Palladium-catalysed cascades triggered by dehydrogenation of secondary or tertiary amines: Access to bridged- and fused-ring heterocycles

Article abstract of DOI:10.1055/s-0028-1087480

Palladium-catalysed cascades triggered by dehydrogenation of secondary or tertiary amines and trapping the intermediate imines with cycloadditions and Mannich reactions result in a range of bridged- and fused-ring heterocyclic motifs in moderate to good y

Full text of DOI:10.1055/s-0028-1087480

LETTER
97
Palladium-Catalysed Cascades Triggered by Dehydrogenation of Secondary
or Tertiary Amines: Access to Bridged- and Fused-Ring Heterocycles
a
a
a
b
A
R
ccess to
B
ridge
o
a
ndFused
n
-Ring
H
etero
a
cycles ld Grigg,* Anoma Somasunderam, Visuvanathar Sridharan, Ann Keep
a
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, UK
Fax +44(113)3436501; E-mail: r.grigg@leeds.ac.uk
Johnson Matthey, Orchard Road, Royston, Hertfordshire SG8 5HE, UK
b
Received 22 September 2008
H
Abstract: Palladium-catalysed cascades triggered by dehydrogena-
tion of secondary or tertiary amines and trapping the intermediate
imines with cycloadditions and Mannich reactions result in a range
of bridged- and fused-ring heterocyclic motifs in moderate to good
yields.
N
CO2Me
EWG
Pd
+
(
a)
EWG
N
H
CO2Me
Key words: cascade reaction, hydrogen transfer, Mannich reaction,
dipolar cycloaddition
Pd
N
N
(b)
EWG
EWG
EWG
O
O
N
To increase the molecular complexity of a simple organic
substrate using efficient (high atom economy), selective,
high-yielding, and environmentally benign methods is
one of the contemporary challenges for synthetic organic
chemists. Carbon–carbon bond formation is a pivotal
method for achieving this goal. We have been involved in
generating azomethine ylides and azomethine imines via
Me
EWG
Scheme 2
1
recipient for the hydrogen removed from the tertiary
amine in the dehydrogenation process.
For our initial studies, we selected cyclic secondary a-
amino acid esters 1 and 2 as precursors (Figure 1). Thus 1
1 mmol) reacted with NMM (2 mmol) in boiling toluene
in the presence of 10 mol% Pd black over 13 hours to af-
ford the bridged ring compound 5 in 82% yield
(Scheme 3). The initial regioselective dehydrogenation of
catalytic dehydrogenation methods utilizing either palla-
dium black, ruthenium black, or Wilkinson’s catalyst.2,3
(
Recently Beller et al. have reported dehydrogenation of
4
primary amines using Shvo’s catalyst whilst Blacker et
al. have reported dehydrogenation of secondary amines
5
utilizing an Ir(III) catalyst. Palladium catalysts have long
1
leads to the formation of cyclic imine 3 followed by 1,2-
been known to dealkylate tertiary amines via an interme-
diate iminium species followed by hydrolysis
prototropy to the azomethine ylide 4. Trapping of 4 with
NMM via an endo transition state (with respect to the NH
bridge) then affords 5. In the NMR spectrum of 5 the
Scheme 1).6
(
bridgehead hydrogen H appears as a singlet at d = 4.75
H
R
a
R
+N
R
R
–
PdH
H2O
ppm indicating that H and H are orthogonal. In an anal-
(
i)
N
+
Pd(0)
NH
+
O
a
b
ogous fashion, 2 afforded 6 (Figure 2) in 68% yield. We
R
R
and others have reported a related cycloaddition process
Scheme 1
on the preformed cyclic imines.7
In this communication we report two novel catalytic cas-
cade combinations (i) palladium-catalysed cascade dehy-
drogenation of cyclic secondary a-amino acid esters →
azomethine ylides → 1,3-dipolar cycloaddition generat-
ing bridged-ring heterocycles with formation of two new
bonds, and 3/4 stereocentres [Scheme 2 (a)] (ii) palladi-
um-catalysed cascade dehydrogenation of tertiary amines
CO Me
2
CO2Me
NH
NH
N
H
1
2
Figure 1
→
iminium ion → intramolecular Mannich reaction →
fused ring heterocycle [Scheme 2 (b)].
H
N
In Scheme 2 (b) N-methylmaleimide (NMM) is also used
to regenerate the active palladium catalyst by acting as a
2
CO Me
O
NMe
H
N
H
O
SYNLETT 2009, No. 1, pp 0097–0099
x
x.
x
x.
2
0
0
8
H
Advanced online publication: 12.12.2008
6
H
DOI: 10.1055/s-0028-1087480; Art ID: D33808ST
Figure 2
©
Georg Thieme Verlag Stuttgart · New York

9
8
R. Grigg et al.
LETTER
H
N
CO2Me
O
CO2Me
CO Me
–
CO Me
2
2
NMM
Pd
NMe
NH
N
N+
Ha
H
Hc
Hb
O
1
3
4
5
Scheme 3
We briefly studied the stereo- and regioselectivity of the
,3-dipolar cycloaddition reactions using benzyl acrylate
H
N
1
CO2Me
and phenyl vinyl sulfone as dipolarophiles. Thus second-
ary amine 1 (1 mmol) reacted regio- and stereospecifically
with benzyl acrylate (2 mmol) in the presence of 10 mol%
Pd black in boiling toluene for 15 hours to afford 7 (50%)
together with a small amount of 8 (10%, Figure 3). The
Hc
CO2Me
CO2Bn
Ha
N
Hd
Hb
7
8
1
H
H
N
stereochemistry of 7 was assigned on the basis of H NMR
N
data. In particular the bridgehead hydrogen H appears as
CO Me
CO2Me
Hc
a
2
a singlet at d = 4.57 ppm. In contrast 1 (1 mmol) reacted
regioselectively with phenyl vinyl sulfone (2 mmol) in the
presence of 10 mol% Pd black in boiling toluene over 20
hours to afford a 1:2.5 mixture of 9 and 10 (40%) together
with 8 (30%). The stereochemistries of 9 and 10 were as-
Hc
SO Ph
2
Hb
Hd
Ha
Ha
10
Hd
Hb
SO2Ph
9
Figure 3
1
signed from their H NMR spectra. The bridgehead hy-
drogen H of 9 appears as a singlet at d = 4.74 ppm
a
in 40% yield. When 18 (1 mol equiv) was allowed to react
in the presence of Pd black (DMF, 120 °C) and NMM
indicating it is an endo cycloadduct with respect to the NH
bridge. The signal for proton H of 10 appears as a doublet
a
(
2 mol equiv), the reaction furnished the cycloadduct 22
at d = 3.95 ppm with a coupling constant of 6.2 Hz which
confirms both the regio-and stereochemistry of the
cycloadduct. In contrast to the previous observations, 10
is the major product. This stereoselectivity may reflect
equilibrium between 9 and 10 over the longer reaction
time.
in 45% yield (Scheme 5). Note that 22 can be regarded as
an endo cycloadduct of the 1,3-dipole 20 or an exo-Diels–
Alder cycloadduct of the isoindole 21. The absence of any
2
3 indicates that conversion of 19 into 21 is significantly
faster than the Mannich cyclisation 19 → 23. In the NMR
spectrum of 22 the bridgehead hydrogen H appears as a
a
In the reactions with less active dipolarophiles than
NMM, the aromatized product 8 is also formed. That is,
when the cycloaddition step is slow, aromatization of the
imine begins to compete. The trend of increasing amounts
of 8 reflects the observed reactivity rate of the dipolaro-
philes: NMM > benzyl acrylate > phenyl vinyl sulfone.
The latter order has been established in our extensive
work on cycloaddition reactions of azomethine ylides.8
singlet at d = 4.48 ppm indicating that H and H are or-
a
b
thogonal.
CO2Me
CO2Me
OHC
1
1
Figure 4
Next we extended the dehydrogenation methodology to
intramolecular Mannich reactions. The tertiary amine 12
In conclusion we have developed two novel cascade com-
binations triggered by initial Pd-catalysed dehydrogena-
tion. Overall these cascades result in the formation of 1–2
new bonds, 1–4 new stereocentres, and one new ring. A
typical experimental protocol is appended.9
(
1 mmol) with a tethered malonate was synthesized by re-
ductive amination of tetrahydroisoquinoline and aldehyde
1 (Figure 4). When 12 (1 mol equiv) reacted with 10
1
mol% Pd black in the presence of NMM (1 mol equiv) in
DMF at 120 °C, it afforded the tricyclic amine 15 in 60%
yield (Scheme 4). In an analogous fashion, 16 afforded 17
N+
N+
N
N
Pd
MeO2C
MeO2C
MeO C
MeO C
–
2
2
MeO2C
MeO C
MeO C
2
2
MeO C
2
12
13
14
15
Scheme 4
Synlett 2009, No. 1, 97–99 © Thieme Stuttgart · New York

LETTER
Access to Bridged- and Fused-Ring Heterocycles
99
N
N
N
N
H
H
CO2Me
MeO2C CO2Me
MeO2C
16
17
CO2Me
CO2Me
N
–
N+
O
N
BH
NMe
H
H
2
MeO C
Ha
MeO2C
Hb O
CO2Me
20
N
N+
CO Me
2
Hb
Pd
2
1
22
MeO2C
MeO2C
CO2Me
CO2Me
18
19
N
MeO2C
CO2Me
2
3
Scheme 5
Acknowledgment
(7) (a) Grigg, R.; Basanagoudar, L. D.; Kennedy, D. A.;
Malone, J. F.; Thianpatanagul, S. Tetrahedron Lett. 1982,
3, 2803. (b) Lakhlifi, A.; Sedqui, B.; Laude, B.; Din, N.;
We thank the ORS, Leeds University and Johnson Matthey for sup-
port.
2
Vebrel, E. J. Can. J. Chem. 1991, 69, 1156.
(
8) (a) Grigg, R.; Sarker, M. A. B. Tetrahedron 2006, 62,
1
0332. (b) Dondas, H. A.; Fiswick, C. W. G.; Gai, X.; Grigg,
References and Notes
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(
(
(
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(
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21 21
4
1
6
.20; N, 4.05. H NMR (300 MHz, CDCl ): d = 7.15–7.07
(
(
3
(
(
(
m, 4 H, ArH), 5.12 (s, 2 H, CH Ph), 4.57 (s, 1 H, H ), 3.79
s, 3 H, CO Me), 3.26 (d, 1 H, J = 16.60 Hz, ArCHH), 3.14
dd, 1 H, J = 8.85, 2.60 Hz H ), 3.02 (d, 1 H, J = 16.60 Hz,
2
a
6) (a) Murahashi, S. T.; Hirano, T.; Yano, T. J. Am. Chem. Soc.
2
1
978, 100, 348. (b) Murahashi, S. I.; Watanabe, T. J. Am.
b
ArCHH), 2.47 (dd, 1 H, J = 13.75, 2.60 Hz, H ), 2.22 (dd,
Chem. Soc. 1979, 101, 7429.
c
+
1
2
H, J = 13.75, 8.85 Hz, H ). MS: m/z (%) = 351 (0.2) [M ],
d
92 (3), 260 (0.4), 189 (100), 157 (18).
Synlett 2009, No. 1, 97–99 © Thieme Stuttgart · New York

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