Sonogashira/N-acyliminium ion aromatic π-cyclisation processes: access to tetra- and pentacyclic lactams

Article abstract of DOI:10.1016/j.tet.2008.06.044

Application of the Sonogashira reaction of N-alkynylimides with 2-iodophenol or 2-iodo-N-tosylaniline affords 2-(N-alkylimino)-benzofurans and indoles in good yield. Selective partial reduction of the latter followed by treatment with TsOH generates N-acyliminium ions, which cyclise to afford tetra- and pentacyclic lactams in good yield. The latter are reduced to the analogous cyclic amines by BH₃.

Full text of DOI:10.1016/j.tet.2008.06.044

Tetrahedron 64 (2008) 8952–8962
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sonogashira/N-acyliminium ion aromatic
p-cyclisation processes: access to
tetra- and pentacyclic lactams
*
Ronald Grigg , Visuvanathar Sridharan, David A. Sykes
Molecular Innovation Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry Leeds University, Leeds LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2008
Received in revised form 29 May 2008
Accepted 12 June 2008
Available online 14 June 2008
Application of the Sonogashira reaction of N-alkynylimides with 2-iodophenol or 2-iodo-N-tosylaniline
affords 2-(N-alkylimino)-benzofurans and indoles in good yield. Selective partial reduction of the latter
followed by treatment with TsOH generates N-acyliminium ions, which cyclise to afford tetra- and
pentacyclic lactams in good yield. The latter are reduced to the analogous cyclic amines by BH3.
Ó 2008 Elsevier Ltd. All rights reserved.
O
N
O
1. Introduction
I
Pd(0)/CuI
Base
N
+
We have developed a number of one pot sequential or cascade
protocols, which employ several types of core organic reactions
(1,3-dipolar cycloaddition, Diels–Alder, retro-Diels–Alder, Michael
addition, Knoevenagel condensations) and palladium catalysed
cascade processes.1–7 These combinations result in products
possessing a high degree of complexity, which would otherwise
require tedious and/or technically demanding multistep syntheses.
Tactical combinations of this general type can adopt two broad
strategies in which palladium catalysed cascade either precedes or
follows the core reaction.
X
XH
O
O
1. X = O
2. X = NTs
N-acyliminiumion
generation
O
N
aromatic
π-cyclisation
N
+
X
X
O
As part of our interest in developing palladium catalysed
cascade reactions in a tactical combination with core reactions, we
have explored combinations of Pd(0)/CuI catalysed construction of
benzofurans and indoles, bearing a tethered imide, followed by N-
acyliminium ion formation and electrophilic attack (intramolecular
Mannich reaction) on the furan/pyrrole moiety furnishing tetra-
cyclic products. N-Acyliminium ion chemistry has played an im-
portant role in the construction of cyclic nitrogen compounds. The
use of electron rich-aromatic rings as nucleophilic partners for N-
acyliminium ions has emerged as a powerful tool for the synthesis
of heterocycles and natural products.8,9 The combination of the
above process with palladium/copper catalysed Sonogashira cou-
pling of terminal alkynes10 (containing an imide as the N-acylimi-
nium ion precursor) with 2-iodophenol 1 or 2-iodo-N-tosylaniline
2 would produce novel polycyclic heterocycles (Scheme 1). Our
studies on this combination form the basis of this paper.
Scheme 1.
2. Results and discussion
The N-alkynylimides are easily synthesised from commercially
available starting materials.11–14 Thus a series of succinic 3a–c,
glutaric 4a–c and phthalic 5a,b alkynylimides were readily pre-
pared in good to excellent yield.
O
O
O
N
O
N
( )n
O
O
N
( )n
( )n
a. n=1
b. n=2
c. n=3
3
a. n=1
b. n=2
c. n=3
a. n=2
b. n=3
4
5
The terminal alkynes 3–5 (2 mmol) were then reacted with
either 2-iodophenol (1 mmol) or 2-iodo-N-tosylaniline
1
2
(1 mmol) in the presence of Pd(PPh3)2Cl2 (5 mol %), CuI (13 mol %)
and Et3N (2 mol equiv) in DMF at 60 ꢀC for 18–24 h to give a series
* Corresponding author. Tel./fax: þ44 113 343 6501.
E-mail address: r.grigg@leeds.ac.uk (R. Grigg).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.044

R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
8953
Table 1
Table 1 (continued)
Pd/Cu catalysed coupling of aryl iodides and alkynesa
Entry
15
Alkyne
Aryl iodide
Product
Yieldb (%)
Entry
1
Alkyne
Aryl iodide
Product
Yieldb (%)
73
O
O
N
N
3a
1
5a
2
80
81
N
( )2
O
O
O
O
N
6
Ts
20
O
2
3
4
4a
3b
4b
1
1
1
72
85
81
O
O
7
O
16
5b
2
N
( )3
O
N
Ts
21
N
( )
a
All reactions were carried out in DMF at 60 ꢀC using either 2-iodophenol 1
O
O
O
2
8
(1 mmol) or 2-iodo-N-tosylaniline
2 (1 mmol), Pd(PPh3)2Cl2 (5 mol %), CuI
(13 mol %) and Et3N (2 mol equiv).
O
b
Isolated yield.
N
( )
2
O
of novel 2-substituted benzofurans and N-tosyl protected indoles
6–21 (Table 1).Indoles were formed in slightly higher yields than
the corresponding benzofurans (Table 1) under the conditions
we employed. Others have also reported related palladium cata-
lysed processes to synthesise 2-substituted benzofurans and
indoles.15
9
O
N
5
6
3c
4c
1
1
82
65
( )
3
O
O
10
O
Next we explored the N-acyliminium ion aromatic p-cyclisation
N
processes. N-Acyliminium ions can be generated in situ from a cy-
clic imide in two distinct steps, the first of which is half-reduction
of the imide to give the intermediate hydroxy lactam, which upon
treatment with acid affords the reactive acyliminium species. Re-
duction of imides 6–21 with lithium triethylborohydride16
(1.7 mol equiv, THF, ꢁ78 ꢀC, 20 min) proved to be a convenient
( )
3
O
O
11
O
7
8
5a
5b
1
1
75
73
N
( )
2
O
O
12
method for the preparation of the
the masked N-acyliminium ions in excellent yield (w90%). Purifi-
cation of -hydroxy lactams has been reported to be problematic,
consequently it was deemed more practical to use the crude
hydroxy lactams directly. Thus boiling the crude -hydroxy lactam
derivatives in toluene with 1 mol equiv of p-TsOH$H2O using
a Dean–Stark trap afforded the desired -cyclisation products 22–
a-hydroxy lactams and furnished
a
O
a
-
N
a
( )3
O
O
13
p
34 in 56–77% yields (Table 2). In general, 6-endo-trig cyclisations
were faster and higher yielding than the corresponding 7-endo-trig
cyclisations, as would be expected from typical relative rates of ring
closure (Table 2, entries 3, 4 and 6), whilst 5-endo-trig cyclisations
failed to proceed (Table 2, entries 1, 2, 9 and 10). Attempted re-
duction/cyclisation of 6, 7, 14 and 15 failed to show any lactam
formation after treatment with 1 mol equiv of p-TsOH$H2O and
boiling in toluene for 1 week. Baldwin’s rules of ring closure suggest
that the 5-endo-trig mode of ring closure is unfavourable.17 Gen-
erally, tosyl protected indoles (Table 2) cyclised in a higher yield
than the corresponding benzofurans (Table 2), suggesting that the
O
O
N
N
9
3a
4a
2
2
88
85
O
N
Ts
14
10
N
O
Ts
15
O
N
former are better
22–33 showed two characteristic peaks arising from the NCHbC (
4.75–5.91) and CHbNCHeq 4.15–5.14) (Fig. 1), which are both
p
-nucleophiles. The 1H NMR spectra of lactams
( )
11
3b
2
83
2
O
N
Ts
d
16
(d
O
deshielded, the former because it is adjacent to both an aromatic
ring and nitrogen (bridgehead hydrogen) whilst the latter is adja-
cent to nitrogen and within the nodal plane (deshielding region) of
the carbonyl group.
Finally selected lactams 22, 25, 29 and 31 were reduced, using
borane/THF complex, to the corresponding amines 34–37 in 61–
81% yields.
N
N
N
12
13
4b
3c
2
2
89
74
( )
N
2
O
Ts
17
O
( )
3
O
N
18
Ts
N
N
O
N
N
14
4c
2
65
( )
N
3
O
37
35
N
O
N
34
Ts
36
O
Ts
Ts
19

8954
R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
Table 2
N-Acyliminium ion aromatic
Table 2 (continued)
p
-cyclisationa
Entry
12
Imide
Product
Time (h)
0.5
Yield (%)b
Entry
Imide
Product
Time (h)
168
Yield (%)b
O
O
O
N
N
1
6
dc
17
74
N
29
O
Ts
O
2
3
4
7
8
9
168
0.5
0.5
dc
64
61
N
N
13
14
18
19
3
3
63
67
O
30
N
Ts
O
O
N
N
O
22
31
N
O
Ts
N
O
O
23
N
15
20
1.1
2.1
77
O
N
32
N
Ts
5
6
7
10
11
12
4
4
1
57
63
73
O
24
O
N
16
21
61
O
N
33
N
Ts
a
All reactions were carried out in boiling toluene using a Dean–Stark trap,
-hydroxy lactam (1 mmol) and p-TsOH$H2O (1 mol equiv).
25
a
O
b
Isolated yield.
Reactions failed to proceed.
c
O
N
3. Conclusions
We have successfully carried out consecutive Sonogashira/N-
O
26
acyliminium ion aromatic
p-cyclisation processes to synthesise
O
a series of novel tetracyclic and pentacyclic lactams in good to ex-
cellent yields. The overall process leads to the formation of three
new bonds and two new fused rings.
N
8
9
13
14
3
69
27
O
4. Experimental
4.1. General
O
N
168
dc
All reagents and solvents were purified according to literature
procedures. The term ether refers to diethyl ether and petroleum
ether refers to the fraction with boiling point 40–60 ꢀC. Melting
N
Ts
O
N
10
11
15
16
168
dc
N
n.O.e 3-9%
Ts
O
( )
n
O
Hβ
N
Hax
Heq
N
( )
0.5
69
m
O
N
28
Ts
Figure 1.

R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
8955
points were obtained on a Reichert hot-stage apparatus and are
uncorrected. Microanalyses were determined using a Carlo Erba
MOD 1106 instrument. Mass spectrometric data were recorded on
a V.G.Autospec instrument operating at 70 eV and accurate mo-
lecular weights were determined using perfluorokerosine as an
internal standard. Infrared spectra were recorded on a Nicolet FTIR
spectrophotometer. Nuclear magnetic resonance spectra were
recorded on QE300, AM400 and DRX500 Bruker instruments op-
erating at 300, 400 and 500 MHz, respectively. Deuterochloroform
was used as the NMR solvent with tetramethylsilane as the internal
standard unless otherwise stated. Chemical shifts are given in parts
procedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with ether gave the
product (7) (1.75 g, 72%) as a colourless solid, which crystallised
from ether as colourless prisms, mp 81–83 ꢀC. (Found: C, 68.95; H,
5.40; N, 5.70. C14H13NO3 requires C, 69.10; H, 5.40; N, 5.75%.) d 1.94–
1.98 (m, 2ꢂ1H, J 6 Hz, CH2), 2.67 (t, 4ꢂ1H, J 6 Hz, 2ꢂCH2), 5.11 (s, 2H,
NCH2), 6.63 (s,1H, ArH), 7.20 (2ꢂt, 2ꢂ1H, J 8 Hz, ArH) and 7.45 (2ꢂd,
2ꢂ1H, J 8 Hz, ArH); m/z (%) 243 (Mþ, 100), 214 (21), 198 (21), 187
(38), 186 (29), 172 (15), 159 (23), 145 (48), 144 (43), 131 (79), 118
(10), 102 (11), 89 (13), 77 (26) and 55 (17) cmꢁ1
.
per million (d) downfield from tetramethylsilane and coupling
4.2.3. 1-(2-Benzofuran-2-yl-ethyl)-pyrrolidine-2,5-dione (8)
constants are given in hertz. The following abbreviations are used:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, dd¼double doublet,
dt¼double triplet, m¼multiplet. Flash column chromatography
was performed using silica gel 60 (230–400 mesh) or Kieselgel
GF254 (Merck 7730).
O
N
O
O
4.2. General method for the preparation of 2-substituted
benzofurans/n-protected indoles from aryl halides and
alkynylimides
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-but-3-
ynyl-pyrrolidine-2,5-dione (2.26 g, 15 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with ether gave the
product (8) (2.07 g, 85%) as a colourless solid, which crystallised
from ether as colourless prisms, mp 144–146 ꢀC. (Found: C, 69.00;
H, 5.60; N, 5.95. C14H13NO3 requires C, 69.10; H, 5.40; N, 5.75%.)
Aryl halide (2 mmol), bistriphenylphosphine palladium(II)
chloride (0.049 g, 0.07 mmol), copper(I) iodide (0.048 g,
0.25 mmol) and triethylamine (0.410 g, 4 mmol) were dissolved in
dry DMF (5 mL) and stirred at ambient temperature for 1 h under
an atmosphere of dry nitrogen. The alkynyl imide (3 mmol) was
then added, and the mixture stirred and heated at 60 ꢀC until TLC
analysis indicated that the reaction had gone to completion. The
DMF was removed under reduced pressure, dichloromethane
(50 mL) added and the mixture washed with 5 M NaOH (3ꢂ50 mL),
water, dried (MgSO4), filtered and filtrate evaporated under re-
duced pressure to afford the crude product, which was purified by
flash chromatography.
d
2.68 (s, 4ꢂ1H, 2ꢂCH2), 3.10 (t, 2H, J 7 Hz, CCH2), 3.92 (t, 2H, J 7 Hz,
NCH2), 6.48 (s, 1H, ArH), 7.20 (2ꢂt, 2ꢂ1H, J 7 Hz, 2ꢂArH), 7.45 (2ꢂd,
2ꢂ1H, J 7 Hz, ArH); m/z (%) 243 (Mþ, 9),145 (13),144 (100),131 (25),
115 (8), 77 (10) and 55 (8).
4.2.4. 1-(2-Benzofuran-2-yl-ethyl)-piperidine-2,6-dione (9)
O
N
O
4.2.1. 1-Benzofuran-2-yl-methyl-pyrrolidine-2,5-dione (6)
O
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-but-3-
ynyl-piperidine-2,6-dione (2.48 g, 15 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with ether gave the
product (9) (2.08 g, 81%) as a colourless solid, which crystallised
from ether as colourless rods, mp 102–103 ꢀC. (Found: C, 69.90; H,
5.90; N, 5.55. C15H15NO3 requires C, 70.00; H, 5.90; N, 5.45%.)
O
N
O
O
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-prop-2-
ynyl-pyrrolidine-2,5-dione (2.06 g, 15 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with 6:1 v/v ether/
petroleum ether gave the product (6) (1.68 g, 73%) as a colourless
solid, which crystallised from ether as colourless needles, mp 121–
122 ꢀC. (Found: C, 67.90; H, 4.90; N, 6.00. C13H11NO3 requires C,
d
1.89–1.95 (m, 2H, J 6 Hz, CH2CH2CH2), 2.60–2.66 (m, 2ꢂ2H, J 6 Hz,
2ꢂCH2), 3.02 (t, 2H, J 7 Hz, CCH2), 4.16 (t, 2H, J 7 Hz, NCH2), 6.45 (s,
1H, ArH), 7.14–7.26 (2ꢂt, 2ꢂ1H, J 6 Hz, 2ꢂArH), 7.45 (2ꢂd, 2ꢂ1H, J
7 Hz, ArH); m/z (%) 257 (Mþ, 7), 144 (100), 131 (14), 115 (7), 77 (8)
and 55 (11); nmax (DCM) 3020, 2970, 1725, 1680, 1180 and 765 cmꢁ1
.
68.10; H, 4.85; N, 6.10%.)
d
2.75 (s, 4H, 2ꢂCH2), 4.82 (s, 2H, NCH2),
4.2.5. 1-(3-Benzofuran-2-yl-propyl)-pyrrolidine-2,5-dione (10)
6.71 (s, 1H, ArH), 7.19–7.26 (m, 2ꢂ1H, ArH) and (2ꢂd, 2ꢂ1H, J 7 Hz,
ArH); m/z (%) 229 (Mþ, 100), 201 (23), 200 (50), 184 (34), 172 (23),
157 (28), 146 (26), 145 (25), 131 (73), 118 (25), 102 (21), 89 (17), 77
(32) and 63 (16); nmax(DCM) 3020, 2950, 1775, 1705, 1165 and
O
O
N
750 cmꢁ1
.
O
4.2.2. 1-Benzofuran-2-yl-methyl-piperidine-2,6-dione (7)
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-pent-4-
ynyl-pyrrolidine-2,5-dione (2.48 g, 15 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with ether gave the
product (10) (2.10 g, 82%) as a colourless solid, which crystallised
from ether as colourless needles, mp 97–99 ꢀC. (Found: C, 69.95; H,
6.00; N, 5.45. C15H15NO3 requires C, 70.00; H, 5.90; N, 5.45%.)
O
N
O
O
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-prop-2-
ynyl-piperidine-2,6-dione (2.26 g, 15 mmol) by the general
d
2.05–2.10 (m, 2H, J 7 Hz, NCH2CH2), 2.56 (s, 4H, 2ꢂCH2), 2.81 (t,
2H, J 7 Hz, ArCH2), 3.63 (t, 2H, J 7 Hz, NCH2), 6.43 (s, 1H, ArH), 7.17–

8956
R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
7.26 (m, 2H, J 8 Hz, 2ꢂArH), 7.44 (2ꢂd, 2ꢂ1H, J 8 Hz, ArH); m/z (%)
4.2.9. 1-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl-methyl]-
pyrrolidine-2,5-dione (14)
257(Mþ, 45), 158 (100), 145 (41), 131 (83), 117 (14), 115 (14), 103 (6)
and 77 (19); nmax (DCM) 3070, 2950, 1785, 1705, 1155 and 760 cmꢁ1
.
O
4.2.6. 1-(3-Benzofuran-2-yl-propyl)-piperidine-2,6-dione (11)
N
N
Ts
O
O
O
N
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (3.00 g, 8.04 mmol) and 1-prop-2-ynyl-pyrrolidine-2,5-dione
(1.65 g, 12.06 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 10:1 v/v ether/ethyl acetate gave the
product (14) (2.72 g, 88%) as a pale yellow solid, which crystallised
from DCM/petroleum ether as colourless prisms, mp 185–187 ꢀC.
(Found: C, 62.60; H, 5.00; N, 7.10; S, 8.30. C20H18N2O4S requires C,
O
Prepared from 2-iodophenol (2.20 g, 10 mmol) and 1-pent-4-
ynyl-piperidine-2,6-dione (2.69 g, 15 mmol) by the general pro-
cedure. After 24 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with ether gave the
product (11) (1.76 g, 65%) as a thick colourless oil. (Found: C, 70.55;
H, 6.60; N, 5.30. C16H17NO3 requires C, 70.85; H, 6.30; N, 5.15%.)
62.80; H, 4.75; N, 7.30; S, 8.40%.)
d 2.31 (s, 3H, CH3), 2.46 (s, 4H,
d
1.79–1.87 (m, 2H, CH2), 2.58 (t, 2ꢂ2H, J 7 Hz, 2ꢂCH2), 2.80 (t, 2H, J
2ꢂCH2), 5.19 (s, 2H, NCH2), 6.18 (s, 1H, ArH), 7.16–7.27 (m, 4H, ArH),
7.33 (d, 1H, J 7.7 Hz, ArH), 7.77 (d, 2H, J 8.1 Hz, ArH) and 8.05 (d, 1H, J
8.4 Hz, ArH); m/z (%) 382 (Mþ, 7), 268 (14), 228 (18), 227 (100), 182
(11), 145 (27), 144 (16), 128 (13), 117 (30), 91 (81), 77 (10), 65 (33)
and 55 (50); nmax (DCM) 3060, 2940, 1780, 1710, 1360, 1180 and
7 Hz, CCH2), 3.90 (t, 2H, J 7 Hz, NCH2), 6.44 (s, 1H, ArH), 7.16–7.20
(2ꢂt, 2ꢂ1H, 2ꢂArH), 7.44 (2ꢂd, 2ꢂ1H, J 7 Hz, ArH); m/z (%) 271 (Mþ,
36), 158 (100), 157 (27), 131 (55), 114 (19), 77 (19) and 55 (15).
760 cmꢁ1
.
4.2.7. 2-(2-Benzofuran-2-yl-ethyl)-isoindole-1,3-dione (12)
4.2.10. 1-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl-methyl]-
piperidine-2,6-dione (15)
O
N
O
O
O
N
N
Prepared from 2-iodophenol (1.32 g, 6.0 mmol) and 2-but-3-
ynyl-isoindole-1,3-dione (1.79 g, 9.0 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with 1:1 v/v ether/
petroleum ether gave the product (12) (1.30 g, 75%) as a pale yellow
solid, which crystallised from ether as colourless needles, mp 135–
136 ꢀC. (Found: C, 74.00; H, 4.50; N, 4.85. C18H13NO3requires C,
Ts
O
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (3.00 g, 8.04 mmol) and 1-prop-2-ynyl-pyrrolidine-2,5-dione
(1.65 g, 12.06 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 10:1 v/v ether/ethyl acetate gave the
product (15) (2.72 g, 88%) as a pale yellow solid, which crystallised
from DCM/petroleum ether as colourless prisms, mp 136–138 ꢀC.
(Found: C, 63.70; H, 5.15; N, 7.15; S, 8.05. C21H20N2O4S requires C,
74.20; H, 4.50; N, 4.80%.)
d 3.19 (t, 2H, J 7 Hz, CCH2), 4.09(t, 2H, J
7 Hz, NCH2), 6.49 (s, 1H, ArH), 7.13–7.26 (m, 2H, ArH), 7.37 (d, 1H, J
7.0 Hz, ArH), 7.45 (d, 2H, J 7.0 Hz, ArH), 7.67–7.73 (m, 2H, ArH) and
7.80–7.86 (m, 1H, ArH); m/z (%) 291 (Mþ, 11), 160 (30),144 (100), 131
(22), 115 (9), 114 (7), 77 (25) and 76 (11); nmax (DCM) 3070, 2950,
63.60; H, 5.10; N, 7.05; S, 8.10%.)
d 2.06–2.10 (m, 2H, CH2), 2.32 (s,
1775, 1710, 1400, 1170 and 790 cmꢁ1
.
3H, CH3), 2.80 (t, 2ꢂ2H, J 7 Hz, 2ꢂCH2), 5.45 (s, 2H, N–CH2), 6.08 (s,
1H, ArH), 7.12–7.26 (m, 4H, ArH), 7.32 (d, 1H, J 7.6 Hz, ArH), 7.82 (d,
2H, J 8.3 Hz, ArH) and 8.03 (d,1H, J 8.4 Hz, ArH); m/z (%) 396 (Mþ, 3),
242 (23), 241 (100), 182 (6), 146 (11), 145 (43), 144 (22), 130 (10), 118
4.2.8. 2-(3-Benzofuran-2-yl-propyl)-isoindole-1,3-dione (13)
(14), 91 (31), 65 (12) and 55 (28) cmꢁ1
.
4.2.11. 1-{2-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-ethyl}-
pyrrolidine-2,5-dione (16)
O
O
N
O
O
Prepared from 2-iodophenol (2.20 g, 10.0 mmol) and 2-pent-4-
ynyl-isoindole-1,3-dione (3.20 g, 15.0 mmol) by the general pro-
cedure. After 18 h, the resulting mixture was worked up in the
normal manner. Flash chromatography eluting with 1:2 v/v ether/
petroleum ether gave the product (13) (2.23 g, 73%) as a colourless
solid, which crystallised from ether as colourless plates, mp 104–
106 ꢀC. (Found: C, 74.45; H, 5.00; N, 4.45. C19H15NO3 requires C,
N
N
Ts
O
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.20 g, 5.9 mmol) and 1-but-3-ynyl-pyrrolidine-2,5-dione
(1.34 g, 8.85 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with ether gave the product (16) (1.95 g,
85%) as a pale yellow solid, which crystallised from DCM/petroleum
ether as colourless plates, mp 138–14 ꢀC. (Found: C, 63.70; H, 5.15;
N, 7.0; S, 8.00. C21H20N2O4S requires C, 63.60; H, 5.10; N, 7.05; S,
74.75; H, 4.95; N, 4.60%.) d 2.16 (q, 2H, J 7 Hz, NCH2CH2), 2.84 (t, 2H, J
7 Hz, CCH2), 3.81 (t, 2H, J 7 Hz, NCH2), 6.44 (s, 1H, ArH), 7.10–7.20
(m, 2H, ArH), 7.34 (d, 1H, J 7.5 Hz, ArH), 7.42 (d, 1H, J 7.9 Hz, ArH),
7.64–7.71 (m, 2H, ArH) and 7.77–7.84 (m, 2H, ArH); m/z (%) 305 (Mþ,
72),161 (51),160 (24),158 (91),145 (100),132 (61),117 (38),115 (24)
and 77 (53); nmax (DCM) 3050, 2940, 1775, 1710, 1400, 1170 and
8.10%.)
d
2.32 (s, 3H, CH3), 3.35 (s, 4H, 2ꢂCH2), 3.35 (t, 2H, J 7 Hz,
730 cmꢁ1
.
ArCH2), 3.95 (t, 2H, J 7 Hz, NCH2), 6.43 (s, 1H, ArH), 7.16–7.29 (m, 4H,

R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
8957
ArH), 7.40 (d, 1H, J 7.5 Hz, ArH), 7.63 (d, 2H, J 8.3 Hz, ArH) and 8.13
(d, 1H, J 8.1 Hz, ArH); m/z (%) 396 (Mþ, 6), 297 (20), 242 (42), 241
(100), 233 (17), 220 (22), 155 (17), 143 (26), 142 (47), 130 (28), 129
(24), 115 (19), 91 (65), 65 (28) and 55 (39); nmax (DCM) 3070, 2950,
chromatography eluting with 10:1 v/v ether/hexane gave the
product (19) (1.63 g, 65%) as a pale yellow solid, which crystallised
from DCM/petroleum ether as colourless needles, mp 105–107 ꢀC.
(Found: C, 65.00; H, 5.90; N, 6.35; S, 7.60. C23H24N2O4S requires C,
1775, 1710, 1360, 1170 and 750 cmꢁ1
.
65.10; H, 5.70; N, 6.60; S, 7.55%.)
d
1.91–2.00 (m, 4H, 2ꢂCH2), 2.30 (s,
3H, CH3), 2.65 (t, 4H, J 7 Hz, 2ꢂCH2), 3.01 (t, 2H, J 7 Hz, ArCH2), 3.90
(t, 2H, J 7 Hz, NCH2), 6.45 (s, 1H, ArH), 7.15–7.25 (m, 4H, ArH), 7.39
(d, 1H, J 7.4 Hz, ArH), 7.59 (d, 2H, J 8.0 Hz, ArH) and 8.12 (d, 1H, J
8.1 Hz, ArH); m/z (%) 424 (Mþ, 3), 298 (2), 270 (19), 269 (71), 157
(29), 156 (100), 155 (18), 143 (21), 130 (25), 91 (34) and 55 (24); nmax
4.2.12. 1-{2-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-ethyl}-
piperidine-2,6-dione (17)
O
(DCM) 3070, 2950, 1735, 1680, 1360, 1175 and 780 cmꢁ1
.
N
N
Ts
O
4.2.15. 2-{2-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-ethyl}-
isoindole-1,3-dione (20)
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.20 g, 5.9 mmol) and 1-but-3-ynyl-piperidine-2,6-dione
(1.46 g, 8.85 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with ether gave the product (17) (2.17 g,
89%) as a colourless solid, which crystallised from ether as colourless
prisms, mp 146–148 ꢀC. (Found: C, 64.05; H, 5.40; N, 6.80; S, 7.90.
O
N
N
Ts
O
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.61 g, 7.0 mmol) and 2-but-3-ynyl-isoindole-1,3-dione
(2.24 g, 10.5 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 1:1 v/v ether/petroleum ether gave
the product (20) (2.49 g, 80%) as a pale orange solid that precipitated
from DCM/petroleum ether as a colourless amorphous solid, mp
163–165 ꢀC. (Found: C, 67.75; H, 4.75; N, 6.10; S, 7.20. C25H20N2O4S
C
22H22N2O4S requires C, 64.35; H, 5.45; N, 6.80; S, 7.80%.) d 1.91–1.95
(m, 2H, CH2), 2.31 (s, 3H, CH3), 2.64 (t, 4H, J 6 Hz, 2ꢂCH2), 3.29 (t, 2H, J
7 Hz, ArCH2), 4.21 (t, 2H, J 7 Hz, NCH2), 6.40 (s, 1H, ArH), 7.162–7.26
(m, 4H, ArH), 7.39 (d,1H, J 7.5 Hz, ArH), 7.64 (d, 2H, J 8.0 Hz, ArH) and
8.13 (d,1H, J 8.3 Hz, ArH); m/z (%) 410 (Mþ, 3), 297 (23), 256 (22), 255
(100), 233 (23), 228 (12), 143 (31), 142 (32), 130 (15), 91 (30) and 55
(25); nmax (DCM) 3050, 2960, 1730, 1680, 1350, 1180 and 750 cmꢁ1
.
requires C, 67.55; H, 4.55; N, 6.30; S, 7.20%.)
d 3.46 (t, 2H, J 7 Hz,
4.2.13. 1-{3-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-propyl}-
pyrrolidine-2,5-dione (18)
CCH2), 4.13 (t, 2H, J 7 Hz, NCH2), 6.45 (s, 1H, ArH), 7.10–7.20 (m, 4H,
ArH), 7.37 (d, 1H, J 7.6 Hz, ArH), 7.64–7.72 (m, 4H, ArH), 7.83 (d, 2H, J
8.5 Hz, ArH) and 8.14 (d, 1H, J 8.5 Hz, ArH); m/z (%) 444 (Mþ, 2), 289
(100), 271 (12), 220 (17), 160 (41), 142 (18), 129 (13), 91 (32) and 77
(16); nmax (DCM) 3050, 2930, 1780, 1720, 1360, 1170 and 730 cmꢁ1
.
O
O
N
N
4.2.16. 2-{3-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-propyl}-
isoindole-1,3-dione (21)
Ts
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.20 g, 5.9 mmol) and 1-pent-4-ynyl-pyrrolidine-2,5-dione
(1.46 g, 8.85 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with ether gave the product (18) (1.78 g,
79%) as a pale yellow solid, which crystallised from DCM/petroleum
ether as colourless prisms, mp 132–133 ꢀC. (Found: C, 64.35; H,
5.40; N, 6.75; S, 7.70. C22H22N2O4S requires C, 64.40; H, 5.40; N,
O
O
N
N
Ts
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.98 g, 8.0 mmol) and 2-pent-4-ynyl-isoindole-1,3-dione
(2.56 g, 12.00 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 1:1 v/v ether/hexane gave the prod-
uct (21) (2.97 g, 81%) as a pale orange solid, which crystallised from
DCM/petroleum ether as colourless prisms, mp 138–139 ꢀC.
(Found: C, 67.85; H, 4.85; N, 5.95; S, 7.00. C26H22N2O4S requires C,
6.80; S, 7.80%.) d 2.02–2.10 (m, 2H, NCH2CH2), 2.34 (s, 3H, CH3), 2.72
(s, 4H, 2ꢂCH2), 3.02 (t, 2H, J 7 Hz, ArCH2), 3.66 (t, 2H, J 7 Hz, NCH2),
6.44 (s, 1H, ArH), 7.17–7.26 (m, 4H, ArH), 7.40 (d, 1H, J 7.0 Hz, ArH),
7.59 (d, 2H, J 8.2 Hz, ArH) and 8.13 (d, 1H, J 7.9 Hz, ArH); m/z (%) 410
(Mþ, 8), 256 (26), 255 (83), 157 (33), 156 (100), 155 (30), 143 (34),
130 (36), 91 (55), 77 (8), 65 (20) and 55 (24); nmax (DCM) 3070,
2950, 1785, 1710, 1360, 1180 and 750 cmꢁ1
.
68.10; H, 4.850; N, 6.10; S, 7.00%.)
d 2.15 (q, 2H, J 7 Hz, NCH2CH2)
4.2.14. 1-{3-[1-(Toluene-4-sulphonyl)-1H-indol-2-yl]-propyl}-
3.05 (t, 2H, J 7 Hz, CCH2), 3.80 (t, 2H, J 7 Hz, NCH2), 6.46 (s, 1H, ArH),
7.15 (d, 2H, J 8.0 Hz, ArH), 7.18–7.22 (m, 2H, ArH), 7.40 (d, 1H, J
7.7 Hz, ArH), 7.58 (d, 2H, J 8.4 Hz, ArH), 7.71–7.74 (m, 2H, ArH), 7.84–
7.88 (m, 2H, ArH), 8.15 (d, 1H, J 8.3 Hz, ArH); m/z (%) 458 (3), 303
(68), 186 (12), 160 (44), 156 (100), 143 (15), 130 (28), 91 (28) and 77
piperidine-2,6-dione (19)
O
N
O
(13); nmax (DCM) 3070, 2950, 1775, 1715, 1400, 1175 and 725 cmꢁ1
.
N
Ts
4.3. General procedure for the reduction of imides to
hydroxy lactams
a-
Prepared from N-(2-iodophenyl)-4-methyl-benzenesulphon-
amide (2.20 g, 5.9 mmol) and 1-pent-4-ynyl-piperidine-2,6-dione
(1.59 g, 8.85 mmol) by the general procedure. After 18 h, the
resulting mixture was worked up in the normal manner. Flash
A
THF solution (1 M) of lithium triethylborohydride
(1.7 mol equiv) was added in one portion to a cooled (ꢁ78 ꢀC)

8958
R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
solution of the appropriate imide (1 mmol) in THF (4 mL). The
resulting solution was stirred for 20 min at ꢁ78 ꢀC and then
quenched by the addition of saturated aqueous NaHCO3 (5–10 mL)
and 30% hydrogen peroxide (1–2 mL). The resulting mixture was
stirred for 20 min at 0 ꢀC, the THF removed in vacuo and the
aqueous residue extracted with DCM (3ꢂ50 mL). The combined
organic layers were washed with saturated aqueous NaCl (10 mL),
dried (Na2SO4) and the solvent removed under reduced pressure to
(0.590 g, 3.10 mmol) by the general procedure. After 0.5 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (23) (0.453 g, 61%) as a yellow solid, which crystallised
from DCM/ether as pale yellow prisms, mp 151–152 ꢀC. (Found: C,
74.45; H, 6.00; N, 6.00. C15H15NO2 requires C, 74.65; H, 6.25; N,
5.80%.)
d (400 MHz) 1.64–1.74 (m, 1H, NCHbCHaCH2), 1.81–1.91 (m,
2ꢂ1H, NCHbCH2CH2), 2.33–2.42 (m, 1H, O]CCHa), 2.55–2.61 (m,
1H, O]CCHb), 2.71–2.75 (m, 2ꢂ1H, NCH2CHa and NCHbCHbCH2),
2.79–2.86 (m, 1H, NCH2CHb), 2.92–3.01 (m, 1H, NCHbCH2C), 4.72 (br
d, 1H, J 10.7 Hz, NCHbC), 5.19 (dd, 1H, J 12.5, 5.3 Hz, NCHaCH2C),
7.18–7.25 (2ꢂt, 2ꢂ1H, J 7 Hz, 2ꢂArH) and 7.42–7.46 (2ꢂd, 2ꢂ1H, J
7 Hz, 2xArH); m/z (%) 241 (Mþ, 100), 224 (827), 212 (16), 186 (12),
171 (57), 170 (50), 157 (10), 148 (13), 144 (11), 135 (10), 128 (15), 115
(22) and 77 (6); nmax (DCM) 3070, 2940, 1675, 1365, 1170 and
afford the crude
ther purification.
a-hydroxy lactam, which was used without fur-
4.4. N-Acyliminium ion aromatic
p-cyclisation: general
procedure for the intramolecular Mannich reaction
p-Toluene sulphonic acid monohydrate (1 mmol) was added to
a stirred solution of the crude
a
-hydroxy lactam (1 mmol) in tolu-
750 cmꢁ1
.
ene (20 mL). A Dean–Stark trap and condenser were attached to the
flask. The reaction was heated at reflux under nitrogen until com-
pletion was indicated by 1H NMR monitoring. The solvent was re-
moved in vacuo, the residue dissolved in DCM (50 mL) and washed
with saturated aqueous NaHCO3 (2ꢂ10 mL), saturated aqueous
NaCl (10 mL), dried (Na2SO4) and the solvent removed under re-
duced pressure to afford the crude product. The residue was puri-
fied by flash chromatography.
4.4.3. 1,2,5,6,7,12c-Hexahydro-3H-[1]benzofuro[3,2-c]pyrrolo[1,2-
a]azepin-3-one (24)
3
2
4
O
1
N
5
6
7
O
4.4.1. 1,5,6,11c-Tetrahydro[1]benzofuro[2,3-g]indolizin-
3(2H)-one (22)
Initial treatment of (10) (0.517 g, 2.01 mmol) with a 1 M lithium
triethylborohydride THF solution (3.4 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.382 g, 2.01 mmol) by the general procedure. After 4 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (24) (0.275 g, 57%) as a pale brown solid, which crystallised
from DCM/ether as pale yellow prisms, mp 136–138 ꢀC. (Found: C,
74.85; H, 6.15; N, 5.60. C15H15NO2 requires C, 74.65; H, 6.25; N,
3
2
1
4
O
N
5
6
O
Initial treatment of (8) (0.871 g, 3.58 mmol) with a 1 M lithium
triethylborohydride THF solution (6.10 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.680 g, 3.58 mmol) by the general procedure. After 0.5 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (22) (0.521 g, 64%) as a colourless solid, which crystallised
from DCM/ether as colourless prisms, mp 210–212 ꢀC. (Found: C,
73.95; H, 5.80; N, 6.05. C14H13NO2 requires C, 74.00; H, 5.75; N,
5.80%.)
d
(400 MHz) 2.01–2.08 (m, 2ꢂ1H, NCH2CH and
NCH2CH2CH), 2.16–2.22 (m, 1H, NCHbCHaCH2C]O), 2.49–2.54 (m,
2ꢂ1H, O]CCH2), 2.68–2.77 (m, 1H, NCHbCHbCH2C]O), 2.90–2.98
(m, 2ꢂ1H, NCHbCH2CH2C and NCH2CH2CH), 3.06 (dtd,1H, J 17.2, 5.8,
1.2 Hz, NCH2CH), 4.36 (dt, 1H, J 14.0, 5.1 Hz, NCHaCH2CH2), 4.91–
4.94 (m, 1H, NCHbC), 7.22 (2ꢂt, 2ꢂ1H, 2ꢂArH) and 7.42 (2ꢂd, 2ꢂ1H,
2ꢂArH); m/z (%) 241 (Mþ, 82), 240 (100), 224 (51),184 (22),170 (19),
157 (16), 128 (14), 115 (12), 102 (6) and 77 (8); nmax (DCM) 3050,
6.15%.) d (400 MHz) 1.87–1.99 (m, 1H, NCHbCHaCH2), 2.44–2.53 (m,
2970, 1685, 1330 and 760 cmꢁ1
.
1H, NCHbCH2CH), 2.58–2.72 (m, 2ꢂ1H, NCHbCHbCH2 and
NCHbCH2CH), 2.78–2.83 (m, 1H, NCH2CHb), 2.92–2.97 (m, 1H,
NCH2CHa), 3.03–3.10 (m, 1H, NCHbCH2C), 4.57 (dd, 1H, J 12.7, 5.8 Hz,
NCHaCH2C), 4.87–4.92 (m, 1H, NCHbC), 7.20–7.29 (2ꢂt, 2ꢂ1H,
2ꢂArH), 7.36–7.46 (2ꢂd, 2ꢂ1H, J 7 Hz, 2ꢂArH); m/z (%) 227 (Mþ,
100), 226 (86), 172 (20), 171 (34), 170 (63), 157 (11), 144 (19), 139 (5),
128 (28), 115 (66), 102 (13), 89 (17), 77 (18) and 55 (29); nmax (DCM)
4.4.4. 2,3,6,7,8,13c-Hexahydro[1]benzofuro[3,2-c]pyrido[1,2-
a]azepin-4(1H)-one (25)
3
2
1
3030, 2940, 1680, 1420, 1040 and 765 cmꢁ1
.
O
4
N
5
4.4.2. 1,2,3,6,7,12c-Hexahydro-4H-[1]benzofuro[3,2-a]quinolizin-4-
one (23)
6
7
O
Initial treatment of (11) (0.684 g, 2.52 mmol) with a 1 M lithium
triethylborohydride THF solution (4.3 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.479 g, 2.52 mmol) by the general procedure. After 4 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (25) (0.361 g, 56%) as a yellow solid, which precipitated
from DCM/ether as an amorphous pale yellow solid, mp 92–94 ꢀC.
(Found: C, 75.20; H, 6.85; N, 5.40. C16H17NO2 requires C, 75.25; H,
3
2
1
4
5
N
O
6
7
O
Initial treatment of (9) (0.798 g, 3.10 mmol) with a 1 M lithium
triethylborohydride THF solution (5.3 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate

R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
8959
6.70; N, 5.50%.)
d
(500 MHz) 1.71–1.79 (m, 2H, CHCH2CH2), 1.80–
4.4.7. 7-[(4-Methylphenyl)sulfonyl]-1,2,5,6,7,11c-hexahydro-3H-
1.86 (m, 1H, NCH2CH), 1.98–2.05 (m, 1H, NCHCH), 2.26–2.33 (m, 1H,
NCHCH), 2.36–2.48 (m, 3H, NCH2CH and O]CCH2), 2.74–2.81 (m,
2H, CHNCH and NCH2CH2CH), 2.87–2.91 (dddd, 1H, J 15.7, 11.7, 7.3,
1.6 Hz, NCH2CH2CH), 4.36 (dd,1H, J 13.7, 6.7 Hz, CHNCH), 4.75 (t,1H,
J 6.7 Hz, NCHC), 7.18–7.24 (m, 2H, ArH) and 7.37–7.42 (m, 2H, ArH);
m/z (%) 255 (Mþ,100), 238 (17), 227 (11),199 (12),185 (95),184 (49),
170 (27), 158 (33), 157 (26), 128 (18), 115 (15) and 77 (8); nmax (DCM)
indolizino[7,8-b]indol-3-one (28)
3
2
1
4
O
N
5
6
N
3070, 2960, 1650, 1460, 1095 and 750 cmꢁ1
.
Ts
4.4.5. 6,13b-Dihydro[1]benzofuro[30,20:3,4]pyrido[2,1-a]isoindol-
9(7H)-one (26)
Initial treatment of (16) (0.527 g, 1.33 mmol) with a 1 M lithium
triethylborohydride THF solution (2.3 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.253 g, 1.33 mmol) by the general procedure. After 0.5 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 17:3 v/v ether/acetone gave the
product (28) (0.348 g, 69%) as a yellow solid that crystallised from
DCM/petroleum ether as colourless prisms, mp 178–180 ꢀC.
(Found: C, 66.20; H, 5.30; N, 7.15; S, 8.50. C21H20N2O3S requires C,
2
N
1
O
3
4
O
Initial treatment of (12) (0.378 g, 1.30 mmol) with a 1 M lithium
triethylborohydride in THF solution (2.2 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.247 g, 1.30 mmol) by the general procedure. After 1 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 8:1 v/v ether/petroleum ether gave
the product (26) (0.262 g, 73%) as a pale yellow solid, which crys-
tallised from ether/acetone as pale yellow prisms, mp 183–185 ꢀC.
(Found: C, 78.35; H, 4.90; N, 4.90. C18H13NO2 requires C, 78.55; H,
66.30; H, 5.30; N, 7.35; S, 8.45%.)
d (500 MHz) 1.76–1.84 (m, 1H,
NCHbCHa), 2.36 (s, 3H, CH3), 2.44 (ddd, 1H, J 16.6, 9.5, 1.5 Hz,
O]CCHa), 2.56–2.64 (m, 1H, O]CCHb), 2.67–2.73 (m, 1H,
NCHbCHb), 2.96–3.01 (m, 2ꢂ1H, NCHaCH2C and NCH2CHbC), 3.31–
3.35 (m, 1H, NCH2CHaC), 4.49–4.54 (m, 1H, NCHbCH2C), 4.83–4.87
(m, 1H, NCHbC), 7.21–7.26 (m, 3H, ArH), 7.33 (t, 2H, J 8.1 Hz, ArH),
7.65 (d, 2H, J 8.3 Hz, ArH) and 8.20 (d, 2H, J 8.3 Hz, ArH); m/z (%) 298
(Mþ, 22), 379 (12), 226 (17), 225 (100), 224 (13), 169 (17), 168 (13),
115 (7), 91 (33) and 65 (13); nmax (DCM) 3070, 2930,1690,1370,1170
and 750 cmꢁ1
.
4.75; N, 5.10%.)
d (400 MHz) 2.82 (dd, 1H, J 16.5, 4.6 Hz, NCH2CHb),
2.99–3.09 (m, 1H, NCH2CHa), 3.31–3.38 (m, 1H, NCHbCH2), 4.88 (dd,
1H, J 13.2, 6.3 Hz, NCHaCH2), 5.84 (s, 1H, NCHbC) and 7.26–7.98 (m,
8H, ArH); m/z (%) 275 (Mþ, 100), 274(Mꢁ1, 95), 257 (11), 246 (32),
218 (15), 189 (22), 182 (24), 169 (12) and 95 (13); nmax (DCM) 3060,
4.4.8. 8-[(4-Methylphenyl)sulfonyl]-2,3,6,7,8,12c-hexahydro-
indolo[3,2-a]quinolizin-4(1H)-one (29)
2940, 1690, 1400, 1120 and 740 cmꢁ1
.
3
2
1
4
5
4.4.6. 6,7,8,14b-Tetrahydro-10H-[1]benzofuro[30,20:3,4]azepino[2,1-
a]isoindol-10-one (27)
N
O
6
7
N
Ts
O
2
N
3
1
Initial treatment of (17) (0.866 g, 2.11 mmol) with a 1 M lithium
triethylborohydride THF solution (3.6 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.401 g, 2.11 mmol) by the general procedure. After 0.5 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 17:3 v/v ether/acetone gave the
product (29) (0.612 g, 74%) as a yellow solid, which crystallised
from DCM/petroleum ether as colourless plates, mp 192–193 ꢀC.
(Found: C, 66.70; H, 5.70; N, 7.05; S, 8.00. C22H22N2O3S requires C,
4
5
O
Initial treatment of (13) (0.977 g, 3.20 mmol) with a 1 M lith-
ium triethylborohydride THF solution (5.4 mL) followed by
workup according to the general procedure gave the crude hy-
droxy lactam, which was reacted with p-toluene sulphonic acid
monohydrate (0.608 g, 3.20 mmol) by the general procedure. After
3 h, the resulting mixture was worked up in the normal manner.
Flash chromatography eluting with 8:1 v/v ether/petroleum ether
gave the product (27) (0.637 g, 69%) as a pale yellow solid, which
crystallised from ether/acetone as colourless needles, mp 212–
213 ꢀC. (Found: C, 78.75; H, 5.20; N, 4.85. C19H15NO2 requires C,
67.00; H, 5.60; N, 7.10; S, 8.15%.)
d 1.49 (dddd, 1H, J 16.6, 11.3, 9.7,
3.4 Hz, NCHbCHaCH2), 1.83–1.90 (m, 1H, NCHbCH2CHb), 1.92–1.96
(m, 1H, NCHbCH2CHa), 2.35 (s, 3H, CH3), 2.37 (ddd, 1H, J 18.0, 12.3,
6.7 Hz, O]CCHa), 2.58 (dd, 1H, J 17.8,5.4 Hz, O]CCHb), 2.69 (td, 1H,
J 12.4, 3.8 Hz, NCHbCH2C), 2.97–3.05 (m, 1H, NCH2CHaC), 3.25 (ddd,
1H, J 15.7, 3.8, 1.7 Hz, NCH2CHb), 4.72–4.75 (m, 1H, NCHbC), 5.14
(ddd, 1H, J 12.9, 5.3, 1.2 Hz, NCHaCH2C), 7.21–7.26 (m, 3H, ArH), 7.31
(td, 1H, J 7.8, 1.1 Hz, ArH), 7.43 (d, 1H, J 7.8 Hz, ArH), 7.66 (d, 2H, J
8.4 Hz, ArH) and 8.20 (d, 1H, J 8.4 Hz, ArH), m/z (%) 394 (Mþ,18), 324
(7), 240 (19), 239 (100), 183 (11), 169 (42), 155 (22), 144 (12), 115
(14), 91 (78), 77 (6), 65 (33) and 55 (20); nmax (DCM) 3070, 2930,
78.85; H, 5.25; N, 4.85%.) d (400 MHz) 1.94–2.03 (m, 1H, NCH2CHb),
2.47–2.53 (m, 1H, NCH2CHa), 2.77–2.89 (m, 2ꢂ1H, NCH2CH2CH2),
3.32–3.40 (m, 1H, NCHbCH2), 4.42–4.51 (m, 1H, NCHaCH2), 5.84 (s,
1H, NCHbC) and 7.29–7.91 (m, 8H, ArH); m/z (%) 289 (Mþ, 100), 288
(Mꢁ1, 77), 272 (23), 260 (41), 231 (16), 202 (14), 189 (13), 176 (13),
130 (20), 115 (14) and 77 (23); nmax (DCM) 3070, 2940, 1695, 1210
and 730 cmꢁ1
.
1640, 1370, 1175 and 750 cmꢁ1
.

8960
R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
4.4.9. 8-[(4-Methylphenyl)sulfonyl]-1,5,6,7,8,12c-hexahydro-
pyrrolo[10,20:1,2]azepino[4,3-b]indol-3(2H)-one (30)
4.4.11. 5-[(4-Methylphenyl)sulfonyl]-5,6,7,13b-tetrahydro-9H-
benzo[1,2]indolizino[7,8-b] indol-9-one (32)
3
2
1
4
N
5
O
2
N
1
O
6
7
3
N
4
Ts
N
Ts
Initial treatment of (18) (0.599 g, 1.46 mmol) with a 1 M lithium
triethylborohydride THF solution (2.5 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.278 g, 1.46 mmol) by the general procedure. After 3 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (30) (0.364 g, 63%) as a yellow solid, which crystallised
from DCM/petroleum ether as pale yellow prisms, mp 159–161 ꢀC.
(Found: C, 67.20; H, 5.70; N, 7.30; S, 8.20. C22H22N2O3S requires C,
Initial treatment of (20) (0.889 g, 2.00 mmol) with a 1 M lithium
triethylborohydride THF solution (3.4 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.380 g, 2.00 mmol) by the general procedure. After 1 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 4:1 v/v ether/petroleum ether gave
the product (33) (0.657 g, 77%) as a pale yellow solid, which crys-
tallised from DCM/petroleum ether as colourless plates, mp
197–198 ꢀC. (Found: C, 70.10; H, 5.00; N, 6.30; S, 7.35. C25H20N2O3S
67.00; H, 5.60; N, 7.10; S, 8.15%.)
d (400 MHz) 1.61–1.70 (m, 1H,
NCH2CH), 1.95–2.03 (m, 1H, NCHCH), 2.11–2.20 (m, 1H, NCH2CH),
2.24–2.32 (m, 1H, O]CCH), 2.34 (s, 3H, CH3), 2.39–2.50 (m, 1H,
O]CCH), 2.51–2.57 (m, 1H, NCHCH), 2.72–2.81 (m, 1H,
NCH2CH2CH), 2.84–2.91 (m, 1H, NCHaCH2CH2C) 3.62 (dt, 1H, J 16.2,
4.1 Hz, NCH2CH2CH), 4.15 (ddd, 1H, J 14.0, 8.2, 5.3 Hz, NCHbCH2CH2),
4.93 (td, 1H, J 7.4, 1.3 Hz, NCHbC), 7.18 (d, 2H, J 8.5 Hz, ArH), 7.22–
7.34 (m, 3H, ArH), 7.56 (d, 2H, J 8.5 Hz, ArH) and 8.25 (d, 1H, J 8.2 Hz,
ArH); m/z (%) 394 (Mþ, 22), 240 (21), 239 (100),183 (16),156 (9),130
(5), 91 (17) and 65 (63); nmax (DCM) 3070, 2955, 1640, 1450, 1200
requires C, 70.10; H, 4.70; N, 6.55; S, 7.50%.) d (400 MHz) 2.27 (s, 3H,
CH3), 2.98–3.07 (m, 1H, NCH2CHa), 3.20 (ddd, 1H, J 13.3, 11.4, 4.0 Hz,
NCHbCH2), 3.41 (dd, 1H, J 17.0, 4.0 Hz, NCH2CHb), 4.81 (dd, 1H, J 13.3,
5.4 Hz, NCHaCH2), 5.87 (s, 1H, NCHbC), 7.13 (d, 2H, J 8.1 Hz, ArH),
7.33–7.46 (m, 2H, ArH), 7.44 (t, 1H, J 7.4 Hz, ArH), 7.52 (t, 1H, J 7.4 Hz,
ArH), 7.61 (d, 2H, J 8.4 Hz, ArH), 7.86–7.95 (m, 3H, ArH) and 8.22 (d,
1H, J 8.0 Hz, ArH); m/z (%) 428 (Mþ, 35), 274 (22), 273 (100), 272
(42), 271 (42), 270 (37), 243 (10), 216 (9), 189 (6), 130 (15), 91 (32)
and 77 (7); nmax (DCM) 3070, 2940, 1705, 1380, 1180 and 740 cmꢁ1
.
and 750 cmꢁ1
.
4.4.12. 5-[(4-Methylphenyl)sulfonyl]-6,7,8,14b-tetrahydro-
isoindolo[20,10:1,2]azepino[4,3-b]indol-10(5H)-one (33)
4.4.10. 9-[(4-Methylphenyl)sulfonyl]-1,2,3,6,7,8,9,13c-octahydro-
4H-pyrido[10,20:1,2]azepino[4,3-b]indol-4-one (31)
3
4
2
5
1
O
N
6
7
O
2
N
3
1
8
N
4
Ts
5
N
Ts
Initial treatment of (19) (0.429 g, 1.01 mmol) with a 1 M lithium
triethylborohydride THF solution (1.7 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.192 g, 1.01 mmol) by the general procedure. After 3 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 9:1 v/v ether/acetone gave the
product (0.278 g, 67%) as a colourless solid, which crystallised from
DCM/petroleum ether as colourless prisms, mp 140–142 ꢀC.
(Found: C, 67.03; H, 5.85; N, 6.70; S, 7.95. C23H24N2O3S requires C,
Initial treatment of (21) (0.926 g, 2.02 mmol) with a 1 M lithium
triethylborohydride THF solution (3.4 mL) followed by workup
according to the general procedure gave the crude hydroxy lactam,
which was reacted with p-toluene sulphonic acid monohydrate
(0.380 g, 2.02 mmol) by the general procedure. After 1 h, the
resulting mixture was worked up in the normal manner. Flash
chromatography eluting with 8:1 v/v ether/petroleum ether gave
the product (33) (0.542 g, 61%) as a pale yellow solid, which pre-
cipitated from DCM/petroleum ether a colourless amorphous solid,
mp 108–110 ꢀC. (Found: C, 70.55; H, 5.30; N, 6.10; S, 7.20.
67.60; H, 5.90; N, 6.85; S, 7.85%.) d(500) 1.40 (ddd, 1H, J 20.7, 13.0,
6.1 Hz, NCH2CHb), 1.70–1.81 (m, 3H, NCHbCHbCH2CH2 and
NCHbCH2CH2CH2), 2.24–2.33 (m, 2H, NCHbCHaCH2CH2 and
NCH2CHa), 2.37 (s, 3H, CH3), 2.39–2.46 (m, 1H, O]CCH), 2.48–2.54
(m, 1H, O]CCH), 2.65 (ddd, 1H, J 13.6, 11.0, 7.0 Hz, CHbNCHb), 2.74
(ddd, 1H, J 15.4, 13.4, 6.1 Hz, NCH2CH2CHa), 3.63 (ddd, 1H, J 15.4, 5.5,
1.8 Hz, NCH2CH2CHb), 4.25 (dd, 1H, J 13.6, 7.6 Hz, CHbNCHa), 4.85
(m, 1H, NCHbC), 7.22 (d, 2H, J 8.2 Hz, ArH), 7.25–7.28 (m, 3H, ArH),
7.32 (t, 2ꢂ1H, J 7.7 Hz, ArH), 7.61 (d, 2H, J 8.4 Hz, ArH) and 8.29 (dd,
1H, J 7.7, 1.8 Hz, ArH); m/z (%) 408 (Mþ, 7), 253 (100), 183 (80), 168
(15), 156 (25), 130 (8) and 91 (17); nmax (DCM) 3025, 2950, 1640,
C26H22N2O3S requires C, 70.55; H, 5.00; N, 6.35; S, 7.25%.)
d
(400 MHz) 1.54–1.63 (m, 1H, NCH2CHb), 2.33 (s, 3H, CH3), 2.35–
2.41 (m, 1H, NCH2CHa), 2.41–2.52 (m, 1H, NCH2CH2CH), 3.14–3.22
(m, 1H, NCHbCH2), 3.50–3.55 (m, 1H, NCH2CH2CH), 4.31 (dd, 1H, J
14.6, 7.9 Hz, NCHaCH2), 5.91 (s, 1H, NCHbC), 7.17 (d, 2H, J 8.6 Hz,
ArH), 7.37–7.48 (m, 5H, ArH), 7.59 (d, 2H, J 8.6 Hz, ArH), 7.74 (d, 1H, J
7.9 Hz, ArH), 7.86 (d,1H, J 8.6 Hz, ArH) and 8.31 (d,1H, J 8.1 Hz, ArH);
m/z (%) 442 (Mþ, 34), 288 (31), 287 (100), 286 (31), 285 (20), 271
(10), 258 (14), 230 (10), 156 (12), 130 (13), 91 (27) and 77 (6); nmax
1365, 1170 and 750 cmꢁ1
.
(DCM) 3070, 2940, 1700, 1370, 1120 and 740 cmꢁ1
.

R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
8961
4.5. General procedure for reduction of lactams to cyclic
4.5.3. 8-[(4-Methylphenyl)sulfonyl]-1,2,3,4,6,7,8,12c-octahydro-
tertiary amines
indolo[3,2-a]quinolizine (36)
A solution of the lactam (1 mmol) in dry THF (5 mL) was added
dropwise over 15 min to a stirred solution of BH3/THF complex
(10 mol equiv, 1 M) at 0 ꢀC under nitrogen. The reaction was
allowed to warm to ambient temperature and stirred for 3 h, then
cooled to 0 ꢀC and 6 N HCl carefully added until hydrogen evolu-
tion had subsided. The mixture was then boiled under reflux for
1 h, and the bulk THF distilled off. After cooling, the reaction
mixture was basified with NaOH pellets, and the product extracted
with DCM (2ꢂ25 mL). The combined organic layers were washed
with saturated aqueous NaCl (10 mL), dried (Na2SO4), and the
solvent removed under reduced pressure to afford the crude
product.
N
N
Ts
Prepared from (29) (0.283 g, 1.10 mmol) and BH3/THF (11.0 mL,
11.0 mmol) by the general procedure. After 3 h, the resulting mix-
ture was worked up in the normal manner. Flash chromatography
eluting with 99:1 v/v ether/triethylamine gave the product (0.20 g,
81%) as a pale yellow oil, which darkened on standing. (Found: C,
69.30; H, 6.55; N, 7.2; S, 8.60. C22H24N2O2S requires C, 69.45; H,
6.35; N, 7.35; S, 8.45%.);
d (500 MHz, CD2Cl2) 1.24 (ddd, 1H, J 24.2,
11.3, 3.7 Hz, NCHCHax), 1.38–1.47 (m, 1H, NCHCH2CHax), 1.55–1.60
(m, 2H, NCHCH2CH2CH2),1.76 (br d, J 12.9 Hz, NCHCH2CHeq), 2.24 (s,
3H, CH3), 2.31–2.38 (m, 2H, NCHCHeq and NCHCH2CH2CH2CH),
2.45 (td, 1H, J 11.4, 10.4, 4.5 Hz, NCHCH2C), 2.85–2.92 (m, 2H,
NCHCH2CH2CH2CH and CHNCHCH2C), 2.97–3.10 (m, 2H,
NCH2CH2C), 3.16 (dd, 1H, J 11.2, 2.4 Hz, NCHC), 7.07–7.16 (m, 4H,
ArH), 7.38 (d, 1H, J 7.5 Hz, ArH), 7.57 (dt, 2H, J 8.4, 2.1 Hz, ArH) and
8.01 (dt, 1H, J 8.3, 0.9 Hz, ArH); m/z (%) 380 (Mþ, 12), 379 (15), 225
(100), 197 (6), 169 (11), 91 (15) and 65 (6); nmax (DCM) 3080, 2940,
4.5.1. 1,2,3,5,6,11c-Hexahydro[1]benzofuro[2,3-g]indolizine (34)
N
O
1450, 1375, 1180 and 750 cmꢁ1
.
Prepared from (22) (0.798 g, 3.48 mmol) and BH3/THF (34.8 mL,
34.8 mmol) by the general procedure. After 3 h, the resulting
mixture was worked up in the normal manner. Flash chromatog-
raphy eluting with 98:2 v/v ether/triethylamine gave the product
(34) (0.428 g, 58%) as a pale yellow oil, which darkened on standing.
(Found: C, 78.75; H, 7.35; N, 6.60. C14H15NO requires C, 78.85; H,
4.5.4. 9-[(4-Methylphenyl)sulfonyl]-1,3,4,6,7,8,9,13c-octahydro-
2H-pyrido[10,20:1,2]azepino[4,3-b]indole (37)
7.10; N, 6.55%.)
d (500 MHz) 1.81–1.98 (m, 3H, NCHCH and
N
NCHCH2CH2), 2.27–2.43 (m, 1H, NCH2CH), 2.63–2.69 (m, 1H,
CHNCHCH2C), 2.78–2.83 (m, 1H, NCHCH2CH2CH), 2.87–2.92 (m, 1H,
NCHCH2CH2CH), 2.99–3.09 (m, 2H, CHNCHCH2C and CHNCH2HC),
3.37–3.42 (m, 1H, CHNCH2CHC), 4.07–4.11 (m, 1H, NCHC), 7.17–7.26
(m, 2H, ArH) and 7.40–7.44 (m, 2H, ArH); m/z (%) 213 (Mþ, 61), 212
(100),185 (39),170 (15),157 (16),128 (14),120 (13),115 (13),107 (9),
92 (6) and 77 (6).
N
Ts
Prepared from (31) (0.341 g, 0.83 mmol) and BH3/THF (0.264 g,
6.96 mmol) by the general BH3 procedure. After 2 h, the resulting
mixture was worked up in the normal manner. Flash chromatog-
raphy eluting with 66:33:1 v/v/v ether/petroleum ether/triethyl-
amine gave the product (37) (0.201 g, 61%) as a colourless oil.
4.5.2. 1,2,3,4,6,7,8,13c-Octahydro[1]benzofuro[3,2-c]pyrido[1,2-
a]azepine (35)
(Found: 394.1720C23H26N2O2S requires 394.1715.)
d (500 MHz,
CD2Cl2) 1.35–1.42 (m, 3H, 3ꢂCH), 1.60–1.62 (m, 2H, CH2), 1.71–1.73
(m,1H, CH), 1.84–1.86 (m, 1H, CH),1.92–1.98 (m, 1H, CH), 2.32 (s, 3H,
CH3), 2.44–2.54 (m, 2H, NCH2 and CH), 2.93 (br d, CH), 3.31 (tdd, 1H,
J 12.9, 6.2, 1.2 Hz), 3.43–3.50 (m, 2H, 2ꢂCH), 7.18–7.25 (m, 4H, ArH),
7.32 (m, 2H, J 7.5 Hz, ArH), 7.55 (d, 2H, J 7.7 Hz) and 8.16 (d, 1H, J
7.7 Hz, ArH); m/z (%) 394 (Mþ, 7), 240 (20), 239 (100), 211 (11), 197
(8), 183 (16), 167 (5), 156 (8) and 91 (18).
N
O
Acknowledgements
Prepared from (25) (0.162 g, 0.63 mmol) and BH3/THF (6.3 mL,
6.3 mmol) by the general procedure. After 3 h, the resulting mix-
ture was worked up in the normal manner. Flash chromatography
eluting with 99:99:2 v/v/v ether/petroleum ether/triethylamine
gave the product (35) (0.124 g, 81%) as colourless needles, mp 67–
69 ꢀC. (Found: C, 79.40; H, 7.70; N, 6.00. C16H19NO requires C, 79.65;
We thank Leeds University and the EPRSC for support and
Johnson Matthey for a loan of Pd(OAc)2
References and notes
H, 7.95; N, 5.80%.)
d(500 MHz) 1.43–1.67 (m, 4H, NCHCH2CH,
1. Grigg, R.; Inman, M.; Kilner, C.; Koppen, I.; Marchbank, J.; Selby, P.; Sridharan, V.
Tetrahedron 2006, 63, 6152–6169.
NCHCHax and NCHCH2CH2CH2), 1.70–1.82 (m, 2H, NCHCH2CH and
NCH2CHCH2C), 2.00–2.03 (m, 1H, NCHCHeq), 2.05–2.11 (m, 1H,
NCH2CHCH2C), 2.65 (td, 1H, J 11.8, 3.0 Hz, NCHCH2CH2CH2CH),
2.72–2.86 (m, 3H, NCH2CH2CH2C and NCH2CH2CHC), 3.01 (br d, 1H,
J 11.9 Hz, NCHCH2CH2CH2CH), 3.24 (dddd, 1H, J 15.7, 11.2, 7.2, 1.5 Hz,
NCH2CH2CHaxC), 3.63 (br d, 1H, J 10.6 Hz, NCHC), 7.15–7.25 (m, 2H,
ArH) and 7.34–7.42 (m, 2H, ArH); m/z (%) 241 (Mþ, 100), 226 (7), 212
(61), 199 (85), 185 (57), 170 (22), 158 (30), 128 (19), 115 (18), 99 (12)
2. Grigg, R.; Gai, X.; Khamnaen, T.; Rajviroongit, S.; Sridharan, V.; Zhang, L.;
Collard, S.; Keep, A. Can. J. Chem. 2005, 83, 990–1005.
3. Dondas, H. A.; Fishwick, C. W. G.; Gai, X.; Grigg, R.; Kilner, C.; Dumrongchai, N.;
Kongkathip, B.; Polysuk, C.; Sridharan, V. Angew. Chem., Int. Ed. 2005, 44, 7570–
7574.
4. (a) Gardiner, M.; Grigg, R.; Kordes, M.; Sridharan, V. Tetrahedron 2001, 57, 7729–
7735; (b) Gai, X.; Grigg, R.; Rajviroongit, S.; Sridharan, V.; Songarsa, S. Tetra-
hedron Lett. 2005, 5899–5902.
5. Fishwick, C. W. G.; Grigg, R.; Sridharan, V.; Virica, J. Tetrahedron 2003, 59, 4451–
4468.
and 77 (10); nmax (DCM) 3060, 2930, 1460, 1120 and 740 cmꢁ1
.

8962
R. Grigg et al. / Tetrahedron 64 (2008) 8952–8962
6. (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.
10. Sonogashira reaction reviews: (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874–922; (b) Doucet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46, 834–871.
11. Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett. 1995,
36, 5979–5982.
7. Fielding, M. R.; Grigg, R.; Sridharan, V.; Thornon-Pett, M.; Urch, C. J. Tetrahedron
2001, 57, 7737–7748.
12. Gesson, J. P.; Jacques, J. C.; Rambaud, D. Bull. Soc. Chim. Fr. 1992, 129, 227–231.
13. Griffiths, J.; Murphy, J. A. Tetrahedron 1992, 48, 5543–5556.
14. Iyer, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1987, 109, 2759–2770.
15. (a) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc., Chem.
Commun. 1992, 41–42; (b) Arcadi, A.; Cacchi, S.; del Rosario, M.; Fabrizi, G.;
Marinelli, F. J. Org. Chem. 1996, 61, 9280–9288; (c) Cacchi, S,; Fabrizi, G.; Ma-
rinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363–1366; (d) Khan, M. W.; Kundu, N.
G. Synlett 1999, 456–458; (e) Zhang, H. C.; Ye, H.; Moretto, A. F.; Brumfield, K.
K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89–92; (f) Wu, T. Y. H.; Ding, S.; Gray, N. S.;
Schultz, P. G. Org. Lett. 2001, 3, 3827–3830.
8. (a) Bailey, P. D.; Morgan, K. M.; Smith, D. I.; Vernon, J. M. Tetrahedron Lett. 1994,
35, 7115–7118; (b) Bailey, P. D.; Morgan, K. M.; Smith, D. I.; Vernon, J. M. Tet-
rahedron 2003, 59, 3369–3378; (c) Bahajaj, A. A.; Moore, M. H.; Vernon, J. M.
Tetrahedron 2004, 60, 1235–1246; (d) Kaluza, Z.; Mostowicz, D.; Dolega, G.;
Mroczko, K.; Wojcik, R. Tetrahedron 2006, 62, 943–953; (e) Dake, G. Tetrahedron
2006, 62, 3467–3492; (f) Pesquet, A.; Daiech, A.; Van, H. L. J. Org. Chem. 2006,
71, 5303–5311.
9. (a) Liu, J.; Swidorski, J. J.; Peters, S. D.; Hsung, R. P. J. Org. Chem. 2005, 70, 3898–
3902; (b) Nilson, M. G.; Funk, R. L. Org. Lett. 2006, 8, 3833–3836; (c) Allin, S. M.;
Gaskell, S. N.; Towler, J. M. R.; Page, P. C. B.; Saha, B.; McKenzie, M. J.; Martin,
W. P. J. Org. Chem. 2007, 72, 8972–8975.
16. Larock, R. C. Comprehensive Organic Transformations; VCH: New York, NY,
1989.
17. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–735.