An Au(I)-catalysed allenamide cyclisation giving access to an α-vinyl-substituted tetrahydroisoquinoline building block

Article abstract of DOI:10.1055/s-0031-1290335

An Au(I)-catalysed intramolecular hydroarylation of an enantiopure allenamide has been achieved and has given access to a key α-vinyl- substititued tetrahydroisoquinoline. Additionally this has been accomplished in very high yield and high diastereoselectivity. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290335

LETTER
565
An Au(I)-Catalysed Allenamide Cyclisation Giving Access to an
a-Vinyl-Substituted Tetrahydroisoquinoline Building Block
A
u(I)-Catalyse
a
d
A
llenam
n
jon itpal Singh, Mark R. J. Elsegood, Marc C. Kimber*
The Department of Chemistry, Loughborough University, Loughborough, Leicester, LE11 3TU, UK
Fax +44(150)9223925; E-mail: M.C.Kimber@lboro.ac.uk
Received 29 November 2011
However, access to a-vinyl-substituted tetrahydro-
isoquinolines using the Pictet–Spengler or Bischler–
Napieralski approaches is somewhat problematic and
therefore unsuitable.5 To overcome this chemical issue a
number of approaches have been disclosed, including; (a)
vinyl organometallic addition to suitable quinoline sub-
strates,6 (b) Pd-catalysed addition to allenamides,7 (c) iri-
dium-8a and palladium-catalysed8b intramolecular allylic
amination, and finally, (d) an intramolecular hydroaryla-
tion on a masked conjugated N-acyl iminium species
(Scheme 2),5,9 and it is this last approach that is the focus
of this letter.
In 2005 Rutjes5 reported a synthetically flexible route to
a-vinyl-substituted tetrahydroisoquinoline building blocks
10 via a Sn(II) or TFA-catalysed cyclisation of allylic
N,O-acetals 7. This was followed in 2007 by Navarro–
Vazquez and Dominquez9 who elegantly illustrated that
allenamides 8 could be cyclised under acidic conditions to
yield a-vinyl-substituted tetrahydroisoquinolines 10 in
good yield. While both authors used a masked conjugated
N-acyl iminium 9 to generate their a-vinyl tetrahydroiso-
quinoline substrates 10, it was only the work of Rutjes
who investigated any diastereoselectivity in their transfor-
mation, which was found to be modest.
Abstract: An Au(I)-catalysed intramolecular hydroarylation of an
enantiopure allenamide has been achieved and has given access to
a key a-vinyl-substititued tetrahydroisoquinoline. Additionally this
has been accomplished in very high yield and high diastereoselec-
tivity.
Key words: alkaloids, allenamide, tetrahydroisoquinoline, Au(I)
catalysis, diastereoselective
Tetrahydroisoquinolines are highly significant synthetic
subunits contained within many biologically active alka-
loids (Scheme 1).1 Contained within many of these alka-
loids is a stereogenic centre at the a-position on the ring
which is commonly installed, either enantio- or diastereo-
selectively, via
a
Pictet–Spengler2 or Bischeler–
Napieralski3 condensations.4 Ideally, a key synthetic
building block for the total synthesis of such targets would
be the a-vinyl substituted tetrahydroisoquinoline 4, since
the vinyl group can be readily manipulated (Scheme 1).5,6
OH OMe
CO2H
H
H
MeO
NMe
H
Me
Me
H
H
N
N
MeO
MeO
Rutjes5
O
OMe
NH
1
3
Navarro–Vazquez
TFA- or Sn(OTf)2-
2
and Dominguez9
catalysed
MeO
Me
TFA-
catalysed
9
N
ref. 5
R
R
EWG
N
X
NH
OR
7
N
8
N
5a X = O
5b X = H2
α-vinyl tetra-
hydroisoquinoline (4)
EWG
EWG
N
ref. 6a
EWG
10
Me
CO2Et
R
N
Scheme 2 Previous N-acyl iminium approaches to a-vinyl tetrahy-
droisoquinolines
6
Recently, we described the Au(I) activation of
allenamides10 and their subsequent reaction with electron-
rich arenes and arylamines to yield functionalised enam-
ide building blocks (Scheme 3).11 This approach to allen-
amide activation,12 under such mild conditions, led us to
consider whether an intramolecular arene cyclisation
could be accomplished. Therefore, in this brief Letter we
Scheme 1 Tetrahydroisoquinoline natural products crispine A (1),
quinocarcin (2), korumpensamine (3), and a-vinyl tetrahydroisoqui-
noline building block 4 and its known conversion to 5 and 6.
SYNLETT 2012, 23, 565–568
Advanced online publication: 06.02.2012
x
x
.
x
x
.
2
0
1
1
DOI: 10.1055/s-0031-1290335; Art ID: D73011ST
© Georg Thieme Verlag Stuttgart · New York

566
S. Singh et al.
LETTER
would like to disclose a concise and yet highly diastereo- rial within an hour (Table 1, entry 1). A switch to the
selective route to a key a-vinyl-substituted tetrahydroiso- AuPPh3NTf2 did give the desired product, but the reaction
quinoline building block.
time was extended considerably (Table 1, entry 2). To
show the requirement of Au(I) catalysts the reaction was
undertaken with AgOTf which gave only starting material
(Table 1, entry 3), while TFA did catalyse the reaction but
gave predominantly decomposition products (Table 1, en-
try 4). Finally, we decreased the catalysts loading of
AuPPh3OTf to 2.5mol% which furnished the cyclized
product in 96% yield but required an extended reaction
time as compared to entry 1 (Table 1).
H
R
H
N
O
Au(I)
R
N
O
R = Bn, H
arene or
arylamine (Nu)
Nu
O
O
11
12
MeO
MeO
MeO
MeO
Au(I)
With these results in hand we then investigated the cycli-
sation the Boc-protected allenamide 21 which was synthe-
sized in three steps from the known acid 19 (Scheme 5).
Unfortunately, exposure of this substrate to our Au(I)-cat-
alyzed cyclisation conditions failed to deliver any of the
desired product with only starting material being returned.
We believe that this maybe a consequence of the bulky
Boc protecting group contained within 21 hampering ac-
tivation of the allenamide by the Au(I) catalyst.
N
EWG
N
this work
EWG
13
14
Scheme 3
To test our approach to Au(I)-catalysed intramolecular
cyclisation we synthesised allenamide 17 in two steps
from the known acid 15 (Scheme 4). Allenamide 17 was
then exposed to a variety of cyclisation conditions as
shown in Table 1.
HO
MeO
a,b,c
NH2⋅HCl
N
HO
MeO
Boc
MeO
MeO
O
MeO
MeO
O
19
20
a
OH
N
Me
d
15
16
H
N
MeO
MeO
MeO
b
O
N
MeO
Boc
O
MeO
MeO
O
MeO
MeO
O
22
21
catalyst
N
N
see
Table 1
Me
Me
Scheme 5 Reagents and conditions: (a) Boc2O, Et3N, H2O, dioxane;
(b) MeI, K2CO3, DMF, NaH; (c) KOt-Bu, propargyl bromide (60%
over 3 steps); (d) AuPPh3OTf or AuPPh3NTf2 (5 mol%), CH2Cl2, r.t.
or reflux, 16 h.
18
17
Scheme 4 Reagents and conditions: (a) DCC, CH2Cl2, DMAP,
N-methylpropargyl amine; (b) THF, KOt-Bu (75% over 2 steps).
Consequently, based on our previous investigations on the
intermolecular allenamide activation we targeted an ox-
azolidinone-protected allenamide 22 as a Boc surrogate.
Table 1 Conditions for the Intramolecular Cyclisation of 17 to 18a
Entry
Catalyst
Temp (°C) Time (h) Yield (%)b
The synthesis began with conversion of L-DOPA (13) to
its Boc-protected methyl ester under standard conditions,
followed by global methylation with MeI and K2CO3 to
give 14 in 92% overall yield over the three steps. Subse-
quent LiBH4 reduction of 14 and treatment of the crude
product with thionyl chloride in THF delivered the oxazo-
lidinone 15 in 88% yield over the two steps. Finally, 15
was alkylated with propargyl bromide to furnish the
alkyne 16 which could then be rearranged under basic
conditions to give the desired chiral allenamide 22 in 62%
yield.13 Alternatively, treatment of 15 under modified
Heaney–Ley conditions14 with propargyl bromide directly
gave 22 in 60% yield. Allenamide 22 proved to be crystal-
line, and crystals suitable for single-crystal X-ray analysis
were obtained. The X-ray15–18 depiction is shown below in
Scheme 6.19
1
2
3
4
5
AuPPh3OTf
AuPPh3NTf2
AgOTf
r.t.
35
1
16
16
16
16
95
91
r.t.
r.t.
r.t.
s.m.
decomp.
96
TFAc
AuPPh3OTfd
a All reactions were performed under an atmosphere of N2 unless oth-
erwise stated and with 5 mol% catalysts unless otherwise stated.
b Isolated yield.
c Conditions: 20 mol%.
d Conditions: 2.5 mol%.
Exposure of 17 to 5 mol% AuPPh3OTf gave the desired
intramolecular cyclisation product in an excellent yield
with TLC showing full consumption of the starting mate-
Synlett 2012, 23, 565–568
© Thieme Stuttgart · New York

LETTER
Au(I)-Catalysed Allenamide Cyclisation
567
achieved. The key step was an Au(I)-catalysed hydroaryl-
ation of a chiral pool derived allenamide delivering the
key building block in high diastereoselectivity. Use of this
building block and this synthetic approach for the synthe-
sis of alkaloid natural products is currently under investi-
gation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett and include
1H NMR and 13C NMR spectroscopic data of 22 and 23 and the
crystallographic data for 22.
Acknowledgment
The authors thank Loughborough University for funding and Mark
Edgar for NMR analysis.
References and Notes
(1) For reviews on tetrahydroisoquinoline natural products and
their synthesis, see: (a) Cuevas, C.; Francesch, A. Nat. Prod.
Rep. 2009, 26, 322. (b) Siengalewicz, P.; Rinner, U.;
Mulzer, J. Chem. Soc. Rev. 2008, 37, 2676.
(c) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341. (d) Scott, J. D.; Williams, R. M. Chem.
Rev. 2002, 102, 1669.
Scheme 6 Reagents and conditions: (a) MeOH, SOCl2; (b) Boc2O,
Et3N, MeOH; (c) MeI, K2CO3, DMF (92% over 3 steps); (d) LiBH4,
THF; (e) SOCl2, THF (88% over 2 steps); (f) NaH, propargyl bromide
(80% in hexane); (g) KOt-Bu, THF (62% over 2 steps); (h) KOt-Bu,
propargyl bromide (80% in hexane), DMSO (60%).
(2) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44,
2030.
(3) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
(4) For recent selected reviews on the Pictet–Spengler reaction,
see: (a) Pulka, K. Curr. Opin. Drug Discovery Dev. 2010,
13, 669. (b) Lorenz, M.; VanLinn, M. L.; Cook, J. M. Curr.
Org. Synth. 2010, 7, 189.
(5) For an Account of this chemical issue, see: Kinderman, S. S.;
Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H.
E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70,
5519 and references contained within.
(6) For examples, see: (a) Bailey, T. S.; Bremner, J. B.; Carver,
J. A. Tetrahedron Lett. 1993, 34, 3331. (b) Andersson, P.
G.; Johansson, F.; Tanner, D. Tetrahedron 1998, 54, 11549.
(7) (a) Griggs, R.; Sansano, J. M. Tetrahedron 1996, 52, 13441.
(b) Evans, P.; Griggs, R.; Imran Ramzan, M.; Sridharan, V.;
York, M. Tetrahedron Lett. 1999, 40, 3021.
(8) (a) Teichert, J. F.; Fañanás-Mastral, M.; Feringa, B. L.
Angew. Chem. Int. Ed. 2011, 50, 688. (b) Lin, C.-F.; Ojima,
I. J. Org. Chem. 2011, 76, 6240.
(9) Navarro-Vásquez, A.; Rodríguez, D.; Martínez-Esperón,
M. F.; García, A.; Saá, C.; Domínguez, D. Tetrahedron Lett.
2007, 48, 2741.
(10) For recent reviews on allenamides, see: (a) Wei, L.-L.;
Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
(b) Deagostino, A.; Prandi, C.; Tabasso, S.; Venturello, P.
Molecules 2010, 15, 2667. (c) Standen, P.; Kimber, M. C.
Curr. Opin. Drug Discovery Dev. 2010, 13, 645.
Treatment of 22 with AuPPh3OTf (5 mol%) in CH2Cl2 de-
livered a single product 23 in quantitative yield.20 The re-
action time was remarkably short, with the reaction
completion within minutes of the addition of the Au(I)
salt, indicating a very facile reaction. Exhaustive NMR
analysis indicated a single product with a de >98% and
with an absolute stereochemistry as shown in Scheme 7.
The relative stereochemistry of the product was assigned
on the basis of a NOESY enhancement between H3 and
the vinylic H2¢ proton.
Treatment of allenamide 22 with AuPPh3NTf2 (5 mol%)
also gave the tetrahydroisoquinoline 23 quantitatively and
in excellent de. It must be noted that this high diastereo-
selectivity is in contrast to the moderate diastereomeric
excess reported by Rutjes5 for similar cyclisations, and the
high yield is a significant improvement over that reported
by Navarro–Vazquez and Dominquez9 for their TFA-
catalysed cyclisations of allenamides.
In summary, a brief, yet high-yielding synthesis of a key
a-vinyl-substituted tetrahydroisoquinoline has been
H
H3
MeO
MeO
Au(I) cat.
O
NOESY
enhancement
H3–H2'
H
O
N
N
CH2Cl2, r.t.,
MeO
MeO
5 min
O
O
H2'
AuPPh3OTf (5 mol%), 98%
AuPPh3(NTf2) (5 mol%), 97%
22
23
de >98%
Scheme 7 Au(I)-catalysed cyclisation of 22
© Thieme Stuttgart · New York
Synlett 2012, 23, 565–568

568
S. Singh et al.
LETTER
(11) (a) Kimber, M. C. Org. Lett. 2010, 12, 1128. (b) Hill, A.
W.; Elsegood, M. R. J.; Kimber, M. C. J. Org. Chem. 2010,
75, 5406.
(12) For other examples of Au(I)-catalysed cyclisations of
allenamides, see: (a) Hyland, C. J. T.; Hegedus, L. S. J. Org.
Chem. 2006, 71, 8658. (b) Manzo, A. M.; Perboni, A. D.;
Broggini, G.; Rigamonti, M. Tetrahedron Lett. 2009, 50,
4696. (c) Faustino, H.; López, F.; Castedo, L.; Mascareñas,
J. L. Chem. Sci. 2011, 2, 633.
P212121, a = 7.2379 (10), b = 11.5884 (15), c = 16.677 (2)
Å, V = 1398.8 (3) Å3, T = 150 K, Z = 4, m (Mo Ka) = 0.095
mm–1, 14225 data measured using a Bruker APEX 2 CCD
diffractometer with graphite-monochromated Mo Ka
radiation (l = 0.71073 Å); 2026 data were unique,
Rint = 0.0329; all unique data used in refinement against
F2 values to give final wR2 = 0.0885 (on F2 for all data),
R = 0.0338 [for 1831 data with F2 > 2s(F2)], absolute
structure could not be determined from the diffraction data;
Friedel pairs were merged. H atoms on C(6) had coordinates
freely refined; all other H atoms were constrained. Programs
used were Bruker SMART,16 SAINT,16 SHELXTL,17,18 and
local programs. CCDC 838703 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(13) (S)-4-(3,4-Dimethoxybenzyl)-3-(propa-1,2-dienyl)
oxazolidin-2-one (22)
To a solution of 15 (0.58 g, 2.45 mmol) in THF (20 mL) at 0
°C under an N2 atmosphere was added NaH (0.12 g, 2.93
mmol), and the mixture stirred at r.t. for 2 h. After this period
propargyl bromide (0.32 mL, 2.88 mmol) was added
cautiously, and the reaction mixture was stirred for a further
24 h at r.t. After this period sat. NH4Cl was added, and the
resultant aqueous layer was extracted with Et2O (2×). The
combined organic layers were then washed with brine, dried
(Na2SO4), filtered, and the solvent removed in vacuo. The
crude product was then dissolved in THF (20 mL) and
cooled to 0 °C followed by addition of KOt-Bu (0.08 g, 0.66
mmol). The reaction mixture was then stirred for 2 h at 0 °C
after which all the starting material had been consumed. The
reaction mixture was then diluted with Et2O and washed
sequentially with H2O and brine. The combined organic
layers were then dried (Na2SO4), filtered, and the solvent
removed in vacuo. The crude product was then purified by
column chromatography (Rf = 0.55, EtOAc–PE = 1:1)
yielding the title compound as a colourless solid (0.40 g,
60%); mp 118–120 °C (from CH2Cl2–PE). IR (solution,
CHCl3): nmax = 3021, 1752, 1516, 1461, 1409, 1262, 1226,
1028 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.84 (t, J = 6.8
Hz, 1 H), 6.76–6.73 (m, 1 H), 6.64–6.62 (m, 1 H), 6.58 (d,
J = 1.6 Hz, 1 H), 5.51 (dd, J = 6.4, 10.0 Hz, 1 H), 5.44 (dd,
J = 6.4, 10.0 Hz, 1 H), 4.20 (t, J = 8.4 Hz, 1 H), 4.08 (dd,
J = 3.6, 8.8 Hz, 1 H), 4.05–4.00 (m, 1 H), 3.80 (s, 3 H), 3.79
(s, 3 H), 3.06 (dd, J = 3.2, 14.0 Hz, 1 H), 2.65 (dd, J = 8.8,
14.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 201.7 (C),
155.0 (C), 149.2 (C), 148.3 (C), 127.7 (C), 121.4 (CH),
112.4 (CH), 111.5 (CH), 111.5 (CH), 96.0 (CH), 87.9 (CH2),
66.6 (CH2), 56.0 (CH3), 55.7 (CH3), 36.6 (CH2). HRMS:
m/z calcd for C15H17NO4 [MNa+]: 298.1055; found:
298.1045. [a]D21 +20.3 (c 1.00, CHCl3).
(16) SMART and SAINT software for CCD diffractometers;
Bruker AXS Inc: Madison/ WI, 2008.
(17) Sheldrick, G. M. SHELXTL User Manual, Version 5; Bruker
AXS Inc.: Madison/ WI, 1994.
(18) Sheldrick, G. M. Acta Crystallogr., Sect. A: 2008, 64, 112.
(19) Tracey, M. R.; Grebe, T. P.; Brennessel, W. W.; Hsung, R.
P. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2004,
60, o830.
(20) To a solution of 22 (100 mg, 0.36 mmol) in CH2Cl2 (2 mL)
at r.t. was added a 5 mol% solution of AuPPh3OTf. [NB: The
5 mol% solution of AgPPh3OTf was prepared from the
addition of AuClPPh3 (9 mg, 0.018 mmol) to AgOTf (4.7
mg, 0.018 mmol) in CH2Cl2 (1 mL), and the resultant
suspension was stirred for 10 min at r.t.]. After 5 min the
starting material was consumed after which the solvent was
removed in vacuo. The crude product was then purified by
column chromatography (Rf = 0.25, 1:1 EtOAc–PE) to yield
23 as a colourless oil (98 mg, quant.). IR (solution, CHCl3):
n
max = 3020, 2936, 1749, 1613, 1518, 1420, 1226, 1115 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.62 (s, 1 H), 6.58 (s, 1 H),
5.98–5.90 (m, 1 H), 5.29–5.24 (m, 3 H), 4.57–4.52 (t, J = 8.4
Hz, 1 H), 4.15–4.12 (dd, J = 8.4, 8.8 Hz, 1 H), 4.05–3.99 (m,
1 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 2.83 (d, J = 7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 156.7 (C), 148.3 (C),
148.0 (C), 136.4 (CH), 125.2 (C), 127.7 (C), 117.5 (CH2),
111.6 (CH), 110.4 (C), 68.5 (CH2), 56.0 (CH3), 55.9 (CH3),
54.7 (CH2), 48.6 (C), 33.8 (CH2). HRMS: m/z calcd for
21
(14) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1973,
499.
C15H17NO4 [MNa+]: 298.1055; found: 298.1044. [a]D
–160.8 (c 1.00, CHCl3).
(15) Crystal Data for 22
C15H17NO4, M = 275.30, orthorhombic, space group
Synlett 2012, 23, 565–568
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.