Palladium-catalysed cyclisation-anion capture processes: In situ 'zipper' generation via intramolecular nucleophilic capture of π-allylpalladium species

Article abstract of DOI:10.1055/s-2006-951525

A palladium-catalysed one-pot reaction for the in situ generation of 'zippers' and subsequent cyclisation-anion capture with phenyl boronic acid produces tricyclic heterocycles with the formation of three C-C bonds, one C-N bond, two rings, two stereocent

Full text of DOI:10.1055/s-2006-951525

LETTER
3021
Palladium-Catalysed Cyclisation–Anion Capture Processes: In situ ‘Zipper’
Generation via Intramolecular Nucleophilic Capture of p-Allylpalladium
Species
P
alladium-Cataly
o
sed Cyclisat
n
ion–Anion
C
a
a
ptur
e
Proc
l
esses d Grigg,* Colin Kilner, Edoardo Mariani, Visuvanathar Sridharan
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
Fax +44(113)3436530; E-mail: r.grigg@leeds.ac.uk
Received 27 April 2006
tion–anion capture processes (Scheme 1). Thus, Pd(0) re-
Abstract: A palladium-catalysed one-pot reaction for the in situ
acts selectively with 2-iodothiophene/vinyltriflate. The
generation of ‘zippers’ and subsequent cyclisation–anion capture
arylpalladium(II)/vinyl-palladium(II) species then reacts
with phenyl boronic acid produces tricyclic heterocycles with the
with allene/CO to give p-allylpalladium(II)/acylpalladi-
um(II) species which are captured intermolecularly by the
nitrogen/oxygen nucleophile to generate the zippers.
These processes resulted in the formation of one new het-
erocyclic ring, one C–O/C–N bond, two C–C bonds and
one tetrasubstituted C-centre. Others have also recently
reported a related in situ ‘zipper’ generation and subse-
quent cyclisation–anion capture processes.9,10
formation of three C–C bonds, one C–N bond, two rings, two ste-
reocentres and one tetrasubstituted C-centre.
Key words: organopalladium chemistry, one-pot sequential reac-
tion, heterocycles
The seminal contributions of Richard Heck to organo-
palladium chemistry are wide-ranging but it is the Heck
Reaction that, in particular, struck a resonating chord with
a wide spectrum of researchers and process chemists.1,2
The popularity of this classic reaction shows no signs of
diminishing its rapid growth as judged by the output of
papers and it is a great pleasure to contribute some of our
work to this tribute to Richard.
S
(i) Pd(0), K2CO3,
toluene, 70 °C
Ph
I
S
I
+
.
+
(ii) PhB(OH)2,
110 °C
N
NH
Ts
Ts
Over the past decade we have developed powerful, widely
applicable, highly regio- and stereoselective palladium-
catalysed cyclisation–anion capture methodology.3,4 Re-
cently two new starter species or ‘zippers’ (carbamoyl and
oxy-carbonyl) have been developed and their cyclisation–
anion capture explored.5,6 Our basic methodology would
advance to a higher level of sophistication if the starter or
‘zipper’ species could be created in situ as part of extend-
ed cascades or sequential one-pot processes. This is a
challenging and novel area that will greatly expand the
synthetic flexibility of the cascades whilst increasing
the molecular diversity of the products. A key strategy
for in situ ‘zipper’ generation is to employ what we
termed relay-switch components such as CO and allenes.3
Such components allow the cascade to be switched be-
tween inter- and intramolecular processes.
70%
S
I
N
Ts
(i) Pd(0), K2CO3,
toluene, 70 °C
I
+ CO
+
O
(ii) Bu3SnC≡CH
TfO
O
OH
81%
I
O
O
Scheme 1
In situ ‘zipper’ generation utilising allene as the relay
switch can be classified into four distinct classes depend-
ing on whether the formation of the p-allyl species (from
aryl iodide and allene) and its subsequent nucleophilic
capture is inter- or intramolecular (Table 1)
Table 1 Synthetic Strategies for in situ ‘Zipper’ Generation via Al-
lene Relay Switches
Class
p-allyl formation
intermolecular
intermolecular
intramolecular
intramolecular
Nucleophilic capture
intermolecular
intramolecular
intermolecular
intramolecular
We have recently reported the palladium-catalysed
(Table 1, class 1) in situ ‘zipper’ generation using CO7
and allene8 as relay switches and their subsequent cyclisa-
1
2
3
4
SYNLETT 2006, No. 18, pp 3021–3024
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951525; Art ID: S10006ST
© Georg Thieme Verlag Stuttgart · New York

3022
R. Grigg et al.
LETTER
In this communication we report successful cyclisation– situ ‘zipper’ generation–cyclisation–anion capture pro-
anion capture cascade processes involving in situ class 2 cess to give tricyclic product 2b in 64% yield.14 The
‘zipper’ generation via intramolecular nucleophilic attack stereochemistry of the product 2b was again confirmed by
on the p-allylpalladium species and their subsequent cy- NOE studies analogous to those reported for 2a.
clisation–anion capture, using boronic acids as anion cap-
ture agents (Scheme 2). A key feature of Scheme 2 is that
S
S
Ph
I
the relative rates of oxidative addition of Pd(0) to the ha-
1. Pd(PPh3)4 (10 mol%),
Cs2CO3 (3 equiv),
toluene, 70 °C, 16 h
lides must be Ar2I > Ar1X for a successful outcome.7,8,11
H
X
O
+
N
2. PhB(OH)2,
100 °C, 22 h
( )
( )
N
H
n
n
.
Ar2
Ar1
R
O
O
X
.
Pd(0)
Ar1
X = Br, I
1a: n = 1
1b: n = 2
2a: n = 1, 65%
2b: n = 2, 64%
Ar2I
+
NH
RB(OH)2
m ( )
( )n
N
m( )
( )n
Scheme 4
O
X = I, Br
Ar2
Ar2
Ph
LnPd
X
Hc
Hb
S
H
X
XPd
Ar1
Ar1
8%
Ha
( )n
S
N
H
( )n
m( )
N
m( )
N
N
B:
O
O
O
Scheme 2
A
B
Figure 1
For our initial studies, we selected 1a,b as trifunctional
aryl iodide/allene/nucleophile substrates. These were suc-
cessfully synthesised via the Crabbe reaction12 of the cor-
responding alkynes (Scheme 3) and were obtained as a
1:1 mixture of bromo and iodo allenes. The bromo species
arises from halogen exchange with copper(I) bromide
used as the catalyst for the Crabbe reaction.
i-Pr2NH, CuBr,
X
I
O
O
H2CO
( )
( )
dioxane, ∆
N
H
N
H
n
n
.
X = Br, I
1a: n = 1, 50%
1b: n = 2, 51%
Scheme 3
Figure 2
First we studied the one-pot sequential ‘zipper’ genera-
tion–cyclisation–anion capture process of 1a (1 mmol)
with 2-iodothiophene (1 mmol), Pd(PPh3)4 (10 mol%) and
Cs2CO3 (3 mmol) in toluene (10 ml) at 70 °C for 16 hours,
at which stage phenyl boronic acid (1 mmol) was added
and the mixture heated at 110 °C for a further 22 hours to
afford the tricyclic compound 2a as a single diastereomer
in 65% yield (Scheme 4). The structure of 2a was estab-
lished by NOE studies (Figure 1, A). Thus, irradiating one
of the benzylic diastereotopic protons Hb caused enhance-
ment of Ha (8%) and Hc (30%). The structure was con-
firmed by a subsequent X-ray crystal structure (Figure 2).
Molecular models indicate the transition state develops a
slight bowl shape as the second C–C bond forms and the
sp3 C–PdLn bond is cleaved. Subsequently, following Su-
zuki coupling, the benzyl group is located on the least
hindered outer face (Figure 1, B). Next, we varied the
chain length between the allene and the nucleophile.
Compound 1b underwent a similar palladium-catalysed in
Finally, we varied the chain length between the nucleo-
phile and the aryl iodide. Compounds 4 were synthesised
from 3 via the Crabbe reaction.12 However, under the pre-
viously developed palladium-catalysed conditions 4a and
4b failed to produce the desired products 5a and 5b in the
presence of 2-iodothiophene (1 mmol). Instead, products
6a and 6b, derived from direct capture of boronic acid,
were isolated in 50–67% yield (Scheme 5).
Failure to observe the cyclisation may reflect, we believe,
the faster rate of the oxidative addition onto the C–Br
bond, probably by the more efficient coordination of the
oxygen atom of the amide due to the difference in elec-
tronegativity of the N atoms in 1 compared to 4. Excess
phosphine has been found to be beneficial in breaking the
undesired coordination of palladium to a proximate
donor.13 This strategy was applied to 4a (1 mmol) which
was reacted with 2-iodothiophene (1 mmol), Pd(PPh3)4
Synlett 2006, No. 18, 3021–3024 © Thieme Stuttgart · New York

LETTER
Palladium-Catalysed Cyclisation–Anion Capture Processes
3023
Br
Br
Acknowledgement
i-Pr2NH,
CuBr, H2O
.
H
H
N
( )
·
N
( )
We thank Leeds University and ORS for support.
n
n
dioxane, ∆
O
O
3a: n = 1
3b: n = 2
4a: n = 1
4b: n = 2
References and Notes
1. Pd(PPh3)4 (10 mol%),
Cs2CO3 (3 equiv),
toluene, 70 °C, 16 h
(1) Reviews: (a) de Meijere, A.; Stulgies, B.; Albrecht, K.;
S
I
Rauch, K.; Wegner, H. A.; Hopf, H.; Scott, L. T.; Eshdat, L.;
Aprahamian, I.; Rabinovitz, M. Pure Appl. Chem. 2006, 78,
813. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron
2005, 61, 11771. (c) Li, C. J. Chem. Rev. 2005, 105, 3095.
(d) Farina, V. Adv. Synth. Catal. 2004, 346, 1553. (e) Link,
J. T. Org. React. (N. Y.) 2002, 60, 157. (f) Heck, R. F. Org.
React. (N. Y.) 1982, 27, 345.
2. PhB(OH)2,
100 °C, 22 h
Ph
S
H
Ph
.
( )
H
n
·
N
N
( )
n
O
(2) Reviews on chiral Heck reactions: (a) Shibasaki, M.; Vogal,
E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533.
(b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945. (c) Shibasaki, M.; Miyazaki, F. Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 1;
John Wiley and Sons Inc.: New York, 2002, 1283.
(3) Reviews: (a) Grigg, R.; Sridharan, V. J. Organomet. Chem.
1999, 576, 65. (b) Grigg, R.; Sridharan, V. Pure Appl.
Chem. 1998, 70, 1047.
(4) (a) Bohmer, J.; Grigg, R.; Marchbank, J. D. Chem. Commun.
2002, 768. (b) Grigg, R.; Savic, V.; Sridharan, V.; Terrier,
C. Tetrahedron 2002, 58, 8613. (c) Grigg, R.; Koppen, M.;
Rasparini, M.; Sridharan, V. Chem. Commun. 2001, 964.
(d) Grigg, R.; MacLachlan, W. S.; MacPherson, D. T.;
Sridharan, V.; Suganthan, S. Tetrahedron 2001, 57, 10335.
(e) Anwar, U.; Casachi, A.; Grigg, R.; Sansano, J. M.
Tetrahedron 2001, 57, 1361. (f) Casachi, A.; Grigg, R.;
Sansano, J. M. Tetrahedron 2001, 57, 607. (g) Grigg, R.;
MacLachlan, W.; Rasparini, M. Chem. Commun. 2000,
2241. (h) Casachi, A.; Grigg, R.; Sansano, J. M.
Tetrahedron 2000, 56, 7553. (i) Fretwell, P.; Grigg, R.;
Sansano, J. M.; Sridharan, V.; Wilson, D. Tetrahedron 2000,
56, 7525.
O
5a: n = 1
5b: n = 2
6a: n = 1
6b: n = 2
Scheme 5
(10 mol%) and Cs2CO3 (3 mmol) in MeCN (10 mL) at
70 °C for 16 hours, then phenyl boronic acid (1 mmol) and
PPh3 (10 mol%) were added and the mixture was heated
at 110 °C for a further 22 hours to afford the tricyclic
compound 5a as a single diastereomer in 64% yield
(Scheme 6). The stereochemistry of 5a was tentatively as-
signed based on NOE studies (Figure 3). Thus, irradiating
one of the benzylic diastereotopic protons Hb caused en-
hancement of Hc (9%) but no enhancement of Ha. Similar-
ly irradiation of the other benzylic diastereotopic proton
Hc caused enhancement of Hb (20%) and but again had no
effect on Ha indicating the trans relationship. We presume
the stereochemical outcome reflects the more relaxed
tether length in the case of 7 the precursor of 5a.
(5) Grigg, R.; Savic, V. Chem. Commun. 2000, 2381.
(6) Grigg, R.; Fielding, M. R.; Urch, C. J. Chem. Commun.
2000, 2239.
(7) Grigg, R.; Mariani, E.; Sridharan, V. Tetrahedron Lett.
2001, 42, 8677.
(8) Grigg, R.; Putnikovic, B.; Urch, C. J. Tetrahedron Lett.
1996, 37, 695.
(9) Szlosek-Pinaud, M.; Diaz, P.; Martinez, J.; Lamaty, F.
Tetrahedron Lett. 2003, 44, 8657.
Br
1. Pd(PPh3)4 (10 mol%),
Cs2CO3 (3 equiv),
MeCN, 70 °C, 16 h
.
H
N
Ph
·
S
S
I
H
+
O
2. PhB(OH)2,
PPh3 (10 mol%),
100 °C, 22 h
4a
N
O
5a (64%)
Scheme 6
(10) Cho, C. S.; Shim, H. S.; Choi, H. J.; Kim, S. C.; Kim, M. C.
Tetrahedron Lett. 2000, 41, 3891.
(11) As Heck and related chemistries develop, the need for more
relative-rate data on ArI/ArX substrates becomes more
desirable. A further aspect of this is the need to generate data
on positional reactivity of polyhalides/triflates etc., for
example, see: (a) Zhang, Z.; Zha, Z.; Gan, C.; Pan, C.; Zhou,
Y.; Wang, Z.; Zhou, M. M. J. Org. Chem. 2006, 71, 4339.
(b) Gai, X.; Grigg, R.; Collard, S.; Muir, J. E. Chem.
Commun. 2001, 1712.
Ph
Hb
S
Hc
Ha
S
H
Br
N
N
O
O
7
5a (NOE)
(12) Searles, S.; Li, Y.; Nassim, B.; Lopes, M. R.; Tran, P. T.;
Crabbe, P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
(13) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001,
66, 8042.
(14) Compound 2b: A mixture of 1b (1 mmol), Cs2CO3 (3
mmol), Pd(Ph3)4 (10 mol%), and 2-iodothiophene (1 mmol)
in toluene (10 mL) was stirred and heated at 70 °C for 16 h
at which stage phenyl boronic acid (1 mmol) was added. The
mixture was heated at 110 °C for 22 h, filtered and the
solvent evaporated under reduced pressure. The crude
product was purified by flash chromatography, (petroleum
Figure 3
Overall these new processes generate three C–C bonds,
one C–N bond, two rings, two stereocentres and one tetra-
substituted C-centre.
In conclusion, we have demonstrated a novel palladium-
catalysed one-pot in situ ‘zipper’ generation coupled to
sequential cyclisation–anion capture processes to access
tricyclic heterocycles.
Synlett 2006, No. 18, 3021–3024 © Thieme Stuttgart · New York

3024
R. Grigg et al.
LETTER
ether–Et2O, 1:3), to give the product in 64% yield as a single
diastereomer, which crystallised from (EtOH–H2O) as
colourless prisms; mp 170–171 °C. IR (film): 2947, 1652
(CO), 1597, 1479,1462, 1428, 1402, 1284, 909 cm–1. 1H
NMR (500 MHz, CDCl3): d = 1.03 (qd, J = 13.2, 3.4 Hz, 1
H, HCHCHN), 1.62 (qdd, J = 13.2, 6.0, 3.2 Hz, 1 H,
HCHCHN), 1.88 (m, 1 H, HCHCH2C=O), 1.95 (m, 1 H,
HCHCH2C=O), 2.24 (m, 1 H, HCHC=O), 2.44 (ddt, J =
18.0, 5.9, 1.5 Hz, 1 H, HCHC=O), 3.62, 3.85 (2 × d, J = 14.2
Hz, 2 H, CH2Ph), 4.08 (dd, J = 11.8, 3.7 Hz, 1 H, CHN), 6.47
(dd, J = 3.6, 1.1 Hz, 1 H, thienyl-H), 6.91 (dd, J = 5.1, 3.6
Hz, 1 H, thienyl-H), 7.06–7.08 (m, 2 H, ArH), 7.14–7.25 (m,
5 H, ArH), 7.31 (td, J = 7.8, 1.3 Hz, 1 H, ArH), 7.34 (dd, J =
7.8, 1.3 Hz,1 H, ArH), 8.19 (d, J = 7.8 Hz, 1 H, ArH). 13
C
NMR (300 MHz, CDCl3): d = 20.70, 24.90, 32.70, 41.90,
54.70, 66.80, 118.10, 124.70, 125.00, 125.20, 125.80,
127.30, 127.40, 128.80, (2 × C), 129.20, 131.20 (2 × C),
135.90,137.10, 143.00, 148.60, 169.10. MS (FAB): m/z
(%) = 360 (M+ + H, 100), 268 (86), 212 (7), 91 (11). Anal.
Calcd for C23H21NOS: C, 76.85; H, 5.90; N, 3.90; S, 8.90.
Found: C, 76.60; H, 5.80; N, 3.85; S, 8.80.
Synlett 2006, No. 18, 3021–3024 © Thieme Stuttgart · New York