Palladium catalysed queuing processes. Part 4: Termolecular cyclisation-anion capture cascades employing allene as a relay switch and secondary amines as nucleophiles

Article abstract of DOI:10.1016/S0040-4020(02)00763-9

Pd(0) catalysed termolecular queuing processes involving oxidative addition to aryl or vinyl halides followed by cyclisation onto a proximate alkyne or alkene, allene (1atm) insertion and capture of the resulting π-allyl palladium(II) species by secondary

Full text of DOI:10.1016/S0040-4020(02)00763-9

Tetrahedron 58 (2002) 8613–8620
Palladium catalysed queuing processes. Part 4: Termolecular
cyclisation–anion capture cascades employing allene as a relay
switch and secondary amines as nucleophilesq
*
Ronald Grigg, Vladimir Savic, Visuvanathar Sridharan and Catherine Terrier
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
Received 10 May 2002; revised 5 June 2002; accepted 27 June 2002
Abstract—Pd(0) catalysed termolecular queuing processes involving oxidative addition to aryl or vinyl halides followed by cyclisation onto
a proximate alkyne or alkene, allene (1 atm) insertion and capture of the resulting p-allyl palladium(II) species by secondary amines affords
benzo-fused 5–8-membered rings in good yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
molecules for the palladium catalysed cyclisation/allenyl-
ation/amination cascades (Scheme 1(a)). The reaction of
1a–c with allene (1 bar) and pyrrolidine or piperidine
(2 equiv.) in toluene at 1108C in the presence of Pd(0)
(generated in situ from Pd(OAc)2 (10 mol%) and triphenyl-
phosphine (20 mol%)) was then investigated.
In earlier papers we outlined the general concept of relay
switch reactants and their impact on our palladium catalysed
queuing processes.2 At present the most fully developed
relay switches are carbon monoxide and allene, both of
which have proved versatile building blocks in palladium
catalysed processes,3–7 whilst bicyclopropylidine is the
most recent relay switch.1
It was found convenient to carry out these reactions in a
Schlenk tube since allene diffuses readily through an
ordinary balloon. Under these conditions the reaction of
1a–c proceeded according to Scheme 1(a) to afford 2–7
(Table 1, entries 1–6) in good yield.
In this paper we describe full details of termolecular
queuing cascades involving palladium catalysed cyclisation
onto a proximate alkene/alkyne8,9 followed by allene
insertion and capture of the resulting p-allyl palladium(II)
species by secondary amines (Scheme 1).
2. Cyclisation onto proximate alkenes
2.1. 5-exo-trig Processes
In this cascade potassium carbonate (2 equiv.) was
employed as base together with tetraethylammonium
Initially we selected 1a–c for evaluation as the ‘zipper’
Scheme 1.
q See Ref. 1.
Keywords: nucleophiles; dienylamines; triazoline.
*
Corresponding author. Tel./fax: þ44-113-233-6501; e-mail: r.grigg@chem.leeds.ac.uk
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00763-9

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Table 1. Three component exo-trig cyclisation–allenylation–amination cascades
Entry
1
Zipper
Nucleophile
Product
Yield (%)a
82
1a
2
3
4
1a
1b
1b
76
66
72
5
6
1c
1c
66
60
7
8
8
8
50b
50
b
All reactions were carried out in toluene at 1108C for 25 h and employed 1 mol (1a–c), allene (1 bar), 10 mol% Pd(OAC)2, 20 mol% PPh3, 2 mol equiv.
K2CO3, 1 mol equiv. Et4NþCl2 and 2 mol equiv. secondary amine.
a
Isolated yield.
Xylene, 1408C.
b
chloride (1 equiv.). Tetraalkylammonium chlorides are
commonly used to accelerate the rates of Heck reac-
tions.8–13 Although the precise role of Et4NCl remains
unclear its mode of action is believed to involve three
effects:
anionic species which both stabilises the palladium(0)
species and promotes oxidative addition.
(iii) in common with other quaternary ammonium salts, it
acts as a phase transfer catalyst.
2.2. 6-exo-trig Processes
(i) it favours the conversion of RPdI species to RPdCl
species in which the palladium centre is more
electrophilic, thereby promoting coordination of the
olefin to the metal and promoting cyclisation.
We have briefly explored the palladium catalysed 6-exo-trig
cyclisation/allenylation/amination cascades with substrate
8. When 8 was treated with allene (1 bar) and pyrrolidine or
piperidine (2 equiv.) in the presence of 10 mol% Pd(OAc)2,
(ii) it results in the formation of polychloro palladium(0)

R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
8615
Scheme 2.
Scheme 3.
20 mol% triphenyl phosphine in toluene at 1108C the direct
capture products 11a and 11b, respectively, were formed. In
order to suppress formation of direct capture products the
allene concentration in solution was decreased by both
increasing the reaction temperature (1408C xylene) and
decreasing the pressure of allene to 0.5 bar (at rt). Under
these modified conditions the desired unsaturated amines 9
and 10 were both obtained in 50% yield (Table 1, entries 7
and 8).
case of 18 the product consisted of a 1:1 mixture of E and
Z-isomers.
The mechanism of formation of these types of products has
been discussed by us15,16 and in the case of 13a and b an
alternative to Scheme 2 is one involving a series of
hydropalladation/carbopalladation/amination
(Scheme 3).
steps
3.2. 6-, 7- and 8-exo-dig Processes
One example of a 6-exo-dig cyclisation/allenylation/amina-
tion cascade was studied. Thus carbocycle 20 was efficiently
assembled in 73% yield from 19 (Table 2, entry 5) under the
same conditions employed for 14.
Common by-products from the reactions collected in Table
1 were the amino dienes 13a and b. This type of product was
first reported by Coulson in 197314 and he proposed that
allene dimerisation occurs via complex 12 (Scheme 2). We
have recently developed this process further with phenols15
and active methylene compounds.16
The (2-iodobenzyl)propargyl ether 21 undergoes a 7-exo-
dig termolecular cascade under the same conditions.
Trapping the p-allyl palladium(II) intermediate with
piperidine afforded tetrahydro-2-benzoxepin 22 (68%)
(Table 2, entry 6), whilst trapping with (S )-(þ)-2-prolinol
gave 23 (71%) (Table 2, entry 7).
3. Cyclisation onto proximate alkynes
3.1. 5-exo-dig Processes
A series of 5-exo-dig cyclisation/allenylation/amination
cascades (Scheme 1(b)) were explored with alkynes 14a
and b.
Finally we explored the possibility of forming an eight
membered ring using the above methodology. Thus 24
reacted (toluene 708C, 20 h) with allene (1 bar) and
piperidine (2 equiv.) to give 1:1.4 mixture of 25 and 26 in
43% combined yield (Table 2, entry 8). Hence formation of
the tetrahydro-2-benzoxocin 25 was less efficient due to a
slower rate of cyclisation allowing a competitive direct
allenylation/amination process. A similar strategy to that
Reaction of 14a and b with allene (1 bar) and secondary
amines (2 equiv.) in the presence of a catalyst system
comprising 10 mol% Pd(OAc)2, 20 mol% PPh3 and K2CO3
(1 mol equiv.) proceeded according to Scheme 1(b) to
afford 15–18 in 60–67% yield (Table 2, entries 1–4). In the

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R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
Table 2 (continued)
Entry Zipper Nucleophile
Table 2. Three component exo-dig cyclisation–allenylation–amination
cascades
Product
Yield
(%)a
Yield
(%)a
Entry Zipper
Nucleophile
Product
c
8
24
43
1
2
14a
14a
61
All reactions were carried out in toluene 708C for 20 h and employed
1 mmol 14–24, allen (1 bar), 10 mol% Pd(OAc)2, 10 mol% PPh3,
1 mol equiv. K2CO3 and 2 mol equiv. amine.
67
a
Isolated yield.
1:1 mixture of E/Z-isomers.
1:1.4 mixture of 25 and 26.
b
c
and this allows competitive processes to predominate in
many cases. Thus 15 and N-methylmaleimide on heating in
boiling toluene for 18 h afforded the benzofuran 27 in 84%
yield. A plausible mechanism for this transformation
involves E/Z-diene isomerisation which sets up the requisite
geometry for a 1,5-H shift (Scheme 4).
3
14a
61
4
14b
60b
Scheme 4.
When triazoline dione 28 was used as dienophile the Diels–
Alder reaction occurred in moderate yield (Scheme 5). Thus
22 and 28 were reacted in toluene at 1108C over 36 h to
afford cycloadduct 29 in 44% yield (Scheme 5).
5
19
73
6
21
68
Scheme 5.
An interesting extended cascade resulted when the vinyl
halide 30 was reacted with allene and either pyrrolidine or
piperidine (MeCN, K2CO3 (1 mol equiv.), 708C, 10 h))
using 10 mol% Pd(PPh3)4 as catalyst. The initial product 31
was not detected under these conditions but transformed
into 32a (77%) and 32b (60%), respectively, by a 6p-
electrocyclisation16 (Scheme 6).
7
21
71
employed to suppress formation of 11a,b merits investi-
gation in this case.
5. Conclusions
The three-component cascades result in the formation of
three new bonds, a 5–8 membered ring and an allylic amine.
The observation of direct capture products in the 6-exo-trig
case but not in the 6-exo-dig cases attests to the faster rate of
exo-dig cyclisations compared to exo-trig cyclisation.
Adjusting the solution concentration of the allene sup-
presses direct capture products.
4. Further reaction of the dienylamines
The potential of heterocyclic dienes to participate in Diels–
Alder reactions has been briefly explored in thermal
uncatalysed reactions. These dienes are not very reactive

R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
8617
(s, 3H, NCH3), 2.6 and 2.75 (2£d, 2H, J¼12.0 Hz, CH2 N),
2.1 and 2.3 (2£d, 2H, J¼12.6 Hz, CH2CvC), 1.85–2.1 (br
m, 4H, N(CH2)2) and 1.3–1.55 (m, 9H, (CH2)3 and CH3).
m/z (%): 298 (Mþ, 0.5), 297 (1), 214 (1), 138 (100), 98 (30),
84 (16).
6.1.2. 1,3-Dimethyl-3-(2-pyrrolidin-1-ylmethyl-allyl)-
1,3-dihydro-indole-2-one 3. Prepared by general procedure
A. Flash chromatography eluting with 9:1 v/v dichloro-
methane–methanol containing 2% aqueous ammonia
afforded the product (76%) as pale yellow prisms, mp
77–788C. Found: C, 76.0; H, 8.75; N, 9.55. C18H24N2O
requires C, 76.0; H, 8.45; N, 9.85%. dH 7.25 (m, 2H, ArH),
7.05 (t, 1H, J¼7.2 Hz, ArH), 6.8 (d, 1H, J¼7.2 Hz, ArH),
4.6 and 4.75 (2£s, 2£1H, CvCH2), 3.2 (s, 3H, NCH3), 2.75
and 2.6 (2£d, 2£1H, J¼12.05 Hz, CH2N), 2.55 and 2.4
(2£d, 2H, J¼12.3 Hz, CH2CvC), 2.2 (br m, 4H, N(CH2)2),
1.7 (br m, 4H, (CH2)2) and 1.4 (s, 3H, CH3). m/z (%): 284
(Mþ, 0.1), 214 (1), 124 (100), 84 (19) and 70 (8).
Scheme 6.
6.1.3. 3-Methyl-3-(2-pyrrolidin-1-ylmethyl-allyl)-1-
(toluene-4-sulfonyl)-2,3-dihydro-1H-indole 4. Prepared
by general procedure A. Flash chromatography eluting
with 1:1 v/v petroleum ether–ether containing 1% aqueous
ammonia afforded the product (66%) as colourless amor-
phous powder, mp 85–888C. Found: C, 70.35; H, 7.65; N,
6.4. C25H32N2O2S requires C, 70.75; H, 7.55; N, 6.6%. dH
7.7 (d, 2H, J¼8.1 Hz, ArH), 7.6 (d, 1H, J¼8.1 Hz, ArH),
7.25–7.1 (m, 3H, ArH), 7.05 (d, 1H, J¼7.5 Hz, ArH), 7.0 (t,
1H, J¼7.5 Hz, ArH), 4.7 and 4.9 (2£s, 2£1H, CvCH2),
3.55 and 4.0 (2£d, 2£1H, J¼10.0 Hz, CH2NTs), 2.2–2.5
(m, 4H, NCH2, CH2CvC), 2.35 (s, 3H, ArCH3), 2.2–1.9 (br
m, 4H, N(CH2)2), 1.3–1.55 (br m, 6H, (CH2)3) and 1.05 (s,
3H, CH3). m/z (%): 424 (Mþ, 0.2), 423 (1), 339 (1), 269
(100), 184 (63), 138 (99) and 98 (61).
6. Experimental
Melting points were determined on a Kofler hot stage
apparatus and uncorrected. Mass spectral data were
obtained from a VG Autospec mass spectrometer operating
at 70 eV. Nuclear magnetic resonance spectra were
recorded on Bruker QE 300 and AM 400 machines
operating at 300 and 400 MHz, respectively. Unless
otherwise specified deuterochloroform was used as solvent
with tetramethylsilane as internal standard. Microanalysis
were obtained using a Carlo Erba MOD 11016 instrument.
Thin layer chromatography was carried out on Whatman
PGIL G/UV polyester plates coated with a 0.2 mm layer of
silica gel 60 (Merck 9385). Column chromatography was
performed with silica gel 60 (Merck 9385). Petroleum ether
refers to the fraction with bp 40–608C. Anhydrous
toluene was commercially available (Aldrich). Compounds
1a–c, 8, 14a,b, 21 and 19 have been previously prepared by
us.7,17–19
6.1.4. 3-Methyl-3-(2-pyrrolidin-1-ylmethyl-allyl)-1-
(toluene-4-sulfonyl)-2,3-dihydro-1H-indole 5. Prepared
by general procedure A. Flash chromatography eluting
with 95:5 v/v dichloromethane–methanol containing 1%
aqueous ammonia afforded the product (72%) as pale
yellow needles, mp 93–948C. Found: C, 69.95; H, 7.4; N,
6.5, S, 8.1. C24H30N2O2S requires C, 70.2; H, 7.3; N, 6.8; S,
7.8%. dH 7.75 (d, 2H, J¼7.4 Hz, ArH), 7.6 (d, 1H,
J¼8.0 Hz, ArH), 7.25–7.15 (m, 3H, ArH), 7.05 (d, 1H,
J¼7.4 Hz, ArH), 7.0 (t, 1H, J¼7.4 Hz, ArH), 4.65 and 4.9
(2£s, 2£1H, CvCH2), 3.55 and 4.05 (2£d, 2£1H,
J¼10.0 Hz, CH2NTs), 2.7 and 2.5 (2£d, 2H, J¼11.0 Hz,
NCH2), 2.2–2.45 (m, 6H, N(CH2)2 and CH2CvC), 2.4 (s,
3H, ArCH3), 1.7 (br, 4H, (CH2)2 and 1.1 (s, 3H, CH3). m/z
(%): 410 (Mþ, 0.2), 339 (1), 255 (72), 184 (53), 124 (100)
and 84 (51).
6.1. General procedure A for three-component
cyclisation allenylation/amination cascades of 1a–c
and 8
A mixture of 1a–c (or 8) (0.5 mmol), secondary amine
(1 mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.1 mmol) potas-
sium carbonate (1 mmol) and Et4NCl (0.5 mmol) in dry
toluene (10 ml) was degassed using two freeze, pump, thaw
cycles. Allene (1 bar) was incorporated into the Schlenk
tube and the solution was heated at 1108C in an oil bath for
20 h. The solution was then concentrated and the residue
purified by column chromatography to afford the product.
6.1.5. 1-[2-(3-Methyl-2,3-dihydro-benzofuran-3-
ylmethyl)-allyl]-pyrrolidine 6. Prepared by general pro-
cedure A. Flash chromatography eluting with 9:1 v/v
petroleum ether–ether containing 1% aqueous ammonia
afforded the product (60%) as a pale yellow oil. Found: C,
79.5; H, 9.2; N, 5.2. C18H25NO requires C, 79.7; H, 9.2; N,
5.2%. dH 7.75 (d, 1H, J¼8.0 Hz, ArH), 7.1 (m, 2H, ArH),
6.85 (t, 1H, J¼7.3 Hz, ArH), 4.8 and 5.0 (2£s, 2£1H,
CvCH2), 4.2 and 4.6 (2£d, 2£1H, J¼8.0 Hz, OCH2), 2.55
(s, 2H, CH2N), 2.3 and 2.65 (2£d, 2£1H, J¼13.6 Hz,
6.1.1. 3-Methyl-3-(2-piperidin-1-ylmethyl-allyl)-1-(tolu-
ene-4-sulfonyl)-2,3-dihydro-1H-indole 2. Prepared by
general procedure A. Flash chromatography eluting with
1:1 v/v petroleum ether 40–608C containing 1% aqueous
ammonia afforded the product (82%) as pale yellow
needles, mp 64–658C. Found: C, 76.25; H, 8.95; N, 9.4.
C19H26N2O requires C, 76.5; H, 8.5; N, 9.4%. dH 7.25 (m,
2H, ArH), 7.05 (t, 1H, J¼7.0 Hz, ArH), 6.8 (d, 1H,
J¼7.0 Hz, ArH), 4.65 and 4.75 (2£s, 2£1H, CvCH2), 3.2

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R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
CH2CvC), 2.0–2.3 (br m, 4H, N(CH2)2), 1.3–1.5 (m, 6H,
(CH2)3) and 1.3 (s, 3H, CH3). m/z (%): 270 (Mþ21, 3), 186
(23), 139 (63), 98 (100) and 84 (44).
(61%) was isolated as a pale yellow oil. Found: C, 79.8; H,
8.15; N, 5.3. C17H21NO requires C, 80.0; H, 8.24; N, 5.49%.
dH 7.91 (d, 1H, J¼8.0 Hz, ArH), 7.18 (t, 1H, J¼7.5 Hz,
ArH), 6.82 (m, 2H, ArH), 5.88 (s, 1H, vCH), 5.44 (s, 1H,
vCH), 5.32 (s, 1H, vCH), 5.11 (d, 2H, J¼2.5 Hz, CH2O),
3.01 (s, 2H, CH2N), 2.37 (bs, 4H, piperidine H), 1.58 (m,
4H, piperidine H), 1.42 (m, 2H, piperidine H). d (13C NMR):
165.2, 141.9, 135.9, 130.3, 124.3, 120.1, 118.9, 115.8,
110.6, 76.1, 65.4, 54.6, 25.9 and 24.4. m/z (%): 255 (Mþ,
41), 240 (6), 172 (21), 157 (10), 136 (12), 128 (23), 115
(11), 98 (100), 84 (15), 77 (7) and 55 (13). Found HRMS:
255.1629, C17H21NO requires: 255.1623.
6.1.6. 1-[2-(3-Methyl-2,3-dihydro-benzofuran-3-
ylmethyl)-allyl]-pyrrolidine 7. Prepared by general pro-
cedure A. Flash chromatography eluting with 1:1 v/v
petroleum ether–ether containing 1% aqueous ammonia
afforded the product (61%) as a pale yellow oil. Found: C,
79.1; H, 8.8; N, 5.2. C17H23NO requires C, 79.4; H, 8.95; N,
5.45%. dH 7.1 (m, 2H, ArH), 6.85 (t, 1H, J¼7.3 Hz, ArH),
6.75 (d, 1H, J¼8.0 Hz, ArH), 4.8 and 5.0 (2£s, 2£1H,
CvCH2), 4.2 and 4.6 (2£d, 2£1H, J¼8.5 Hz, OCH2), 2.7
and 2.75 (2£d, 2H, J¼9.0 Hz, NCH2), 2.3–2.6 (m, 6H,
CH2CvC) and N(CH2)2), 1.75 (br m, 4H, (CH2)2) and 1.4
(s, 3H, CH3). m/z (%): 256 (Mþ21, 6) 186 (17), 125 (51), 84
(100) and 70 (44).
6.2.2. {1-[2-Benzofuran-(3E )-ylidenemethyl-ally]-pyrro-
lidine-2-yl}-methanol 16. Prepared by general procedure
B. The product (67%) was isolated as a pale yellow oil.
Found HRMS: 271.1564, C17H21NO2 requires: 271.1572.
dH 7.91 (d, 1H, J¼8.0 Hz, ArH), 7.18 (t, 1H, J¼7.4 Hz,
ArH), 6.83 (m, 2H, ArH), 5.84 (s, 1H, vCH), 5.42 (s, 1H,
vCH), 5.37 (s, 1H, vCH), 5.12 (d, 2H, J¼2.6 Hz, CH2O),
3.65 (dd, 1H, J¼3.5, 10.7 Hz, pyrrolidine H), 3.48 (d, 1H,
J¼13.3 Hz, CH2N), 3.39 (d, 1H, J¼10.6 Hz, pyrrolidine H).
3.11 (m, 1H, pyrrolidine H), 2.95 (d, 1H, J¼13.3 Hz,
CH2N), 2.78 (bs, 1H, OH), 2.66 (m, 1H, pyrrolidine H), 2.34
(q, 1H, J¼7.6 Hz, pyrrolidine H) and 1.62–1.98 (m, 4H,
pyrrolidine H). m/z (%): 271 (Mþ, 13), 240 (100), 171 (66),
150 (12), 128 (19), 114 (35), 84 (18), 70 (11) and 43 (8).
6.1.7. 1-[2-(4-Methyl-isochroman-4-ylmethyl)-ally]-
piperidine 9. Prepared from 8 by general procedure
A. Flash chromatography eluting with 9:1 v/v petroleum
ether–ether containing 1% aqueous ammonia afforded the
product (50%) as a pale yellow oil. Found: C, 80.0; H, 9.5;
N, 4.65. C19H27NO requires C, 80.0; H, 9.45; N, 4.9%. dH
7.4 (d, 1H, J¼7.5 Hz, ArH), 7.1–7.2 (m, 2H, ArH), 6.9 (d,
1H, J¼7.5 Hz, ArH), 4.8 and 5.0 (2£s, 2£1H, CvCH2), 4.8
(s, 2H, PhCH2O), 3.5 and 3.9 (2£d, 2£1H, J¼11.5 Hz,
OCH2), 2.3–2.65 (m, 4H, CH2CvC and NCH2), 2.1 (br m,
4H, N(CH2)2), 1.3–1.6 (m, 6H, CH2)3) and 1.25 (s, 3H, CH3).
m/z (%): 285 (Mþ, 1.8), 139 (43), 98 (100) and 84 (44).
6.2.3. 2-[2-Benzofuran-(3E )-ylidenemethyl-ally]-1,2,3,4-
tetrahydro-isoquinoline 17. Prepared by general procedure
B. The product (61%) was isolated as a pale yellow oil.
Found HRMS: 303.1629, C21H21NO requires: 303.1623. dH
7.96 (d, 1H, J¼8.1 Hz, ArH), 7.03–7.18 (m, 4H, ArH), 6.93
(m, 1H, ArH), 6.78 (m, 2H, ArH), 5.95 (s, 1H, vCH), 5.52
(s, 1H, vCH), 5.43 (s, 1H, vCH), 5.11 (d, 2H, J¼2.6 Hz,
CH2O), 3.65 (s, 2H, NCH2Ar), 3.25 (s, 2H, vCCH2N), 2.87
(t, 2H, J¼5.6 Hz, CH2N) and 2.74 (t, 2H, J¼5.6 Hz,
ArCH2). d (13C NMR): 165.3, 141.6, 136.3, 134.8, 134.4,
130.4, 128.7, 126.6, 126.1, 125.6, 124.4, 124.2, 120.1,
118.5, 116.3, 110.7, 76.1, 64.3, 56.2, 50.4 and 29.0. m/z (%):
303 (Mþ, 33), 286 (6), 184 (23), 172 (28), 157 (11), 146
(100), 132 (42), 117 (22), 103 (11), 91 (14), 84 (42), 77 (12)
and 42 (24).
6.1.8. 1-[2-(4-Methyl-isochroman-4-ylmethyl)-ally]-pyr-
rolidine 10. Prepared from 8 by general procedure A. Flash
chromatography eluting with 95:5 v/v dichloromethane–
methanol containing 1% aqueous ammonia afforded the
product (50%) as a pale yellow oil. Found: C, 79.6; H, 9.5;
N, 5.4. C18H25NO requires C, 79.7; H, 9.2; N, 5.2%. dH 7.35
(d, 1H, J¼7.3 Hz, ArH), 7.1–7.2 (m, 2H, ArH), 6.95 (d, 1H,
J¼7.5 Hz, ArH), 4.8 and 5.05 (2£s, 2£1H, CvCH2), 4.8 (s,
2H, PhCH2O), 3.5 and 3.9 (2£d, 2H, J¼11.5 Hz, OCH2),
2.75 and 2.85 (2£d, 2H, J¼13.8 Hz, CH2N), 2.3–2.6 (m,
6H, CH2CvC and N(CH2)2), 1.75 (br m, 4H, (CH2)2) and
1.25 (s, 3H, CH3). m/z (%): 271 (Mþ, ,1), 124 (43), 119
(18), 91 (12), 84 (100) and 70 (45).
6.2.4. 1-Benzenesulfonyl-3-[2-piperidin-1-ylmethyl-
prop-2-en-(E )-ylidene]-2,3-dihydro-1H-indole 18. Pre-
pared by general procedure B. The product (60%) was
isolated as a pale yellow oil. Found HRMS: 394.1711,
C23H26N2O2S requires: 394.1715. dH 7.89 (d, 1H,
J¼7.8 Hz, ArH), 7.81 (d, 2H, J¼7.8 Hz, ArH), 7.76 (d,
1H, J¼7.8 Hz, ArH), 7.54 (m, 1H, ArH), 7.42 (t, 2H,
J¼7.8 Hz, ArH), 7.22 (t, 1H, J¼7.8 Hz, ArH), 6.89 (t, 1H,
J¼7.8 Hz, ArH), 5.89 (s, 1H, vCH), 5.27 (s, 2H, vCH),
4.56 (d, 2H, J¼2.6 Hz, CH2 ring), 2.95 (s, 2H, CH2N), 2.34
(bs, 4H, piperidine H), 1.55 (m, 4H, piperidine H), 1.41 (m,
2H, piperidine H). m/z (%): 394 (Mþ, 8), 311 (13), 253
(100), 168 (57), 154 (24), 141 (12), 98 (97), 86 (16), 77 (50),
69 (8) and 41 (22).
6.2. General procedure B for cascade cyclisation–allene
insertion–anion capture reactions of 14, 19, 21 and 24
A Schlenk flask containing a mixture of aryl halide
(1.2 mmol), secondary amine (2.4 mmol), K2CO3
(1.2 mmol), Pd(OAc)2 (0.12 mmol) and PPh3 (0.24 mmol)
in toluene (15 ml) was evacuated (water pump) and then
filled with nitrogen two times. After a third evacuation the
flask was filled with allene (1 bar) and the mixture was
heated at 70–758C (oil bath temperature) for 17–20 h. The
solvent was evaporated under reduced pressure, the residue
dissolved in CH2Cl2, washed with water, dried (MgSO4),
filtered and the filtrate evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2,
petroleum ether–ether–ammonia) to afford the product.
6.2.5. 4-[2-Piperidine-1-ylmethyl-prop-2-en-(Z )-yli-
dene]-3,4-dihydro-1H-naphthalene-2,2-dicarboxylic
acid dimethyl ester 20. Prepared by general procedure
B. The product (73%) was isolated as a pale yellow oil.
6.2.1. 1-[2-Benzofuran-(3E )-ylidenemethyl-ally]-piper-
idine 15. Prepared by general procedure B. The product

R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
8619
Found HRMS: 383.2077, C23H29NO4 requires: 383.2096.
dH 7.57 (d, 1H, J¼7.9 Hz, ArH), 7.14 (m, 2H, ArH), 7.03
(m, 1H, ArH), 5.99 (s, 1H, vCH), 5.07 (s, 1H, vCH), 5.00
(s, 1H, vCH), 3.75 (s, 6H, CO2CH3), 3.31 (s, 2H, CH2N),
2.92 (s, 4H, ArCH2þCH2Cv), 2.37 (m, 4H, piperidine H),
1.58 (m, 4H, piperidine H) and 1.42 (m, 2H, piperidine H). d
(13C NMR): 171.2, 142.4, 134.6, 134.3, 132.4, 128.4, 128.3,
128.1, 127.6, 125.1, 116.3, 64.2, 55.1, 54.6, 52.7, 40.0, 35.0,
25.9 and 24.4. m/z (%): 383 (Mþ, 14), 352 (4), 324 (5), 179
(9), 165 (19), 136 (17), 98 (85), 86 (7), 71 (36), 57 (42) and
43 (100).
product (71%) was isolated as a pale yellow oil. Found
HRMS: 299.1878. C19H25NO2 requires: 299.1885. dH 7.19
(m, 4H, ArH), 6.09 (s, 1H, vCH), 5.03 (s, 1H, vCH), 4.72
(s, 1H, vCH), 4.63 (s, 2H, ArCH2O), 4.03 (bs, 2H, CH2O),
3.51 (dd, 1H, J¼3.5, 9.0 Hz, pyrrolidine H), 3.32 (bd, 1H,
pyrrolidine H), 3.19 (d, 1H, J¼13.2 Hz, CH2N), 2.93 (m,
1H, pyrrolidine H), 2.71 (d, 2H, J¼13.5 Hz, CH2N), 2.51 (t,
2H, J¼4.4 Hz, CH2Cv), 2.11 (m, 1H, pyrrolidine H) and
1.89–1.62 (m, 4H, pyrrolidine H). m/z (%): 299 (Mþ, 1),
268 (100), 169 (7), 153 (13), 141 (18), 128 (18), 114 (38), 91
(7), 77 (5), 70 (17), 57 (8) and 41 (15).
6.3. General procedure C for the synthesis of 21 and 24
6.3.5. (1-{2-[4,5-Dihydro-1H-benzo-[o]oxepin-(6Z)-ylide-
nemethyl]-allyl}-piperidine 25. The product (25%) was
isolated as a pale yellow oil. Found HRMS: 297.2086.
C20H27NO requires: 297.2093. dH 7.24 (m, 3H, ArH), 7.03
(m, 1H, ArH), 6.09 (s, 1H, vCH), 4.81 (s, 1H, vCH), 4.62
(s, 3H, ArCH2OþvCH), 3.75 (m, 2H, CH2O), 2.60 (bs, 2H,
CH2N), 2.49 (bm, 2H, CH2Cv), 2.04 (bs, 4H, piperidine
H), 1.71 (m, 2H, CH2CH2CH2) and 1.24–1.58 (m, 6H,
piperidine H). m/z (%): 297 (Mþ, 37), 268 (46), 212 (11),
199 (11), 183 (10), 177 (8), 167 (12), 153 (13), 145 (9), 136
(26), 128 (13), 115 (10), 98 (100), 85 (11), 69 (6), 57 (12)
and 43 (26).
NaH (4.3 mmol, 60% in mineral oil) was added to a stirred
solution of alcohol (4-pentyn-1-ol or 3-butyl-1-ol,
4.0 mmol) in DMF (35 ml) at 08C. Stirring was continued
for 30 min followed by dropwise addition of 2-iodobenzyl
chloride (4.0 mmol) in DMF (3 ml). The mixture was stirred
for a further 15 h allowing it to warm to room temperature.
Ether was then added, the mixture washed with saturated
brine, the organic layer dried (MgSO4), filtered and the
filtrate evaporated under reduced pressure. The residue was
purified by flash column chromatography (SiO2, petroleum
ether–ether) to afford the product.
6.3.6. 1-[2-(2-Pent-4-ynyloxymethyl-phenyl)-ethyl]-
piperidine 26. The product (18%) was isolated as a pale
yellow oil. Found HRMS: 297.2090. C20H27NO requires:
297.2093. dH 7.45 (m, 1H, ArH), 7.25 (m, 2H, ArH), 7.19
(m, 1H, ArH), 5.42 (s, 1H, vCH), 5.05 (d, 1H, J¼1.4 Hz,
vCH), 4.49 (s, 2H, ArCH2O), 3.54 (t, 2H, J¼6.1 Hz,
CH2O), 3.11 (s, 2H, CH2N), 2.45 (bm, 4H, piperidine H),
2.33 (m, 2H, CH2CH2C), 1.94 (t, 1H, J¼2.8 Hz, CH), 1.82
(q, 2H, J¼6.7 Hz, CH2CH2CH2), 1.51–1.61 (m, 4H,
piperidine H) and 1.38–1.51 (m, 2H, piperidine H). m/z
(%): 297 (Mþ, 5), 230 (56), 145 (24), 129 (17), 115 (15), 98
(100), 84 (46), 69 (7), 55 (16) and 41 (25).
6.3.1. 1-(But-3-ynyloxymethyl)-2-iodo-benzene 21. Pre-
pared by general procedure C. The product (61%) was
isolated as a colourless oil. Found: C, 46.05; H, 3.7.
C11H11OI requires: C, 46.15; H, 3.85. dH 7.83 (d, 1H,
J¼7.8 Hz, ArH), 7.46 (d, 1H, J¼7.8 Hz, ArH), 7.38 (t, 1H,
J¼7.8 Hz, ArH), 6.99 (t, 1H, J¼7.8 Hz, ArH), 4.54 (s, 2H,
ArCH2O), 3.67 (t, 2H, J¼7.1 Hz, OCH2), 2.58 (m, 2H,
OCH2CH2) and 2.02 (t, 1H, J¼0.3 Hz, CH). m/z (%): 286
(Mþ, 7), 258 (7), 231 (30), 217 (100), 159 (26), 129 (27),
105 (9), 90 (57), 63 (22) and 39 (34).
6.3.2. 1-Iodo-2-(pent-4-ynyloxymethyl)-benzene 24. Pre-
pared by general procedure C. The product (85%) was
isolated as a colourless oil. Found: C, 47.7; H, 4.25.
C12H13OI requires: C, 48.0; H, 4.33. dH 7.82 (d, 1H,
J¼8.0 Hz, ArH), 7.42 (d, 1H, J¼8.0 Hz, ArH), 7.35 (t, 1H,
J¼8.0 Hz, ArH), 6.98 (t, 1H, J¼8.0 Hz, ArH), 4.48 (s, 2H,
ArCH2O), 3.66 (t, 2H, J¼6.1 Hz, OCH2), 2.37 (m, 2H,
OCH2CH2CH2), 1.96 (t, 1H, J¼2.8 Hz, CH) and 1.87 (q,
2H, J¼6.4 Hz, CH2CH2CH2). m/z (%): 300 (Mþ, 7), 285
(36), 252 (11), 231 (37), 217 (1000), 173 (23), 145 (39), 131
(24), 117 (13), 90 (67), 78 (22) and 41 (28).
6.3.7. 1-[(E )-3-(2,3-Dihydro-benzofuran-3-yl)-2-methyl-
allyl]-piperidine 27. A mixture of diene (21) (0.064 g,
0.25 mmol) and NMM (0.31 g, 0.27 mmol) in toluene
(5 ml) was boiled under reflux for 18 h. The solvent was
evaporated under reduced pressure and the residue purified
by column chromatography (SiO2, 7:3:0.1 v/v/v petroleum
ether–ether–ammonia) to afford the product (0.054 g, 84%)
as a colourless oil that solidified upon standing, mp 39–
40.58C. Found: C, 79.95; H, 8.25; N, 5.3. C17H21NO
requires: C, 80.0; H, 8.24; N, 5.49. dH 7.63 (s, 1H, ArH),
7.59 (d, 1H, J¼7.8 Hz, ArH), 7.44 (d, 1H, J¼8.0 Hz, ArH),
7.25 (m, 2H, ArH), 6.39 (s, 1H, vCH), 3.03 (s, 2H, CH2N),
2.38 (bs, 4H, piperidine H), 1.93 (s, 3H, CH3), 1.56–1.63
(m, 4H, piperidine H) and 1.41–1.52 (m, 2H, piperidine H).
m/z (%): 255 (Mþ, 83), 240 (31), 172 (62), 157 (21), 143
(20), 128 (57), 115 (19), 98 (100), 84 (60), 75 (15) and 43
(82).
6.3.3. 1-{2-[3,4-Dihydro-1H-benzo-[o]oxepin-(5Z)-yli-
denemethyl]-allyl}-piperidine 22. The product (68%)
was isolated as a pale yellow oil. Found HRMS:
283.1928. C19H25NO requires: 283.1936. dH 7.15 (m, 4H,
ArH), 6.11 (s, 1H, vCH), 4.97 (s, 1H, vCH), 4.79 (s, 1H,
vCH), 4.66 (s, 2H, ArCH2O), 4.03 (bm, 2H, CH2O), 2.66
(s, 2H, CH2N), 2.47 (t, 2H, J¼5.1 Hz, CH2Cv), 2.04 (bs,
4H, piperidine H) and 1.23–1.58 (m, 6H, piperidine H). m/z
(%): 283 (Mþ, 42), 254 (15), 230 (8), 198 (17), 185 (6), 167
(14), 155 (28), 136 (42), 128 (30), 115 (27), 98 (100), 84
(40) and 55 (35).
6.3.8. 20-Phenyl-70-(piperidin-1-ylmethyl)-3,4-dihydro-
1H-10H,80H-spiro[2-benzoxepine-5,50-[1,2,4]triazolo[1,2-
a]pyridazine]-10,30(20H)-dione 29. A mixture of diene (21)
(0.048 g, 0.17 mmol) and triazoline dione (28) (0.032 g,
0.19 mmol) in toluene (3 ml) was boiled under reflux for
24 h. An additional amount of (28) (0.016 g, 0.09 mmol)
was then added and the mixture heated under reflux for a
6.3.4. (1-{2-[3,4-Dihydro-1H-benzo-[o]oxepin-(5Z)-ylide-
nemethyl]-allyl}-pyrrolidine-2-yl)-methanol 23. The

8620
R. Grigg et al. / Tetrahedron 58 (2002) 8613–8620
further 12 h. The solvent was evaporated under reduced
pressure and the residue purified by column chromato-
graphy (SiO2, 50:1 v/v ether–ammonia) to afford the
product (0.034 g, 44%) as a viscose oil. Found HRMS:
458.2327, C27H30N4O3 requires 458.2318. dH 7.08–7.59
(m, 9H), 6.03 (s, 1H), 5.02 (d, 1H, J¼15.1 Hz), 4.70 (d, 1H,
J¼15.1 Hz), 4.49 (d, 1H, J¼15.9 Hz), 4.20 (d, 1H,
J¼16.9 Hz), 3.97 (m, 2H), 3.39 (m, 1H), 3.00 (m, 2H),
2.31 (bs, 4H), 2.05 (dd, 1H, J¼4.1, 13.9 Hz), 1.42–1.62 (m,
4H) and 1.38–1.42 (m, 2H). m/z (%): 458 (100), 373 (37),
339 (6), 282 (28), 255 (7), 225 (19), 182 (7), 167 (13), 154
(8), 141 (10), 112 (42), 98 (55), 84 (50), 69 (39), 55 (24) and
45 (21).
6H, J¼7.2 Hz, OCH2Me ). d (13C NMR): 172.3, 136.6,
131.1, 130.1, 118.9, 62.3, 61.4, 58.5, 54.3, 43.0, 41.3, 26.3,
23.4 and 14.0. m/z (%): 347 (Mþ, 87), 346 (100), 302 (8),
274 (48), 201 (62), 175 (27), 129 (64), 109 (38), 84 (61) and
70 (42).
Acknowledgments
We thank the EPSRC and Leeds University for support.
References
6.4. General procedure for the cascade cyclisation–
allene insertion–anion capture reaction of vinyl halide
zipper (30)
1. Part 3: Grigg, R.; von Seebach, M.; de Meijere, A. E. J. Org.
Chem. 2002. in press.
2. Grigg, R.; Redpath, J.; Sridharan, V.; Wilson, D. M.
Tetrahedron 2001, 57, 1347–1359. Anwar, U.; Casaschi, A.;
Grigg, R.; Sansano, J. M. Tetrahedron 2001, 57, 1361–1367.
3. Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576,
65–67.
A Schlenk flask with a mixture of vinyl halide (0.3 mmol),
secondary amine (0.6 mmol), K2CO3 (0.3 mmol) and
Pd(PPh3)4 (0.03 mmol) in acetonitrile (15 ml) was evacu-
ated (water pump) and then filled with nitrogen two times.
After the third evacuation the flask was filled with allene
and the mixture was heated at 70–758C (oil bath
temperature) for 17–20 h. The solvent was evaporated
under reduced pressure, the residue dissolved in CH2Cl2,
washed with water, dried (MgSO4), the solvent evaporated
under reduced pressure and the residue purified by column
chromatography (SiO2, petroleum ether–ether–ammonia)
to afford the product.
4. Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
Rev. 2000, 100, 3067–3125.
¨
5. Grigg, R.; Koppen, I.; Rasparini, M.; Sridharan, V. J. Chem.
Soc., Chem. Commun. 2001, 964–965.
6. Coperet, C.; Negishi, E. I. Org. Lett. 1999, 1, 165–167.
Negishi, E. I.; Coperter, C.; Ma, S.; Liou, S.; Liu, F. Chem.
Rev. 1996, 365.
7. Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan, V.
J. Chem. Soc., Chem. Commun. 2000, 645–646. Anwar, U.;
Grigg, R.; Sridharan, V. J. Chem. Soc., Chem. Commun. 2000,
933–934.
6.4.1. 6-(3,4-Dihydro-2H-quinolin-1-ylmethyl)-1,3,4,5-
tetrahydro-indene-2,2-dicarboxylic acid diethyl ester
32a. The product (77%) was isolated as a colourless oil.
Found: C, 73.2; H, 7.7; N, 3.2. C25H31NO4 requires: C,
73.35; H, 7.58; N, 3.42). dH 7.11 (m, 3H, ArH), 7.09 (m, 1H,
ArH), 5.81 (s, 1H, vCH), 4.21 (q, 4H, J¼7.2 Hz,
OCH2Me), 3.58 (s, 2H, ArNCH2), 3.10 (s, 2H, CH2N),
3.02 (bs, 4H, ArNCH2), 2.88 (t, 2H, J¼6.2 Hz, CH2N), 2.69
(t, 2H, J¼6.0 Hz, ArCH2), 2.31 (bt, 2H, CH2Cv), 2.19 (bt,
2H, CH2Cv) and 1.25 (t, 6H, J¼7.0 Hz, OCH2Me ). d (13C
NMR): 172.3, 135.4, 135.1, 134.4, 131.8, 130.0, 128.6,
126.6, 126.0, 125.5, 120.2, 64.2, 61.5, 59.0, 58.5, 56.2, 50.6,
43.1, 41.3, 29.0, 26.0, 23.4 and 14.0. m/z (%): 409 (Mþ, 45),
336 (15), 275 (11), 201 (33), 171 (28), 145 (32), 132 (56),
104 (28), 84 (100) and 47 (30).
8. Grigg, R.; Savic, V. Tetrahedron Lett. 1996, 37, 6565–6568.
9. Grigg, R.; Sridharan, V.; Terrier, C. Tetrahedron Lett. 1996,
37, 4221–4224.
10. Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
11. Jeffery, T. Tetrahedron Lett. 1985, 26, 2667–2670.
12. Jefferey, T. J. Chem. Soc., Chem. Commun. 1984, 1287–1289.
13. Carlstorom, A. S.; Frejd, T. J. Org. Chem. 1991, 56,
1289–1293.
14. Coulson, D. R. J. Org. Chem. 1973, 38, 1483–1490.
15. Grigg, R.; Kongkathip, B.; Kongkathip, N.; Luangamin, S.;
Dondas, H. A. Tetrahedron 2001, 57, 9187–9197.
16. Grigg, R.; Kongkathip, B.; Kongkathip, N.; Luangamin, S.;
Dondas, H. A. Tetrahedron 2001, 57, 7965–7978.
17. Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.;
Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D.
Tetrahedron 1997, 53, 11803–11826.
6.4.2. 6-Pyrrolidine-1-ylmethyl-1,3,4,5-tetrahydro-
indene-2,2-dicarboxylic acid diethyl ester 32b. The
product (60%) was isolated as a colourless oil. Found: C,
68.95; H, 8.5; N, 3.85. C20H29NO4 requires: C, 69.16; H,
8.36; N, 4.03). dH 5.75 (s, 1H, vCH), 4.20 (q, 4H,
J¼6.9 Hz, OCH2Me), 3.04 (2£s, 6H, CH2CCH2þCH2N),
2.46 (bm, 4H, pyrrolidine H), 2.29 (m, 2H, CH2Cv), 2.20
(m, 2H, CH2Cv), 1.78 (m, 4H, pyrrolidine H) and 1.24 (t,
18. Burns, B.; Grigg, R.; Santhakumar, V.; Sridharan, V.;
Stevenson, P.; Worakun, T. Tetrahedron 1992, 48,
7297–7320.
19. Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52,
11479–11502.