A general approach to N-heterocyclic scaffolds using domino Heck-aza-Michael reactions

Article abstract of DOI:10.1039/c0ob00835d

Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-β-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of

Full text of DOI:10.1039/c0ob00835d

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PAPER
A general approach to N-heterocyclic scaffolds using domino
Heck–aza-Michael reactions†
Daniel L. Priebbenow,a Scott G. Stewartb and Frederick M. Pfeffer*a
Received 6th October 2010, Accepted 11th November 2010
DOI: 10.1039/c0ob00835d
Palladium-catalyzed domino Heck–aza-Michael reactions for the synthesis of a series of C1-substituted
tetrahydro-b-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process
involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene,
followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.
The tetrahydro-b-carboline, tetrahydroisoquinoline and isoin-
Introduction
doline scaffolds are all present in important biologically-active
compounds. Tetrahydro-b-carbolines (THbCs or tryptolines)
form the core of the antihypertensive agent reserpine (1)
(Fig. 1), along with a range of other biologically-active natural
products.10–17 Likewise, the tetrahydroisoquinoline ring system
forms the central part of a number of naturally-occurring
alkaloids,18–22 including the antitumor natural product quinocar-
cinol 2.23,24 In comparison, isoindoline-based natural products are
not as prevalent. Nevertheless, this scaffold is found in a range of
potential pharmaceutical agents,25–28 such as compound 3 (Fig. 1),
synthesized as a ligand for the melanocortin subtype-4 receptor
(MC4R).29
In the ongoing pursuit of environmentally friendly reaction
processes, domino reactions have emerged as a powerful tool
for synthetic chemists.1,2 These domino processes generate a high
level of molecular complexity in one efficient step, minimising
solvent use, reagents, time and energy.1 A domino reaction
is defined as “the execution of two or more bond-forming
transformations under identical reaction conditions, in which the
latter transformations take place at the functionalities formed
by the preceding transformation”.1,2 The more feasible domino
reactions are those where all transformations occur under similar
reaction conditions, for example, where each of the reaction steps
is palladium-catalysed.2–5 Likewise, because of the reliance of base
in many Pd cross-coupling reactions, domino reactions involving
both a Pd-catalysed and a base-initiated synthetic step are also
plausible.
In spite of this possibility, the domino Heck–Michael method-
ology for the formation of heterocycles has not been widely
reported.6–8 Domino Heck–aza-Michael reactions have been ap-
plied to a series of unique benzo-fused sultams,7 and isoin-
dolinones using terminal alkene esters.8 However, attempts to
expand the scope of these methods to related substrates have
proved problematic. Recently, our group has reported a domino
Heck–aza-Michael reaction for the synthesis of a series of C1-
substituted tetrahydro-b-carbolines.9 Herein, we report that the
scope of this novel domino process has been successfully expanded
to include other N-heterocycles, namely tetrahydroisoquinolines
and isoindolines.
aSchool of Life and Environmental Sciences, Deakin University, Geelong,
3217, Victoria, Australia. E-mail: fred.pfeffer@deakin.edu.au; Fax: +61 3
5227 1040; Tel: +61 3 5227 1439
Fig.
1 Biologically-active compounds containing the tetrahydro-b-
carboline (1), tetrahydroisoquinoline (2) and isoindoline (3) N-heterocyclic
core.
bSchool of Biomedical, Biomolecular and Chemical Sciences, University of
Western Australia, Crawley, 6009, Western Australia, Australia. E-mail:
sgs@cyllene.uwa.edu.au; Fax: +61 8 6488 1005; Tel: +61 8 6488 3180
As the importance of these classes of compounds grows in
a medicinal chemistry setting, so does the focus on a general
method for their synthetic preparation. Tetrahydro-b-carbolines
and tetrahydroisoquinolines have traditionally been prepared by
† Electronic supplementary information (ESI) available. 1H and 13C NMR
spectra for compounds listed in the experimental section. See DOI:
10.1039/c0ob00835d
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reacting tryptamine or phenethylamine with a suitable aldehyde;
namely the Pictet–Spengler reaction.30–34 Similarly, the Bischler–
Napieralski reaction affords these ring systems through the
cyclodehydration of an appropriately substituted amide.32,35–39
Alternatives to the Pictet–Spengler or the Bischler–Napieralski
reactions are limited. One of the most recent, the Ferracioli synthe-
sis of tetrahydroisoquinolines, involves palladium-catalyzed ortho-
alkylation/vinylation followed by an aza-Michael reaction.40
Isoindolines substituted at the C1-position have also been accessed
using an aryl radical cyclization of N-benzylenaminone esters.41
More recently, 1,3-disubstituted isoindolines have been synthe-
sized using a Brønsted acid-catalyzed 1,2-addition followed by an
aza-Michael addition.42
selection of a suitable protecting group for the tethered amine is
important when considering the Michael addition step. An ideal
protecting group would control the amine reactivity, avoiding the
likelihood of an intermolecular 1,4-addition, prior to the Heck
reaction.
As the Heck reaction at the C2 position of substituted
tryptamines is known from previous investigations within the
group,5 it was trialled first. Readily available ortho-halogenated
benzylamines and phenethylamines were also identified as ideal
substrates for this investigation, as the ortho-tethered amine is
well positioned for the aza-Michael addition to form a new N-
heterocycle, following the initial Heck reaction.
Tetrahydro-b-carbolines
A general approach to N-heterocycles using a domino Heck–
aza-Michael strategy would complement existing methods and in
some instances provide a more attractive option, for example,
when suitable aldehydes for the Pictet–Spengler reaction are
not readily available.14,17,43 In order to be applied to a range
of substrates, the domino process needs to occur under mild
conditions using a readily available catalyst, base and with
inexpensive electron deficient alkenes. As a wide range of suitable
acrylates (such as acrolein, acrylonitrile, acrylic acid, etc.) are
commercially available, the C1 functionality of the new heterocycle
can be customised by appropriate alkene selection. To this end, we
herein describe our recent efforts to expand our domino Heck–
aza-Michael methodology from THbCs to include tetrahydroiso-
quinolines and isoindolines.
The detailed optimisation of a domino Heck–aza-Michael reac-
tion for the synthesis of tetrahydro-b-carbolines has previously
been described by our group.9 As the Heck reaction of 2-
bromoindoles has been reported,5,45,46 the limiting factor was the
aza-Michael reaction. A key finding of our THbC investigation
was that the tosyl protecting group of the tethered amine (superior
to Boc, Ac and trifluoroacetyl) allowed the aza-Michael reaction
to take place subsequent to the initial cross-coupling reaction.
Following optimisation, the highest yields for the domino process
between halogenated indole-N-Boc substrate 10 and butyl acrylate
were obtained by using the Pd(PPh3)4, K2CO3 and toluene catalytic
system.
The versatility of this domino Heck–aza-Michael reaction was
then investigated using a number of suitably conjugated terminal
alkenes (Scheme 2). The two-step domino process, forming a
new 6-membered N-heterocycle, performed well for the alkenes
employed, except in the case of acrylic acid, with isolated
yields ranging from 64–83% (compounds 11–16).‡ In addition
to these previously reported scaffolds,9 this domino process has
now been expanded to include 3-buten-2-one, which afforded
ketone-functionalised THbC 17 (78% yield). These tetrahydro-
b-carboline scaffolds contain a series of C1 functionalities that
allow for further synthetic manipulation and possible application
as part of total syntheses.9
Results and discussion
In planning the Heck–aza-Michael domino process, a suitable
halogenated aryl ring system for a rapid Heck reaction with an
electron-withdrawn terminal alkene was sought. Aryl bromides 4
were selected due to the higher commercial cost of aryl iodides.
Initial C–H activation was also envisaged but deemed to be too
slow and less regioselective in the initial step of the domino
sequence.44
The ring size of the newly formed N-heterocycle (compounds 7–
9, Scheme 1) is governed by the length of the alkyl chain connecting
the amine to the aryl portion of starting material 4. Similarly, the
Scheme 2 The synthesis of tetrahydro-b-carbolines using a domino
Heck–aza-Michael process.
Tetrahydroisoquinolines
Given the success of this initial series of domino reac-
tions to generate tetrahydro-b-carbolines 7, the synthesis of
‡ The unreactive nature of acrylic acid may be explained by the poor
solubility of the corresponding carboxylate ion.
Scheme 1 Generic plan for the domino Heck–aza Michael reaction.
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Table 1 Investigations into the domino reaction of aryl bromide 26
Entry
Palladium catalysta (10 mol%)
Base
Solvent
Major productb
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
K2CO3
Na2CO3
Cy2NMe
NEt3
K2CO3
NEt3
K2CO3
K2CO3
Cy2NMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
PhMe
22
21
Pd2(dba)3/P(tBu)3
Pd(OAc)2/PPh3
Pd2(dba)3·CHCl3
Pd(OAc)2/PPh3
Pd2(dba)3/DavePhos
Pd(OAc)2/PPh3
Herrmann–Beller palladacyclef
21
21
NRd
21
20 (79)e
20 (80)e
20 (67)e
PhMe
DMF–MeCN–H2Oc
a Palladium catalyst and ligand used in a 1 : 1 molar ratio. b As determined by 1H NMR analysis of the crude reaction mixture. For immediate identification
1
of product ratios in the H NMR spectra d: 5.46 (red), 4.60 (green), 7.84 (blue) and 6.28 (purple). c DMF–MeCN–H2O (5 : 5 : 1). d NR = No reaction.
e Yield (%). f The Herrmann–Beller catalyst is [trans-di-(m-acetato)-bis[ortho-(di-ortho-tolylphosphino)benzyl]dipalladium(II)].
tetrahydroisoquinolines 9 using a domino Heck–aza-Michael re-
action was investigated. As in the case of the THbCs, the tosyl (Ts)
protecting group was employed to control amine nucleophilicity,9
and the desired domino substrate (sulfonamide 19) was prepared
in 86% yield. Using this substrate, a series of trial reactions were
carried out to determine if a domino Heck–aza-Michael process
was feasible. These reactions were initially performed by treating
aryl bromide 19 with butyl acrylate, a palladium catalyst, base and
successful in enabling the aza-Michael reaction to occur (albeit
intermolecularly).
To ensure rapid formation of the Heck adduct, the highly
reactive and electron-rich Pd2(dba)3/DavePhos catalyst system,
developed by Buchwald and Hartwig, was used in combination
with K2CO3.47§ To our delight, this catalytic system furnished
desired tetrahydroisoquinoline 20 in high yield (Table 1, entry 7).
Following further trials, other catalytic systems (Table 1, entries
8 and 9) also resulted in clean conversion of domino precursor 19
to tetrahydroisoquinoline 20. These additional successes indicate
that a judicious choice of base and solvent is crucial for promoting
the desired aza-Michael cyclisation (compare Table 1, entries 4 and
8). In assessing each of these procedures, the Pd(OAc)2/PPh3 and
K2CO3 in toluene catalytic system was deemed the most attractive
due to its relatively low cost and commercial availability.
A range of acrylates were subject to this domino process
to afford a series of C1-substituted tetrahydroisoquinolines 9
(Table 2). The resulting products from this series of reactions
contain a range of functionalities, including ester, ketone and
nitrile (Table 2, entries 1–5). In each of these cases, there seems
to be no clear differentiation in the yield, suggesting that small
differences in the electronics of each of these acrylates does not
dramatically affect the domino process. Unfortunately, reactions
attempted with both acrolein and acrylic acid did not furnish the
desired tetrahydroisoquinolines, even though the reaction with
acrolein had been successfully employed in a THbC domino Heck–
aza-Michael reaction (Scheme 2).9
◦
solvent in a pressure vessel, and heating to 120 C for 16 h. The
identification of the products (20–22) was performed by means of
1H NMR spectroscopy of the crude reaction mixture (Table 1).
The ideal catalytic system for this domino process would rapidly
produce Heck product 21, with the base and solvent promoting
the aza-Michael addition to form desired tetrahydroisoquinoline
20, but not to an extent where intermolecular 1,4-nucleophilic
addition of the acrylate occurs prior to the Heck reaction.
In the first attempt, the optimum conditions identified for the
synthesis of THbCs (Pd(PPh3)4, K2CO3, PhMe; Table 1, entry 1)
produced adduct 22 exclusively, i.e. the aza-Michael reaction is
favoured but the Heck reaction is slow.
A
number of alternative Pd catalysts (Pd(PPh3)4,
Pd2(dba)3/P(tBu)3 and Pd(OAc)2/PPh3) combined with
a
range of bases (Table 1, entries 2–4) were subsequently trialled;
however, only Heck adduct 21 was produced. It is apparent that
whilst the Heck reaction was proceeding, the base used (Na2CO3,
Cy2NMe and NEt3; Table 1, entries 2, 3 and 4, respectively)
in each of these trials was not strong enough to induce either
intra- or intermolecular aza-Michael addition, as only traces
of these products were observed. From the previous work on
THbCs, it is known that the aza-Michael process is sensitive to
subtle variations in the base used. Again, for the synthesis of
tetrahydroisoquinolines, slightly changing the base (e.g. from
K2CO3 to Na2CO3; Table 1, entries 1 and 2) either facilitates
or reduces the likelihood of the aza-Michael reaction. Of the
bases trialled to this point (Table 1, entries 1–6), only K2CO3 was
Isoindolines
With the successful development of domino Heck–aza-Michael
reactions for the formation of two 6-membered N-heterocyclic
§ The possibility of a C–N cross-coupling was disregarded due to the
strained ring system that would be generated as part of this process.
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Table 2 Synthesis of a series of C1-substituted tetrahydroisoquinolines
Pd(PPh3)4 but changing the base and solvent (Table 3, entries 2–
4) also proved unsuccessful. The highly active catalytic system of
Pd2(dba)3/P(tBu)3 minimised the formation of aza-Michael–Heck
product 33; however, complete conversion of the Heck adduct to
the desired isoindoline was not realised (Table 3, entry 5).48
A high yield of desired isoindoline 31 was observed when
Pd(OAc)2/PPh3 and triethylamine were used in either toluene or
DMF (Table 3, entries 8 and 9). The use of other highly active
Pd catalysts also proved successful when teamed with an amine
base in DMF. Again, it was apparent that a suitable base (in this
case, an organic base rather than an inorganic base) was crucial to
effect the desired cyclisation following the Heck reaction.
Even though the Pd2dba3/DavePhos catalytic system (Table 3,
entry 10) provided isoindoline 31 in the highest yield, it was not
significantly greater than that obtained when the Pd(OAc)2/PPh3
system was used (Table 3, entry 9). This latter system was
subsequently used for the remainder of this investigation due to
its low cost and commercial availability.
Entry Alkene
R
Product Yield (%)
n
1
2
3
4
5
6
7
8
Butyl acrylate
Methyl acrylate
CO2 Bu
CO2Me
20
23
80
83
76
82
2-Hydroxyethyl acrylate CO2(CH2)2OH 24
Acrylonitrile
3-Buten-2-one
Acrylamide
Acrolein
CN
25
26
27
28
29
COCH3
CONH2
CHO
79
Tracea
NRb
NRb
Acrylic acid
CO2H
a Trace = less than 10%, as determined by 1H NMR. b NR = No reaction.
This optimized domino system was then used with a range of
acrylates to afford a series of C1-substituted isoindolines (Table 4).
The products synthesised contain a range of functionalities,
including carboxylic acid, ester, ketone, amide and nitrile. This
time, the use of acrylic acid resulted in the formation of isoindoline
acetic acid 38, presumably due to the increased solubility of
the carboxylate ion in the triethylamine/DMF solvent system.
Unfortunately, the use of acrolein49 once again did not yield the
desired isoindoline.
systems, our attention turned to a third scaffold. To expand the
scope of this methodology to include 5-membered N-heterocycles,
an appropriately substituted benzylamine 30, was prepared in 99%
yield as a precursor to C1-substituted isoindolines 8.
As with both the THbCs and tetrahydroisoquinolines, a range
of conditions were evaluated for the preparation of the desired
isoindoline 31 (Table 3). Bromosulfonamide 30, butyl acrylate, a
palladium catalyst, base and solvent were combined in a pressure
vessel, and heated to 120 ◦C for 16 h. Following a simple work up,
the major product was identified by 1H NMR spectroscopy.
The first trial with tetrakis(triphenylphosphine) palladium
(Pd(PPh3)4) afforded mixtures of the three predicted products,
31, 32 and 33 (Table 3, entry 1). Repeating the reaction with
Conclusions
Following the successful development of a domino Heck–aza-
Michael reaction for the synthesis of the tetrahydro-b-carbolines,9
Table 3 Preliminary investigations into the formation of isoindolines
Entry
Palladium catalysta (10 mol%)
Base
Solvent
Major productb
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3
Na2CO3
Cs2CO3
K2CO3
Cy2NMe
NEt3
K2CO3
NEt3
NEt3
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
PhMe
PhMe
PhMe
DMF
PhMe
DMF
PhMe
PhMe
Mixture (31/32/33)
Mixture (31/32/33)
NRd
NRd
Pd2(dba)3/P(tBu)3
Pd2(dba)3·CHCl3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd2(dba)3/DavePhos
Pd2(dba)3/XPhos
Pd2(dba)3/SPhos
Herrmann–Beller palladacyclef
31/32
NRd
NRd
31 (74)e
9
DMF
DMF
DMF
31 (77)e
10
11
12
13
31 (79)e
31 (62)e
DMF
31 (48)e
DMF–MeCN–H2Oc
31 (54)e
a Palladium and ligand used in a 1 : 1 molar ratio. b As determined by 1H NMR analysis of the crude reaction mixture. For immediate identification of
product ratios in the 1H NMR spectra d: 5.28 (red), 5.10 (green), 7.62 (blue) and 6.38 (purple). c DMF–MeCN–H2O (5 : 5 : 1). d NR = No reaction. e Yield
(%). f The Herrmann–Beller catalyst is [trans-di-(m-acetato)-bis[ortho-(di-ortho-tolylphosphino)benzyl]-dipalladium(II)].
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Table 4 Synthesis of a series of C1-substituted isoindolines
domino processes studied herein, the role of ring size and sterics
appears to be minor.
In conclusion, high yielding domino Heck–aza-Michael reac-
tions to access C1-substituted tetrahydro-b-carbolines, tetrahy-
droisoquinolines and isoindolines have been successfully devel-
oped as a general approach to N-heterocycles. These reactions
employ mild conditions, and readily available palladium catalysts
and acrylates. The mild conditions described suggest this domino
process may be applied to more complex substrates and key
transformations in total syntheses. As indicated, the use of other
highly active palladium catalysts may benefit the scope of this
process and its functional group tolerance.
Entry Alkene
R
Product Yield (%)
n
1
2
3
4
5
6
7
8
Butyl acrylate
Methyl acrylate
2-Hydroxyethyl acrylate CO2(CH2)2OH 35
Acrylamide
Acrylonitrile
Acrylic acid
3-Buten-2-one
Acrolein
CO2 Bu
CO2Me
31
34
77
Unknowna
84
CONH2
CN
CO2H
COCH3
CHO
36
37
38
39
40
71
68
85
86
NRb
Experimental
a This domino process also performed well using methyl acrylate; however,
the isoindoline product could not be separated from the remaining starting
material by column chromatography. b NR = No reaction.
General experimental
All proton (1H NMR) and carbon (13C NMR) spectra were
recorded on a 270 MHz FT-NMR, 400 MHz FT-NMR or
300 MHz FT-NMR spectrometer as indicated. Samples were
dissolved in deuterated chloroform (CDCl3). Proton peaks are
reported as follows: chemical shift d (ppm) (multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
integral, coupling constant J (Hz), assignment). Carbon peaks
are reported as chemical shift d (ppm). High resolution mass
spectra (HRMS) were recorded on a TOF mass spectrometer
with the following conditions: drying gas, nitrogen (7 mL min-1,
350 ◦C); nebulizer gas, nitrogen (16 psi); capillary voltage, 4.0 kV;
vaporizer temperature 350 ◦C; and cone voltage, 60 V. HPLC grade
methanol was used as the mobile phase. Samples were dissolved
in acetonitrile (less than 1 mg per mL). IR spectra were acquired
on an FT-IR instrument using KBr discs and are reported in wave
numbers (cm-1). Column chromatography was performed using
silica gel, 60 (70-230 mesh). Petroleum spirits (pet. sp) refers to
the fraction boiling at 40–60 ◦C. All solvents used were AR grade.
Pd(PPh3)4 was prepared according to a literature procedure.50
Full experimental details for the preparation of compounds 10–
16 are described in an earlier communication.9
the scope of this new methodology has been expanded to include
the tetrahydroisoquinoline and isoindoline N-heterocyclic scaf-
folds. The key considerations of the domino Heck–aza-Michael
methodology were identified as (i) the relatively quick formation
of the Heck adduct (controlled through appropriate selection of
Pd catalyst) and (ii) the nucleophilicity of the tethered amine
(mediated through careful selection of the protecting group, base
and solvent).
In determining the appropriate conditions for the Heck reac-
tion, a palladium catalyst was required that facilitated a fast,
high-yielding reaction between the aryl halide and the alkene in
the presence of a mild base and a relatively non-polar solvent.
It is important that the acrylate is consumed rapidly by the
Heck process so that the intermolecular aza-Michael reaction
cannot take place. For the Heck reaction at the indole 2-position,
Pd(PPh3)4 afforded the highest yields. In the case of the benzyl- and
phenethylamine aryl halides, the use of Pd(OAc)2/PPh3 proved
optimal.
More importantly, an appropriate base is required; one that
is able to sufficiently promote aza-Michael reaction, but not
to the extent that it occurs before a high concentration of
the Heck adduct is realised. Indeed, the outcome of reactions
that were repeated, varying only the base used, ranged from a
rapid intermolecular Michael reaction prior to the Heck reaction
through to the desired domino Heck–aza-Michael process. For
the synthesis of both THbCs and tetrahydroisoquinolines, K2CO3
was required to effect the cyclisation; however, in the case of the
isoindolines, the new N-heterocycle formed in the presence of a
milder amine base (either NEt3 or Cy2NMe).
Other parameters that could limit reaction progress included
(i) the size of the N-heterocycle being formed, and (ii) the sterics
associated with the Heck reaction and subsequent Michael addi-
tion. If the steric bulk of the proximal sulfonamide (benzylamine
vs. phenethylamine) was a critical factor, the initial Heck reaction
would be faster for the formation of compounds 11 and 20 over
isoindoline 31. Furthermore, for 5-membered isoindoline series
8, a strained transition state in the Michael addition step may
also hinder the progress of the domino reaction. Nevertheless, as
little difference in the overall yields were observed for each of the
Specific experimental
(R,S)-2-(9-tert-Butoxycarbonyl-2-(p-toluenesulfonyl)-3,4-tetra-
hydro-1H-carbolin-1-yl)propan-2-one (17). A sealed tube con-
taining 2-bromoindole 10 (300 mg, 0.61 mmol), Pd(PPh3)4 (70 mg,
10 mol%), K2CO3 (252 mg, 1.82 mmol) and 3-buten-2-one (51 mg,
0.73 mmol) in toluene (3 mL) was flushed with argon, then
heated at 120 ◦C for 16 h. The reaction mixture was cooled to
room temperature, filtered, and the solvent removed in vacuo.
Purification by column chromatography (1 : 4 EtOAc : pet. sp.)
afforded tetrahydro-b-carboline 17 as a pale yellow oil (228 mg,
0.47 mmol, 78%). FT-IR (n, cm-1, KBr) 1716vs, 1465, 1386, 1327,
1159, 698; 1H NMR (270 MHz, CDCl3, d) 7.96 (dt, J = 0.9, 8.3 Hz,
1H), 7.61 (d, J = 8.3 Hz, 2H), 7.12–7.27 (m, 3H), 7.00 (dd, J =
0.6, 8.6 Hz, 2H), 6.23 (dd, J = 3.3, 10.6 Hz, 1H), 4.05 (dd, J = 6.5,
15.3 Hz, 1H), 3.38–3.50 (m, 1H), 3.08 (dd, J = 3.5, 14.2 Hz, 1H),
2.70 (dd, J = 10.6, 14.2 Hz, 1H), 2.41–2.58 (m, 2H), 2.35 (s, 3H),
2.14 (s, 3H), 1.73 (s, 9H); 13C NMR (75 MHz, CDCl3, d) 206.0,
150.1, 143.5, 136.8, 135.2, 133.5, 129.1, 128.5, 127.0, 124.5, 122.8,
117.9, 115.6, 114.5, 84.8, 50.5, 48.8, 37.7, 29.2, 28.3, 21.2, 19.2;
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HRMS-ESI (m/z) [C26H30N2O5S + Na]+ calc. 505.1768, found
505.1790.
3H), 2.32 (s, 3H); 13C NMR (67.5 MHz, CDCl3, d); 170.7, 143.3,
137.2, 135.3, 133.1, 129.5, 129.1, 127.3, 127.2, 126.6, 126.5, 53.5,
52.0, 43.4, 39.7, 26.9, 21.5; HRMS-ESI (m/z) [C19H21NO4S + Na]+
calc. 382.1084, found 382.1080.
N-(2-Bromophenethyl)-p-toluenesulfonamide (19). To a cooled
solution (0 ◦C) of 2-bromophenethylamine (400 mg, 2.0 mmol)
and triethylamine (242 mg, 2.4 mmol) in CH2Cl2 (10 mL) was
added p-toluenesulfonyl chloride (420 mg, 2.2 mmol) in one
portion. The reaction mixture was stirred for 2 h. at ambient
temperature. The reaction mixture was then washed with HCl
(1 M, 2 ¥ 10 mL), NaOH (Aq. 5% w/w, 2 ¥ 10 mL) and brine
(10 mL). The organic layer was separated, dried (MgSO4) and
concentrated under reduced pressure to afford phenethylamine 19
as a colorless oil (624 mg, 1.76 mmol, 88%). FT-IR (n, cm-1, KBr)
3152, 1598, 1233, 1059, 754, 647; 1H NMR (270 MHz, CDCl3, d)
7.69 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 1.2, 7.9 Hz, 1H), 7.26 (d,
J = 8.1 Hz, 2H) 7.03–7.20 (m, 3H), 4.57 (brt, J = 6.2 Hz, 1H),
3.21 (q, J = 6.9 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H);
13C NMR (75 MHz, CDCl3, d); 143.4, 137.1, 133.0, 131.1, 129.7,
129.0, 128.2, 127.7, 127.1, 124.4, 42.5, 36.3, 21.5; HRMS-ESI
(m/z) [C15H16BrNO2S + Na]+ calc. 375.9977, found 375.9979.
(R,S)-2-Hydroxyethyl 2-(2-tosyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)acetate (24). General procedure A was followed using 2-
bromophenethylamine 19 (100 mg, 0.28 mmol), 2-hydroxyethyl
acrylate (39 mg, 0.34 mmol), Pd(OAc)2 (6 mg, 10 mol%), PPh3
(7 mg, 10 mol%), potassium carbonate (116 mg, 0.84 mmol) and
toluene (3 mL). Purification by column chromatography (2 : 3
EtOAc : pet. sp.) afforded tetrahydroisoquinoline 24 as a pale
yellow oil (83 mg, 0.21 mmol, 76%). FT-IR (n, cm-1, KBr) 2924,
1737, 1597, 1336, 1158, 1091, 756, 659, 547; 1H NMR (270 MHz,
CDCl3, d) 7.61 (d, J = 8.4 Hz, 2H), 7.06–7.15 (m, 5H), 6.91 (m,
1H), 5.47 (t, J = 5.9 Hz, 1H), 4.21–4.31 (m, 2H), 3.71–3.78 (m,
2H), 3.50–3.59 (m, 2H), 2.91 (ddd, J = 1.5, 8.2, 14.8 Hz, 1H),
2.78 (dd, J = 5.7, 14.8 Hz, 1H), 2.60–2.65 (m, 2H), 2.31 (s, 3H);
13C NMR (75 MHz, CDCl3, d); 170.0, 143.2, 137.1, 135.2, 133.0,
129.5, 129.0, 127.2, 127.1, 126.7, 126.6, 126.4, 62.5, 53.4, 43.3, 39.6,
26.7, 21.4; HRMS-ESI (m/z) [C20H23NO5S + Na]+ calc. 412.1189,
found 412.1178.
General procedure A for tetrahydroisoquinoline formation
(R,S)-2-(2-Tosyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetonitrile
A sealed tube containing a 2-bromophenethylamine 19 (1.0
equiv.), Pd(OAc)2 (10 mol%), PPh3 (10 mol%), K2CO3 (3.0 equiv.)
and alkene (1.2 equiv.) in toluene (3 mL) was flushed with argon
and then heated at 120 ◦C for 16 h. The reaction mixture was
cooled to room temperature, filtered, the solvent removed in vacuo
and the crude product purified by column chromatography using
the solvent system specified.
(25). General procedure
A
was followed using 2-
bromophenethylamine 19 (100 mg, 0.28 mmol), acrylonitrile
(18 mg, 0.34 mmol), Pd(OAc)2 (6 mg, 10 mol%), PPh3 (7 mg,
10 mol%), potassium carbonate (116 mg, 0.84 mmol) and toluene
(3 mL). Purification by column chromatography (1 : 9 EtOAc : pet.
sp.) afforded tetrahydroisoquinoline 25 as a pale yellow oil (75 mg,
0.23 mmol, 82%). FT-IR (n, cm-1, KBr) 2249, 1652, 1401, 1162,
1006, 862, 702, 548; 1H NMR (270 MHz, CDCl3, d) 7.69 (d, J =
8.4 Hz, 2H), 7.13–7.22 (m, 5H), 7.07 (m, 1H), 5.17 (t, J = 5.7 Hz,
1H), 3.64–3.74 (m, 1H), 3.48–3.57 (m, 1H), 2.98 (dd, J = 4.0,
5.9 Hz, 2H), 2.64–2.92 (m, 2H), 2.37 (s, 3H); 13C NMR (75 MHz,
CDCl3, d); 144.1, 135.8, 134.1, 132.7, 130.0, 129.2, 128.2, 127.4,
127.1, 126.9, 117.3, 52.8, 41.1, 28.0, 27.7, 21.6; HRMS-ESI (m/z)
[C18H18N2O2S - H]- calc. 325.1016, found 325.1009.
(R,S)-Butyl 2-(2-tosyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ace-
tate (20). General procedure
A was followed using 2-
bromophenethylamine 19 (100 mg, 0.28 mmol), butyl acrylate
(44 mg, 0.34 mmol), Pd(OAc)2 (6 mg, 10 mol%), PPh3 (7 mg,
10 mol%), potassium carbonate (116 mg, 0.84 mmol) and toluene
(3 mL). Purification by column chromatography (1 : 4 EtOAc : pet.
sp.) afforded tetrahydroisoquinoline 20 as a pale yellow oil (90 mg,
0.22 mmol, 80%). FT-IR (n, cm-1, KBr) 2959, 1732, 1338, 1161,
1091, 756, 660, 548; 1H NMR (270 MHz, CDCl3, d) 7.63 (d, J =
8.4 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.08–7.10 (m, 3H), 6.95
(m, 1H), 5.46 (t, J = 6.9 Hz, 1H), 4.04 (dt, J = 3.5, 6.7 Hz, 2H),
3.71–3.80 (m, 1H), 3.47–3.58 (m, 1H), 2.88 (dd, J = 7.2, 14.6 Hz,
1H), 2.63–2.74 (m, 3H), 2.32 (s, 3H), 1.58 (m, 2H), 1.32 (m, 2H),
0.90 (t, J = 7.4 Hz, 3H); 13C NMR (67.5 MHz, CDCl3, d); 170.4,
143.3, 137.2, 135.5, 133.1, 129.5, 129.0, 127.3, 127.2, 126.7, 126.5,
64.8, 53.4, 43.6, 39.7, 30.6, 27.0, 21.5, 19.1, 13.8; HRMS-ESI (m/z)
[C22H27NO4S + H]+ calc. 402.1734, found 402.1734.
(R,S)-1-(2-Tosyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-
one (26). General procedure
A was followed using 2-
bromophenethylamine 19 (100 mg, 0.28 mmol), 3-buten-2-one
(24 mg, 0.34 mmol), Pd(OAc)2 (6 mg, 10 mol%), PPh3 (7 mg,
10 mol%), potassium carbonate (116 mg, 0.84 mmol) and toluene
(3 mL). Purification by column chromatography (1 : 9 EtOAc : pet.
sp.) afforded tetrahydroisoquinoline 26 as a pale yellow oil (76 mg,
0.22 mmol, 79%). FT-IR (n, cm-1, KBr) 3412, 2924, 1713, 1597,
1335, 1159, 1091, 758, 663, 550; 1H NMR (270 MHz, CDCl3, d)
7.63 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 7.07–7.09 (m,
3H), 6.94 (m, 1H), 5.50 (t, J = 6.2 Hz, 1H), 3.67–3.74 (m, 1H),
3.46–3.56 (m, 1H), 3.05 (dd, J = 5.9, 16 Hz, 1H), 2.82 (dd, J =
6.4, 16 Hz, 1H), 2.64–2.69 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H);
13C NMR (75 MHz, CDCl3, d); 205.4, 143.4, 136.7, 136.2, 132.8,
129.5, 128.8, 127.2, 127.0, 126.7, 126.6, 52.7, 52.1, 40.1, 30.4, 27.2,
21.5; HRMS-ESI (m/z) [C19H21NO3S + Na]+ calc. 366.1134, found
366.1135.
(R,S)-Methyl 2-(2-tosyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
acetate (23). General procedure A was followed using 2-
bromophenethylamine 19 (200 mg, 0.56 mmol), methyl acrylate
(58 mg, 0.67 mmol), Pd(OAc)2 (12 mg, 10 mol%), PPh3 (14 mg,
10 mol%), potassium carbonate (232 mg, 1.68 mmol) and toluene
(3 mL). Purification by column chromatography (1 : 9 EtOAc : pet.
sp.) afforded tetrahydroisoquinoline 23 as a pale yellow oil
(168 mg, 0.47 mmol, 83%). FT-IR (n, cm-1, KBr) 3464, 2924,
1744, 1333, 1158, 932, 750, 665, 546; 1H NMR (270 MHz, CDCl3,
d) 7.64 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.08–7.10 (m,
3H), 6.95 (m, 1H), 5.47 (t, J = 7.2 Hz, 1H), 3.77 (m, 1H), 3.65 (s,
3H), 3.53 (m, 1H), 2.90 (dd, J = 7.6, 14.6 Hz, 1H), 2.62–2.75 (m,
N-(2-Bromobenzyl)-p-toluenesulfonamide (30). To a cooled
solution (0 ◦C) of 2-bromobenzylamine hydrochloride (400 mg,
1.80 mmol) and triethylamine (401 mg, 3.96 mmol) in CH2Cl2
(10 mL) was added p-toluenesulfonyl chloride (378 mg, 1.98 mmol)
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in one portion. The reaction mixture was stirred for 2 h at ambient
temperature. The reaction mixture was then washed with HCl
(1 M, 2 ¥ 10 mL), NaOH (aq. 5% w/w, 2 ¥ 10 mL) and brine
(10 mL). The organic layer was separated, dried (MgSO4) and
concentrated under reduced pressure to afford benzylamine 30 as
a colorless oil (610 mg, 1.79 mmol, 99%). FT-IR (n, cm-1, KBr)
3087, 1622, 1159, 785, 667; 1H NMR (270 MHz, CDCl3, d) 7.69
(d, J = 8.4 Hz, 2H), 7.43 (dd, J = 1.2, 7.9 Hz, 1H), 7.19–7.30 (m,
4H), 7.07 (dt, J = 1.7, 7.7 Hz, 1H), 5.11 (brt, J = 5.9 Hz, 1H), 4.21
(d, J = 6.2 Hz, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3, d);
143.5, 136.9, 135.5, 132.8, 130.5, 129.6, 129.5, 127.7, 127.1, 123.5,
47.5, 21.5; HRMS-ESI (m/z) [C14H14BrNO2S - H]- calc. 337.9856,
found 337.9862.
10 mol%), PPh3 (8 mg, 10 mol%), triethylamine (88 mg, 0.87
mmol) and DMF (3 mL). Purification by column chromatography
(1 : 1 EtOAc : pet. sp.) afforded isoindoline 36 as a pale yellow oil
(68 mg, 0.21 mmol, 71%). FT-IR (n, cm-1, KBr) 3419, 2924, 1682,
1330, 1162, 1093, 667; 1H NMR (270 MHz, CDCl3, d) 7.75 (d, J =
8.2 Hz, 2H), 7.18–7.29 (m, 5H), 7.10–7.14 (m, 1H), 5.86 (brs, 1H),
5.40 (brs, 1H), 5.18 (m, J = 3.2, 3.9 Hz, 1H), 4.73 (dd, J = 2.0,
13.8 Hz, 1H), 4.53 (d, J = 13.8 Hz, 1H), 3.15 (dd, J = 3.7, 15.0 Hz,
1H), 2.90 (dd, J = 7.1, 15.0 Hz, 1H), 2.36 (s, 3H); 13C NMR
(75 MHz, CDCl3, d); 172.0, 144.2, 139.2, 135.0, 133.2, 130.1, 128.3,
128.2, 127.8, 123.3, 122.4, 62.6, 54.2, 43.7, 21.6; HRMS-ESI (m/z)
[C17H18N2O3S + H]+ calc. 331.1111, found 331.1126.
(R,S)-2-(2-Tosylisoindolin-1-yl)acetonitrile (37). General pro-
cedure B was followed using 2-bromobenzylamine 30 (100 mg,
0.29 mmol), acrylonitrile (18 mg, 0.35 mmol), Pd(OAc)2 (7 mg,
10 mol%), PPh3 (8 mg, 10 mol%), triethylamine (88 mg, 0.87 mmol)
and DMF (3 mL). Purification by column chromatography (1 : 6
EtOAc : pet. sp.) afforded isoindoline 37 as a pale yellow oil (62 mg,
0.20 mmol, 68%). FT-IR (n, cm-1, KBr) 3429, 2361, 2254, 1352,
1350, 1160, 756, 664, 559; 1H NMR (270 MHz, CDCl3, d) 7.76 (d,
J = 8.2 Hz, 2H), 7.18–7.33 (m, 6H), 5.11 (m, 1H), 4.80 (dd, J = 2.7,
13.8 Hz, 1H), 4.55 (d, J = 13.8 Hz, 1H), 3.16 (s, 1H), 3.14 (d, J =
1.0 Hz, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3, d); 144.4,
136.7, 135.8, 133.8, 130.1, 129.1, 128.4, 127.5, 122.9, 122.6, 116.7,
61.5, 53.9, 26.9, 21.5; HRMS-ESI (m/z) [C17H16N2O2S + H]+ calc.
313.1005, found 313.1013.
General procedure B for isoindoline formation
A sealed tube containing a 2-bromobenzylamine 30 (1.0 equiv.),
Pd(OAc)2 (10 mol%), PPh3 (10 mol%), triethylamine (3.0 equiv.)
and alkene (1.2 equiv.) in DMF was flushed with argon and then
heated at 120 ◦C for 16 h. The reaction mixture was cooled to room
temperature, filtered, the solvent removed in vacuo and the crude
product purified by column chromatography using the solvent
system specified.
(R,S)-Butyl 2-(2-tosylisoindolin-1-yl)acetate (31). General
procedure B was followed using 2-bromobenzylamine 30 (100 mg,
0.29 mmol), butyl acrylate (45 mg, 0.35 mmol), Pd(OAc)2 (7 mg,
10 mol%), PPh3 (8 mg, 10 mol%), triethylamine (88 mg, 0.87 mmol)
and DMF (3 mL). Purification by column chromatography (1 : 9
EtOAc : pet. sp.) afforded isoindoline 31 as a pale yellow oil (86 mg,
0.22 mmol, 77%). FT-IR (n, cm-1, KBr) 3444, 2960, 1731, 1348,
1164, 1095, 666, 553; 1H NMR (270 MHz, CDCl3, d) 7.75 (d, J =
8.2 Hz, 2H), 7.18–7.27 (m, 5H), 7.10–7.13 (m, 1H), 5.27 (m, J = 3.0,
3.7 Hz, 1H), 4.73(dd, J = 2.5, 13.8 Hz, 1H), 4.53 (d, J = 13.8 Hz,
1H), 4.09 (t, J = 6.7 Hz, 2H), 3.30 (dd, J = 3.9, 16.5 Hz, 1H), 2.86
(dd, J = 7.9, 16.5 Hz, 1H), 2.36 (s, 3H), 1.53–1.63 (m, 2H), 1.23–
1.40 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d); 171.0, 143.7, 139.6, 135.5, 134.0, 129.8, 128.1, 127.9, 127.6,
122.7, 122.4, 64.6, 62.1, 53.9, 42.8, 30.6, 21.5, 19.1, 13.7; HRMS-
ESI (m/z) [C21H25NO4S + Na]+ calc. 410.1397, found 410.1380.
(R,S)-2-(2-Tosylisoindolin-1-yl)acetic acid (38). General pro-
cedure B was followed using 2-bromobenzylamine 30 (100 mg.
0.29 mmol), acrylic acid (25 mg, 0.35 mmol), Pd(OAc)2 (7 mg,
10 mol%), PPh3 (8 mg, 10 mol%), triethylamine (88 mg, 0.87
mmol) and DMF (3 mL). Purification by column chromatography
(3 : 1 EtOAc : pet. sp.) afforded isoindoline 38 as a pale yellow oil
(82 mg, 0.25 mmol, 85%). FT-IR (n, cm-1, KBr) 3435 (vs), 2923,
1697, 1574, 1397, 1339, 1162, 1094, 666, 555; 1H NMR (270 MHz,
CDCl3, d) 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H),
7.18–7.22 (m, 3H), 7.10–7.13 (m, 1H), 5.28 (m, 1H), 4.73 (dd,
J = 2.2, 13.9 Hz, 1H), 4.53 (d, J = 13.9 Hz, 1H), 3.39 (dd, J = 3.9,
16.5 Hz, 1H), 2.91 (dd, J = 7.9, 16.5 Hz, 1H), 2.36 (s, 3H); 13C NMR
(75 MHz, CDCl3, d); 176.5, 143.9, 139.2, 135.4, 133.8, 129.9, 128.3,
128.1, 127.6, 122.7, 122.5, 61.8, 53.9, 42.7, 21.5; HRMS-ESI (m/z)
[C17H17NO4S + Na]+ calc. 354.0771, found 354.0759.
(R,S)-2-Hydroxyethyl 2-(2-tosylisoindolin-1-yl)acetate (35).
General procedure B was followed using 2-bromobenzylamine 30
(100 mg, 0.29 mmol), 2-hydroxyethyl acrylate (40 mg, 0.35 mmol),
Pd(OAc)2 (7 mg, 10 mol%), PPh3 (8 mg, 10 mol%), triethylamine
(88 mg, 0.87 mmol) and DMF (3 mL). Purification by column
chromatography (2 : 3 EtOAc : pet. sp.) afforded isoindoline 35
as a pale yellow oil (91 mg, 0.24 mmol, 84%). FT-IR (n, cm-1,
KBr) 3523, 2924, 1732, 1343, 1162, 1094, 754, 666, 555; 1H NMR
(270 MHz, CDCl3, d) 7.74 (d, J = 8.2 Hz, 2H), 7.19–7.28 (m, 5H),
7.09–7.16 (m, 1H), 5.31 (m, 1H), 4.73 (dd, J = 2.5, 14.1 Hz, 1H),
4.50 (d, J = 13.8 Hz, 1H), 4.32 (m, 1H), 4.19 (m, 1H), 3.81 (m, 2H),
3.17 (dd, J = 4.9, 15.8 Hz, 1H), 2.99 (dd, J = 5.9, 16.0 Hz, 1H),
2.36 (s, 3H), 2.33 (brt, 1H); 13C NMR (75 MHz, CDCl3, d); 171.1,
144.0, 139.3, 135.5, 133.8, 129.9, 128.3, 128.0, 127.6, 122.6, 122.5,
66.6, 62.3, 61.0, 53.9, 43.0, 21.5; HRMS-ESI (m/z) [C19H21NO5S +
Na]+ calc. 398.1033, found 398.1024.
(R,S)-1-(2-Tosylisoindolin-1-yl)propan-2-one
(39). General
procedure B was followed using 2-bromobenzylamine 30 (100 mg,
0.29 mmol), 3-buten-2-one (24 mg, 0.35 mmol), Pd(OAc)2 (7 mg,
10 mol%), PPh3 (8 mg, 10 mol%), triethylamine (88 mg, 0.87
mmol) and DMF (3 mL). Purification by column chromatography
(1 : 4 EtOAc : pet. sp.) afforded isoindoline 39 as a pale yellow oil
(82 mg, 0.25 mmol, 86%). FT-IR (n, cm-1, KBr) 3448, 2923, 1714,
1342, 1161, 667, 559; 1H NMR (270 MHz, CDCl3, d) 7.74 (d, J =
8.2 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.16–7.20 (m, 3H), 7.07–7.12
(m, 1H), 5.30 (m, 1H), 4.75 (dd, J = 2.4, 13.9 Hz, 1H), 4.50 (d,
J = 13.9 Hz, 1H), 3.50 (dd, J = 3.4, 17.8 Hz, 1H), 2.99 (dd, J =
7.7, 18.0 Hz, 1H), 2.36 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz,
CDCl3, d) 206.5, 143.8, 140.2, 135.1, 133.5, 129.9, 128.7, 128.0,
127.7, 122.9, 122.3, 61.1, 53.9, 52.2, 30.8, 21.5; HRMS-ESI (m/z)
[C18H19NO3S + Na]+ calc. 352.0978, found 352.0993.
(R,S)-2-(2-Tosylisoindolin-1-yl)acetamide (36). General pro-
cedure B was followed using 2-bromobenzylamine 30 (100 mg,
0.29 mmol), acrylamide (25 mg, 0.35 mmol), Pd(OAc)2 (7 mg,
1514 | Org. Biomol. Chem., 2011, 9, 1508–1515
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26 M. J. Fisher, R. T. Backer, S. Husain, H. M. Hsiung, J. T. Mullaney,
T. P. O’Brian, P. L. Ornstein, R. R. Rothhaar, J. M. Zgombick and K.
Briner, Bioorg. Med. Chem. Lett., 2005, 15, 4459–4462.
27 B. Portevin, C. Tordjman, P. Pastoureau, J. Bonnet and G. De Nanteuil,
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28 T. L. Stuk, B. K. Assink, R. C. Bates, D. T. Erdman, V. Fedij, S. M.
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29 Q. Shi, P. L. Ornstein, K. Briner, T. I. Richardson, M. B. Arnold, R. T.
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Z. P. Wu, C. Y. Xie, J. M. Zgombick and M. J. Fisher, Bioorg. Med.
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