Heavier alkaline earth catalyzed ene-yne cyclizations: Atom-efficient access to tetrahydroisoquinoline frameworks

Article abstract of DOI:10.1021/ol502600g

Tetrahydroisoquinoline frameworks may be accessed with 100% atom efficiency through the alkaline earth catalyzed addition of primary amines to ene-yne substrates through a sequence of intermolecular alkene and intramolecular alkyne hydroamination steps.

Full text of DOI:10.1021/ol502600g

Letter
pubs.acs.org/OrgLett
Heavier Alkaline Earth Catalyzed Ene-yne Cyclizations: Atom-Efficient
Access to Tetrahydroisoquinoline Frameworks
Stephanie Reid,† Anthony G. M. Barrett,*,† Michael S. Hill,*,‡ and Panayiotis A. Procopiou§
†Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, U.K.
‡Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
§GlaxoSmithKline Medicines Research Center, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: Tetrahydroisoquinoline frameworks may be
accessed with 100% atom efficiency through the alkaline
earth catalyzed addition of primary amines to ene-yne
substrates through a sequence of intermolecular alkene and
intramolecular alkyne hydroamination steps.
etrahydroisoquinoline (THIQ) ring systems are constit-
uents of a wide range of alkaloids and synthetic organic
An initial NMR scale reaction between 1-phenyl-2-(o-
styrenyl)ethyne and n-propylamine in C6D6 in conjunction
with [Sr{N(SiMe3)2}2] was undertaken (Scheme 1) employing
T
and pharmaceutical compounds.1 Methods for their preparation
have, therefore, become increasingly desirable over the past few
decades.2 The Bischler−Napieralksi, Pictet−Spengler, and
Pomeranz−Fritsch reactions are among the most long-standing
synthetic methods for the preparation of isoquinoline
derivatives.3 Other methods include intramolecular oxetane
ring openings,4 multicatalytic three component coupling
reactions with gold complexes,5 oxetane directed aza-Diels−
Alder reactions of indoles,6 and reductive amination/aza-
Michael sequences.7 The development of enantioselective,
catalytic acyl-Pictet−Spengler reactions8 has also been achieved
as well as calcium-catalyzed Pictet−Spengler reactions.9 Their
utility notwithstanding, each of these systems requires multistep
protocols and/or initial condensation reactions to provide the
necessary imine intermediates, and catalytic routes to 1-
benzyltetrahydroisoquinolines, such as the alkaloids coclaurine
and roefractine,10,11 are scarce. In this contribution we describe
a route to THIQ derivatives, which proceeds with absolute
atom economy. This process is mediated by a sequence of
heavier alkaline earth-catalyzed intermolecular alkene and
intramolecular alkyne hydroamination steps to afford exocyclic
enamine THIQ frameworks, which are primed for further
reaction.12
Scheme 1
the 40:20:1 ratio of substrate/amine/catalyst utilized by Marks
for divinylbenzene hydroamination.16 Whereas heating for an
initial period of 14 h at 90 °C provided only 37% conversion to
{2-[o-(2-phenylethynyl)phenyl]ethyl}-propylamine, an increase
of the reaction temperature to 120 °C for a further 3.5 h
provided 16% of the product of intramolecular ring closure, the
desired THIQ product, 1-methylene-3,4-dihydro-2H-isoquino-
line (1), along with further intermolecular alkene hydro-
amination (38%) (Scheme 1). Counter to expectation, these
observations inferred that intermolecular hydroamination
proceeded chemoselectively at the alkene moiety rather than
the more sterically hindered but electronically activated
acetylene substituent. A reaction performed under identical
conditions but with a [Ca{N(SiMe3)2}2] precatalyst did not
result in any viable yield of the cyclized product.
We have previously reported that the intermolecular
hydroamination of vinylarenes, 1,3-dienes, and alkynes may
be achieved with a broad scope of amines including primary,
secondary, and N-heterocyclic amines through the action of
group 2-based catalysts.13 The hydroamination of alkynes is
generally viewed as being more facile than that of alkenes
because of the higher reactivity and electron density of CC
bonds,14 while the more entropically demanding intermolecular
hydroamination of alkenes is less developed than its intra-
molecular variant.15 We, thus, speculated that sequences of
kinetically distinct reaction steps could be incorporated into
syntheses, which exploit the potential for multiple C−N bond
forming processes encapsulated in a single ene-yne substrate.
These encouraging observations prompted further develop-
ment of the precatalyst through use of the heteroleptic anilido-
imine supported alkaline earth reagents (I−IV, Scheme 1),
which have been reported by Sarazin and co-workers17 to
Received: October 16, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
provide superior hydroamination activity over the homoleptic
metal bis(trimethylsilyl)amides.18 Compounds I−IV were
found to be effective catalysts for the intermolecular hydro-
amination of the styrene unit followed by alkyne cyclo-
hydroamination with n-propylamine to afford 1-methylene-3,4-
dihydro-2H-isoquinoline (1) in good to excellent yields using a
moderately low catalyst loading of 10 mol % (Table 1).
Table 2. Hydroamination of 1-Phenyl-2-(o-styrenyl)ethyne
with Primary Alkyl Amines Catalyzed by III
a
Table 1. Hydroamination of 1-Phenyl-2-(o-styrenyl)ethyne
a
with n-Propylamine Catalyzed by I−IV
b
entry
cat.
loading (mol %) time (h) conversion 1/X/amine (%)
1
I
10
10
5
12
43
16
16
15
14
12
6:4:90
23:12:65
32:68
43:57
71:29
99
c
2
I
3
4
5
6
7
II
III
II
III
IV
5
10
10
10
99
a
Substrate:amine = 2:1, 5−10 mol % of catalyst, C6D6, [amine] = 0.33
b
1
M, 130 °C. Monitored by H NMR. Conversion based on ratio of
THIQ product/intermediate/unreacted amine. Temperature 140 °C.
c
Consistent with the previous reports of Sarazin and co-
workers, the catalytic activity was observed to increase with
increasing atomic weight of the group 2 element employed.
These effects are rationalized by extra rigidity encountered
within the iminoanilide ligand framework in comparison to
previously studied β-diketiminate ligands.15 The Mg precatalyst
I displayed the lowest activity and was ineffective for the
cyclization of the N-propylphenethylamine intermediate
(entries 1 and 2). Although the Ba precatalyst IV provided
the highest activity (entry 7), the Sr complex III provided
quantitative conversion to the exocyclic enamine THIQ
product after 14 h at 130 °C (entry 6). With its combination
of acceptably high activity and greater ease of precatalyst
synthesis, the strontium species III was, thus, selected for
further study.
The scope of the hydroamination of 1-phenyl-2-(o-styrenyl)-
ethyne catalyzed by III was examined with a range of
commercially available primary alkyl amines (Table 2).
Although cyclization could be achieved using 5 mol % of III,
use of 10 mol % of the precatalyst provided significantly
increased conversions. In all cases, regioselective styrene
hydroamination to provide the anti-Markovnikov product was
observed to have occurred first followed by insertion of the
alkyne into the resulting Sr−N bond. The fastest rate of
catalysis was achieved with n-propyl amine, which provided
quantitative conversion to 1 in under 15 h (entry 1). Products
formed from amines containing bulky substituents near the C−
NH2 moiety were generally formed in lower yields than N-
methylene substituted amines. Good yields with the more bulky
amines could be obtained, however, if the temperature was
increased from 130 to 140 °C (entries 5−6, 9, 11−12),
allowing purification and characterization of the otherwise
hydrolytically sensitive products in their reduced form (NaBH4,
compounds 22−37, Supporting Information).
a
Reaction conditions: [cat]/[amine]/[substrate] = 1:10:20 in C6D6 at
b
1
130 °C, [amine] = 0.33 M, catalyst = III. Determined by H NMR
spectroscopy. Temperature 140 °C. No conversion of amine to
intermolecular addition intermediate product nor subsequent
cyclization. Extra 5 mol % of catalyst added and heated further for
the time specified.
c
d
Whereas cyclopropylmethylamine was successfully cyclized
(entry 3), the cyclopentyl-substituted methylamine displayed
no evidence for the formation of the alkene hydroamination-
phenethylamine product (entry 13), even under more forcing
conditions over 6 days, while the intermediate cyclobutylme-
thylamine provided only moderate conversion (entry 12).
e
Presumably, the rate of cyclization of cycloalkanemethylamines
depends on a balance between steric factors, ring strain, and
B
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Organic Letters
Letter
a
Table 3. Hydroamination of 1-Phenyl-2-(o-styrenyl)ethyne with Substituted Benzyl Amines Catalyzed by III
b
b
entry
1
R1
R2
R3
R4
time (h)
conversion (%)
E/Z
1.2:1, 1:2
H
H
H
H
12.5, 29
10, 15
99(13), 99(13)
c
2
H
H
OMe
OtBu
OMe
H
H
68(14), 72(14)
1:1.1, 1:1.8
c
3
4
5
6
7
H
H
H
13, 28, 12
55(15), 63(15), 85(15)
1:0.9, 1:2, 1:2
d
H
OMe
OMe
OMe
H
H
12.5
H
OMe
H
15, 32
12.5, 27
10, 15
77(16), 85(16)
83(17), 90(17)
1:1.3, 1:2.6
1:0.67, 1:1.3
1:1, 1:1.5
H
H
OMe
H
OMe
80(18), 82(18)
a
b
1
Reaction conditions: [cat]/[amine]/[substrate] = 1:10:20 in C6D6 at 140 °C, [amine] = 0.33 M. Determined by H NMR spectroscopy.
c
d
Compound number in parentheses. Extra 5 mol % of catalyst added and heated further for amount of time specified. No conversion of amine to
intermolecular addition intermediate product nor subsequent cyclization.
destabilizing effects encountered within the ring to allow a
favorable conformation in the THIQ framework. The E:Z
product ratio was also affected by the steric demands of the
amine substrate with more sterically encumbered amines
providing the Z isomer as the major product. In the case of
3-methoxyphenethylamine (entry 10) cyclization was unsuc-
cessful. During the course of heating at 140 °C over 5 days, this
reaction was accompanied by double hydroamination of the
secondary amine intermediate. For reactions with methyl-
benzylamine (Table 2, entry 14) and benzyl amine (Table 3,
entry 1) 15 mol % of catalyst was required to achieve a
quantifiable conversion.
Table 4. Hydroamination of Aryl-2-(o-styrenyl)ethynes with
n-Propylamine Catalyzed by III
a
The results illustrated in Table 3 indicate that in some cases
successful catalytic turnover is dependent on the position of
aromatic substitution. Notably, the disubstituted (3,4-
dimethoxyphenyl)methanamine provided no conversion
under the reaction conditions (entry 4). In contrast, the
methoxyphenyl)methanamine (entry 2) displayed enhanced
reactivity in comparison to its tert-butoxy-substituted analogue
(entry 3). In all cases the first observed product was that of the
E alkene. Upon further heating an increase in proportion of the
1
a
Z alkene product (E stilbene) was apparent by H NMR
Reaction conditions: [cat]/[amine]/[substrate] = 1:10:20 in p-
xylene-d10 at 130 °C, [amine] = 0.33 M. Determined by H NMR.
b
1
spectroscopy. This was most pronounced in the reactions with
benzyl amine (entry 1) and 3,5-dimethoxybenzylamine (entry
5) whose Z alkene formation doubled upon further heating for
the amount of time specified. It is well documented that Z
stilbene readily isomerizes to E stilbene under thermal
conditions.19
phenethylamine intermediate B takes place before cyclization,
indicating that intramolecular addition of Sr−C to the alkynyl
group does not occur prior to protonolysis of species A. As its
concentration increases, the amine B will compete effectively
with the primary amine substrate to effect protonolysis and
provide the necessary strontium amide species C. Intra-
molecular cyclization of C may then occur either through the
formation and subsequent protonolysis of the illustrated alkyl
strontium intermediate D or concerted insertion and substrate-
assisted protonolysis reminiscent of that deduced in our
previous mechanistic studies of magnesium and calcium-
catalyzed intramolecular hydroamination.15 Irrespective of the
precise details of this process, protonolysis by B or residual
amine substrate will release the Z-stilbene THIQ product E.
This Z-stilbene in turn may isomerize to its E-isomer F under
the thermal conditions of the catalysis.
No hydroamination products were observed when the
phenyl substituent of the 1-phenyl-2-(o-styrenyl)ethyne was
replaced by H, Me, SiMe3, or benzyl indicating the necessity of
π-arene electron withdrawal in the insertive transition state.
The presence of substituents on the exocyclic aromatic ring of
the diarylacetylene functionality also led to a decrease in cyclic
product formation in reactions with n-propylamine, irrespective
of their electron donating or withdrawing character (Table 4,
entries 1−3). These catalyses were also hindered by polymer-
ization side reactions, which were most pronounced for the
halogen-substituted substrates with the appearance of extremely
broadened resonances in the alkyl region of the NMR spectra.
The 2,1 addition of the amine to the alkene component of
the ene-yne substrate and the predominance of the E-alkene
isomer of the THIQ product lead us to suggest the provisional
mechanism illustrated in Scheme 2. Production of the
In summary, intermolecular alkene hydroamination may be
coupled with intramolecular alkyne hydroamination, catalyzed
by inexpensive and abundant alkaline earth precatalysts to
provide entry to a variety of THIQ frameworks. Although
C
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Organic Letters
Letter
Scheme 2
(6) Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Angew. Chem., Int.
Ed. 2013, 52, 2027.
limited to diaryl alkyne substitution, a broad reaction scope is
available from variation of the primary amine reaction partner.
The catalysis provides chemo- and regioselective C−N bond
formation providing the corresponding exocyclic enamine
products. The rich potential of this reactivity may be further
emphasized by one pot elaboration of the enamine products,
which could be reduced to the tetrahydroisoquinolines using
NaBH4 (compounds 22−37, Supporting Information) or
oxidized using iodosobenzene to the corresponding benzolac-
tam (compound 38, Supporting Information). Preliminary
analysis suggests a dual cycle mechanism involving initial
intermolecular alkene hydroamination and subsequent rate
limiting alkyne insertion into the pendant Sr−N bond followed
by rapid protonolysis to yield the cyclic enamine. We are
continuing to elaborate upon this reactivity and to extend the
substrate scope available to this atom-efficient domino process.
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details for compounds 1−38 and character-
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(18) Barrett, A. G. M.; Crimmin, M. R.; Hill, M. S.; Procopiou, P. A.
Proc. R. Soc. A 2010, 466, 927.
(19) Kwasniewski, S. P.; Claes, L.; Franco
AUTHOR INFORMATION
̧ is, J. P.; Deleuze, M. S. J.
■
Phys. Chem. B. 2003, 118, 7823.
Corresponding Authors
*E-mail: msh27@bath.ac.uk.
*E-mail: agm.barrett@imperial.ac.uk.
Notes
The authors declare no competing financial interest.
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