N

1''

1'

8

1

2'

8a

7

6

(ﬁlm) 3055, 1599, 1345, 1265 and 1165 cm^ꢂ1; d_H

N

0

(500 MHz, CDCl₃), 7.96–7.94 (2H, m, CH⁴), 7.65–7.59

3

4a

5

0

(2H, m, 2ꢁArH⁵and ArH⁸), 7.53–7.49 (2H, m, 2ꢁArH⁵),

7.30–7.22 (5H, m, 5ꢁArH), 7.17–7.15 (2H, m, 2ꢁArH),

7.11–7.09 (1H, m, ArH), 7.66 (1H, d, J 1.5 Hz, ]CH),

Prepared by the general procedure from (5c) (275 mg,

1.00 mmol) and benzylamine (214 mg, 2.00 mmol). Column

chromatography afforded the product (6c) (182 mg, 62%) as

a pale yellow oil. (Found HRMS: 295.1450; C₁₈H₁₈N₂O₂

(MH⁺) requires 295.1446); n/max (ﬁlm) 3029, 1634, 1601,

1555, 1494 and 1483 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.73–

7.71 (1H, m, ArH), 7.33–7.21 (7H, m, ArH), 7.12–7.09

4.86 (1H, d, J 1.5 Hz, ]CH), 4.49 (1H, dd, J 9.1 and

3.4 Hz, CH¹), 3.81 (1H, dd, J 15.0 and 9.1 Hz, CH¹), 3.58

0

00

(2H, 2ꢁd, J 13.2 Hz, 2ꢁCH¹), 3.47 (1H,₀d, J 15.9 Hz,

CH³), 3.32 (1H, dd, J 15.0 and 3.4 Hz, CH¹), 3.06 (1H, d,

0

J 15.9 Hz, CH³); d_C(126 MHz, CDCl₃), 140.5 (C³), 138.0

00

(C²), 135.7 (C^4a), 133.5 (]C), 133.4 (C⁵), 132.3, 129.4,

129.1, 128.8, 128.2, 128.1, 127.7, 127.5, 127.2, 123.6 (C⁸),

(1H, m, ArH), 5.73 (1H, d, J 1.7 Hz, ]CH), 5.02 (1H, d, J

1.7 Hz, ]CH), 4.79 (1H, dd, J 11.9 and 11.2 Hz, CH¹),

4.59 (1H, dd, J 1₀1₀.2 and 4.5 Hz, CH¹), 4.49 (1H, dd, J 11.9

0

00

110.6 (CH₂), 61.5 (C¹), 61.0 (C¹), 58.7 (C¹), 48.0 (C³);

m/z (%) (FAB) 353 (M⁺, 11), 262 (16) and 234 (100).

and 4.5 Hz, CH¹), 3.89 (1H, dt, J 15.8 and 1.7 Hz, CH³₀),

0

3.72 (1H, d, J 13.2 Hz, CH¹), 3.61 (1H, d, J 13.2 Hz, CH¹),

3.4.6. 2-(4-Methylene-2-thiophen-2-ylmethyl-1,2,3,4-tet-

rahydroisoquinolin-1-yl)-1-phenyl-ethanone (7a).

3.33 (1H, d, J 15.8 Hz, CH³); d_C(126 MHz, CDCl₃), 138.1

0

(C²), 135.6 (]C), 133.3 (C^4a), 130.2 (C^8a), 129.0, 128.7,

6'

5'

128.3, 1₀2₀8.1, 127.7, 127.4, 124.2 (C⁸), 111.1 (]CH₂),

0

78.6 (C¹), 60.4 (C¹), 57.8 (C¹), 49.1 (C³); m/z (%) (CI)

4'

3'

295 (MH⁺, 4), 250 (29), 236 (100), 230 (28) and 144 (52).

1'

O

1''

3''

8

1

3.4.4. Methyl (2-benzyl-4-methylene-1,2,3,4-tetrahydro-

1-isoquinolinyl)-acetate (6d).

2''

8a

4a

7

6

N

3

4''

S

5''

5

MeO₂C

N

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and 2-thiophenemethylamine (226 mg,

2.00 mmol). Column chromatography afforded the product

(7a) (323 mg, 90%) as a pale yellow gum. (Found: C,

76.60; H, 5.80; N, 3.80; C₂₃H₂₁NOS requires C, 76.90; H,

5.90; N, 3.90%); n/max (ﬁlm) 3064, 2917, 1682, 1597,

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and benzylamine (214 mg, 2.00 mmol). Column

chromatography afforded the product (6d) (73%) as a pale

yellow oil. (Found: C, 77.90; H, 7.05; N, 4.70; C₂₀H₂₁NO₂

requires C, 78.15; H, 6.90; N, 4.55%); IR (ﬁlm) 3028,

2949, 1739 and 1436 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.70

(1H, dd, J 6.0 and 4.2 Hz, ArH), 7.34–7.22 (7H, m,

7ꢁArH), 7.09 (1H, dd, J 5.1 and 3.2 Hz, ArH), 5.70 (1H,

d, J 1.5 Hz, CH₂]), 4.96 (1H, t, J 0.9 Hz, CH₂]), 4.30

(1H, dd, J 10.3 and 4.8 Hz, CH), 3.91 (1H, ddd, J 15.8, 1.5

and 0.9 Hz, CCH₂N), 3.69 (3H, s, CO₂Me), 3.67 and 3.57

(2ꢁ1H, AB, 2ꢁd, J 13.2 Hz, NCH₂Ph), 3.28 (1H, dd, J

15.8 and 1.5 Hz, CCH₂N), 2.89 (1H, dd, J 14.5 and

10.3 Hz, CH₂CO), 2.65 (1H, dd, J 14.5 and 4.8 Hz,

CH₂CO); m/z (EI) (%) 307 (M⁺, 1), 234 (100) and 91 (95).

1481 and 1448 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.97–7.93

0

(2H, m, ArH⁴), 7.71–7.68 (1H, m, ArH⁵), 7.55 (1H, t, 7.9,

0

ArH⁶), 7.45 (2H, t, J 7.9 Hz, ArH⁵), 7.25–7.21 (2H, m,

00

ArH⁸and ArH), 7.17–7.15 (2H, m, ArH⁵and ArH), 6.86

00

(1H, dd, J 5.1 and 3.3 Hz, ArH⁴), 6.76 (1H, d, J 3.3 Hz,

00

CH³), 5.7 (1H, s, ]CH), 4.98 (1H, t, J 0.8 Hz, ]CH),

4.63 (1H, t, J 7.2 Hz, CH¹), 3.94 (1H, d, J 15.6 Hz, CH³),

00

3.86₀₀(1H, d, J 13.8 Hz, CH¹), 3.75 (1H, dd, J 13.8 Hz,

0

CH¹), 3.63 (1H, dd, J 15.5 and 7.2 Hz, CH¹), 3.39 (1H, ₀d,

J 15.6 Hz, CH³), 3.21 (1H, dd, J 1₀5.5 and 7.2 Hz, CH¹);

00

d_C(126 MHz, CDCl₃), 198.4 (C²), 143.0 (C²), 137.4

0

(C³), 136.5 (C]), 136.0 (C^8a), 132.9 (C⁶), 132.2 (C^4a),

0

128.5 (C⁴), 128.4 (C^{(6 or 7)}), 128.3 (C⁵), 127.9 (C⁸), 126.9

00

(C⁵), 126.2 (C³), 125.6 (C⁴), 125.0 (C⁽⁶

⁷⁾), 123.6

or

00

(C⁵), 110.0 (]CH₂), 59.0 (C¹), 52.7 (C¹), 49.8 (C³), 45.6

3.4.5. 1-Benzenesulfonylmethyl-4-methylene-2-benzyl-

1,2,3,4-tetrahydroisoquinoline (6e).

0

(C¹); m/z (%) (FAB) 360 (MH⁺, 34), 262 (22) and 240 (100).

6'

5'

3.4.7. (4-Methylene-2-thiophen-2-ylmethyl-1,2,3,4-tetra-

hydroisoquinolin-1-yl)-acetonitrile (7b).

4'

3'

O₂S

NC

1'

8

1''

8

1

1''

3''

5''

¹N

8a

2''

7

6

7

6

N

3

4''

S

3

4a

5

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6159

Prepared by the general procedure from (5b) (255 mg,

1.00 mmol) and 2-thiophenemethylamine (226 mg,

2.00 mmol). Column chromatography afforded the product

(7b) (162 mg, 58%) as a colourless oil. (Found HRMS:

281.1111; C₁₇H₁₇N₂S (MH⁺) requires 281.1112); n/max

(ﬁlm) 3069, 2249, 1632, 1570, 1484 and 1446 cm^ꢂ1; d_H

(7d) (87%) as a pale yellow liquid. (Found: C, 69.10; H,

6.05; N, 4.60; S, 10.30; C₁₈H₁₉NO₂S requires: C, 69.00;

H, 6.10; N, 4.45; S, 10.25%); IR (ﬁlm) 3051, 2948, 1737

and 1436 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.69–7.65 (1H, m,

ArH), 7.28–7.20 (3H, m, 3ꢁArH), 7.11–7.07 (1H, m,

ArH), 6.93–6.89 (1H, m, ArH), 6.82–6.80 (1H, m, ArH),

5.68 (1H, d, J 1.3 Hz, CH₂]), 4.98 (1H, t, J 0.9 Hz,

CH₂]), 4.35 (1H, dd, J 10.3 and 5.2 Hz, CH), 3.91 (1H,

ddd, J 15.8, 1.3 and 0.9 Hz, CCH₂N), 3.89 and 3.74

(2ꢁ1H, 2ꢁd, J 14.9 Hz, NCH₂Ar), 3.73 (3H, s, CO₂Me),

3.38 (1H, dd, J 15.8 and 0.9 Hz, CCH₂N), 2.87 (1H, dd, J

14.5 and 10.3 Hz, CH₂CO) and 2.66 (1H, dd, J 14.5 and

5.2 Hz, CH₂CO); m/z (EI) (%) 313 (M⁺, 1), 240 (89), 216

(44) and 97 (100).

(500 MHz, CDCl₃), 7.71–7.68 (1H, m, ArH⁸), 7.31–7.25

00

(3H, m, ArH⁶, ArH⁷and ArH⁵), 7.14–7.09 (1H, m,

00

ArH⁵), 6.95–6.90 (1H, m, ArH⁴), 6.90–6.89 (1H, m,

00

ArH³), 5.71 (1H, d, J 1.8 Hz, ]CH), 5.05 (1H, d, J

1.8 Hz, ]CH), 4.14 (1H, dd, J 8.6 and 6.2 Hz, CH¹), 3.93

00

(1H, d, J 13.4 Hz, CH³), 3.91 (1H, d, J 15.8 Hz, CH¹),

00

3.83 (1H, d, J 13.4 Hz, CH³), 3.51 (1H,₀d, 15.8 Hz, CH¹),

2.90 (1H, dd, J 16.9 and 8.6 Hz, CH¹), 2.71 (1H, dd, J

0

16.9 and 6.2 Hz, CH¹); d_C(126 MHz, CDCl₃), 142.2

00

(C²), 135.8 (C⁴), 132.7 (C^8a), 132.3 (C^4a), 128.6 (C⁷),

3.4.10. 1-Benzenesulfonylmethyl-4-methylene-2-thio-

phen-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline (7e).

00

128.0, 127.9, 126.5 (C⁴), 126.0 (C³), 125.5, 124.0 (C⁸),

0

118.1 (C²), 1₀10.7 (]CH₂), 57.7 (C¹), 52.8 (C³), 50.3

00

6'

5'

(C¹), 24.8 (C¹); m/z (%) (CI) 281 (MH⁺, 100).

4'

3'

3.4.8. 4-Methylene-1-nitromethyl-2-thiophen-2-yl-

methyl-1,2,3,4-tetrahydroisoquinoline (7c).

O₂S

1'

8

1''

3''

¹N

8a

2''

7

6

4''

O₂N

1''

S

3

4a

5''

8

1'

3'

5'

¹N

3

5

8a

2'

7

4'

S

6

4a

5

Prepared by the general procedure from (5e) (370 mg,

1.00 mmol) and 2-thiophenemethylamine (226 mg,

2.00 mmol). Column chromatography afforded the product

(7e) (213 mg, 54%) as a colourless oil. (Found HRMS:

418.0713; C₂₂H₂₁NO₂S₂Na (MNa⁺) requires 418.0706);

Prepared by the general procedure from (5c) (275 mg,

1.00 mmol) and 2-thiophenemethylamine (226 mg,

2.00 mmol). Column chromatography afforded the product

(7c) (191 mg, 64%) as a pale yellow oil. (Found: C, 64.20;

H, 5.30; N, 9.30; C₁₆H₁₅N₂O₂S requires C, 64.20; H, 5.05;

N, 9.40%); n/max (ﬁlm) 3055, 1553, 1483, 1447, 1424 and

1381 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.72–7.70 (1H, m,

ArH⁵), 7.33–7.28 (2H, ₀m, ArH⁶and ArH⁷), 7.24 (1H, dd, J

5.1 and 1.2 Hz, ArH³), 7.12–7.10₀(1H, m, ArH⁸), 6.92

n/max (ﬁlm) 3056, 1481, 1443 and 1426 cm^ꢂ1; d_H

0

(500 MHz, CDCl₃), 8.01–7.98 (2H, m, ArH⁴), 7.64–7.60

0

(2H, m, ArH⁵), 7.55–7.51 (2H, m, ArH⁵and ArH), 7.28–

7.22 (3H, m, ArH⁷, ArH⁶and ArH), 7.14–7.11 (1H, m,

00

ArH⁸), 6.91 (1H, dd, J 5.1 and 3.4 Hz, ArH⁴), 6.80–6.79

(1H, m, ArH), 5.66 (1H, d, J 1.7 Hz, ]CH), 4.89 (1H, d, J

(1H, dd, J 5.1 and 3.4 Hz, ArH⁴), 6.84–6.82 (1H, m,

1.8 Hz, ]CH), 4.49 (1H, dd, J 8.9 and 3.7 Hz, CH¹), 3.81

0

00

ArH⁵), 5.73 (1H, d, J 1.7 Hz, ]CH), 5.07 (1H, d,₀₀J

1.9 Hz, ]CH), 4.79 (1H, dd, J 10.9 and 11.8 Hz, CH¹),

4.64 (1H, dd, J 10.9 ₀₀and 4.5 Hz, CH¹), 4.50 (1H, dd, J

11.8 and 4.5 Hz, CH¹), 3.93 (1H, dt, J 15.9 and 1.8 Hz,

CH³), 3.92 (1H, dd, J 13.9 and 0.8 Hz, CH⁴), 3.78 (1H, d,

J 13.9 Hz, CH⁴), 3.46 (1H,₀d, J 15.9 Hz, CH³); d_C

(126 MHz, CDCl₃), 142.0 (C²), 135.3 (C⁴), 133.2 (C^4a),

130.0 (C^8a), 128.8 (C⁶C⁷), 128.1 (C^{(6 or 7}), 127.8 (C⁸), 126.3

(1H, d, J 13.5 Hz, CH¹), 3.79 (1H, dd, J 15.0 and 9.0 Hz,

0

00

CH¹), 3.69 (1H, d, J 13.5 Hz, CH¹), 3.42 (1H, d, ₀J

16.0 Hz, CH³), 3.34 (1H, dd, J 15.0 and 3.8 Hz, CH¹),

3.16 (1H, d, J 16.0 Hz, CH³); d_C(126 MHz, CDCl₃), 141.2

00

0

(C²), 140.3 (C³), 135.4 (C⁴₀), 133.4 (C⁵), 133.2 (C^8a),

0

132.2 (C^4a), 129.1, 128.8 (C⁴), 128.2, 127.8 (C⁵), 127.6,

00

126.8, 126.2 (C⁴), 125₀.₀4, 123.6, 110.8 (]CH₂), 61.5

0

(C¹), 58.3 (C¹), 52.3 (C¹), 48.1 (C³); m/z (%) (FAB) 396

0

(C³), 126.0 (C⁵), 125.5 (C⁴),₀124.2 (C⁵), 111.3 (]CH₂),

(MH⁺, 29), 291 (68), 240 (22) and 97 (100).

00

78.7 (C¹), 60.0 (C¹), 52.6 (C¹), 49.5 (C³); m/z (%) (FAB)

301 (MH⁺, 44) and 240 (100).

3.4.11. 2-(2-Cyclopropyl-4-methylene-1,2,3,4-tetra-

hydroisoquinolin-1-yl)-1-phenyl-ethanone (8a).

3.4.9. Methyl [4-methylene-2-(2-thienylmethyl)-1,2,3,4-

tetrahydro-1-isoquinolinyl]-acetate (7d).

6'

5'

4'

3'

MeO₂C

2''

1'

O

N

S

8

1''

1

8a

4a

2''

7

6

N

3

5

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and 2-thiophenemethylamine (226 mg,

2.00 mmol). Column chromatography afforded product

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and cyclopropylamine (114 mg, 2.00 mmol).

6160

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

Column chromatography afforded the product (8a) (242 mg,

80%) as a pale yellow oil. (Found: C, 83.00; H, 6.75; N, 4.60;

C₂₁H₂₁NO requires C, 83.10; H, 7.00; N, 4.60%); n/max

requires C, 68.80; H, 6.55; N, 11.50%); n/max (Nujol

mull) 1547, 1334, 1252 and 1221 cm^ꢂ1; d_H(500 MHz,

CDCl₃), 7.72–7.69 (1H, m, ArH⁵), 7.31–7.28 (2H, m,

ArH⁶and ArH⁷), 7.18–7.14 (1H, m, ArH⁸), 5.69 (1H, d, J

(ﬁlm) 3064, 2941 1682, 1633, 1597 and 1482 cm^ꢂ1; d_H

0

(500 MHz, CDCl₃), 7.91 (1H, d, J 8.3 Hz, ArH⁴), 7.90

1.7 Hz, ]CH), 5.12 (1H, d, J 1.9 Hz, ]CH), 4.77 (1H,

dd, J 11.3 and 4.2 Hz, CH¹), 4.69 (1H, t, J 11.8 Hz, CH¹),

0

(1H, d, J 8.5 Hz, ArH⁴), 7.70–7.66 (1H, m, ArH⁵), 7.54

0

(1H, tt, J 7.4 and 1.8 Hz, ArH⁶), 7.46 (2H, t, J 6.9 Hz,

4.47 (1H, dd, J 11.9 and 4.2 Hz, CH¹), 3.90 (1H, dt, J

15.6 and 1.9 Hz, CH³), 3.52 (1H, d, J 15.6 Hz, CH³),

0

2ꢁArH⁵), 7.25–7.16 (3H, m, ArH⁶, ArH⁷and ArH⁸), 5.66

00

(1H, s, ]CH), 5.05 (1H, s, ]CH), 4.72 (1H, dd, J 9.0 and

2.07–2.03 (1H, m, CH¹), 0.49–0.38 (4H, m, CH²); d_C

5.2 Hz, CH¹), 3.94 (1H, d, J 15.3 Hz, CH³), 3.56 (1H, dd,

(126 MHz, CDCl₃), 136.3 (C⁴), 133.4 (C^4a), 130.9 (C^8a),

0

J 15.7 and 9.0 Hz, CH¹), 3.46 (1H,₀d 15.3 Hz, CH³), 3.07

128.5 (C⁶), 127.9 (C⁷), 127.7 (C⁸), 124.2 (C⁵), ₀₀110.3

0

(1H,₀₀dd, J 15.7 and 5.2 Hz, CH¹), 1.97–1.93 (1H, m,

(]CH₂), 78.7 (C¹), 61.2 (C¹), 50.1 (C³), 34.5 (C¹), 7.4

00

CH¹), 1.25–1.19 (4H, m, 4ꢁCH²); d_C(126 MHz,

(C²), 7.2 (C²); m/z (%) (FAB) 245 (MH⁺, 41), 198 (100),

184 (85), 156 (57), 142 (31) and 129 (24).

0

CDCl₃), 198.7 (C²), 137.6, 137.6, 136.9 (C⁴), 132.8 (C⁶),

0

132.3 (C^4a), 128.5 (C⁵), 128.2 (C⁴), 128.1, 127.8, 126.8,

123.7 (C^{(5 or 8)}), 108.9 (]CH₂), 59.5 (C¹), 51.2 (C³), 44.6

3.4.14. Methyl (2-cyclopropyl-4-methylene-1,2,3,4-tetra-

hydro-1-isoquinolinyl)-acetate (8d).

0

00

(C¹), 34.6 (C¹), 7.0 (C²), 6.9 (C²); m/z (%) (ES) 326

(MNa⁺, 100).

MeO₂C

N

3.4.12. (2-Cyclopropyl-4-methylene-1,2,3,4-tetrahydro-

isoquinolin-1-yl)-acetonitrile (8b).

2'

NC

2''

1'

1

8

1''

8a

2''

7

6

N

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and cyclopropylamine (114 mg, 2.00 mmol).

Column chromatography afforded the product (8d) (80%)

as a pale yellow oil. (Found: C, 74.45; H, 7.25; N, 5.70;

C₁₆H₁₉NO₂requires: C, 74.70; H, 7.45; N, 5.45%); IR

(ﬁlm) 3007, 2948, 1736 and 1436 cm^ꢂ1; d_H(250 MHz,

CDCl₃), 7.70–7.66 (1H, m, ArH), 7.28–7.19 (2H, m,

2ꢁArH), 7.15–7.11 (1H, m, ArH), 5.65 (1H, d, J 1.8 Hz,

CH₂]), 5.05 (1H, t, J 0.9 Hz, CH₂]), 4.47 (1H, dd, J

10.3 and 5.1 Hz, PhCHN), 3.89 (1H, dd, J 15.4, 1.8 and

0.9 Hz, CCH₂N), 3.68 (3H, s, CO₂Me), 3.47 (1H, dd, J

15.4 and 0.9 Hz, CCH₂N), 2.80 (1H, dd, J 14.7 and

10.3 Hz, CH₂CO), 2.59 (1H, dd, J 14.7 and 5.1 Hz,

3

4a

5

Prepared by the general procedure from (5b) (255 mg,

1.00 mmol) and cyclopropylamine (114 mg, 2.00 mmol).

Column chromatography afforded the product (8b)

(129 mg, 47%) as a pale yellow amorphous solid, mp 122–

124 ^ꢀC. (Found: C, 81.40; H, 7.40; N, 12.70; C₁₅H₁₆N₂re-

quires C, 80.30; H, 7.20; N, 12.50%); n/max (Nujol mull)

2243, 1410, 1315 and 1252 cm^ꢂ1; d_H(500 MHz, CDCl₃),

7.69–7.67 (1H, m, ArH⁵), 7.30 (2H, m, ArH⁶, ArH⁷),

7.19–7.15 (1H, m, ArH⁸), 5.66 (1H, d, J 1.7 Hz, ]CH),

5.10 (1H, t, J 1.0 Hz, ]CH), 4.27 (1H, dd, J 9.2 and

5.4 Hz, CH¹), 3.80 (1H, dt, J 15.3 and 1.9 Hz, CH³), 3.55

CH₂CO), 1.98 (1H, m, NCH), 0.54–0.38 (4H, m,

00

2ꢁCH²); d_C(75 MHz, CDCl₃), 172.1, 137.4, 136.0,

132.4, 128.2, 127.6, 126.9, 123.7, 109.1, 59.8, 51.6, 50.8,

41.1, 34.5, 7.4, 7.1; m/z (EI) (%) 257 (M⁺, 57), 184 (100),

141 (79) and 128 (60).

(1H,₀d, J 15.3 Hz, CH³), 2.81 (1H, dd, J 16.8 and 9.2 Hz,

0

CH¹), 2.65 (₀1₀H, dd, J 16.8 and 5.4 Hz, CH¹), 2.05–2.08

00

(1H, m, CH¹), 0.65–0.60 (1H, m, CH²), 0.60–0.46 (3H,

00

m, 3ꢁCH²); d_C(126 MHz, CDCl₃), 136.9 (C⁴), 134.0

(C^8a), 132.6 (4^a), 128.4, 127.7, 127.6, 124.1 (C⁵), 118.5

3.4.15. 1-Benzenesulfonylmethyl-2-cyclopropyl-4-

methylene-1,2,3,4-tetrahydroisoquinoline (8e).

0

00

(C²), 109.8 (]CH₂), 59.8 (C¹), 50.9 (C³), 34.7 (C¹), 24.0

0

00

(C¹), 7.5 (C²), 7.1 (C²); m/z (%) 224 (M⁺, 55), 209 (29),

196 (37), 184 (100), 169 (43), 157 (40), 142 (48), 128 (76)

and 115 (61).

6'

5'

4'

3'

O₂S

2''

1'

3.4.13. 2-Cyclopropyl-4-methylene-1-nitromethyl-

1,2,3,4-tetrahydroisoquinoline (8c).

8

1

N ^1''

8a

2''

7

6

3

4a

O₂N

1''

1

2'

5

8

1'

2'

8a

7

6

N

3

4a

Prepared by the general procedure from (5e) (370 mg,

1.00 mmol) and cyclopropylamine (114 mg, 2.00 mmol).

Column chromatography afforded the product (8e)

(234 mg, 69%), which was crystallised from dichloro-

methane as colourless prisms, mp 126–128 ^ꢀC. (Found: C,

70.70; H, 6.00; N, 3.90; C₂₀H₂₁NO₂S requires C, 70.80; H,

6.25; N, 4.10%); n/max (Nujol mull) 3055, 1483, 1446 and

1421 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.89–7.87 (2H, m,

5

Prepared by the general procedure from (5c) (275 mg,

1.00 mmol) and cyclopropylamine (114 mg, 2.00 mmol).

Column chromatography afforded the product (8c)

(166 mg, 68%) as a pale yellow amorphous solid, mp 58–

60 ^ꢀC. (Found: C, 68.90; H, 6.60; N, 11.30; C₁₄H₁₆N₂O₂

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6161

2ꢁArH), 7.62 (2H, tt, J 7.4 and 1.2 Hz, 2ꢁCH), 7.52 (2H, tt,

J 7.4 and 1.7 Hz, 2ꢁArH), 7.26 (1H, td, J 7.5 and 1.5 Hz,

ArH), 7.22 (1H, td, J 7.6 and 1.8 Hz, ArH), 7.13 (1H, m,

ArH), 5.60 (1H, d, J 2.0 Hz, ]CH), 4.94 (1H, d, J 2.0 Hz,

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and (R)-(+)-a-methylbenzylamine (242 mg,

2.00 mmol). Column chromatography afforded the product

(10a) (264 mg, 72%) as a pale yellow oil which comprised

of a 1:1 mixture of diastereoisomers. (Found: C, 84.70; H,

6.70; N, 3.90; C₂₆H₂₅NOS requires C, 85.00; H, 6.85; N,

3.80%); n/max (ﬁlm) 3060, 1681, 1598, 1491 and

1448 cm^ꢂ1; m/z (%) (FAB) 368 (MH⁺, 31), 248 (97), 144

(33) and 105 (100).

]CH), 4.62 (1H, dd, J 10.4 and 3.7 Hz, CH¹), 3.70 (1H,

00

dd, J 15.2 and 10.4 Hz, CH¹), 3.30 (1H, dt, J 16.0 and

0

2.0 Hz, CH³), 3.28 (1H, dd, J 15.2 and 3.7 Hz, CH¹), 3.03

00

(1H, d, J 16.0 Hz, CH³), 1.91 (1H, sextet, J 3.6 Hz, CH¹),

00

0.74 (1H, ddt, J 9.7, 6.1 and 3.8 Hz, CH²), 0.42–0.31 (2H,

00

m, CH²), 0.22 (1H, ddt, J 9.6, 5.9 and 3.6 Hz, CH²); d_C

0

(126 MHz, CDCl₃), 140.9 (C³), 136.4 (C^4a), 133.6, 133.2,

132.4 (C⁴), 128.7, 128.6, 128.1, 127.7, 127.4, 123.7, 109.7

The two diastereoisomers were separated by column chro-

matography eluting with 2:3 v/v ether/petrol containing tri-

ethylamine (10%).

00

(]CH₂), 60.3 (C¹), 58.3 (C¹), 49.8 (C³), 34.6 (C¹),

00

6.72 (C²); m/z (%) (FAB) 340 (MH⁺, 100), 198 (78) and

143 (23).

Diasteroisomer A: d_H(250 MHz, CDCl₃), 8.00 (2H, 2ꢁd,

J 8.5 Hz, 2ꢁArH), 7.72–7.65 (1H, m, ArH), 7.61–7.44

(3H, m, 3ꢁArH), 7.28–7.17 (6H, m, 6ꢁArH), 7.16–7.08

(2H, m, 2ꢁArH), 5.63 (1H, s, ]CH), 5.00 (1H, dd, J

8.6 and 5.3 Hz, CH), 4.72 (1H, s, ]CH), 3.81 (1H, d, J

15.7 Hz, CH), 3.68 (1H, dd, J 15.1 and 8.6 Hz, CH),

3.56 (1H, q, J 6.6 Hz, CH), 3.18 (1H, dd, J 15.1 and

5.3 Hz, CH), 3.11 (1H, d, J 15.7 Hz, CH), 1.14 (3H, d,

J 6.6 Hz, Me).

3.4.16. 2-(2-Allyl)-4-methylene-1,2,3,4-tetrahydroisoqui-

nolin-1-yl-1-phenyl-ethanone (9a).

6'

5'

4'

3'

3''

1'

1

2''

O

8

8a

4a

1''

7

6

N

3

Diastereoisomer B: d_H(250 MHz, CDCl₃), 7.75 (2H, 2ꢁd,

J 8.5 Hz, 2ꢁArH), 7.64 (1H, dd, J 9.1 and 1.6 Hz, ArH),

7.46 (1H, t, J 7.2 Hz, ArH), 7.32 (2H, t, J 7.5 Hz, 2ꢁArH),

7.15–6.87 (8H, m, 8ꢁArH), 5.64 (1H, s, ]CH), 4.97 (1H,

s, ]CH), 4.33 (1H, t, J 7.2 Hz, CH), 3.99 (1H, d,

J 16.0 Hz, CH), 3.79 (1H, d, J 16.0 Hz, CH), 3.46 (1H, q,

J 6.6 Hz, CH), 3.76 (1H, dd, J 14.4 and 7.2 Hz, CH),

3.09 (1H, dd, J 14.5 and 7.2 Hz, CH), 1.21 (3H, d,

J 6.6 Hz, Me).

5

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and allylamine (114 mg, 2.00 mmol). Column

chromatography afforded the product (9a) (187 mg, 62%)

as a yellow oil. (Found: C, 83.20; H, 6.75; N, 4.70;

C₂₁H₂₁NO requires C, 83.10; H, 7.00; N, 4.60%); n/max

(ﬁlm) 3067, 2911, 1683, 1641, 1597 and 1582 cm^ꢂ1; d_H

0

(500 MHz, CDCl₃), 7.95–7.92 (2H, m, 2ꢁArH⁴), 7.68–

0

3.4.18. Methyl [4-methylene-2-(1-phenylethyl)-1,2,3,4-

tetrahydro-1-isoquinolinyl]-acetate (10d).

7.65 (1H, m, ArH⁵), 7.54 (1H, tt, J 7.4 and 1.3 Hz, ArH⁶),

0

7.48–7.43 (2H, m, 2ꢁArH⁵), 7.22–7.19 (2H, m, ArH⁶,

ArH⁷), 7.14–7.11 (1H, m, ArH⁸), 5.75 (1H, ddt, J 16.3,

00

10.4 and 6.4 Hz, ]CH²), 5.66 (1H, d, J 1.8 Hz, ]CH),

MeO₂C

N

00

5.07–5.02 (2H, m, 2ꢁ]CH³), 5.0 (1H, t, J 1.0 Hz,

]CH), 4.6 (1H, dd, J 7.9 and 5.6 Hz, CH¹), 3.94 (1H, dt,

J 15₀.4 and 1.9 Hz, CH³), 3.61 (1H, dd, J 16.0 and 8.1 Hz,

CH¹), 3.42 (1H,₀d, J 15.5 Hz, CH³), 3.16 (1H, dd, J 16.0

and 5.6 Hz, CH¹), 3.14 (1H, ddt, J 13.6, 6.2 and 1.4 Hz,

00

CH¹), 3.05 (1H, dt, J 13.6, 6.7 and 1.2 Hz, CH¹); d_C

0

Prepared from (5a) (288 mg, 1.00 mmol) and R-(+)-a-

methylbenzylamine (242 mg, 2.00 mmol). Column chroma-

tography afforded product isomer A (34%) and isomer B

(40%).

(126 MHz, CDCl₃), 198.5 (C²), 137.5 (C³), 136.9 (C⁴),

00

0

136.3 (C^8a), 135.9 (C²), 132.9 (C⁶), 132.2 (C^4a), 128.6

0

00

(C⁵), 128.3, 128.2, 127.9, 126.8, 123.5, 117.4 (C³), 109.3

00

0

(]CH₂), 57.8 (C¹), 57.0 (C¹), 50.7 (C³), 44.9 (C¹);

m/z (%) (FAB) 304 (MH⁺, 31), 262 (13), 184 (100) and

105 (33).

Isomer A: Pale yellow oil. [a]_Dꢂ70.2 (0.114 g/100 ml).

(Found: C, 78.20; H, 7.05; N, 4.50; C₂₁H₂₃NO₂requires

C, 78.45; H, 7.20; N, 4.35%); IR (ﬁlm) 3027, 2973, 1736

and 1436 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.69–7.64 (1H, m,

ArH), 7.32–7.18 (7H, m, 7ꢁArH), 7.16–7.12 (1H, m,

ArH), 5.61 (1H, d, J 1.8 Hz, CH₂]), 4.77 (1H, dd, J 10.5

and 5.2 Hz, NCHCH₂), 4.72 (1H, t, J 1.0 Hz, CH₂]),

3.77 (1H, ddd, J 16.1, 1.8 and 1.1 Hz, CCH₂N), 3.78 (3H,

s, CO₂Me), 3.60 (1H, q, J 6.5 Hz, CH), 3.13 (1H, dd, J

16.1 and 1.0 Hz, CCH₂N), 2.93 (1H, dd, J 14.3 and

10.5 Hz, CH₂CO), 2.70 (1H, dd, J 14.3 and 5.2 Hz,

CH₂CO), 1.27 (3H, d, J 6.5 Hz, Me); m/z (%) (EI) 321

(M⁺, 1), 248 (89), 216 (41), 144 (78), 115 (50), 105 (100)

and 77 (49).

3.4.17. 2-((R)-1-Phenylethyl-4-methylene-1,2,3,4-tetra-

hydroisoquinolin-1-yl)-1-phenyl-ethanone (10a).

6'

5'

4'

3'

1'

O

1

8

8a

4a

2''

7

6

1''

N

3

5

6162

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

0

Isomer B: Pale yellow oil, which crystallised from ether/

petroleum ether as pale yellow prisms, mp 54–55 ^ꢀC. [a]_D

+86.2 (0.116 g/100 ml). (Found: C, 78.15; H, 7.25; N,

4.40; C₂₁H₂₃NO₂requires C, 78.45; H, 7.20; N, 4.50%);

IR (ﬁlm) 3030, 2977, 1739 and 1436 cm^ꢂ1; d_H(250 MHz,

CDCl₃), 7.00 (1H, dd, J 7.3 and 2.0 Hz, ArH), 7.32–7.14

(7H, m, 7ꢁArH), 6.91 (1H, dt, J 2.0 and 0.5 Hz, ArH),

5.69 (1H, s, CH₂]), 5.01 (1H, s, CH₂]), 4.13 (1H, dd, J

10.0 and 5.4 Hz, NCHCH₂), 4.00 and 3.75 (2ꢁ1H, AB,

2ꢁd, J 16.3 Hz, CCH₂N), 3.63 (3H, s, CO₂Me), 3.54 (1H,

q, J 6.4 Hz, CH), 2.43 (1H, dd, J 14.0 and 10.0 Hz,

CH₂CO), 2.25 (1H, dd, J 14.0 and 5.4 Hz, CH₂CO) and

1.27 (3H, d, J 6.5 Hz, Me); m/z (%) (ES) 344 (M⁺+Na, 1)

and 322 (72).

7.7 Hz, CH¹), 3.64–3.60 (2H, m, CH³₂), 3.55 (1H, q,

00

0

J 6.5 Hz, CH¹), 3.17 (1H, dd, J 14.8 and 4.5 Hz, CH¹),

1.32 (3H, d, J 6.5 Hz, Me); d_C(126 MHz, CDCl₃), 143.8

00

0

(C²), 140.4 (C²), 136.5, 134.4, 133.4, 132.4, 129.0, 128.6,

128.4, 128.3, 128.1, 127.7, 127.4, 127.3, 123.4, 109.3

0

00

(]CH₂), 61.1 (C¹), 60.0 (C¹), 55.2 (C¹), 47.5 (C³), 21.0

0

(C²); m/z (%) (ES) 404 (MH⁺, 100).

3.4.20. Methyl {2-[2-(methyoxymethyl)-1-pyrrolidinyl]-

4-methylene-1,2,3,4-tetrahydro-1-isoquinolinyl}acetate

(11d).

MeO₂C

N

CH₂OMe

3.4.19. 1-Benzenesulfonylmethyl-4-methylene-2-((R)-1-

phenylethyl)-1,2,3,4-tetrahydroisoquinoline (10e).

6'

5'

Prepared from (5d) (288 mg, 1.00 mmol) and SAMP

(268 ml, 2.00 mmol). Column chromatography afforded

product 11d major (53%) and product 11d minor (25%).

4'

3'

O₂S

1'

8

1

8a

2''

7

1''

11d major: Pale yellow oil. [a]_D+58.8 (0.102 g/100 ml).

(Found: C, 68.80; H, 7.85; N, 8.30; C₁₉H₂₆N₂O₃requires

C, 69.05; H, 7.95; N, 8.50%); IR (ﬁlm) 2949, 1733 and

1436 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.62 (1H, dd, J 7.9

and 1.2 Hz, ArH), 7.25–7.18 (3H, m, 3ꢁArH), 5.53 (1H,

s, CH₂]), 5.02 (1H, s, CH₂]), 4.50 (1H, t, J 5.8 Hz

CCHN), 3.69 (3H, s, CO₂Me), 3.66 (2H, m, CCH₂N and

CH₂O), 3.39 (1H, d, J 11.9 Hz, CCH₂N), 3.33 (3H, s,

OMe), 3.20 (1H, t, J 8.8 Hz, CH₂O), 2.99 (1H, m,

OCH₂CHN), 2.99 and 2.61 (2ꢁ1H, 2ꢁm, CH₂), 2.76

(2H, d, J 5.8 Hz, CH₂CO), 1.86 and 1.68 (2ꢁ1H, 2ꢁm,

CH₂), 1.60–1.47 (2H, m, CH₂); d_C(125 MHz, CDCl₃)

172.9 (CO), 140.9 (C_q), 137.9 (C_q), 133.0 (C_q), 128.5

(CH), 126.6 (CH), 126.5 (CH), 124.0 (CH), 107.3 (CH₂),

75.9 (CH₂), 61.0 (CH), 59.0 (Me), 58.9 (CH), 51.3 (Me),

48.4 (CH₂), 41.7 (CH₂), 41.3 (CH₂), 27.1 (CH₂), 21.5

(CH₂); m/z (%) (EI) 330 (M⁺, 56), 285 (100), 257 (100),

156 (55), 142 (73), 128 (56), 115 (55), 85 (45) and 70

(45).

N

3

6

4a

5

Prepared by the general procedure from (5e) (370 mg,

1.00 mmol) and (R)-(+)-a-methylbenzylamine (242 mg,

2.00 mmol). Column chromatography afforded the product

(10e) (290 mg, 72%), which comprised of a separable 1:1

mixture of diastereoisomers.

Diastereoisomer A: crystallised from ethanol/water as

colourless needles (145 mg, 36%), mp 184–186 ^ꢀC. [a]_D

+62.2 (0.051 g/50 ml). (Found: C, 73.30; H, 6.40; N, 3.70;

C₂₅H₂₅NO₂S requires C, 74.40; H, 6.25; N, 3.50%); n/max

(Nujol mull) 1305, 1147 and 1085 cm^ꢂ1; d_H(500 MHz,

CDCl₃), 8.05–8.03 (2H, m, ArH), 7.69–7.63 (2H, m, ArH),

7.60–7.52 (2H, m, ArH), 7.30–7.15 (4H, m, ArH), 7.09

(1H, m, ArH), 5.60 (1H, d, J 1.7 Hz, ]CH), 4.98 (1H, dd,

J 9.2 and 3.2 Hz, CH¹), 4.65 (1H, d, J 1.8 Hz, ]CH), 3.94

0

(1H,₀₀dd, J 14.9 and 9.2 Hz, CH¹), 3.51 (1H, q, J 6.5 Hz,

11d minor: Pale yellow oil. [a]_Dꢂ146.7 (0.150 g/100 ml).

(Found: C, 68.80; H, 8.05; N, 8.45; C₁₉H₂₆N₂O₂

requires C, 69.05; H, 7.95; N, 8.50%); IR (ﬁlm)

2950, 1735 and 1436 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.65

(1H, dd, J 7.7 and 1.4 Hz, ArH), 7.26–7.19 (2H, m,

2ꢁArH), 7.13 (1H, dd, J 7.5 and 1.5 Hz, ArH), 5.55 (1H,

d, J 1.6 Hz, CH₂]), 5.07 (1H, t, J 0.9 Hz, CH₂]),

4.52 (1H, dd, J 10.5 and 4.5 Hz, CCHN), 4.02 (1H, ddd, J

15.2, 1.6 and 0.9 Hz, CCH₂N), 3.72 (3H, s, CO₂Me), 3.59

(1H, dd, J 15.2 and 0.9 Hz, CCH₂N), 3.45 (1H, dd, J 3.3

and 9.0 Hz, CH₂O), 3.36 (3H, s, OMe), 3.26 (1H, dd, J 9.0

and 7.0 Hz, CH₂O), 2.96 (1H, m, OCH₂CHN), 2.78 (1H,

dd, J 14.6 and 10.5 Hz, CH₂CO), 2.74 and 2.33 (2ꢁ1H,

2ꢁm, CH₂), 2.66 (1H, dd, J 14.6 and 4.5 Hz, CH₂CO),

1.73 (1H, m, CH₂), 1.58–1.49 (3H, m, CH₂); d_C

(125 MHz, CDCl₃) 172.0 (CO), 139.1 (C_q), 137.3 (C_q),

133.4 (C_q), 128.3 (CH), 126.7 (CH), 126.4 (CH), 123.7

(CH), 108.1 (CH₂), 75.4 (CH₂), 59.9 (CH), 59.1 (Me),

54.7 (CH), 53.2 (CH₂), 51.5 (Me), 48.6 (CH₂), 42.4 (CH₂),

25.2 (CH₂), 21.4 (CH₂); m/z (%) (EI) 330 (M⁺, 27), 285

CH¹), 3.43 (1H, d, J 16.6 Hz, CH³), 3.35 (1H, dd, J 14.9

0

and 3.2 Hz, CH¹), 2.97 (1H, d, J 16.6 Hz, CH³), 1.28 (3H,

00

d, J 6.5 Hz, Me); d_C(126 MHz, CDCl₃), 144.9 (C²),

0

140.9 (C³), 135.7, 133.3, 133.0, 132.7, 129.1, 128.8,

128.2, 127.9, 127.7, 127.6, 127.5, 126.9, 123.5, 110.1

0

00

(]CH₂), 61.1 (C¹), 58.8 (C¹), 53.8 (C¹), 47.9 (C³), 21.8

0

(C²); m/z (%) (FAB) 404 (MH⁺, 100), 298 (34), 248 (79),

144 (26) and 105 (43).

Diastereoisomer B: crystallised from ethanol water as

colourless needles (147 mg, 36%), mp 172–174 ^ꢀC. [a]_D

ꢂ88.4 (0.051 g/50 ml). (Found: C, 73.30; H, 6.40; N, 3.70;

C₂₅H₂₅NO₂S requires C, 74.20; H, 6.40; N, 3.60%); n/max

(Nujol mull) 1304, 1146 and 1084 cm^ꢂ1; d_H(500 MHz,

CDCl₃), 7.79–7.77 (2H, m, ArH), 7.65–7.59 (2H, m, ArH),

7.51–7.46 (2H, m, ArH), 7.33–7.26 (3H, m, ArH), 7.23–

7.20 (3H, m, ArH), 7.19–7.12 (1H, m, ArH), 6.70 (1H, d,

J 7.01, ArH), 5.67 (1H, s, ]CH), 5.0 (1H, s, ]CH), 4.36

(1H, dd, J 7.7 and 4.5 Hz, CH¹), 3.72 (1H, dd, J 14.8 and

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6163

(82), 257 (100), 156 (61), 142 (91), 128 (71), 85 (45) and 70

(45).

7.21 (1H, dd, J 7.7 and 7.3 Hz, ArH⁷), 7.15 (1H, d, J

00

7.3 Hz, ArH⁵), 7.07 (2H, d, J 8.1 Hz, ArH²), 5.50 (1H, s,

]CH), 5.28 (1H, dd, J 6.8 and 6.4 Hz, CH¹), 5.08 (1H, s,

3.4.21. 2-{4-Methylene-2-[(4-methylphenyl)sulfonyl]-

1,2,3,4-tetrahydroisoquinolin-1-yl}-1-phenyl-ethanone

(12a).

]CH), 4.49 (1H, d, J 6.3 Hz, CH³), 4.25 (1H, d, J 16.3,

0

CH³), 2.96 (1H, dd, J 16.7 and 6.4 Hz, CH¹), 2.89 (1H,

0

00

dd, J 16.7 and 6.8 Hz, CH¹), 2.31 (3H, s, CH³); d_C

(75 MHz, CDCl₃): 143.7, 135.6, 134.8, 131.7, 131.6,

129.4, 128.6, 128.4, 127.4, 126.9, 124.5, 116.7, 111.2,

53.5, 45.7, 25.9, 21.5; m/z (%) (ES) 339 (MH⁺, 30), 184

(38) and 143 (100).

6'

5'

4'

O

1'

3.4.23. Methyl {4-methylene-2-[(4-methylphenyl)sul-

fonyl]-1,2,3,4-tetrahydroisoquinolin-1-yl}acetate (12d).

O O

1''

8

5

1

S

2''

7

6

N

2

3''

1''

2''

4'

O

1'

O

1''

2''

8

5

S

1

2''

7

6

Prepared by the general procedure from 5a (0.144 g,

0.50 mmol), p-toluenesulfonamide (0.083 g, 0.60 mmol),

Pd₂dba₃(0.011 g, 0.0125 mmol), tri-2-furylphosphine

(0.012 g, 0.05 mmol), K₂CO₃(0.138 g, 1.00 mmol), allene

(0.2 bar) and toluene (2 ml). Column chromatography elut-

ing with 3:1 hexane/ether afforded the product (12a) as

colourless needles (0.163 g, 78%), mp 94–96 ^ꢀC. HRMS:

440.1302, C₂₅H₂₃NO₃SNa requires: 440.1291; n/max

N

2

1''

3''

Prepared by the general procedure from 5d (0.144 g,

0.50 mmol), p-toluenesulfonamide (0.083 g, 0.60 mmol),

Pd₂dba₃(0.011 g, 0.0125 mmol), tri-2-furylphosphine

(0.012 g, 0.05 mmol), K₂CO₃(0.138 g, 1.00 mmol), allene

(0.2 bar) and toluene (2 ml). Column chromatography elut-

ing with 3:1 hexane/ether afforded the product (12d) as

colourless needles (0.161 g, 87%), mp 179–181 ^ꢀC.

(ﬁlm) 1682, 1345 and 1159 cm^ꢂ1; d_H(500 MHz, CDCl₃),

00

7.89 (2H, d, J 7.3 Hz, ArH¹),₀₀7.55 (1H, t, J 7.3 Hz,

0

ArH⁴), 7.42–7.49 (4H, m, ArH¹, ArH⁵), 7.35 (1H, d, J

7.0 Hz, ArH⁵), 7.06–7.14 (3H₀,₀m, ArH⁶, ArH⁷and ArH⁸),

6.97 (2H, d, J 7.7 Hz, ArH²), 5.73 (1H, dd, J 6.9 and

5.8 Hz, CH¹), 5.48 (1H, s, ]CH), 5.07 (1H, s, ]CH),

HRMS: 372.1284, C₂₀H₂₂NO₄S requires: 372.1275); n/

ꢂ1

max (ﬁlm) 1475, 1398, 1171 and 1038 cm

; d_H

4.59 (1H, d, J 16.6 Hz, CH²), 4.29 (1H, d, J 16.6 Hz,

00

(500 MHz, CDCl₃): 7.46 (2H, d, J 8.0 Hz, ArH¹), 7.32

(1H, d, J 7.7 Hz, ArH⁵), 7.15 (d, J 6.8 Hz, ArH⁸), 7.05–

7.10 (2H, m, ArH⁶and ArH⁷), 5.46 (1H, dd, J 8.6 and

6.2 Hz, CH¹), 5.45 (1H, s, ]CH), 5.02 (1H, s, ]CH),

0

CH²), 3.54 (1H, dd, J 16.2 and 5.8 Hz, CH¹), 3.38 (1H, dd,

0

00

J 16.2 and 6.9 Hz, CH¹), 2.24 (3H, s, CH³); d_C(75 MHz,

CDCl₃): 196.3, 143.0, 136.7, 136.0, 135.8, 135.2, 133.3,

131.1, 129.0, 128.7, 128.2, 127.4, 127.3, 127.0, 124.0,

110.0, 53.3, 46.0, 45.6, 29.7, 21.4; m/z (%) (ES) 440

(MNa⁺, 10) and 298 (100).

4.57 (1H, d, J 17.0 Hz, CH²), 4.24 (1H, d, J 17.0 Hz,

0

CH²), 3.73 (3H, s, CH⁴), 2.86 (1H, dd, J 14.7 and

0

8.6 Hz, CH¹), 2.73 (1H, dd, J 14.7 and 6.2 Hz, CH¹),

00

2.25 (3H, s, CH³); d_C(75 MHz, CDCl₃), 170.6, 143.5,

136.5, 135.6, 134.5, 131.4, 129.4, 128.7, 127.9, 127.8,

127.0, 124.4, 110.4, 54.9, 52.5, 45.7, 42.0, 21.8; m/z (%)

765 (2MNa⁺, 11), 372 (MNa⁺, 19), 298 (62), 217 (56)

and 143 (100).

3.4.22. {4-Methylene-2-[(4-methylphenyl)sulfonyl]-

1,2,3,4-tetrahydroisoquinolin-1-yl}acetonitrile (12b).

N

1'

O

S

O

3.5. General procedure for the three-component

allenylation/nucleophilic capture/Michael addition

cascade using carbon nucleophiles, and (5a and 5e)

1''

8

5

2''

1

7

6

N

3

1''

3''

2''

A Schlenk tube was charged with aryl iodide (1.00 mmol),

carbon pronucleophile(2.00 mmol), cesium carbonate

(276 mg, 2.00 mmol, 2.00 mol equiv), palladium acetate

(22 mg, 0.10 mmol, 0.10 mol equiv), triphenylphosphine

(52 mg, 0.20 mmol, 0.20 mol equiv) and acetonitrile

(20 ml) and subjected to two freeze-pump-thaw cycles.

Allene gas (1 bar) was then added and the reaction mixture

heated at 50–60 ^ꢀC for 18 h. After cooling to rt, excess

allene gas was vented, the mixture ﬁltered and the solids

washed with ether (3ꢁ50 ml). The organic extracts

were combined, dried (MgSO₄), ﬁltered and the ﬁltrate

evaporated under reduced pressure. The residue was puriﬁed

by column chromatography eluting with 2:3 v/v ether/

petrol.

Prepared by the general procedure from 5b (0.128 g,

0.50 mmol), p-toluenesulfonamide (0.083 g, 0.60 mmol),

Pd₂dba₃(0.011 g, 0.0125 mmol), tri-2-furylphosphine

(0.012 g, 0.05 mmol), K₂CO₃(0.138 g, 1.00 mmol), allene

(0.2 bar) and toluene (2 ml). Column chromatography

eluting with 9:1 hexane/ethyl acetate afforded the product

(12b) as colourless needles (0.115 g, 68%), mp 132–

134 ^ꢀC. (Found: C, 67.15; H, 5.35; N, 8.45; S, 9.20;

C₁₉H₁₈N₂SO₂requires C, 67.43; H, 5.36; N, 8.28; S,

9.47%); n/max (ﬁlm) 1597, 1346, 1161 and 1090 cm^ꢂ1

;

00

d_H(500 MHz, CDCl₃), 7.55 (2H, d, J 8.1 Hz, ArH¹),

7.43 (1H, d, J 7.7 Hz, ArH⁸), 7.26 (1H, t, J 7.3 Hz, ArH⁶),

6164

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

3.6. General procedure for the three-component

allenylation/nucleophilic capture/Michael addition

cascade using carbon nucleophiles, and (5d)

0.8 Hz, CCH₂C]), 2.60 (1H, dd, J 15.9 and 5.3 Hz,

CH₂CO), 2.45 (1H, dd, J 15.9 and 8.0 Hz, CH₂CO); m/z

(%) (EI) 332 (M⁺, 4), 241 (63), 213 (84), 199 (100) and

141 (65).

Reaction conditions as above except the process was run in

toluene for 18 h at 110 ^ꢀC and 1.20 mmol of pronucleophile

was used.

3.6.3. 1-Benzenesulfonylmethyl-4-methylene-3,4-di-

hydro-1H-naphthalene-2,2-dicarboxylic acid dimethyl

ester (14e).

3.6.1. Dimethyl 4-methylene-1-(2-oxo-2-phenylethyl)-

3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (14a).

6'

5'

4'

3'

6'

5'

O₂S

1'

4'

3'

CO₂Me

8

1

8a

7

6

1'

O

3

CO₂Me

8

1

4a

8a

5

7

3

6

4a

5

Prepared by the general procedure from (5e) (370 mg,

1.00 mmol) and dimethyl malonate (260 mg, 2.00 mmol).

Column chromatography afforded the product (14e)

(195 mg, 47%) as a colourless oil, which crystallised from

ethanol/water as colourless needles, mp 114–116 ^ꢀC.

(Found: C, 63.70; H, 5.10; C₂₂H₂₂O₆S requires C, 63.80;

H, 5.35%); n/max (Nujol mull) 1730, 1336, 1295, 1276

and 1243 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.89–7.87 (2H, m,

2ꢁArH), 7.63 (1H, tt, J 2.5 and 1.2 Hz, ArH), 7.56–7.50

(3H, m, 3ꢁArH), 7.33 (1H, dd, J 7.9 and 1.5 Hz, ArH),

7.21 (1H, td, J 7.4 and 1.5 Hz, ArH), 7.16 (1H, td, J 7.7

and 1.5 Hz, ArH), 5.57 (1H, s, ]CH), 5.08 (1H, s, ]CH),

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and dimethyl malonate (260 mg, 2.00 mmol).

Column chromatography afforded the product (14a)

(234 mg, 62%) as a colourless oil, which crystallised from

ethanol/water as colourless prisms, mp 79–81 ^ꢀC. (Found:

C, 73.00; H, 5.85; C₂₃H₂₂O₅requires C, 72.90; H, 5.80%);

n/max (Nujol mull) 1743, 1719, 1683, 1580, 1299 and

1278 cm^ꢂ1; d_H(500 MHz, CDCl₃), 7.89 (2H, 2ꢁd, J 8.5

and 8.3 Hz, 2ꢁArH), 7.59–7.57 (1H, m, ArH), 7.53 (1H,

tt, J 7.4 and 1.3 Hz, ArH), 7.44–7.40 (2H, m, 2ꢁArH),

7.19–7.12 (3H, m, 3ꢁArH), 5.64 (1H, t, J 0.9 Hz, ]CH),

5.13 (1H, t, J 0.9 Hz, ]CH), 4.59 (1H, dd, J 6.7

and 5.4 Hz, CH¹), 3.67 (3H, s, Me₀), 3.57 (3H, s, Me), 3.38

(1H, dd, J 17.5 and 5.4 Hz, CH¹), 3.29 (1H, dd, J 15.8

4.35 (1H, t, J 4.5 Hz, CH¹), 3.76 (3H, s, Me), 3.70 (1H,

0

dd, J 14.8 and 4.5 Hz, CH¹), 3.59 (3H, s, Me), 3.26 (1H,

0

dd, 14.8 and 4.5 Hz, CH¹), 3.23 (1H, dd, J 15.8 and

1.9 Hz, CH³), 2.95 (1H, dt, J 15.8 and 1.9 Hz, CH³); d_C

(126 MHz, CDCl₃), 170.2 (C]O), 169.7 (C]O), 139.9,

and 0.9 Hz, CH³), 3.20 (1H, d, J 15.8 and 0.9 Hz, CH³),

0

3.12 (1H, d, J 17.5 and 6.7 Hz, CH¹); d_C(126 MHz,

CDCl₃), 197.3 (C^8a), 170.9 (C]O), 170.3 (C]O), 138.6,

138.3, 136.9, 133.1, 132.3, 129.2, 128.6, 128.5, 128.1,

137.7, 136.5, 133.7, 132.3, 129.3, 129.2, 128.8, 128.0,

0

127.5, 124.1, 112.0 (]CH₂), 59.0 (C¹), 58.2 (C²), 53.2

(Me), 53.0 (Me), 37.8 (C¹), 34.5 (C³); m/z (%) (CI) 437

(MNa⁺, 100), 415 (85) and 355 (27).

126.9 (C⁴), 124.0 (]CH₂), 111.5, 57.7, 52.9 (Me), 52.8

0

(Me), 42.9 (C¹), 38.7 (C¹), 34.0 (C³); m/z (%) (ES) 401

(MNa⁺, 100).

3.6.4. Methyl (2,2-dicyano-4-methylene-1,2,3,4-tetra-

hydro-1-naphthalenyl)-acetate (15d).

3.6.2. Dimethyl 1-(2-methoxy-2-oxo-ethyl)-4-methylene-

3,4-dihydro-2,2(1H)-naphthalenedicarboxylate (14d).

MeO₂C

CN

MeO₂C

CO₂Me

CN

CO₂Me

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and dimethyl malonate (127 ml, 1.20 mmol).

Column chromatography afforded the product (14d) (64%)

as a pale yellow gum. (Found: C, 65.30; H, 6.30;

C₁₈H₂₀O₆requires C, 65.05; H, 6.10%); IR (ﬁlm) 3035,

2954, 1736 and 1436 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.60–

7.56 (1H, m, ArH), 7.23–7.16 (3H, m, 3ꢁArH), 5.62 (1H,

d, J 2.2 Hz, CH₂]), 5.11 (1H, d, J 0.8 Hz, CH₂]), 4.23

(1H, dd, J 8.0 and 5.3 Hz, CH), 3.74 (3H, s, CO₂Me), 3.64

and 3.55 (2ꢁ3H, 2ꢁs, 2ꢁCCO₂Me), 3.24 (1H, d, J

16.0 Hz, CCH₂C]), 3.05 (1H, ddd, J 16.0, 2.2 and

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and malononitrile (79 mg, 1.20 mmol). Column

chromatography afforded the product (15d) (42%) as a col-

ourless oil. (Found: C, 72.30; H, 5.60; N, 10.35; C₁₆H₁₄N₂O₂

requires C, 72.15; H, 5.30; N, 10.50%); IR (ﬁlm) 3029,

2954, 1735 and 1437 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.72–

7.68 (1H, m, ArH), 7.36–7.27 (2H, m, 2ꢁArH), 7.23–7.18

(1H, m, ArH), 5.87 (1H, d, J 1.4 Hz, CH₂]), 5.29 (1H, d,

J 1.4 Hz, CH₂]), 4.12 (1H, dd, J 8.5 and 4.1 Hz, CH),

3.77 (3H, s, CO₂Me), 3.25 (2H, t, J 1.4 Hz, CCH₂C]),

3.02 (1H, dd, J 16.4 and 4.1 Hz, CH₂CO), 2.75 (1H, dd,

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6165

J 16.4 and 8.5 Hz, CH₂CO); m/z (%) (EI) 266 (M⁺, 8), 240

(81), 179 (100), 166 (66) and 128 (60).

J 18.1 Hz, CH₂CO), 3.82 (3H, s, CO₂Me), 3.20 (1H, dd,

J 18.1 and 9.0 Hz, CH), 3.02 (2H, s, CCH₂C]); m/z (%)

(EI) 355 (M⁺ꢂHSO₂Ph, 23), 323 (70), 294 (55), 281 (70),

215 (76), 154 (48), 141 (76), 77 (100) and 51 (52).

3.6.5. 2-(2,2-Bis-benzenesulfonyl-4-methylene-1,2,3,4-

tetrahydronaphthalen-1-yl)-1-phenyl-ethanone (16a).

3.6.7. 3⁰⁰,3⁰⁰-Dimethyl-4-methylene-1-(2-oxo-2-phenyl-

ethyl)-3,4-dihydro-1H-naphthalene-spiro[2,2]cyclohex-

ane-1⁰⁰,1⁰⁰-dione (17a).

6'

5'

4'

3'

6'

5'

1'

O

SO₂Ph

1

8

8a

4a

4'

3'

7

6

3

_1'O

4''

2''

O

5

8

1

8a

4a

7

6

³O

5

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and bis(phenylsulfonyl)methane (592 mg,

2.00 mmol). Column chromatography afforded the product

(16a) (141 mg, 52%) as a colourless oil, which crystallised

from ethanol/water as colourless needles, mp 152–154 ^ꢀC.

(Found: C, 68.40; H, 4.75; C₃₁H₂₆O₅S₂requires C, 68.60;

H, 4.85%); n/max (Nujol mull) 1683, 1334, 1154 and

1075 cm^ꢂ1; d_H(500 MHz, CDCl₃), 8.21 (2H, d, J 7.9 Hz,

2ꢁArH), 8.12 (2H, d, J 7.4 Hz, 2ꢁArH), 8.06 (2H, d, J

9.1, 2ꢁArH), 7.70 (1H, t, J 7.4 Hz, ArH), 7.63 (1H, t, J

7.4 Hz, ArH), 7.59–7.45 (8H, m, 8ꢁArH), 7.15–7.11 (2H,

Prepared by the general procedure from (5a) (334 mg,

1.00 mmol) and dimedone (280 mg, 2.00 mmol). Column

chromatography afforded the product (17a) (216 mg, 56%)

as a pale yellow amorphous solid, mp 57–59 ^ꢀC. (Found

HRMS: 387.1955; C₂₆H₂₆O₃(MH⁺) requires 387.1960); n/

max (Nujol mull) 1727, 1693, 1596 and 1579 cm^ꢂ1; d_H

(500 MHz, CDCl₃), 7.77–7.75 (2H, m, ArH), 7.58 (1H, dd,

J 7.8 and 0.8 Hz, ArH), 7.50 (1H, t, J 7.3 Hz, ArH), 7.38

(2H, t, J 7.8 Hz, 2ꢁArH), 7.17 (1H, td, J 8.8 and 1.3 Hz,

ArH), 7.12 (1H, d, J 7.3 Hz, ArH), 7.08 (1H, td, J 7.3 and

1.3 Hz, ArH), 5.69 (1H, t, J 1.6 Hz, ]CH), 5.25 (1H, t, J

1.6 Hz, ]CH), 4.46–4.44 (1H, m, CH¹), 3.30 (1H, dt, J

17.7₀and 1.6 Hz, CH³), 3.18 (1H, dd, ₀₀J 17.7 and 8.1 Hz,

CH¹), 3.15 (1H, d, J 14.3 Hz, CH²), 3.04 (1H, d, J

m, 2ꢁArH), 6.83–6.81 (1H, m, ArH), 5.59 (1H, d, J

0

1.8 Hz, ]CH), 4.94 (1H, d, J 19.3 Hz, CH¹), 4.87 (1H, d,

0

J 8.1 Hz, CH¹), 4.61 (1H, s, ]CH), 3.98 (1H, dd, J 19.3

and 8.1 Hz, CH¹), 3.03 (1H, d, J 15.7 Hz, CH³), 2.96 (1H,

0

d, J 15.7 Hz, CH³); d_C(126 MHz, CDCl₃), 198.4 (C²),

137.7, 136.5, 136.5, 136.4, 135.6, 134.7, 134.6, 133.5,

132.7, 132.1, 131.6, 129.1, 129.0, 128.7, 128.5, 128.1,

00

0

13.6 Hz, CH²), 2.94 (1H, td, J 17.7 and 3.4 Hz, CH¹and

00

CH³), 2.44 (1H, dd, J 14.3 and 2.5 Hz, CH²), 2.24 (1H,

126.5, 126.5, 123.5, 112.7 (]CH₂), 90.2 (C²), 42.0 (C¹),

00

0

dd, J 1₀3.6 and 2.5 Hz, CH²), 1.22 (3H, s, Me⁴), 0.81 (3H,

37.0 (C¹), 36.6 (C³); m/z (%) (ES) 565 (MNa⁺, 100), 543

(42), 371 (63), 338 (69) and 331 (42).

0

s, Me⁴); d_C(126 MHz, CDCl₃), 207.7 (C¹), 206.4 (C¹),

0

197.3 (C²), 139.49, 136.6, 135.1, 134.7, 133.4, 128.6,

128.2, 128.1, 128.0, 127.9, 124.8, 111.3 (]CH₂), 69.4

3.6.6. Methyl (4-methylene-2,2-bis(phenylsulfonyl)-

1,2,3,4-tetrahydro-1-naphthalenyl)-acetate (16d).

00

0

(C²), 51.8 (C²), 50.8 (C²), 42.8 (C¹), 41.2 (C¹), 31.0

00

(C³), 30.4 (C⁴), 28.2 (C³), 26.9 (C⁴); m/z (%) (CI) 387

(MH⁺, 10), 369 (22), 236 (41), 219 (100) and 96 (37).

MeO₂C

SO₂Ph

3.6.8. Methyl (4,4-dimethyl-4⁰-methylene-2,6-dioxo-3⁰,4⁰-

dihydro-1⁰H-spiro[cyclohexane-1,2⁰-naphthalen]-1⁰-yl)-

acetate (17d).

SO₂Ph

O

MeO₂C

Prepared by the general procedure from (5d) (288 mg,

1.00 mmol) and bis(phenylsulfonyl)methane (356 mg,

1.20 mmol). Column chromatography afforded the product

(16d) (60%) as a white powder, which crystallised from

ethyl acetate/petroleum ether as colourless prisms, mp 139–

140 ^ꢀC. (Found: C, 62.80; H, 4.95; S, 12.80; C₂₆H₂₃O₆S₂re-

quires C, 63.00; H, 4.70; S, 12.95%); IR (ﬁlm) 3065, 2952,

1733, 1447, 1329 and 1155 cm^ꢂ1; d_H(250 MHz, CDCl₃),

8.15–8.04 (4H, m, ArH), 7.71–7.61 (2H, m, ArH), 7.57–

7.48 (4H, m, ArH), 7.38 (1H, dd, J 7.7 and 1.4 Hz, ArH),

7.24 (1H, d, J 6.0 Hz, ArH), 7.22–7.13 (1H, m, ArH), 6.99

(1H, d, J 7.8 Hz, ArH), 5.53 (1H, s, CH₂]), 4.64 (1H, s,

CH₂]), 4.45 (1H, d, J 9.0 Hz, CH₂CO), 4.26 (1H, d,

O

Prepared from (5d) (288 mg, 1.00 mmol) and dimedone

(168 mg, 1.20 mmol). Column chromatography afforded

the product (17d) (64%) as a pale yellow oil. (Found: C,

73.85; H, 7.4; C₂₁H₂₄O₄requires C, 74.1; H, 7.1%); IR

(ﬁlm) 2955, 1729, 1695 and 1436 cm^ꢂ1; d_H(500 MHz,

CDCl₃), 7.58 (1H, dd, J 1.2 and 1.2 Hz, ArH), 7.23–7.20

(1H, m, ArH), 7.16–7.12 (1H, m, ArH), 7.09 (1H, dd, J 7.7

6166

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

and 7.7 Hz, ArH), 5.56 and 5.19 (2ꢁ1H, 2ꢁt, J 1.9 Hz,

CH₂]), 4.06 (1H, m, CH), 3.59 (3H, s, CO₂Me), 3.17

(1H, dt, J 17.4 and 1.9 Hz, CCH₂C]), 3.08 (1H, dd, J

14.2 and 0.5 Hz, CCH₂CO), 2.94 (1H, d, J 13.6 Hz,

CCH₂CO), 2.89 (1H, dt, J 17.4 and 1.9 Hz, CCH₂C]),

2.47 (1H, dd, J 14.2 and 2.5 Hz, CCH₂CO), 2.38 (2H, m,

CH₂CO₂Me), 2.22 (1H, dd, J 13.6 and 2.5 Hz, CCH₂CO),

1.20 and 0.80 (2ꢁ3H, 2ꢁs, Me); m/z (%) (ES) 363

(M⁺+Na, 100).

suspension of lithium aluminium hydride (0.49 g,

12.90 mmol, 1.80 mol equiv) in ether (20 ml) at 0 ^ꢀC. The

reaction mixture was allowed to reach rt, stirred at rt for

3 h, and quenched by the sequential dropwise addition of

water (0.5 ml), aqueous sodium hydroxide (15%, 0.5 ml)

and water (3 ml). The precipitate was ﬁltered and the solids

washed with ether (4ꢁ10 ml). The combined organic ﬁl-

trates were dried (MgSO₄) ﬁltered and the ﬁltrate evaporated

under reduced pressure to afford the product (27) (0.89 g,

47%) as a pale yellow oil, which was used without further

puriﬁcation. (Found HRMS: 267.1167; C₁₃H₁₈N₂O₂S

(MH⁺) requires 267.1168); n/max (ﬁlm) 3368, 2924, 1955,

1597, 1494 and 1450 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.70

(2H, d, J 8.3 Hz, 2ꢁArH), 7.30 (2H, d, J 8.3 Hz, 2ꢁArH),

4.92 (1H, pentet, J 6.8 Hz, ]CH), 4.74–4.70 (2H, m,

CH₂), 3.85 (2H, dt, J 7.1 and 2.5 Hz, CH₂), 3.21 (2H, t, J

6.3 Hz, CH₂), 2.87 (2H, t, J 6.3 Hz, CH₂), 2.43 (3H, s,

Me), 1.33 (2H, br s, NH₂).

3.6.9. N-Buta-2,3-dien-1-yl-N-(2,2-dimethoxyethyl)-4-

methylbenzenesulfonamide (24). Prepared by the literature

method.¹⁶

3.6.10. N-Buta-2,3-dienyl-N-(2-oxoethyl)-4-methylbenz-

ene-4-sulfonamide (25). Prepared by the literature

method.¹⁶

3.6.11. N-Buta-2,3-dienyl-N-(2-(Z)-hydroxyimino-ethyl)-

4-methylbenzenesulfonamide (26).

3.7. General procedure for the three-component

allenylation/anion-capture/Michael addition cascade

using (27)

OH

N

A stirred mixture of aryl iodide (0.50 mmol), (27) (266 mg,

1.00 mmol, 2.00 mol equiv), potassium carbonate (138 mg,

1.00 mmol, 2.00 mol equiv), palladium acetate (11 mg,

0.05 mmol, 0.05 mol equiv) and triphenylphosphine

(26 mg, 0.10 mmol, 0.10 mol equiv) in acetonitrile (10 ml)

was heated at 55 ^ꢀC for 18 h. The mixture was cooled to

rt, ﬁltered and the solids washed with ether (2ꢁ10 ml).

The combined organic ﬁltrates were evaporated under

reduced pressure and the organic residue was partitioned

between ether (25 ml) and saturated aqueous ammonium

chloride (25 ml). The two layers were separated and the

organic layer washed with brine (25 ml), dried (MgSO₄),

ﬁltered and the ﬁltrate evaporated under reduced pressure.

The residue was puriﬁed by column chromatography eluting

with ether/petrol mixtures.

N

Ts

A solution of sodium acetate trihydrate (4.20 g, 30 mmol,

3.00 mol equiv) and hydroxylamine hydrochloride (1.38 g,

20.00 mmol, 2.00 mol equiv) in water (10 ml) was added

dropwise over 30 min at rt to a stirred solution of (22)

(2.65 g, 10.00 mmol, 1.00 mol equiv) in methanol (20 ml).

The reaction mixture was then heated at 80 ^ꢀC for 20 min

and allowed to stand at rt for 1 h. The solution was parti-

tioned between water (20 ml) and dichloromethane

(20 ml). The layers were separated and the aqueous layer

extracted with dichloromethane (2ꢁ10 ml). The combined

organic extracts were carefully evaporated under reduced

pressure. The residue was puriﬁed by column chromato-

graphy eluting with 1:1 v/v ether/petrol to give Z-(26)

(1.91 g, 68%) as a colourless oil, which crystallised from

ethanol/water as colourless needles, mp 108–110 ^ꢀC. (Found

HRMS: 281.0960; C₁₃H₁₆N₂O₃S (MH⁺) requires 281.0961);

3.7.1. 2-[11-Methylene-2-(4-methyl-phenyl-sulfonyl)-

1,3,4,6,6a,10a,11,12-octahydro-2H-pyrazino[1,2-b]iso-

quinolin-6-yl]-1-phenyl-ethanone (28).

n/max (Nujol mull) 3203, 1957, 1599, 1338 and 1159 cm^ꢂ1

;

6'

5'

d_H(250 MHz, CDCl₃), 7.71 (2H, d, J 8.2 Hz, 2ꢁArH), 7.62

(1H, br s, OH), 7.33 (2H, d, J 8.2 Hz, 2ꢁArH), 6.79 (1H, t, J

4.4 Hz, CH), 4.98 (1H, pentet, J 6.9 Hz, ]CH), 4.77–4.71

(2H, m, CH₂), 4.10 (2H, d, J 4.4 Hz, CH₂), 3.84 (2H, dt, J

6.9 and 2.2 Hz, CH₂), 2.44 (3H, s, Me); m/z (%) 280 (M⁺,

4), 257 (57), 104 (100) and 77 (47).

4'

3'

1'

O

7

4

1

⁶N

6a

8

9

3

O

12

N

10a

S

10

H

O

2''

3.6.12. N-(2-Amino-ethyl)-N-buta-2,3-dienyl-4-methyl-

benzenesulfonamide (27).

3''

Prepared by the general procedure from (5a) (167 mg,

0.50 mmol). Column chromatography afforded the anti-

product (28) (111 mg, 47%) as a colourless amorphous solid,

mp 132–134 ^ꢀC. (Found HRMS: 473.1894; C₂₈H₂₈N₂O₃S

(MH⁺) requires 473.1894); n/max (Nujol mull) 1680,

1593, 1578 and 1165 cm^ꢂ1; anti-(28)₀: d_H(500 MHz,

NH₂

N

Ts

A solution of (26) (2.0 g, 7.10 mmol, 1.00 mol equiv) in

ether (4 ml) was added dropwise over 30 min to a stirred

CDCl₃), 7.79 (2H, d, J 7.1 Hz, 2ꢁArH⁴), 7.61 (2H, d, J

00

8.2 Hz, 2ꢁArH²), 7.51–7.49 (2H, m, 2ꢁArH), 7.39 (2H,

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6167

00

t, J 8.0 Hz, 2ꢁArH), 7.28 (2H, d, J 8.2 Hz, 2ꢁArH³), 7.18

(1H, td, J 7.5 and 1.6 Hz, ArH), 7.13–7.05 (2H, m, ArH⁷and

ArH), 5.81 (1H, d, J 2.0 Hz, ]CH), 5.38 (1H, d, J 2.0 Hz,

]CH), 4.49 (1H, dd, J 7.3 and 5.7 Hz, CH⁶), 3.79–3.77

J 7.1 Hz, CH⁶), 3.72–3.70 (1H, m, CH¹²), 3.48 (1H, br d,

CH¹), 3.26 (1H, br s, CH³), 3.01 (1H, br s, CH¹), 2.97–

2.93 (1H, m, CH⁴), 2.89–2.88 (1H, br t, CH³), 2.84–2.81

0

(1H, m, CH⁴), 2.77 (1H, dd, J 16.6 and 7.1 Hz, CH¹), 2.48

0

(1H, m, CH¹²), 3.51 (1H, br d, CH¹), 3.41 (1H, dd, J 15.9

(1H, dd, J 16.6 and 7.1 Hz, CH¹), 2.42 (3H, s, Me); d_C

(126 MHz, CDCl₃), 143.9, 137.2, 134.4, 132.4, 132.0,

129.8, 128.5, 128.2, 127.8, 126.8, 124.7, 117.9, 113.3

(]CH₂), 60.8 (C⁶), 54.2₀(C¹²), 50.0 (C¹), 49.4 (C³), 45.8

(C⁴), 21.5 (Me), 20.3 (C¹).

0

and 5.7 Hz, CH¹), 3.35 (1H, br d, CH³), 3.06 (1H, dd, J

0

15.9 and 7.3 Hz, CH¹), 2.93 (1H, dd, J 8.2 and 4.6 Hz,

CH⁴), 2.75–2.43 (3H, m, CH⁴, CH³and CH¹), 2.39 (3H, s,

0

Me); d_C(126 MHz, CDCl₃)₀, 198.6 (C²), 143.7, 138.9,

0

138.2 (C³), 137.3, 133.2 (C⁶), 132.4, 132.0 (C^10a), 129.7

00

(C²), 128.6, 128.0, 127.9, 127.8, 127.5, 126.6, 124.4,

Enhancement (%)

112.1 (CH₂), 59.8 (C⁶), 55.6 (C¹²), 50.7 (C¹), 49.7 (C⁴),

0

45.7 (C³), 39.2 (C¹), 21.5 (Me); m/z (%) (ES) 473 (MH⁺,

100), 353 (17) and 270 (36).

4

1

Irradiated

proton

2.97– 2.84–

2.93 2.81

ppm ppm

6

12

3.48 3.01 2.77 2.48 ═CH₂

7

ppm ppm ppm ppm

6

—

0

4.3

—

4.8

—

4.4

—

1.8

4.3

—

2.2

2.8

—

1.5

—

10

—

Enhancement (%)

4

2.93

ppm

1

3.51

ppm

1

3.41

ppm

1

12

—

Irradiated

proton

6

12

0

3.06

ppm

═CH₂

—

4

2.97–2.93

ppm

9.2

—

10.6

—

6

—

4.0

—

4.0

—

1.6

4.6

—

1.3

2.1

—

1

10

3.7

5.4

3.9

—

8.1

—

4.3

3.7

—

3.48 ppm

12

0

—

1.6

—

1

—

7.4

—

3.01 ppm

4

10.1

—

2.93 ppm

1

3.8

3.7

—

23.2

—

2.77 ppm

1

8.0

5.5

3.1

—

4.1

—

3.51 ppm

1

—

22.9

—

2.48 ppm

1

2.4

2.9

—

22.8

—

3.41 ppm

1

—

21.3

—

3.06 ppm

syn-(29): d_H(500 MHz, CDCl₃, 6:1 enriched sample), 7.69

00

(2H, d, J 8.3 Hz, 2ꢁArH²), 7.49 (1H, d, J 6.9 Hz, ArH),

00

7.36 (2H, dd, J 8.3 Hz, 2ꢁArH³), 7.31–7.28 (2H, m,

2ꢁArH), 7.09 (1H, d, J 6.9 Hz, ArH), 5.60 (1H, s, ]CH),

5.03 (1H, s, ]CH), 4.00–3.92 (2H, m, CH⁶and CH¹),

3.69–3.61 (1H, br s, CH⁴), 3.23 (1H, br d, CH¹²), 3.13 (1H,

3.7.2. (D/L) 11-Methylene-2-(4-methyl-phenyl-sulfo-

nyl)-1,3,4,6,6a,10a,11a,12-octahydro-2H-pyrazino[1,2-

b]isoquinolin-6-yl-acetonitrile (29).

br d, CH³), 2.76 (1H, td, J 10.9 and 2.8 Hz, CH³), 2.68

0

(1H, dd, J 16.7 and 4.8 Hz, CH¹), 2.62 (2H,₀br d, CH¹and

CH⁴), 2.56 (1H, dd, J 16.7 and 5.8 Hz, CH¹), 2.46 (3H, s,

Me); d_C(126 MHz, CDCl₃, 6:1 enriched sample), 144.0,

140.3, 134.7, 133.4, 132.5, 129.9, 128.7, 127.9, 127.8,

126.0, 125.0, 117.6, 109.2 (]CH₂), 60.8 (C⁶), 57₀.3 (C¹²),

50.2 (C³), 48.9 (C¹), 46.1 (C⁴), 21.6 (Me), 20.3 (C¹).

NC

1'

7

4

1

⁶N

6a

8

9

3

O

12

N

10a

S

10

H

O

2''

3''

3.7.3. 6-Benzenesulfonylmethyl-11-methylene-2-(4-

methyl-phenyl-sulfonyl)-1,3,4,6,6a,10a,11,12-octahydro-

2H-pryazino[1,2-b]isoquinoline (30).

Prepared by the general procedure from (5b) (128 mg,

0.5 mmol). Column chromatography eluting with 2:3 v/v

ether petrol afforded the product (29) (132 mg, 67%) as

a 2:1 mixture of anti/syn diastereoisomers. (Found: C,

67.10; H, 5.80; N, 10.50; C₂₂H₂₃N₃O₂S requires C, 67.20;

H, 5.90; N, 10.70%); n/max (Nujol mull) 2720, 1347, 1303

and 1165 cm^ꢂ1; m/z (%) (ES) 394 (MH⁺, 100).

6'

5'

4'

3'

O₂S

1'

7

4

1

⁶N

6a

8

9

3

O

12

N

10a

S

anti-(29): crystallised from the mixture as colourless needles

10

H

O

from ethanol/water, mp 124–126 ^ꢀC; d_H(500 MHz, CDCl₃),

2''

00

7.65–7.62 (2H, m, ArH²), 7.60 (1H, ₀d₀d, J 7.7 and 1.5 Hz,

ArH¹⁰), 7.47–7.24 (4H, m, 2ꢁArH³and 2ꢁArH), 7.13

(1H, dd, J 7.4 and 1.6 Hz, ArH⁷), 5.86 (1H, d, J 2.0 Hz,

]CH), 5.43 (1H, d, J 1.8 Hz, ]CH), 4.00 (1H, t,

3''

Prepared by the general procedure from (5e) (185 mg,

0.5 mmol). Column chromatography afforded the product

6168

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

(30) (132 mg, 52%) as a colourless oil, which comprised of

an inseparable 1:1 mixture of syn/anti diastereoisomers.

(Found HRMS: 509.1568; C₂₇H₂₈N₂O₄S₂(MH⁺) requires

509.1569); n/max (Nujol mull) 1336, 1298, 1169 and

3.7.5. (D/L) (7-Methylene-1-nitro-1,3,4,6,7,11b-hexahy-

dro-2H-pyrido[2,1-a]isoquinolin-2-yl)-acetic acid methyl

ester (33). A mixture of (5c) (1.00 mmol, 1.00 mol equiv),

(32) (3.00 mmol, 3.00 mol equiv), potassium carbonate

(1.38 g, 10.00 mmol, 10.00 mol equiv), palladacycle (13)

(20 mg, 0.05 mmol, 0.05 mol equiv) and acetonitrile

(10 ml) in a Schlenk tube was subjected to two freeze-

pump-thaw cycles and then allene gas (1 bar) was added

and the reaction mixture heated at 50 ^ꢀC for 18 h. After cool-

ing to rt, excess allene gas was vented, the crude reaction

mixture ﬁltered and the solids washed with ether

(3ꢁ50 ml). The organic ﬁltrates were combined, dried

(MgSO₄), ﬁltered and the ﬁltrate evaporated under reduced

pressure. The residue was puriﬁed by column chromato-

graphy eluting with 7:3 v/v ether/petrol to afford the product

(33) (148 mg, 47%) as a 4.7:1 mixture of separable diaste-

reoisomers.

1126 cm^ꢂ1

;

anti-(30): d_H(500 MHz, CDCl₃, 9:1 enriched sample), 7.80

00

(2H, d, J 6.8 Hz, 2ꢁArH), 7.59 (2H, d, J 8.1 Hz, 2ꢁArH²),

00

7.58–7.56 (1H, m, ArH¹⁰), 7.40 (2H, d, J 8.1 Hz, 2ꢁArH³),

7.28–7.21 (5H, m, 5ꢁArH), 7.09 (1H, dd, J 5.6 and 3.5 Hz,

ArH⁷), 5.87 (1H, s, ]CH), 5.40 (1H, s, ]CH), 4.35 (1H, dd,

J 9.0 and 4.2 Hz, CH⁶), 3.67 (1H, dd, J 14.9 and 9.0 Hz,

0

CH¹), 3.39 (2H, br s, CH¹²and CH¹), 3.19 (1H, dd, J 14.9

0

and 4.2 Hz, CH¹), 3.15–3.13 (1H, br s, CH³), 2.85–2.80

(1H, m, CH⁴), 2.58–2.52 (2H, m, CH⁴and CH³), 2.51 (3H,

s, Me), 2.04 (1H, br s, CH¹); d_C(126 MHz, CDCl₃), 143.7,

0

140.9 (C³), 135.6 (C¹¹), 133.0, 132.5, 132.4, 129.7, 128.8,

128.4, 127.9, 127.8, 127.6, 127.0 (₀C⁷), 126.5, 124.4 (C¹⁰),

113.4 (]CH₂), 59.1 (C⁶), 58.4 (C¹), 51.8 (C¹²), 48.0 (C⁴),

47.3 (C¹), 45.3 (C³), 21.6 (Me).

CO₂Me

1'

H

O₂N

1

3

4

2

11

¹²N

11a

10

9

H

Enhancement (%)

6

7a

8

4

Irradiated

proton

6

12

4

2.83

ppm

1

═CH₂

7

2.584

–2.52

ppm

3.39 2.04 3.67 2.48

ppm ppm ppm ppm

6

—

6.7

—

Enhancement (%)

12

4.4

4.3

2.8

1.5

Irradiated

proton

H¹²

H¹

H²

H^3l

H³ⁱⁱ

H⁶ⁱ

H⁶ⁱⁱ

H⁷

4

2.83 ppm

4

2.584–2.52

ppm

9.2

—

10.6

—

H¹²

H¹

H²

H³ⁱ

H³ⁱⁱ

H⁶ⁱ

H⁶ⁱⁱ

—

0

—

0

10.5

0

—

5.9

—

2.8

4.2

3.1

—

9.8

—

1.6

3.2

—

1

—

10

—

8.1

—

3.9

—

3.7

—

5.4

—

3.39 ppm

7.4

—

19.3

5.1

—

1

25.7

2.04 ppm

11.5

—

23.3

—

1

—

2.5

—

23.1

—

27.8

5.4

3.67 ppm

1

4.6

22.0

7.2

2.48 ppm

Major diastereoisomer: obtained as colourless thick oil.

(Found: C, 64.40; H, 6.50; N, 8.70; C₁₇H₂₀N₂O₄requires

C, 64.50; H, 6.35; N, 8.60%); n/max (Nujol mull) 1724,

1633, 1542, 1287 and 1170 cm^ꢂ1; d_H(500 MHz, CDCl₃),

7.73 (1H, d, J 8.0 Hz, ArH⁸), 7.27 (1H, t, J 7.5 Hz, ArH⁹),

7.16 (1H, t, J 7.5 Hz, ArH¹⁰), 6.88 (1H, d, J 7.8 Hz,

ArH¹¹), 5.66 (1H, s, ]CH), 5.05 (1H, s, ]CH), 4.79 (1H,

t, J 10.2 Hz, CH¹), 4.30 (1H, d, J 10.2 Hz, CH¹²), 3.91

(1H, d, J 14.1 Hz, CH⁶), 3.68 (3H, s, OMe), 3.43 (1H, d, J

14.1 Hz, CH⁶), 3.24 (1H, td, J 14.1 and 3.1 Hz, CH⁴), 3.15

syn-(30): d_H(500 MHz, CDCl₃, 4:1 enriched sample), 7.84

00

(2H, d, J 7.7 Hz, 2ꢁArH), 7.65 (2H, d, J 8.1 Hz, 2ꢁArH²),

00

7.47 (1H, t, J 7.4 Hz, ArH), 7.39 (2H, d, J 8.1 Hz, 2ꢁArH³),

7.29–7.22 (6H, m, 6ꢁArH), 5.64 (1H, br s, ]CH), 5.05 (1H,

br s, ]CH), 4.43 (1H, br s, CH¹), 3.55–3.43 (3H, m, CH),

3.31 (1H, br s, CH), 3.05 (1H, br s, CH), 2.78–2.63 (1H,

br s, CH), 2.61–2.38 (6H, m, 3ꢁCH and Me).

3.7.4. (E)-3-Methyoxycarbonyl-allyl-ammoniumtriﬂuoro-

acetate (32). (E)-4-tert-Butoxycarbonylamino-but-2-enoic

acid ethyl ester (31) (1.15 g, 5.0 mmol)¹⁸was dissolved in

triﬂuoroacetic acid (10 ml) at 0 ^ꢀC and allowed to warm to

rt over 30 min. The organic solvent was evaporated under re-

duced pressure to give the amine salt 32 (1.19 g, 0.98 mmol)

as a pale yellow oil, which was used without further puriﬁ-

cation. n/max (ﬁlm) 3131, 1783, 1209 and 1165 cm^ꢂ1; d_H

(250 MHz, CDCl₃), 6.86 (1H, dt, J 15.7 and 7.2 Hz, CH),

6.02 (1H, d, J 15.7 Hz, CH), 3.76 (3H, s, Me), 3.39–3.19

(2H, m, CH₂), 2.67 (2H, q, J 7.2 Hz, CH₂); m/z (%) (FAB)

130 (MH⁺, 100).

(1H, dd, J 14.1 and 4.1 Hz, CH⁴), 2.87–2.79 (1H, m, CH²),

0

2.40 (1H, dd, J 16.2₀and 3.4 Hz, CH¹), 2.27 (1H, dd, J

16.2 and 8.4 Hz, CH¹), 1.85 (1H, ddd, J 13.8, 4.1 and 3.1,

CH³), 1.73 (1H, br d, J 13.8 Hz, CH³); d_C(126 MHz,

CDCl₃), 171.2 (C]O), 138.4 (C⁷), 132.6, (C^11a), 131.3

(C^7a), 128.4 (C⁹), 128.2 (C¹⁰), 127.0 (C¹¹), 124.1 (C⁸),

108.7 (]CH₂), 88.4 (C¹), 63.2 (C¹²), 52.3 (C⁴), 51.8 (Me),

0

51.4 (C⁶), 38.2 (C²), 36.4 (C¹), 23.5 (C³); m/z (%) (FAB)

317 (MH⁺, 100), 270 (50), 196 (45) and 143 (22).

Minor diastereoisomer: (undetermined stereochemistry due

to overlapping peaks): obtained as colourless thick oil.

R. Grigg et al. / Tetrahedron 63 (2007) 6152–6169

6169

Polysuk, C.; Sridharan, V. Angew. Chem., Int. Ed. 2005, 44,

7570–7574.

(Found: C, 64.40; H, 6.35; N, 8.70; C₁₇H₂₀N₂O₄requires C,

64.50; H, 6.35; N, 8.60%); n/max (Nujol mull) 1721, 1629,

1282 and 1165 cm^ꢂ1; d_H(250 MHz, CDCl₃), 7.67–7.61

(1H, m, ArH), 7.34–7.19 (3H, m, 3ꢁArH), 5.58–5.54 (2H,

m, ]CH and CH²), 5.06 (1H, s, ]CH), 3.77–3.71 (4H,

m, CH¹²and Me), 3.55 (1H, d, J 12.6 Hz, CH⁴), 3.21 (1H,

8. (a) Gardiner, M.; Grigg, R.; Kordes, M.; Sridharan, V.

Tetrahedron 2001, 57, 7729–7735; (b) Aftab, T.; Grigg, R.;

Ladlow, M.; Sridharan, V.; Thornton-Pett, M. A. Chem.

Commun. 2002, 1754–1755; (c) Gai, X.; Grigg, R. E.;

Rajviroongit, S.; Sridharan, V.; Songarsa, S. Tetrahedron Lett.

2005, 5899–5902.

dq, J 11.6 and 2.5 Hz, CH), 3.14 (1H, d, J 12.6 Hz, CH⁴),

0

2.60–2.40 (4H, m, CH², CH₂¹), 2.19 (1H, ddd, J 16.7, 11.6

and 3.1 Hz, CH³), 1.71–1.62 (1H, m, CH³).

9. Grigg, R.; Martin, W.; Morris, J. T.; Sridharan, V. Tetrahedron

2005, 61, 11380–11392.

10. (a) Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Washington,

M. L.; Woodall, D. E.; Yoganathan, G. Tetrahedron Lett. 2000,

41, 7125–7128; (b) Grigg, R.; Liu, A.; Shaw, D.; Suganthan,

S.; Washington, M. L.; Woodall, D. E.; Yoganathan, G.

Tetrahedron Lett. 2000, 41, 7129–7133; (c) Grigg, R.;

Sridharan, V.; Collard, S.; Gai, X.; Keep, A.; Khamnaen, T.;

Rajviroongit, S.; Zhang, L. Can. J. Chem. 2005, 83, 990–1005.

11. For recent reviews, see: (a) Mather, B. D.; Viswanathan, K.;

Miller, K. M.; Long, T. E. Prog. Polym. Sci. 2006, 31, 487–

531; (b) Lieby-Muller, F.; Simon, C.; Constancieux, T.;

Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432–438; (c)

Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur.

J. Org. Chem. 2006, 26–49; (d) Tunge, J. A.; Burger, E. C.

Eur. J. Org. Chem. 2005, 1715–1726; (e) Bolm, C.; Rantanen,

T.; Schiffers, I.; Zami, L. Angew. Chem., Int. Ed. 2005, 44,

1758–1763; (f) Naoki, T.; Hideo, N. New Methods for the

Asymmetric Synthesis of Nitrogen Heterocycles; Vicario, J. L.,

Badia, D., Carrillo, L., Eds.; Research Signpost: Trivandrum,

India, 2005; pp 149–163; (g) Diez, E.; Fernandez, R.;

Lassaletta, J. M.; Martin-Zamara, E.; Vazquez, J. New

Methods for the Asymmetric Synthesis of Nitrogen

Heterocycles; Vicario, J. L., Badia, D., Carrillo, L., Eds.;

Research Signpost: Trivandrum, India, 2005; pp 165–196; (h)

Comelles, J.; Mareno-Manas, M.; Vallribera, A. Arkivoc

2005, 9, 207–238; (i) Jha, S. C.; Joshi, N. N. Arkivoc 2002, 7,

167–196; (j) Chritoffers, J. Chem.—Eur. J. 2003, 9, 4862–

4867.

12. For a collection of reviews, see: Metal Catalysed Cascade

Reactions; Muller, T. J. J., Ed.; Topics in Organometallic

Chemistry; Springer: Berlin, Heidelberg, 2006; Vol. 19.

13. (a) Gai, X.; Grigg, R. E.; Ramzan, M.; Sridharan, V.; Collard,

S.; Muir, J. Chem. Commun. 2000, 2053–2054; (b) Grigg, R.;

Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44,

6979–6982; (c) Grigg, R.; Zhang, L.; Collard, S.; Ellis, P.;

Keep, A. J. Organomet. Chem. 2004, 689, 170–173; (d)

Evans, P.; Hogg, P.; Grigg, R.; Nurnabi, M.; Hinsley, J.;

Sridharan, V.; Suganthan, S.; Korn, S.; Collard, S.; Muir,

J. E. Tetrahedron 2005, 61, 9696–9704.

Acknowledgements

We thank the EPSRC, the ORS and Leeds University for

support, Johnson Matthey for a loan of Pd(OAc)₂, the Green

Chemistry Centre for Industrial Collaboration and Yorkshire

Forward for funding.

References and notes

€

1. Preliminary communication: Gai, X.; Grigg, R.; Koppen, I.;

Marchbank, J.; Sridharan, V. Tetrahedron Lett. 2003, 44,

7445–7448.

2. Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Kahn, F. A. Chem.

Rev. 2000, 100, 3067–3126.

3. Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576,

65–87.

4. (a) Grigg, R.; Koppen, I.; Rasparini, M.; Sridharan, V. Chem.

€

Commun. 2001, 964–965; (b) Grigg, R.; Kongkathip, N.;

Kongkathip, B.; Luangkamin, S.; Dondas, A. H. Tetrahedron

2001, 57, 7965–7978; (c) Gai, X.; Grigg, R.; Collard, S.;

Muir, J. E. Chem. Commun. 2001, 1712–1713; (d) Grigg, R.;

Kongkathip, N.; Kongkathip, B.; Luangkamin, S.; Dondas,

H. A. Tetrahedron 2001, 57, 9187–9197; (e) Grigg, R.;

Khamnaen, T.; Rajviroongit, S.; Sridharan, V. Tetrahedron

Lett. 2002, 43, 2601–2603; (f) Grigg, R.; Savic, V.;

Sridharan, V. Tetrahedron 2002, 58, 8613–8620; (g) Grigg,

R.; Kilner, C.; Mariani, E.; Sridharan, V. Synlett 2006, 3021–

3024; (h) Grigg, R.; Cook, A. Tetrahedron 2006, 62, 12172–

12181.

5. (a) Gai, X.; Grigg, R.; Collard, S.; Muir, J. E. Chem. Commun.

2000, 1765–1766; (b) Hopkins, C. D.; Malinakova, H. C. Org.

Lett. 2004, 6, 2221–2224; (c) Hopkins, C. D.; Guan, L.;

Malinakova, H. C. J. Org. Chem. 2005, 70, 6848–6862.

6. (a) Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan, V.

Chem. Commun. 2000, 645–646; (b) Cooper, I. R.; Grigg, R.;

MacLachlan, W. S.; Thoronton-Pett, M.; Sridharan, V. Chem.

Commun. 2002, 1372–1373; (c) Cooper, I. R.; Grigg, R.;

MacLachlan, W. S.; Sridharan, V.; Thoronton-Pett, M.

Tetrahedron Lett. 2003, 44, 403–405; (d) Cooper, I. R.;

Grigg, R.; Hardie, M. J.; MacLachlan, W. S.; Sridharan, V.;

Thomas, W. A. Tetrahedron Lett. 2003, 44, 2283–2285; (e)

Cleghorn, L.; Cooper, I. R.; Fishwick, C. W. G.; Grigg, R. E.;

Sridharan, V.; MacLachlan, W. S.; Rasparini, M.

J. Organomet. Chem. 2003, 687, 483–493; (f) Cleghorn,

L. A. T.; Grigg, R.; Kilner, C.; MacLachlan, W. S.;

Sridharan, V. Chem. Commun. 2005, 3071–3073; (g) Grigg,

R.; McCaffrey, S.; Sridharan, V.; Fishwick, C. W. G.; Kilner,

C.; Korn, S.; Bailey, K.; Blacker, J. Tetrahedron 2006, 62,

12159–12171.

14. Jousse-Karinnthi, C.; Zouhiri, F.; Mahutean, J.; Desmaele, D.

Tetrahedron 2003, 59, 2093–2099.

15. Searles, S.; Li, Y.; Nassim, B.; Lopes, M. R.; Tran, P. T.;

Crabbe, P. J. Chem. Soc., Perkin Trans. 1 1984, 747–751.

16. Kang, S.-K.; Ha, Y.-H.; Ko, B.-S.; Lim, Y.; Jung, J. Angew.

Chem., Int. Ed. 2002, 41, 343–345.

17. CCDC 632378 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

from the Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

18. Allan, R. D.; Dickenson, H. W.; Johnston, G. A. R.;

Kazlauskas, R.; Tran, H. W. Aust. J. Chem. 1985, 38, 1651–

1656.

19. Davey, W.; Gwilt, J. R. J. Am. Chem. Soc. 1957, 79, 1015–

1017.

7. Dondas, H. A.; Fishwick, C. W. G.; Gai, X.; Grigg, R.; Kilner,

C.; Dumrongchai, N.; Kongkathip, B.; Kongkathip, B.;

Article Doi

Synthesis of carbo- and heterocycles via palladium catalysed cascade allene insertion-nucleophile incorporation-Michael addition processes

DOI: 10.1016/j.tet.2007.03.044

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2007.03.044

Full text of DOI:10.1016/j.tet.2007.03.044

Products guided by the article

R&D Labs maybe for 944418-04-6

Relevant to this article

Hot Product