Asymmetric induction in domino Heck-aza-Michael reactions

Article abstract of DOI:10.1016/j.tetlet.2012.01.037

Domino Heck-aza-Michael reactions are an efficient method for the rapid synthesis of functionalised N-heterocycles. An asymmetric version of this domino process has been developed to access chiral 1,3-disubstituted N-heterocycles from amino acid precursors in excellent yields (68-81%) with moderate to high diastereoselectivity (up to 92% de).

Full text of DOI:10.1016/j.tetlet.2012.01.037

Tetrahedron Letters 53 (2012) 1468–1471
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Asymmetric induction in domino Heck-aza-Michael reactions
Daniel L. Priebbenow a, Scott G. Stewart b, , Frederick M. Pfeffer a,
⇑
a School of Life and Environmental Sciences, Deakin University, Geelong 3217, Victoria, Australia
b School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley 6009, Western Australia, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2011
Revised 21 December 2011
Accepted 10 January 2012
Available online 18 January 2012
Domino Heck-aza-Michael reactions are an efficient method for the rapid synthesis of functionalised N-
heterocycles. An asymmetric version of this domino process has been developed to access chiral 1,3-
disubstituted N-heterocycles from amino acid precursors in excellent yields (68–81%) with moderate
to high diastereoselectivity (up to 92% de).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective
Domino reaction
Palladium
N-heterocycles
Chiral C1-substituted N-heterocyclic scaffolds are prevalent in
many biologically important natural products and medicinal
chemistry agents, including ajmalicine (1) and quinocarcinol (2)
(Fig. 1).1 As such, the synthetic methods employed for the prepara-
tion of ring systems of such N-heterocycles must allow for the
introduction of the desired chiral centre at the C1-position.
Recent publications have described rapid and high yielding
domino Heck-aza-Michael reactions for the synthesis of C1-substi-
tuted N-heterocycles (including tetrahydro-b-carbolines, tetrahy-
droisoquinolines and isoindolines),2 however a method that is
efficient and highly stereoselective has not yet been reported. To
this end, we herein describe the development of an asymmetric
domino Heck-aza-Michael process for the synthesis of a range of
n=0,1
domino
Heck-aza-Michael
reaction
n=0,1
R1
R1
Ar
Ar
R2
NHTs
NTs
R2
X
*
3
4
Scheme 1. The proposed stereoselective domino Heck-aza-Michael reaction
employing chiral amine substrates.
5
NTs
Pd(OAc)2/PPh3
NHTs
Br
K2CO3 PhMe
,
*
H
N
CO2Me
73%
NH2.HCl
O
8
CO2H
H
O
70:30 dr
CO2Me
Cl
N
H
Me
O
6
7
1
NMe
N
N
H
H
1
Scheme 2. The asymmetric three-component domino Heck-aza-Michael reaction.
H
OMe
OH
MeO
chiral 1,3-disubstituted N-heterocycles (general structure 4) from
amino acid derived precursors (3) in good yields with moderate
to high diastereoselectivity (Scheme 1).
2
1
O
Figure 1. Natural products containing a chiral C1-substituent.
During previous investigations into a three-component domino
Heck-aza-Michael protocol with 2-bromophenethylamine sub-
strates,2b for example compound 5, the use of
L-valine methyl ester
(7) afforded the tetrahydroisoquinoline amide 8 as a 3:7 mixture of
diastereomers (Scheme 2). Unfortunately, further attempts to ex-
ploit this approach using other amino acids, (À)-pantolactone acry-
late or (+)-menthol acrylate did not improve the diastereoselectivity.
⇑
Corresponding author. Tel.: +61 3 5227 1439; fax: +61 3 5227 1040.
E-mail addresses: sgs@cyllene.uwa.edu.au (S.G. Stewart), fred.pfeffer@deakin.
edu.au (F.M. Pfeffer).
Tel.: +61 8 6488 3180; fax: +61 8 6488 1005.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.037

D. L. Priebbenow et al. / Tetrahedron Letters 53 (2012) 1468–1471
1469
Table 1
Optimisation of the asymmetric domino process for tetrahydroisoquinoline synthesis
3-buten-2-one
OTBDMS
Pd. Cat, base, solvent
OTBDMS
110 oC, 16 h
NTs
NHTs
Br
N
Ts
OTBDMS
*
12
13
14
O
a
Entry
Pd catalyst
Base
Major products (% conversion)
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cy2NMe
Na2CO3
THIQ 13 (30%)
THIQ 13 (50%), indoline 14 (50%)
Indoline 14 (100%)
THIQ 13 (10%), indoline 14 (90%)
Indoline 14 (100%)
Pd2(dba)3/DavePhos
Pd2(dba)3/P(tBu)3
Pd2(dba)3/PPh3
Pd(OAc)2/P(tBu)3
Pd(OAc)2/PPh3
b
No reaction
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
No reaction
THIQ 13 (70%)d, indoline 14 (30%)
c
K2CO3
Reaction conditions: Reaction was performed in a sealed tube containing the aryl halide (1.0 equiv), 3-buten-2-one (1.2 equiv), Pd catalyst (10 mol %), and base (3.0 equiv) in
PhMe (4 mL). The reaction mixture was then heated to 120 °C for 16 h.
a
Palladium catalyst loading: 10 mol %. Pd–ligand ratio was 1:1.
The C–N cross coupling adduct was isolated in a yield of 97%.
5.0 equiv of K2CO3 and 2.0 equiv of 3-buten-2-one were used.
The domino adduct was isolated in a yield of 68%.
b
c
d
As such, attention turned to the use of chiral amine starting
materials, which have been used to great effect in asymmetric syn-
thesis, especially in the case of stereoselective aza-Michael addi-
tion.2g,3 Initial investigations into the asymmetric domino Heck-
12 (Scheme 4). In this way, amine 12 should become more nucle-
ophilic than its precursor 10, whilst retaining the requisite stereo-
genic centre—in fact the additional steric bulk of the tert-
butyldimethylsilyl ether should further improve the stereoselec-
tivity of this domino process.
aza-Michael reaction using chiral amines were performed with L-
2-bromophenylalanine (9). Following protection of the amine with
a tosyl group in a 92% yield (this was identified as the optimal pro-
tecting group in previous studies),2a–c the domino substrate 10 was
subjected to the previously identified domino Heck-aza-Michael
conditions for tetrahydroisoquinoline synthesis (Scheme 3).2c
Following a simple work-up, analysis of the crude product reac-
tion mixture indicated that only a Heck reaction had occurred and
no domino reaction product 11 was observed. It was reasoned that
the methyl ester in close proximity to the sulfonamide was
inductively drawing electron density away from the sulfonamide,
making it much less nucleophilic than in the case of 2-bromophen-
ethylamine 5 previously employed by our group.2c
The stereoselective synthesis of tetrahydroisoquinolines (THI-
Qs) with this new precursor was then investigated using a range
of catalytic conditions and the major product in each attempt
was initially assessed by 1H NMR spectroscopy (Table 1). It was
noteworthy that during these optimisation studies, the major by-
product identified was due to the intramolecular C–N (or Buch-
wald–Hartwig) cross-coupling to form the five-membered indoline
scaffold 14, even when traditional catalysts for this type of reaction
were not employed.à
The first reaction was trialled using the conditions previously
reported for the synthesis of tetrahydroisoquinolines (Table 1, en-
try 1).2c The major product identified from this reaction was the
Heck-aza-Michael adduct 13, however, the conversion was poor
(<30%). To increase the rate of the intermolecular Heck reaction,
other catalytic conditions employing electron-rich phosphines
were trialled (Table 1, entries 2–5). In these reactions, conversion
into the desired domino product was increased (up to 50%, entry
2), however, formation of the indoline 14 through an intramolecu-
lar C–N cross-coupling reaction (Buchwald–Hartwig reaction) was
favoured under these more active catalytic conditions. In fact, com-
plete conversion (97% isolated yield) to this indoline 14 was rea-
lised when the P(tBu)3ÁHBF4 salt was employed as a ligand
(Table 1, entries 3 and 5).4 Further attempts using the Pd(OAc)2/
PPh3 catalyst with two alternative bases failed to produce the dom-
ino adduct (Table 1, entries 6 and 7).
In an effort to improve the nucleophilicity of the nitrogen of
phenylalanine 10, the ester was reduced to the corresponding alco-
hol using NaBH4 and subsequently converted into the TBDMS ether
n-butyl acrylate
Pd(OAc)
K2CO3 PhMe,
110 oC, 16 h
2/PPh3
CO2Me
NTs
CO2Me
NHR
,
Br
*
O
nBu
11
R = H
9
TsCl, NEt3,
CH2Cl2
O
92%
R = Ts 10
Eventually it was discovered that by increasing the equivalents
of both the alkene (from 1.2 to 2.0), and base (from 3.0 to 5.0),
the domino reaction produced tetrahydroisoquinoline 13 in 70%
conversion (with 30% of the C–N adduct 14 also identified, Table 1,
entry 8). Following column chromatography, the tetrahydroiso-
quinoline ketone 13 was isolated in a yield of 68%. The diastereo-
meric excess was determined by chiral HPLC, confirming the
Scheme
tetrahydroisoquinolines.
3. Attempted
stereoselective
synthesis
of
1,3-disubstituted
CO2Me i) NaBH4
,
EtOH/THF
OTBDMS
ii) TBDMS-Cl,
imidazole, DMF
NHTs
NHTs
Br
Br
64%
10
12
à
Although always considered
a possibility, the product formed due to C–N
Scheme 4. Modification of the domino precursor for the asymmetric synthesis of
tetrahydroisoquinolines.
coupling had not been observed during previous investigations into the domino Heck-
aza-Michael process.2a–c

1470
D. L. Priebbenow et al. / Tetrahedron Letters 53 (2012) 1468–1471
O
TBDMSO
OTBDMS
OTBDMS
OTBDMS
3-buten-2-one
Pd(PPh3)4,
R
NTs
NHTs
NHTs
Br
18
K2CO3, PhMe
Br
Pd (OA c)2/PPh3
K2CO 3, PhMe
110 oC, 16 h
110 oC, 16 h
NTs
R
12
N
N
Boc
Boc
O
19
O
81% yield, 60% d.e.
R = Me, 68% yield, 85% d.e. 13
15
R = OnBu, 73% yield, 92% d.e.
Scheme 7. The asymmetric domino Heck-aza-Michael reaction for the synthesis of
a C1-substituted tetrahydro-b-carboline.
Scheme 5. The asymmetric domino Heck-aza-Michael reaction for the synthesis of
chiral 1,3-disubstituted tetrahydroisoquinolines.
isoindoline 17 (Scheme 6) was again identified as the cis-isomer by
means of NOE experiments.
asymmetric domino reaction had afforded the major diastereomer
in 85% de. When n-butyl acrylate was employed as the alkene sub-
strate in the asymmetric domino reaction, the butyl ester tetrahy-
droisoquinoline 15 was produced in a 73% yield with 92% de
(Scheme 5).
The third N-heterocycle pursued using an asymmetric domino
Heck-aza-Michael reaction was
a tetrahydro-b-carboline. The
introduction of a stereocentre at the C1-position of the tetrahy-
dro-b-carboline (THbC), using tryptophan with a protected carbox-
ylic acid moiety, has been employed using the Pictet–Spengler
reaction.5 Following a similar procedure to that employed for the
THIQ and isoindoline precursors, the domino substrate 18 was pre-
The cis-diastereomer was determined to be the major isomer
formed during this domino process, with both the C1 and C3 pro-
ton resonances exhibiting a through space NOE interaction with
the aromatic protons of the tosyl protecting group, closest to the
sulfonyl motif, an interaction that can only be achieved if both
these protons are syn related (Fig. 2). The stereochemistry was im-
parted during aza-Michael addition, where following formation of
the Heck adduct, the chiral amine was held in such a position that
it could only attack the planar double bond from one side preferen-
tially, resulting in the formation of cis-isomer as the major product.
It was further proposed that the additional bulk of the silyl ether
group, and the resultant unfavourable steric interaction with the
proximal tosyl group, retained the position of the chiral amine
intermediate during the domino reaction, even at high tempera-
tures, enhancing the stereoselectivity of this process.
pared from L-tryptophan methyl ester (refer to Supplementary
data). The asymmetric domino process was again attempted, this
time using 3-buten-2-one (Scheme 7).2a
Following a simple work-up, the crude product was purified
by column chromatography to afford the desired tetrahydro-b-
carboline ketone 19 in an 81% yield as an inseparable mixture
of diastereomers (Scheme 7). Following analysis by chiral
HPLC, the diastereomeric ratio of the product was identified
as 80:20 and the major product formed from this domino
process was the cis-isomer (again determined using NOE
experiments).
In summary, a general asymmetric domino Heck-aza-Michael
process, using precursors derived from chiral amino acids, was suc-
cessfully developed for the synthesis of 1,3-disubstituted tetrahy-
dro-b-carbolines, tetrahydroisoquinolines and isoindolines in
good yields (68–81%) and with moderate to excellent diastereose-
lectivity (60–92% de). Further extension of the substrate scope to
include additional alkenes and the role of the silyl protecting group
are currently under investigation.
The asymmetric domino Heck-aza-Michael reaction was then
investigated for the synthesis of chiral 1,3-disubstituted isoindo-
lines. Reaction of the phenylglycine based domino substrate 16
with n-butyl acrylate (Scheme 6) was performed using the condi-
tions previously identified for isoindoline formation.2c
The butyl ester isoindoline 17 was isolated in a 79% yield. The
stereoselectivity of this domino process was confirmed by chiral
HPLC (revealing an 87% de). In accordance with previous experi-
ments, the major diastereomer from the reaction sequence to form
Supplementary data
Supplementary data (experimental procedures and selected
NMR spectra) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2012.01.037.
TBDMSO
O
O
R
S
N
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