An aromatic amination approach towards ancistrocladinium A/B

Article abstract of DOI:10.1055/s-0029-1219561

We report a high yielding approach to N-aryl tetrahydroisoquinolines and tetrahydroquinolines in one step from readily available starting materials. We have used this methodology to prepare the full carbon skeleton of the ring system of ancistrocladinium

Full text of DOI:10.1055/s-0029-1219561

LETTER
939
An Aromatic Amination Approach towards Ancistrocladinium A/B
Aromatic
Aminae
n
chtowards
A
j
ncistro
a
cladinium
m
A/B in R. Buckley,a Steven D. R. Christie,*a Mark R. J. Elsegood,a Claire M. Gillings,a Philip C. Bulman Page,*b
William J. M. Pardoea
a
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
Fax +44(1509)223925; E-mail: s.d.christie@lboro.ac.uk
School of Chemistry, University of East Anglia, Norwich, Norfolk NR4 7TJ, UK
b
Fax +44(1603)593008; E-mail: p.page@uea.ac.uk
Received 18 December 2009
MeO
X–
Abstract: We report a high yielding approach to N-aryl tetrahy-
droisoquinolines and tetrahydroquinolines in one step from readily
available starting materials. We have used this methodology to pre-
pare the full carbon skeleton of the ring system of ancistrocladinium
A in one step.
MeO
TFA–
N+
N+
OMe
OMe
OMe
OMe
OMe
OMe
Me
Key words: amination, natural products, palladium, Buchwald–
Hartwig, tetrahydroquinoline, tetrahydroisoquinoline
ancisheynine
ancistrocladinium A
HO
Me
Atropoisomerism is now a common structural motif in or-
ganic chemistry, particularly in catalysis and ligand de-
sign, for example, in the BINAP-derived systems. There
are even a few natural products which contain axial
chirality1–4 and these have been the subject of increasing
interest in recent years. For example, the naphthylisoquin-
oline alkaloids (Figure 1) are a rapidly expanding class of
important secondary metabolites from tropical lianas of
the Ancistrocladaceae and Dioncophyllaceae families.
N
HO
MeO
OMe
ancistroheynine
MeO
OMe
TFA–
OH OMe
MeO
N+
Me
HO
OMe
These natural products are of interest for their significant
pharmacological activities,1,3 for example, against Plas-
modium falciparum,4 and their unprecedented biosynthet-
ic origin through the acetate-malonate pathway.5 Of
particular significance to us were the recently isolated iso-
quinoline-based natural products ancisheynine and ancis-
trocladinium A/B5,6 which are based on an isoquinolinium
backbone, the chemistry of which we have considerable
experience.7
Me
NH
ancistrocladinium B
OMe
ancistrocladine
RO
OH
HO
Me
N
NH
OMe
MeO
MeO
OMe
OMe
Me
These unique azabinaphthyl structures contain an atropoi-
someric unit by virtue of restricted rotation about the C–N
bond. We believed that this C–N bond could be construct-
ed using the Buchwald–Hartwig amination reaction.8,9
Buchwald–Hartwig amination of tetrahydroisoquinolines
has previously been reported, however, only a few sub-
strates were examined and product yields were unsatisfac-
tory (<50%).10
ancistroheynine A (R = Me)
ancistroheynine B (R = H)
dioncophylline A
OH
OMe
HO
HO
Me
NH
MeO
HO
NH
OMe
We have previously reported a Buchwald–Hartwig ap-
proach to N-heterocyclic carbene ligands; and we decided
to apply this methodology to the synthesis of the key C–N
bond in ancistrocladinium A.11 Initial amination studies
were directed towards the synthesis of ancisheynine by di-
rect amination of bromobenzene with isoquinoline using
OH
dioncophylline C
dioncopeltine A
Figure 1 Secondary metabolites from tropical lianas of the
Ancistrocladaceae and Dioncophyllaceae families
Pd2(dba)3, BINAP, and sodium tert-butoxide in toluene.
Unfortunately, we only recovered unreacted starting ma-
terials. Hence we decided to attempt reactions using the
SYNLETT 2010, No. 6, pp 0939–0943
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219561; Art ID: D37109ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

940
B. R. Buckley et al.
LETTER
saturated tetrahydroisoquinoline system. Experiments try 4) and the bromo-aniline (presumably due to some de-
were conducted with bromobenzene, tetrahydroisoquino- gree of polymerization, Table 1, entry 8).
line, Pd2(dba)3, BINAP, and sodium tert-butoxide in tolu-
ene. This time an excellent yield of the corresponding
aminated product was observed (93%, Table 1, entry 1).12
Application of this methodology to a range of aryl bro-
mides afforded the desired N-arylated products in good to
excellent yields (Scheme 1, Table 1). The only exceptions
to this were the bulky triisopropyl derivative (Table 1, en-
Pd2(dba)3
( )-BINAP
Br
+
Ar
N
NaOt-Bu, toluene
reflux, 4–8 h
NH
Ar
Scheme 1 General scheme for the N-arylation of tetrahydroisoquin-
olines
Table 1 Synthesis of Aryl Tetrahydrisoquinolines 1–9a
Entry
Bromide
Product
Yield (%)b
93
Br
N
N
N
1
1
2
3
Br
Br
2
3
4
86
89
Br
starting material
–
Br
N
5
68
MeO
OMe
4
NO2
Br
N
6
7
8
69
78
51
NO2
5
Br
Br
Br
N
6
NH2
Br
N
NH2
7
Synlett 2010, No. 6, 939–943 © Thieme Stuttgart · New York

LETTER
Aromatic Amination Approach towards Ancistrocladinium A/B
941
Table 1 Synthesis of Aryl Tetrahydrisoquinolines 1–9a (continued)
Entry
9
Bromide
Product
Yield (%)b
96
Br
N
N
8
9
Br
10
99
a Conditions: Pd2(dba)3, ( ) BINAP, NaOt-Bu, toluene, reflux, 4–18 h.
b Isolated yield.
–BPh4
Pleasingly, amination of 1-bromonaphthalene with tet-
rahydroisoquinoline worked in excellent yield to afford
the full carbon skeleton of the ring system of ancistrocla-
dinium A in one step (compound 8). Installation of the
iminium bond can easily be achieved by treatment of the
N-arylated tetrahydroisoquinoline with NBS in dichlo-
romethane. For example, 8 was treated with NBS in re-
fluxing dichloromethane to afford the corresponding
dihydroisoquinolinium salt 10 in 81% yield which was
isolated as its tetraphenylborate derivative for ease of ma-
nipulation (Scheme 2).13
N +
N
i. NBS, CH2Cl2, 3 h
ii. NaBPh4, MeCN, 5 min
81%
8
10
Scheme 2 Formation of iminium salts using NBS
Table 2). The structure of compound 18 was also con-
firmed by X-ray crystallography (Figure 2).14
Following our success with the isoquionoline derivatives
we also examined the reactions using tetrahydroquinoline
(Scheme 3, Table 2). Again good to excellent yields of the
desired aminated products were observed and a similar
trend in product yield was obtained; for example, the
aniline derivative 17 was formed in low yield (entry 7,
Pd2(dba)3
( )-BINAP
Br
+
Ar
NaOt-Bu, toluene
reflux, 4–8 h
N
N
H
Ar
Scheme 3 General scheme for the N-arylation of tetrahydroquinolines
Table 2 Synthesis of Aryl Tetrahydquinolines 11–19a
Entry
Bromide
Product
Yield (%)b
Br
1
94
N
11
Br
N
2
89
12
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942
B. R. Buckley et al.
LETTER
Table 2 Synthesis of Aryl Tetrahydquinolines 11–19a
Entry
3
Bromide
Product
Yield (%)b
Br
87
N
13
Br
4
5
6
7
8
9
64
69
78
56
94
87
N
MeO
MeO
14
Br
NO2
N
N
N
NO2
15
Br
Br
Br
16
Br
NH2
NH2
17
18
19
Br
N
Br
N
a Conditions: Pd2(dba)3, ( ) BINAP, NaOt-Bu, toluene, reflux, 4–18 h.
b Isolated yield.
Synlett 2010, No. 6, 939–943 © Thieme Stuttgart · New York

LETTER
Aromatic Amination Approach towards Ancistrocladinium A/B
943
Blacker, A. J.; Marples, B. A. Tetrahedron 2006, 62, 6607.
(d) Page, P. C. B.; Buckley, B. R.; Rassias, G. A.; Blacker,
A. J. Eur. J. Org. Chem. 2006, 803.
(8) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
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Poulton, A. M.; Elsegood, M. R. J.; McKee, V.
J. Organomet. Chem. 2005, 690, 6210.
(12) General Procedure
A 50 mL round-bottomed flask was charged with Pd2(dba)3
(0.088 mmol), ( )-BINAP (0.18 mmol), and toluene (6 mL).
The resulting solution was degassed for 10 min before being
heated to 110 °C for 15 min. The reaction mixture was
allowed to cool to r.t. before NaOt-Bu (4.1 mmol), the aryl
bromide (2.2 mmol), and tetrahydroquinoline or
tetrahydroisoquinoline (4.4 mmol) were added. The
resulting mixture was heated under reflux for 4–16 h, before
being cooled to r.t. and filtered through a pad of Celite®.
Solvents were removed under reduced pressure and the
crude material purified by column chromatography (silica
gel, 99:1 light PE–EtOAc).
Figure 2 X-ray crystal structure of compound 18
Data for Compound 9
Colorless solid, 99% yield (0.56 g). IR (thin film): nmax
In conclusion we have developed a high yielding ap-
proach to N-aryl tetrahydroisoquinolines and tetrahydro-
quinolines in one step from readily available starting
materials. We have used this methodology to prepare the
full carbon skeleton of the ring system of ancistrocladini-
um A in one step, and we are currently pursuing this meth-
odology for the total synthesis of several secondary
metabolites from the tropical lianas of the Ancistrocla-
daceae and Dioncophyllaceae families.
=
1627, 1265, 740 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.04
(2 H, t, J = 11.6 Hz, CH2CH2), 3.67 (2 H, t, J = 11.6 Hz,
CH2CH2), 4.51 (2 H, s, CH2), 7.17–7.21 (5 H, m, ArH),
7.26–7.28 (1 H, m, ArH), 7.33–7.36 (1 H, m, ArH), 7.39–
7.41 (1 H, m, ArH), 7.76–7.68 (3 H, m, ArH). 13C NMR (100
MHz, CDCl3): d = 29.19 (CH2), 47.18 (CH2), 51.13 (CH2),
109.37 (ArCH), 118.73 (ArCH), 123.01 (ArCH), 126.10
(ArCH), 126.29 (ArCH), 126.42 (ArCH), 126.58 (ArCH),
126.60 (2 ArCH), 127.46 (ArCH), 128.07 (ArC), 128.64
(ArCH), 128.84 (ArCH), 134.36 (ArC), 134.76 (ArC),
148.39 (ArCN). MS (FAB+): m/z (%) = 259 (100) [M+], 258
(64). HRMS (ES): m/z calcd for [C19H17N]: 259.1361; found
[M+]: 259.1365.
Acknowledgment
This investigation has enjoyed the support of Loughborough Uni-
versity. We are indebted to The Royal Society for an Industry Fel-
lowship (to P.C.B.P.) and Research Councils UK for a RCUK
Fellowship (to B.R.B.).
(13) We have found that isolation of isoquinolinium salts as
crystalline solids can be easily achieved when counterion
exchange with sodium tetraphenylborate is carried out. See,
for example, ref. 7a.
(14) Crystal Data for 18
References and Notes
C19H17N, M = 259.34, a = b = 7.0515 (8), c = 28.297 (3) Å,
a = b = g = 90°, V = 1407.0(3) Å3. pale yellow crystal,
1.04 × 0.47 × 0.25 mm3, Dcalc = 1.224 g cm–3, m = 0.071
mm–1; 13580 data, 1247 unique (Rint = 0.0757). Data were
measured on a Bruker APEX II diffractometer with MoKa
radiation at 150 K.15 Data were corrected for absorption. The
structure was solved by direct methods and refined on F2
values.16,17 Half the molecule is unique and the structure is
50/50 disordered at C(2A)/C(2X) and at N(1)/C(10).
R = 0.0489 [for 1134 observed data with F2 > 2s(F2)] and
wR = 0.1278 (for all data). Crystal data have been deposited
with the Cambridge Crystallographic Data Centre. CCDC:
758059. Data can be retrieved in CIF format by quoting the
relevant deposition number in an e-mail request to
deposit@ccdc.cam.ac.uk.
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(7) (a) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.;
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Synlett 2010, No. 6, 939–943 © Thieme Stuttgart · New York