The development of domino reactions incorporating the heck reaction: The formation of N-heterocycles

Article abstract of DOI:10.1002/ejoc.201101305

The methodological development of a series of domino or cascade reactions affording a series of N-heterocycles is described. The rapid formation of these ring systems is in each case associated with the incorporation of a Heck reaction at either an early

Full text of DOI:10.1002/ejoc.201101305

FULL PAPER
DOI: 10.1002/ejoc.201101305
The Development of Domino Reactions Incorporating the Heck Reaction:
The Formation of N-Heterocycles
James E. Rixson,[a] Thomas Chaloner,[a] Charles H. Heath,[a] Lutz F. Tietze,[b] and
Scott G. Stewart*[a]
Keywords: Domino reactions / Cascade reactions / Nitrogen heterocycles / Palladium / Homogeneous catalysis
The methodological development of a series of domino or
cascade reactions affording a series of N-heterocycles is de-
scribed. The rapid formation of these ring systems is in each
case associated with the incorporation of a Heck reaction at
either an early or a late stage of the domino process. A range
of catalytic conditions and substrate modifications for op-
timisation of domino Tsuji–Trost/Heck, Buchwald–Hartwig/
Heck and Heck/carbopalladation reaction sequences are re-
ported.
Reactions such as these have been useful in the pro-
duction of biologically active molecules[1–2] such as scopa-
dulcic acid A,[4] manzamine A,[5] biyouyanagin A[6] and α-
tocopherol.[7] Likewise, a process in which a base-mediated
step is combined with a palladium-catalysed step might also
seem more promising, because bases are often used in con-
junction with Pd-mediated cross-coupling reactions. Such
palladium-catalysed domino reactions are becoming more
frequently published and cited in the literature.[8]
Recently, studies within our group have focussed on
domino reactions in which at least one step involves a palla-
dium-catalysed Heck reaction. Recently we reported dom-
ino Heck/aza-Michael reactions based on rapid cross-cou-
pling of the aryl halides 1 and 3 prior to any nucleophilic
attack at carbon (Scheme 1). In these instances we were able
to produce a range of tetrahydro-β-carbolines 2, isoquinol-
ines 4 and isoindolines, but not before careful consideration
of the type of catalytic system.[9] By reversing the type of
reaction order we also reported the use of a series of
domino Tsuji–Trost/Heck reactions in the synthesis
Introduction
Recent developments in domino reaction chemistry have
provided more effective methods for the synthesis of a range
of complex ring systems and molecules. 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 function-
alities formed by the preceding transformation”.[1] Such
transformations are attractive to industry and research
laboratories because of their potential for saving solvents,
reagents, time and energy. Domino reactions have been use-
ful in the preparation of complex molecules including sev-
eral natural products.[2] Alternatively, one prime example of
the potential for large-scale preparation of pharmaceuticals
has been highlighted by Hayashi’s group in their prepara-
tion of the anti-influenza drug (–)-oseltamivir phosphate
(Tamiflu™).[3] In this synthesis, two single-pot domino pro-
cesses are utilised, one incorporating a Michael/Horner–
Wardsworth–Emmons reaction sequence.
In most cases the more realistic domino reactions are
those in which all transformations occur under similar reac-
tion conditions, such as domino reactions utilising two pal-
ladium-catalysed steps.
of the azepino[4,5-b]indoles
6 and 3-benzazepines 8
(Scheme 1), hence with nucleophilic addition processes in
the early stages of the reaction sequences.[10] Because these
domino reactions are assumed to go through two catalytic
cycles they have also been described as pseudo-domino re-
actions.[11] As part of the fine tuning of the Tsuji–Trost/
Heck domino reaction, a two-base system that utilises one
base for each of the individual reactions was recognised as
the most efficient. In our continuing studies we have sought
to explore other possible domino reactions in combination
with the Heck reaction to generate a new series of N-hetero-
cycles.
[a] The School of Biomedical, Biomolecular & Chemical Sciences,
The University of Western Australia,
Crawley, WA 6009, Australia
Fax: +61-8-6488 1005
E-mail: sgs@cyllene.uwa.edu.au
[b] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstraße 2, 37077 Göttingen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101305 or from
the author.
In this report the indole, isoquinoline, benzazepine and
azepinobenzindolizidine ring systems (Figure 1) were cho-
sen as targets because of their prevalence in both pharma-
544
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Domino Reactions Incorporating the Heck Reaction
the production either of natural products for biological
evaluation or of simpler analogues on an industrial scale.
This paper investigates a range of palladium-mediated dom-
ino reactions incorporating the Heck reaction. These pro-
cesses include Tsuji–Trost/Heck reaction sequences tar-
geting indoles and tetrahydroisoquinolines, Buchwald–
Hartwig/Heck reaction sequences applied in the synthesis
of benzazepines, and Heck/carbopalladation reaction se-
quences for the synthesis of azepinobenzindolizidines.
Results and Discussion
Domino Tsuji–Trost/Heck Reaction Combinations for the
Synthesis of Indoles
The indole ring system has been prepared by numerous
approaches, beginning with the Fischer indole synthesis[16]
and followed by other comprehensive methods.[17] More re-
cent methods utilising palladium catalysis have also been
incorporated into successful synthetic programs,[18] some en
route to biologically active compounds. In order to utilise
our Tsuji–Trost/Heck domino approach towards this ring
system we first sought an efficient method for the two indi-
vidual reactions in this process. The 5-exo-trig intramolecu-
lar Heck reactions of the aryl halides 12 (Scheme 2), bear-
ing amine tethers, have been reported by several groups
with mixed success. These reactions depend on either the
halide, the groups attached to the aromatic ring or the type
of olefinic system.[19] In these reports the 5-exo-trig reac-
tions predominate to afford the olefins 14, which then nor-
mally aromatise upon further stirring or workup to form
the sought after indole ring systems 13.[20]
Scheme 1. Domino Tsuji–Trost/Heck sequences and Heck/aza-
Michael sequences in the formation of various N-heterocycles.
ceuticals and natural products. The indole ring system can
be found in biologically active natural products such as vin-
cristine and reserpine (9).[12] Likewise, laudanosine (10) is
an excellent example of an isoquinoline natural product,
but is simple in comparison with the structurally complex
antitumour agent ecteinascidin 743.[13] The 3-benzazepine
ring system is present in the cephalotaxus alkaloids[14] and
in simpler entities such as lennoxamine (11), found in Ber-
beris darwinii.[15] Efficient production of the N-heterocyclic
cores of such compounds is paramount when investigating
Scheme 2. Intramolecular Heck reactions in preparations of
indoles.
The precursor 15 (Scheme 3) for our study could be pre-
pared efficiently through simple tosylation of 2-iodoaniline.
The tosyl group was chosen to provide an NH proton
slightly more acidic than that in the trifluoroacetamide used
previously in the group.[9a] The preparations of indoles
Figure 1. The natural products 9, 10 and 11, containing indole,
isoquinoline, and benzazepine ring systems.
Scheme 3. Allylation of N-tosyl-2-iodoaniline (15).
Eur. J. Org. Chem. 2012, 544–558
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545

S. G. Stewart et al.
FULL PAPER
through the initial allylation of 15 with allyl bromide was proposed by Fu [Pd2(dba)3·CHCl3, P(tBuP)3HBF4 and
tested with and without the assistance of a palladium cata- Cs2CO3, Cy2NMe][25a] was studied, but in this case the only
lyst.[10a]
domino product isolated was 18 (8%, Table 1, Entry 3).
Modification of the base and solvent in each of the trial This phenomenon was attributed to a process in which an
reactions revealed the optimum reaction system with the initial intermolecular Heck reaction occurred,[27] followed
addition of a Pd(PPh3)4 catalyst (10 mol-%). As in our pre- by a later CN coupling.[28] To test the possibility that there
vious domino reaction methodology study with similar was a halide effect playing a part in the domino process, or
amines, allylation of compound 15 in the presence of the more specifically the secondary Heck reaction, the allyl-
Pd catalyst (presumably through a π-allyl palladium inter- ating agent was changed to allyl chloride. (Entries 4 to 6,
mediate) occurred at a much faster rate than the simple Table 1). This series of reactions confirmed this allylating
SN2Ј reaction.[10a] DMF was also found to be an effective agent to be superior in combination with Pd(PPh3)4
solvent for this Tsuji–Trost reaction, with complete conver- (10 mol-%) and triethylamine, but large amounts of the al-
sion of the aryl iodide 15 into the olefin 16 (Scheme 3) lylated sulfonamide 16 still remained. A change of allylating
achieved efficiently regardless of the allylating agent used. agent to allyl acetate produced moderate amounts of the
The increase in the rate of the Tsuji–Trost reaction in DMF domino product (26–34%) though not enough for a viable
might also be attributed to the role played by a high-po- process. The bidentate dppf ligand was also used because
larity solvent in assisting dissociation of the bromide/chlor- of its potential to form an active (1:1) palladium bis-ligated
ide/acetate ion from the L2Pd(η2) intermediate to form the precursor, but this reaction still only produced moderate
reactive η3-allyl cation complex, as reported previously.[21]
amounts of both compounds 16 and 17. In our case a
Once large quantities of the allyl sulfonamide 16 were to breakthrough came on treatment of the aryl iodide 15 with
hand, the intramolecular Heck reaction was trialled as the the palladacycle 19 (Table 1, Entry 9) discovered by Herr-
eventual proposed second step of the domino reaction. The mann and Beller.[29] This reaction showed complete con-
use of DMF as an effective solvent for the intramolecular sumption of the allyl product 16, immediately detectable by
Heck reaction was taken into account. A series of reactions tlc, and directly offered a new lead in the investigation of
with Pd(PPh3)4 and other common palladium-based cata- the domino process. The Herrmann–Beller catalyst 19 of-
lysts were initially chosen.[22,23] N-Tosyl-3-methylindole (17, fers several advantages over the other catalytic systems pre-
Scheme 4) was synthesised in a reasonable yield (71%) in
the presence of Pd(OAc)2 under phosphane-free Jeffery’s
Table 1. Initial investigation of Tsuji–Trost/Heck domino condi-
tions with N-tosyl-2-iodoaniline (15).
conditions.[24] At this stage no attempts were made to inves-
tigate the Heck cyclisation reaction with more electron-rich
phosphanes, as published by the groups of Fu and Buch-
wald; instead, optimisation of the domino process was ex-
amined.[25] During the course of our initial investigations,
Beck’s group proposed an allylation/Heck cyclisation se-
quence in a separate investigation involving aryl chlorides
and use of the Buchwald ligand (up to 67% yield).[26] Al-
though this work highlighted good process with aryl chlor-
ides in reasonable yields and with moderate turnovers, we
were wary of substrate scope and the use of the Buchwald
ligands and possible competing C–N cross-coupling.
X[a] Base
Catalyst[c]
Temp. Add.
reagent/
ligand
Yield [%]
[°C]
16
17
18
1
2
3
Br Cs2CO3 Pd(OAc)2
Br Cs2CO3 Pd(PPh3)4
Br Cs2CO3, Pd2(dba)3·
CHCl3
60
60
80
–
–
90
71
Ͻ0.2
3
–
–
–
8
P(tBu)3 81
HBF4
Cy2NMe
Cl Et3N
Scheme 4. Heck cyclisation of N-allyl-N-tosyl-2-iodoaniline (16).
4
5
6
7
8
Pd(PPh3)4
80
90–100
–
–
Ͼ45 48
Ͼ70 22
–
–
–
–
–
Cl Cs2CO3 Pd(PPh3)4
Cl Cs2CO3 Pd(PPh3)4
OAc Cs2CO3 Pd(PPh3)4
OAc Cs2CO3 Pd2(dba)3·
CHCl3
85–90 nBu4NCl Ͻ85 15
75–80 Ͻ65 34
70–90 dppf 21 31
After the successful investigation of the individual Tsuji–
Trost and Heck reactions, the domino process was then at-
tempted under a series of reaction conditions (Table 1). In
the initial attempts, conditions leading to the formation of
the intermediate 16 were maintained over a longer period,
which led to small amounts of the domino product 17 being
isolated (Table 1, Entries 1 and 2). In an effort to accelerate
–
9
OAc Cy2NMe HB cat[b]
90–100
–
trace 26
16
[a] In each reaction 1–2 equiv. of the allylating reagent were used.
[b] The Herrmann–Beller (HB) catalyst is trans-bis(μ-acetato)-
bis[o-(di-o-tolylphosphanyl)benzyl]dipalladium(II) (19) and was
used at 5 mol-%. [c] All catalysts were used at 10 mol-% except 19
the secondary Heck reaction process, the catalytic system (5 mol-%).
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Domino Reactions Incorporating the Heck Reaction
viously investigated. This catalytic system allows reactions more reactive in the intermolecular Heck reaction and poss-
to be carried out at high temperatures without rapid cata- ibly less reactive in the Tsuji–Trost reaction. The reaction
lyst decomposition and with a palladacycle considered a with allyl chloride was selective for the allylated intermedi-
slow release precatalyst (SRPC), a clear advantage in intra- ate 16, which is possibly attributable to the chloride ion
molecular cross-coupling reactions.[30]
hindering the initial stages of the Heck catalytic cycle.
Additionally, it has been suggested that this catalyst fol-
On use of Cs2CO3 in combination with the HB catalyst
lows an alternative Pd(II/IV) catalytic cycle rather than the (Entry 6, Table 2) an excellent yield of 86% of the desired
traditional Pd(0/II) pathway, which could have distinct influ- indole was achieved, with this process also being repeatable
ences on the nature of the domino-type process in which on a larger scale. Additionally, to confirm that the HB cata-
both steps involve Pd.[29a,31] In the initial series of reactions lyst was the active precursor species in this process an ad-
conducted with the Herrmann–Beller palladacycle 19 ditional reaction was carried out with Pd(OAc)2 and the
(5 mol-%, Entries 1–4, Table 2) it is clear that the intermedi- P(o-tol)3 ligand (Entry 7, Table 2). In this case only the in-
ate 16 was further consumed in the reaction except when termediate 16 was generated.
allyl chloride was used (Entry 5, Table 2). It should be men-
tioned at this stage that the choice of Cy2NMe was made
Domino Tsuji–Trost/Heck Reaction Combinations for the
Synthesis of Tetrahydroisoquinolines
because of its higher boiling point and that to date the use
of this base in reactions in the presence of the Hermann–
Beller palladacycle 19 is otherwise unreported. A change in
the base to KOAc greatly improved the yield of the indole
17 but did not stop the formation of the isomeric product
18. A change in the allylating agent from the allyl acetate
to allyl bromide improved the yield of the desired indole 17
and almost eliminated the formation of its regioisomer 18.
This result can be attributed to allyl acetate being slightly
The synthesis of tetrahydroisoquinolines through intra-
molecular Heck reactions has been investigated by a few
groups, but this process is in general far less reliable than
the previously discussed formation of the indole ring sys-
tem. Usually the product bearing the exocyclic double bond
formed through a 6-exo-trig cyclisation predominates.[32] In
previous reports, the second steps of our planned domino
reaction sequences, intramolecular Heck reactions of allyl-
ated amines, often produce unwanted palladacycle inter-
mediates. These intermediates, which have previously been
isolated by Broggini and Balme, ultimately hinder β-hydride
elimination and significantly lower the yields of the Heck
reactions.[32] Therefore, because this was the second step in
our proposed domino reaction sequence, we imagined that
the yields of the tetrahydroisoquinoline might be lower than
in the cases in which the indole ring system was targeted.
In this context we deemed the protecting group on the ni-
trogen to be essential for potential improvement of the
Heck reaction. To mirror the results from the earlier indole
domino reactions, we investigated both trifluoroacetate and
tosyl nitrogen-protecting groups, and hence prepared the
compounds 20 and 21 (Scheme 5). Additionally, the benzyl
protecting group was also trialled (compound 22) for its
possibly steric hindrance of the formation of stable and un-
wanted palladacycle intermediates, as observed by other
groups, as well as for its potential to improve the rate of
the allylation reaction.[32a,32b] The three protected amines
(20–22) were prepared by standard allylation procedures
(see the Exp. Section). Treatment of each of these olefins
under identical catalytic conditions (Scheme 5), suggested
that in this instance the toluenesulfonamide was the most
Table 2. Investigation of the domino reaction with N-tosyl-2-
iodoaniline (15) and the Herrmann–Beller catalyst.[a]
X[b] Base
Catalyst
Temp.
[°C]
Add.
ligand
Yield [%]
16
17
18
1
2
3
4
OAc Cy2NMe HB[a]
OAc Cy2NMe HB[a]
OAc KOAc
Br KOAc
90–100
120
120
r.t. to
120
r.t. to
120
–
–
–
–
trace
trace
trace
80
26
33
66
16
16
16
22
2
HB[a]
HB[a]
5
6
7
Cl Cs2CO3 HB[a]
Br Cs2CO3 HB[a]
–
–
84
15
86
–
0.7
–
r.t. to
120
trace
Br KOAc
Pd(OAc)2 70
P(o-tol)3 Ͼ 90
–
[a] The Herrmann–Beller catalyst (HB) is trans-bis(μ-acetato)-bis[o-
(di-o-tolylphosphanyl)benzyl]dipalladium(II) (19) and was used at
5 mol-%. [b] In each reaction 1–2 equiv. of the allylating reagent
were used.
Scheme 5. Intramolecular Heck reactions of the olefins 20–22.
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S. G. Stewart et al.
FULL PAPER
reactive system for the intramolecular Heck reaction. Insta- At lower temperatures this catalyst seems to be much less
bility of compounds 20–22 was also evident in this process, active and either starting material remains or decomposi-
with reasonable quantities of decomposition products being tion occurs. Alteration of the catalytic system to Pd2(dba)3
observed in these trials.
with a range of various electron-rich phosphanes, including
Investigations into the domino process were initiated by Buchwald’s bis-aryl phosphanes, also failed to improve the
application of reaction conditions similar to those that had conversion of the sulfonamide 26 into the isoquinoline
been successful in the indole ring formation (Entries 1 and domino product 24 (Table 3, Entries 12–16). The most ef-
2, Table 3). In these cases we isolated only the allylated ficient process for this domino reaction was thus a 22%
compound 21, depending on the reaction time. Modifica- yield (Entry 2, Table 3) and so we decided to take a more
tion of the base or use of allyl acetate was unsuccessful drastic approach and to trial an alternative amine-protect-
in combination with the Hermann–Beller palladacycle (19). ing group.
This was surprising, because we were anticipating that use
We next investigated the trifluoroacetate moiety as a pro-
of a system that would slowly release Pd0 might possibly tecting group, similar to that utilised earlier in the domino
limit the formation of an unwanted intermediate amine pal- reactions in the formation of 3-benzazepines and azepino-
ladacycle and improve the reaction yield. Interestingly in indoles.[10a] Initially we investigated the domino reaction
each of these cases, the starting material was consumed. under a range of reaction conditions, with use of Pd(PPh3)4
Use of Pd(PPh3)4 (10 mol-%) as a catalyst (Table 3, En- (10 mol-%) or HB catalyst (5 mol-%) (Entries 1–4, Table 4).
tries 6–9) seemed to result in rapid consumption of the The best conditions for the conversion of the amide 27 into
starting material without significant mass return, suggest- compound 23 through a Tsuji–Trost/Heck reaction domino
ing either decomposition or precipitation of a Pd intermedi- process was with use of Pd(PPh3)4 (10 mol-%) in DMF
ate hindering the formation of tetrahydroisoquinoline 24. (49%).
Table 4. Domino Tsuji–Trost/Heck reaction sequence[a] to afford
the N-trifluoroacetyl-tetrahydroisoquinoline 23.
Table 3. Domino Tsuji–Trost/Heck reaction sequence with the N-
tosyl-tetrahydroisoquinoline 26.
Catalyst
Base
Temp. Time Solvent
[°C] [h]
Yield [%]
20
23
X[a] Base
Catalyst
Temp.
[°C]
Additive Add.
ligand
Yield [%]
1
2
3
Pd(PPh3)4
HB[b]
Pd(PPh3)4
Cs2CO3 80
Cs2CO3 80
Cs2CO3 80
18
18
18
DMF
DMF
PhMe/
DMF (9:1)
DMF
0
0
0
49
19
27
21
24
1
2
3
4
5
6
Br
Br
Cs2CO3 HB[b]
r.t. to 120
100
120
120
50–90
–
–
–
–
–
–
–
–
Ͼ90
45
15
–
–
6
48
14
–
–
–
–
22
–
–
–
–
–
9
–
–
–
–
Cs2CO3 HB[b]
4
5
6
Pd(PPh3)4
Cs2CO3 45
2.5
48
18
64
12
0
trace
23
52
OAc CsCO3 HB[b]
OAc KOAc HB[b]
Pd(PPh3)4 1 mol-% Cs2CO3 80
Pd(PPh3)4 + PPh3 Cs2CO3 80
(100 mol-%)
DMF
DMF
Br
Br
7[c] Cl
Cs2CO3 HB[b]
Et3N Pd (PPh3)4 60
Et3N Pd(PPh3)4 80
[a] Pd (10 mol-%), solvent (2 mL) and allyl bromide (2 equiv.) un-
less stated otherwise. [b] The Hermann–Beller catalyst (HB) is
trans-bis(μ-acetato)-bis[o-(di-o-tolylphosphanyl)benzyl]dipallad-
ium(II) (19).
8
OAc Et3N Pd(PPh3)4 60
9[c] OAc Et3N Pd(PPh3)4 40–70[d]
10[c] OAc Et3N Pd(OAc)2 40–80[d]
11 OAc Et3N Pd(OAc)2 45–80[d]
12 OAc Cs2CO3 Pd2(dba)3· 50
CHCl3
–
PPh3
toluene
4 equiv.
base
PPh3
P(tBu)3
HBF4
P(tBu)3
HBF4
XPhos
Ͻ14
This yield was reasonable in view of the perceived com-
plexity of the second intramolecular Heck reaction and the
fact that it is incorporated as part of a domino process.
At lower temperatures reasonable amounts of the allylated
compound 20 were isolated in the absence of the tetra-
hydroisoquinoline 23. A reduction in catalytic loading (En-
try 5, Table 4), potentially to circumvent the rapid forma-
tion of any palladacycle intermediates, was also trialled.
Similarly, the use of phosphane in excess, as reported by
Balme’s group, for the intermolecular Heck reaction was
attempted in order to improve the yield of the domino
product.[32b] In this case this set of reaction conditions (En-
try 6, Table 4) was successful, with a yield of 52% of the
domino product tetrahydroisoquinoline 23, excellent con-
sidering the difficulty of the formation of these ring systems
in Heck-type processes.
13 OAc Cs2CO3 Pd2(dba)3· 45–80[d]
CHCl3
41
–
–
–
–
–
–
14 Br
15 Br
16 Br
17 Br
Cs2CO3 Pd2(dba)3· 100
CHCl3
Cs2CO3 Pd2(dba)3· 100
CHCl3
Cs2CO3 Pd2(dba)3· 100
CHCl3
Cs2CO3 Pd2(dba)3· 100
CHCl3
toluene
toluene
toluene
toluene
Davephos trace
XantPhos
dppf
–
–
[a] All reactions were completed in DMF, with 2 equiv. of the al-
lylating agent. [b] Hermann–Beller catalyst (HB) is trans-bis(μ-acet-
ato)-bis[o-(di-o-tolylphosphanyl)benzyl]dipalladium(II) (19) and
was used at 5 mol-%. [c] In these reactions large quantities of the
starting material 26 were also reisolated. [d] Reactions were held
at the first temperature indicated for 5 h and then at the second
temperature overnight.
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Domino Reactions Incorporating the Heck Reaction
In the final example of this ring system we also investi- the literature, possibly due to the need for ordered chemose-
gated the domino reaction sequence with a benzyl-protected lectivity for the two cross-coupling reactions, because they
amine. Despite our poor result for the intramolecular Heck both utilise aryl and vinyl halides as their starting sub-
reaction we were in this case able to obtain some (21%) of strates. Substrate reactivity is vital, depending on whether
the benzyl-protected tetrahydroisoquinoline 25 with use of the C–N cross-coupling is designed to occur as the first
the palladacycle 19. In this example it was clear that the bond-forming process[33] or the second.[34] To construct a
allyl species 22 was extremely unstable in the presence of a substrate for this domino reaction we prepared compound
range of palladium catalysts and that this was the factor 29 (Scheme 6), bearing both an aryl and vinyl bromide. This
preventing reasonable conversion into the domino product. compound has been employed in total syntheses[35] and in
Reducing the catalytic loading (Entries 4 and 5, Table 5) other domino-type processes.[36] Many of the reported dom-
had a dramatic effect on the initial Tsuji–Trost reaction, ino processes involving this compound (and its derivatives)
with large quantities of the starting material 28 remaining involve double C–N cross-coupling to afford indole N-het-
in the reaction mixtures.
erocycles. Previously, in the case of C–C bond formation,
this compound had shown some selectivity towards the vi-
nyl bromide under palladium-catalysed reaction condi-
tions.[35,37]
Table 5. Domino Tsuji–Trost/Heck reaction sequence[a] to afford
the N-benzyl-tetrahydroisoquinoline 25.
The dibromide 29 was prepared by transformation of or-
tho-bromobenzaldehyde into the 1,2-dibromovinyl com-
pound, followed by nBu3SnH reduction.[35] Additionally, a
Wittig reaction process with the same starting material (or-
tho-bromobenzaldehyde) was effective in producing larger
quantities of compound 29, although a small degree of con-
tamination with the E-isomer after chromatography was
also observed.[36a,36b,38]
As part of the development of this domino reaction we
initially investigated the chemoselectivity of a Buchwald–
Hartwig reaction with the substrate 29. For the C–N cross-
coupling reaction we first sought a simple amine and so
were attracted to pyrrolidine. Several reaction attempts with
the ligands popularised by Buchwald only produced the di-
meric compound 31 (Scheme 6),[39] together with a small
amount of cyclic triyne. In this case it is assumed that com-
pound 31 was formed through initial elimination of HBr
and a subsequent Sonogashira-type reaction with a second
molecule of the vinyl bromide 29 (Scheme 6). After this re-
sult, which had shown no indication of a C–N reaction, we
required a slightly more reactive coupling partner that
would react prior to the dimerisation of compound 29. We
thus considered the corresponding amide: pyrroldinone. A
C–N cross-coupling reaction of this amide with Pd2-
(dba)3·CHCl3, DavePhos and Cs2CO3 afforded the desired
Catalyst
Temp.
[°C]
r.t. to 40–80[b] 20
r.t. to 40–80[b] 20
r.t. to 40–80[b] 20
Time Solvent Yield [%]
[h]
22
25
1
2
3
4
5
Pd(PPh3)4
Pd(OAc)2
HB[c]
DMF
DMF
DMF
PhMe
PhMe
23
25
0
0
0
12
8
21
0
HB[c],[d]
80
80
20
20
[c][d]
Pd(OAc)2
0
[a] Allyl bromide (2 equiv.) was used in each example. [b] Room
temp. for 2 h, 40 °C for 1.5 h, 80 °C for 16 h. [c] The Hermann–
Beller catalyst (HB) is trans-bis(μ-acetato)-bis[o-(di-o-tolylphos-
phanyl)benzyl]dipalladium(II) (19). [d] Pd catalyst (0.08 mol-%),
and in these examples large amounts of the starting material 28
remained,.
Buchwald–Hartwig/Heck Reaction Sequence for the
Synthesis of 3-Benzazepines
To expand the scope of domino reaction methodology
involving Heck reactions, we also envisaged the incorpora-
tion of Buchwald–Hartwig cross-coupling reactions.[25b]
The combination of these two reactions is extremely rare in
Scheme 6. C–N cross-coupling reactions of the dibromide 29.
Eur. J. Org. Chem. 2012, 544–558
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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549

S. G. Stewart et al.
enamide (Z)-32 (Scheme 6), in excellent yields (90%). Be- Table 6. Investigations into domino Buchwald–Hartwig/Heck reac-
FULL PAPER
tion sequences[a]
.
cause the Z geometrical isomer was unstable, the light-pro-
moted conversion into the E isomer was also carried out.[40]
In this instance we were encouraged by the chemoselective
nature of this reaction for the vinyl bromide over the aryl
bromide. To investigate the copper variant of this reaction
we also trialled the Ullmann–Goldberg reaction; in this in-
stance treatment of 29 with pyrroldinone, CuI and N,N-
dimethylethylenediamine furnished the required amide (E)-
32 in 95% yield.
Base
Amide Ligand
(equiv.)
Solvent Pd
Pd/ Yield
L
Given the excellent chemoselective nature of the C–N
cross-coupling of pyrrolidinone and the dibromo com-
pound 29 we explored the possibility of also incorporating
a vinyl (or olefinic) substituent in an amide of this type.
Unfortunately, the corresponding amide (5-vinylpyrrolidin-
2-one) was not commercially available and methods for the
production of this compound are quite lengthy for a meth-
odological study of this kind. In this case we decided upon
the simpler compound 33 (Table 6), containing the two
functionalities for C–N and C–C cross-coupling. Applica-
tion of the conditions used for the original Buchwald–Hart-
wig cross-coupling reaction of pyrrolidinone to the reaction
with N-allylacetamide (33) provided none of the desired
domino product 35 or of the precursor 34 (Entry 1,
Table 3). Increasing the amount of N-allylacetamide (33) to
two equivalents (DavePhos, 10 mol-%), however, initiated
the formation both of the domino product 35 and of the
C–N cross-coupling precursor 34. To test the rates of each
of these single steps in the domino process the reaction was
stopped after 2.5 hours and in this process a 35% yield of
the C–N cross-coupling product 34 was obtained (Entry 3,
Table 6), with only trace amounts of the domino product
35. Increasing the amount of amide from 2 to 4 or 6 equiv.
also improved the overall yield of the domino product 35
(Entries 4 and 5, Table 6). Under the last set of conditions
a 50% yield of the domino product was achieved (Entry 5),
but because of the impractical nature of using several equiv-
alents of the amide an improved series of catalytic condi-
tions were sought. Changing the base, solvent and Pd-to-
ligand ratio (10 mol-% catalyst) also failed to have any sig-
nificant influence on the reaction.
Modification of the biaryl ligand system was also investi-
gated and in the case of SPhos (Entry 16, Table 6), contain-
ing two methoxy groups, the reaction proceeded in similar
manner to when DavePhos was applied, with a 12% yield
of the domino product 35. Other Buchwald ligands
(JohnPhos, XPhos, cyclohexyl JohnPhos and tert-butyl
XPhos) unfortunately failed to initiate the domino process
or to form any of the single C–N cross-coupling product,
possibly indicating the need for an electron-donating group
on the lower ring of the phosphane ligand. The key to im-
provement of the domino process was the use of an alterna-
tive ligand scaffold.[41] With a low Pd-to-ligand ratio (1:1
or 1:2) and the application of XantPhos (10 mol-%) this
domino reaction was exceptional, with yields of the benza-
zepine 35 of 82 and 83%, respectively (Entries 23 and 24,
[mol-%] ratio 34
35
1
2
Cs2CO3
Cs2CO3
1
2
2
4
6
2
2
2
2
DavePhos PhMe
10
10
10
10
10
10
10
10
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
0
0
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos DMF
11
35
0
0
13
0
33
trace
46
50
9
0
0
17
3[b] Cs2CO3
4
5
6
Cs2CO3
Cs2CO3
K3PO4
7[c] tBuOK
8
9
Cs2CO3
Cs2CO3
0
0
DavePhos 1,4- di- 10
oxane
10 Cs2CO3
11 Cs2CO3
12 Cs2CO3
13 Cs2CO3
14 Cs2CO3
15 Cs2CO3
16 Cs2CO3
17 Cs2CO3
18 Cs2CO3
2
2
2
2
2
2
2
2
2
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
DavePhos PhMe
JohnPhos PhMe
10
10
10
20
5
10
10
10
10
1:2
1:1
4:1
2:1
2:1
2:1
2:1
2:1
2:1
trace trace
trace trace
trace 19
0
7
15
9
0
0
15
SPhos
XPhos
cyclo-
PhMe
PhMe
PhMe
12
trace trace
0
0
hexyl
JohnPhos
tert-butyl PhMe
XPhos
19 Cs2CO3
2
10
2:1
0
0
20 Cs2CO3
21 Cs2CO3
22 Cs2CO3
23 Cs2CO3
24 Cs2CO3
2
2
2
2
2
o-tol
PhMe
10
10
10
10
10
2:1
2:1
2:1
1:1
1:2
0
0
0
0
0
0
0
33
82
83
DavePhos PhMe
XantPhos PhMe
XantPhos PhMe
XantPhos PhMe
[a] All reactions were carried out at 100 °C with Pd2(dba)3·CHCl3
and the specified ligand. [b] Reaction was carried out for 2.5 h.
[c] Reaction produced only the elimination product 2-bromoethyn-
ylbenzene.
XantPhos in relation to other ligands used for C–N cross-
coupling.[42] In earlier studies by Hartwig, ligands with
slightly smaller bite angles are proposed to be more reactive
for aryl bromides.[43] Given that many of the studied reac-
tions either go to completion or there is only a small
amount of the allyl amide 34 remaining, it is assumed that
the Heck reaction has the lower activation energy barrier
of the two single-step processes. This was apparent when
the olefin 34 was treated with Pd(PPh3)4 (10 mol-%) under
standard Heck reaction conditions to afford a 73% yield of
the desired 3-benzazepine 35.
Domino Heck/Heck Carbopalladation to
Azepinobenzindolizines
The original classification of a “Zipper” palladium-cata-
Table 6). In our analysis the clear difference in yields with lysed domino reaction is one of several general modes of
this ligand could be attributed to the wide bite angle of domino carbopalladation, which has been described by sev-
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Eur. J. Org. Chem. 2012, 544–558

Domino Reactions Incorporating the Heck Reaction
Table 7. Domino Heck/carbopalladation reaction sequence to afford the tetracycle 39.
Entry Catalyst[a]
Base (equiv.)
Concentration
Solvent
Time
Ratio 37/39
Isolated yields
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3 (1)
K2CO3 (8)
NBu4OAc (2)
NBu4OAc (2)
NEt3 (3)
55 mmolL–1
97 mmolL–1
54 mmolL–1
56 mmolL–1
80 mmolL–1
89 mmolL–1
DMF
DMF
DMF
DMF/PhMe 1:1 3 h
DMF
DMF
3 h
5 h
3 h
1:1
37:39 49%; 38 40%
37:39 52%; 38 27%
37:39 73%; 38 0%
37:39 68%; 38 0%
37:39 57%; 38 14%
37:39 43%; 38 0%
1.00:0.88
1.00:0.21
1.00:0.17
1.00:1.18
1.00:0.41
21 h
24 h
DBU (3)
[a] Pd(PPh3)4 was used at 10 mol-% loading for all reactions.
eral groups.[44] In 2009 we described a similar domino pro- cause of the high overall yields already obtained with
cess for the bis-allyl compound 36 (Table 7), in which an Pd(PPh3)4. The original conditions (Entry 1, Table 7) gave
initial Heck reaction of the allylacetamide group at the in- a 1:1 ratio of the indoleazepine 37 and the tetracycle 39,
dole C2 position first produces the azepine ring, and a sub- and with an increase in the equivalents of K2CO3 (Entry 2,
sequent second Heck carbopalladation could occur with the Table 7) only a small change in the ratio of these two prod-
indole allyl group to afford the azepino-benzindolizine ring ucts was observed. The low solubility of K2CO3 in DMF,
system 39. Unusually, the other possible reaction pathway even at 100 °C, could explain why this excess base would
involving the indole allyl group and the 2-bromoindole have little effect on the reaction ratio outcome. To solve
functionality forming the formation of a five-membered this problem we used NBu4OAc, a more DMF-soluble base,
ring was not followed, possibly due to the more strained (Entry 3, Table 7). Under these conditions none of the deal-
ring configuration.
lylated product was formed and furthermore the ratio was
In our original report of the reaction behaviour of the changed significantly in favour of the simpler azepinoindole
bisallylated indole 36 we isolated three compounds: the N- 37. This result, culminating in a 73% yield of the two de-
allylazepinoindole 37, the azepino-indole 38 and the azep- sired compounds (37 and 39) was significant in view of the
ino-benzindolizidine 39 (Table 7). The products 37 and 39 complexity of the process. Changing the solvent polarity
presumably arise from a similar Pd intermediate, with the (Entry 4, Table 7) again increased the ratio slightly in favour
indoleazepine 37 resulting from immediate β-hydride elimi- of the allyl azepinoindole 37. Use of the organic base trieth-
nation and the tetracycle 39 from additional carbopallad- ylamine (Entry 5, Table 7) gave the opposite result to
ation. The last compound 38, formed through deallylation, NBu4OAc, with the ratio changing slightly in favour of the
is the major obstacle in the production of the domino prod- tetracycle 39, although some of the de-allylated product 38
uct 39. Because the original reaction conditions had pro- was also produced. The stronger organic base DBU was
duced this mixture of three interesting compounds it also trialled, favouring the formation of the azepinoindole
seemed a useful method with which to probe the relative 37. Unfortunately, we were not able to control the Heck
productiveness of the two different pathways leading to reaction to give either 39 or 37 exclusively. It seems that
these compounds under a range of conditions. The N-het- the type of base had a distinctive influence on the reaction
erocyclic ring system contained in compound 39 is of cur- pathway, but there seems to be no distinction from inor-
rent interest because alkaloids with the same 6–5–7–6-mem- ganic to organic bases. It can be said from these trials, how-
bered ring system have been reported in the literature. Al- ever, that more soluble bases lead either to less or to no
though this ring system is relativity rare, notable examples formation of the deallylated product, which at least simpli-
can be found; they include the chippiine indole alkaloids, fied the transformation to some degree.
the prototype compound of which, chippiine, was extracted
The formation of 39 is unique amongst these reactions
from the African species Tabernaemontana chippi.[45] We because in most cases the substrates are tailored to elimin-
were interested to see whether or not variation of the type ate the possibility of premature β-hydride elimination.[46]
of base would lead to changes in the 37/39 ratio, because The literature reports several other examples of palladium-
the base is involved in the reductive elimination of the intra- catalysed domino reactions in which additional carbopal-
molecular Heck reaction.
ladation steps have occurred instead of β-hydride elimi-
Additionally, any base that would hinder the formation nation.[47] In some cases deliberate efforts to control or sup-
of the deallylated compound 36 would also be advan- press β-hydride elimination have been made, although these
tageous. Changes to the catalyst were not considered be- are still generally limited to isolated examples.[48]
Eur. J. Org. Chem. 2012, 544–558
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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551

S. G. Stewart et al.
FULL PAPER
afforded the protected aniline 15 (2.26 g, 67%) as a colourless solid.
Conclusions
1H NMR and 13C NMR spectroscopic data were consistent with
We have designed a range of domino reactions incorpo- those described in the literature.[54–55] Rf = 0.27 (EtOAc/hexane
1:9). 1H NMR (400 MHz, CDCl3): δ = 7.66–7.61 (m, 4 H), 7.30
rating the Heck reaction as one of the synthetic steps.
Through these reactions we have efficiently produced a
series of N-heterocycles including indoles, tetrahydroisoqui-
nolines, 3-benzazepines and azepinobinzindolizidines.
(ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 7.21 (XXЈ part of AAЈ XXЈ system,
2 H), 6.82 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.80 (brs, 1 H), 2.38 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.4, 139.2, 137.6,
136.0, 129.8, 129.6, 127.6, 127.0, 122.6, 92.4, 21.7 (CH3) ppm. IR:
Through optimisation of the various reaction parameters
ν
= (KBr) 3286 (N–H), 1474 [asymmetric S(=O)2], 1394, 1330,
˜
max
for each of these domino reactions we have been able to
achieve good to excellent yields in each of the domino pro-
cesses by changing either the substrate or the catalytic sys-
tem. These reaction examples represent a sound guide for
use in production of the discussed N-heterocycles in more
complex and highly functionalised systems.
1158 [symmetric S(=O)2] cm–1. MS (EI): m/z (%) = 372.9 (79)
[M]+, 217.9 (41) [M – C7H7SO2]+, 155.0 (35) [M – C6H5IN]+, 139.0
(25) [M – C6H5INO]+, 91.0 (100) [M C6H5INSO2]+.
N-Allyl-N-tosyl-2-iodoaniline (16)
Method A: K2CO3 (40 mg, 0.3 mmol) was added in one portion to
a magnetically stirred solution of allyl bromide (0.1 mL, 1.2 mmol)
and the aryl iodide 12 (109 mg, 0.3 mmol) in THF (2 mL). After
this addition, the reaction mixture was heated to 50 °C for 4 h and
then allowed to cool to room temperature. The resulting mixture
was concentrated under reduced pressure, quenched with water
(5 mL) and extracted with Et2O (3ϫ15 mL). The combined or-
ganic layers were dried (MgSO4) and concentrated under reduced
pressure to give a yellow oil. Flash chromatography (EtOAc/hexane
1:9) afforded the alkene 16 (81 mg, 67%) as a colourless oil.
Experimental Section
General Protocol: Starting materials and reagents were obtained
from Sigma–Aldrich or Merck chemical companies. trans-Bis(μ-
acetato)-bis[o-(di-o-tolylphosphanyl)benzyl]dipalladium(II)
(HB
catalyst, 19) was prepared and purified by the procedure of Herr-
mann et al.[49] N-Methyldicyclohexylamine was distilled under re-
[50]
duced pressure and stored under argon. Pd2(dba)3·CHCl3
and
Method B: Pd(PPh3)4 (31 mg, 0.03 mmol) was added to a magneti-
cally stirred mixture of Cs2CO3 (187 mg, 0.57 mmol), nBu4NHSO4
(12 mg, 0.035 mmol), allyl bromide (0.05 mL, 0.6 mmol) and the
aryl iodide 15 (101 mg, 0.27 mmol) in toluene/DMF (10:1,
1.65 mL). The resulting mixture was then heated to 60 °C for 18 h.
The reaction mixture was concentrated under reduced pressure and
the resulting crude oil was fused to silica gel. Flash chromatography
(EtOAc/hexane 2:8) afforded the alkene 16 (104 mg, 93%) as a
colourless oil. The spectroscopic data for this sample were consis-
tent with those described in the literature.[23a] Rf = 0.34 (EtOAc/
[51]
Pd(PPh3)4 were prepared as described previously. Allyl chloride
was distilled over CaCl2 prior to use. All reactions were performed
under argon and at ambient temperature unless stated otherwise.
All solvents used in reactions were anhydrous unless noted other-
wise. Anhydrous solvents were distilled from the appropriate drying
agent[52] or acquired from a Pure Solv 5-Mid Solvent Purification
System (Innovative Technology Inc.). 1H and 13C NMR spectra
were acquired with Varian 300, Varian 400, Bruker AV 500 or
Bruker AV 600 spectrometers and all signals (δ) are reported in
parts per million (ppm). H and 13C assignments were made with
1
1
hexane 1:9). H NMR (400 MHz, CDCl3): δ = 7.89 (dd, J = 8.0,
the aid of DEPT, COSY, HSQC and HMBC sequences where ap-
propriate. Chemical shifts were referenced to the residual (partially)
undeuterated solvents and are reported in parts per million (ppm).
Infrared spectra samples were prepared by the KBr disc method
and samples were acquired with a Perkin–Elmer Spectrum One
spectrometer at 2 cm–1 resolution. Melting points were recorded
with a Reichart heated-stage microscope. The reported retention
factors (Rf) were acquired by TLC performed on Merck silica gel
(60 F254) precoated aluminium sheets. Column chromatography
was performed with silica gel 60 (0.04–0.063) supplied by Merck.
Chromatography solvents were distilled prior to use. HPLC was
performed with a Grace–Apollo 250ϫ10 mm, 5 micron, C18 semi-
preparative column coupled to a UV detector. The trifluoroacetam-
ide 27 and the benzylamine 28 were prepared by standard literature
procedures,[53] except that compound 28 was purified by column
chromatography (EtOAc/hexane 1:19).
1.6 Hz, 1 H), 7.66 (AAЈ part of AAЈ XXЈ system, 2 H), 7.29 (XXЈ
part of AAЈ XXЈ system, 2 H), 7.25 (ddd, J = 8.0, 8.0, 1.6 Hz, 1
H), 7.01 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.92 (dd, J = 8.0, 1.6 Hz,
1 H), 5.86 (m, 1 H), 5.03 (dtd, J = 8.9, 1.8, 1.2 Hz, 1 H), 4.97 (dtd,
J = 17.2, 1.8, 1.2 Hz, 1 H), 4.22–4.08 (m, 2 H), 2.44 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 143.9, 141.3, 140.5, 136.6, 132.5,
131.1, 130.0, 129.7, 128.7, 128.3, 119.8 (CH=CH2), 103.3
(CH=CH ), 54.7 (CH ), 21.7 (CH ) ppm. IR (neat): ν = 3062
˜
max
2
2
3
(C–H), 2922 (C–H), 2864 (C–H), 1595, 1465, 1353 [asymmetric
S(=O)2], 1164 [symmetric S(=O)2] cm–1. MS (EI+): m/z (%) = 412.9
(20) [M]+, 286 (42) [M – I]+, 155 (39) [M – C6H4INC3H5]+, 130
(100), 91 (48) [M – C6H4INC3H5SO2]+.
3-Methyl-N-tosylindole (17): Pd(OAc)2 (8 mg, 0.036 mmol) was
added to a stirred solution of Cs2CO3 (295 mg, 0.97 mmol), PPh3
(9 mg, 0.036 mmol) and the alkene 16 (150 mg, 0.36 mmol) in
DMF (1.5 mL). The reaction mixture was then heated to 40 °C for
12 h. The resulting mixture was allowed to cool to room tempera-
ture and extracted with EtOAc (100 mL). The organic layer was
washed with water (5ϫ5 mL), dried (MgSO4) and concentrated
under reduced pressure to give a brown oil. Flash chromatography
(EtOAc/hexane 1:19) afforded the indole 17 as a light brown solid
(71%). Rf = 0.6 (EtOAc/hexane 2:8). 1H NMR (400 MHz, CDCl3):
δ = 7.98 (m, 1 H), 7.74 (AAЈ part of AAЈ XXЈ system, 2 H), 7.45
(m, 1 H), 7.30 (m, 2 H), 7.23 (ddd, J = 8.0, 8.0, 0.8 Hz, 1 H), 7.19
(XXЈ part of AAЈ XXЈ system, 2 H), 2.32 (s, 3 H), 2.24 (d, J =
1.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8, 135.6,
135.4, 131.9, 129.9, 126.9, 124.7, 123.2, 123.1, 119.5, 118.7, 113.8,
N-Tosyl-2-iodoaniline (15): N-Tosyl-2-iodoaniline (15) was synthe-
sised by a modification of the procedure of Larock and Zenner.[54]
2-Iodoaniline (1.98 g, 9.0 mmol) was added in one portion at ambi-
ent temperature to a magnetically stirred solution of p-toluenesulf-
onyl chloride (1.86 g, 9.8 mmol) in pyridine (5 mL). The resulting
brown mixture was heated to 70 °C for 3 h and then allowed to
cool to ambient temperature. Excess pyridine was removed under
reduced pressure to give a brown solid. The solid was dissolved in
CH2Cl2 (25 mL) and washed with water (3ϫ5 mL), CuSO4
(10 mL, 0.1 m in water) and brine (5 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to give a
yellow solid. Flash column chromatography (EtOAc/hexane 1:9)
21.7 (CH ), 9.8 (CH ) ppm. IR (KBr): νmax = 1445, 1364 [asymmet-
˜
3
3
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Domino Reactions Incorporating the Heck Reaction
ric S(=O)2], 1173 [symmetric S(=O)2] cm–1. MS (EI+): m/z (%) =
Entry 2: The Herrmann–Beller catalyst 19 (54 mg, 0.058 mmol) was
285 (52) [M]+, 130 (100) [M – SO2C6H4CH3]+, 91 (18) [M – added to a magnetically stirred solution of Cy2NMe (0.4 mL,
C9H8NSO2]. Spectroscopic data for this sample were consistent
1.9 mmol) and 15 (201 mg, 0.54 mmol) in DMF (4 mL). The reac-
tion mixture was degassed, allyl acetate (0.06 mL, 0.56 mmol) was
added, and the mixture was immediately heated to 120 °C and
stirred at this temperature for 16 h. The reaction mixture was al-
lowed to cool to room temperature, diluted with EtOAc and then
washed sequentially with water (5ϫ1 mL) and brine (1 mL). The
organic layer was then dried (MgSO4), concentrated under reduced
pressure and fused to silica gel. Flash chromatography (EtOAc/
hexane 1:19) afforded the indoles 17 (50 mg, 33%) and 18 (24 mg,
16%).
with those described in the literature.[56]
Selected Reaction Procedures for Table 1. 3-Methyl-N-tosylindole
(17)
Entry 1: Pd(OAc)2 (11 mg, 0.049 mmol) was added to a magneti-
cally stirred solution of Cs2CO3 (346 mg, 1.06 mmol), allyl bromide
(0.05 mL, 0.7 mmol) and 15 (132 mg, 0.35 mmol) in DMF (2 mL).
After this addition, the reaction mixture was stirred at room tem-
perature for 16 h and then stirred at 60 °C for a further 5 h. The
resulting mixture was allowed to cool to room temperature, diluted
with EtOAc and then washed sequentially with water (5ϫ1 mL)
and brine. The organic layer was then dried (MgSO4), concentrated
under reduced pressure and fused to silica gel. Flash chromatog-
raphy (EtOAc/hexane 1:19) afforded the alkene 16 (132 mg, 90%)
and the indole 17 (2.2 mg, 0.2%).
Entry 6: The Herrmann–Beller catalyst 19 (52 mg, 0.055 mmol) was
added to a magnetically stirred solution of Cs2CO3 (855 mg,
2.6 mmol) and the aryl iodide 15 (355 mg, 0.95 mmol) in DMF
(10 mL). The reaction mixture was degassed and then treated with
allyl bromide (0.125 mL, 1.43 mmol). After the addition, the reac-
tion mixture was heated to 70 °C over 30 min and then stirred at
120 °C for 12 h. The resulting mixture was allowed to cool to room
temperature, extracted with EtOAc (200 mL) and washed with
water (5ϫ5 mL) and brine (15 mL). The organic layer was dried
(MgSO4) and concentrated under reduced pressure and the re-
sulting oil was fused to silica gel. Flash chromatography (EtOAc/
hexane 1:19) afforded the indole 17 (234 mg, 86%) as a colourless
solid.
Entry 3: Pd2(dba3)·CHCl3 (17 mg, 0.016 mmol) was added to a
magnetically stirred solution of Cs2CO3 (114 mg, 0.35 mmol),
Cy2NMe (0.08 mL, 0.38 mmol), P(tBu)3HBF (10 mg, 0.034 mmol),
allyl bromide (0.06 mL, 0.7 mmol) and the aryl iodide 15 (119 mg,
0.32 mmol) in DMF (1 mL). The reaction mixture was stirred for
1 h at room temperature, heated to 80 °C over 30 min and then
stirred at this temperature for 16 h. The resulting mixture was al-
lowed to cool to room temperature, diluted with EtOAc and then
washed sequentially with water (5ϫ1 mL) and brine. The organic
layer was then dried (MgSO4), concentrated under reduced pres-
sure and fused to silica gel. Flash chromatography (EtOAc/hexane
N-Allyl-2,2,2-trifluoro-N-(2-iodobenzyl)acetamide
(20):
NaH
(13 mg, 60% dispersed in mineral oil, 0.33 mmol) was added on
one portion to a magnetically stirred solution of the trifluoroaceta-
1:19) afforded the alkene 16 (107 mg, 81%) and the indole 18 mide 27 (100 mg, 0.304 mmol) in DMF (2 mL). The mixture was
(4 mg, 8%).
stirred for 5 min before addition of allyl bromide (53 μL,
0.608 mmol). The resulting mixture was stirred at room tempera-
ture for 6 h before being concentrated under reduced pressure. The
resulting residue was subjected to column chromatography (EtOAc/
hexane 1:19) to give the alkene 20 as a colourless oil (98 mg,
0.265 mmol, 87%). Rf = 0.36 (EtOAc/hexane 1:19). 1H NMR
(500 MHz, CDCl3): δ = 7.87 (m, 1 H) 7.38 (m, 0.4 H) 7.34 (m, 0.6
H) 7.08 (m, 1 H) 7.01 (m, 1 H) 5.78 (m, 1 H) 5.31 (m, J = 10 Hz,
0.4 H) 5.28 (m, J = 10 Hz, 0.6 H) 5.25 (m, J = 18 Hz, 0.6 H) 5.18
(m, J = 18 Hz, 0.4 H) 4.68 (s, 0.6 H) 4.61 (s, 0.4 H) 3.97 (m, 2
H) ppm. 13C NMR: δ = (125.8 MHz, CDCl3) 157.8 (C=O), 157.5
(C=O), 140.02, 140.0, 137.3, 137.1, 131.5, 130.4, 129.8, 129.7,
128.9, 128.9, 128.1, 127.0, 119.9, 119.7, 98.8, 97.8, 55.2, 55.2, 53.7,
2-Methyl-N-tosylindole (18): 1H NMR (300 MHz, CDCl3): δ = 8.16
(m, 1 H), 7.66 (AAЈ part of AAЈ XXЈ system, 2 H), 7.52 (m, 1 H),
7.4 (m, 1 H), 7.29 (m, 1 H), 7.2 (XXЈ part of AAЈ XXЈ system, 2
H), 6.34 (s, 1 H), 2.6 (s, 3 H), 2.35 (s, 3 H) ppm. Spectroscopic
data for this sample were consistent with those described in the
literature.[57]
Entry 4: Pd(PPh3)4 (32 mg, 0.028 mmol) was added to a magneti-
cally stirred solution of triethylamine (0.06 mL, 0.83 mmol), allyl
chloride (0.04 mL, 0.49 mmol) and the aryl iodide 15 (91.8 mg,
0.25 mmol) in DMF (3 mL). After this addition, the reaction mix-
ture was degassed and stirred at room temperature for 1 h. Further
allyl chloride (0.04 mL, 0.49 mmol) was added, after which the re-
action mixture was heated to 80 °C and stirred for 16 h. The reac-
tion mixture was allowed to cool to room temperature, diluted with
EtOAc (20 mL) and then washed sequentially with water
(5ϫ1 mL) and brine. The organic layer was then dried (MgSO4),
concentrated under reduced pressure and fused to silica gel. Flash
chromatography (EtOAc/hexane 1:19) afforded the alkene 16
(82 mg, 45%) and the indole 17 (34 mg, 48%).
49.6, 49.6, 49.2 ppm. IR (thin film): ν
= 3064 (C–H), 3014 (C–
˜
max
H), 2928 (C–H), 1697 (C=O), 1566, 1437, 1358, 1283, 1208 (C–F),
1143 (C–F), 1015, 749 cm–1. MS (EI+): m/z (%) = 370 (Ͻ1) [M +
H]+, 369 (Ͻ1) [M]+, 328 (12) [M – allyl]+, 243 (11), 242 (95) [M –
I–]+, 217 (42), 86 (88), 84 (100). HRMS (EI+): calcd. 368.9838
[M]+; found 368.9846.
N-Allyl-N-(2-iodobenzyl)-4-methylbenzenesulfonamide (21): NaH
(13 mg, 60% dispersed in mineral oil, 0.33 mmol) was added in one
portion to a magnetically stirred solution of the sulfonamide 26
(117 mg, 0.304 mmol) in DMF (2 mL). The resulting mixture was
stirred for 5 min, treated with allyl bromide (53 μL, 0.608 mmol)
and stirred at room temperature for a further 6 h, before being
concentrated under reduced pressure. The resulting residue was
subjected to column chromatography (EtOAc/hexane 1:19) to give
Selected Reaction Procedures for Table 2
Entry 1: The Herrmann–Beller catalyst 19 (24 mg, 0.026 mmol) was
added to a magnetically stirred solution of Cy2NMe (0.14 mL,
0.66 mmol), allyl acetate (0.06 mL, 0.56 mmol) and the aryl iodide
15 (96.4 mg, 0.26 mmol) in DMF (4 mL). The reaction mixture was
degassed and was then immediately heated to 100 °C and stirred at
this temperature for 16 h. The reaction mixture was allowed to cool
the aryl iodide 21 as a colourless oil (121 mg, 0.283 mmol, 93%).
1
to room temperature, diluted with EtOAc (20 mL) and then washed Rf = 0.59 (EtOAc/hexane 2:8). H NMR (400 MHz, CDCl3): δ =
sequentially with water (5ϫ1 mL) and brine. The organic layer was
then dried (MgSO4), concentrated under reduced pressure and
fused to silica gel. Flash chromatography (EtOAc/hexane 1:19) af-
forded the indoles 17 (19 mg, 26%) and 18 (16 mg, 16%).
7.8–7.73 (m, 3 H), 7.51 (dd, J = 7.6, 1.6 Hz, 1 H), 7.37–7.31 (m, 3
H), 6.96 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H), 5.55–5.44 (m, 1 H), 5.04
(m, 1 H), 5.0 (dtd, J = 8.0, 2.4, 1.2 Hz, 1 H), 4.35 (s, 2 H), 3.8 (d,
J = 6.8 Hz, 2 H), 2.45 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
Eur. J. Org. Chem. 2012, 544–558
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
553

S. G. Stewart et al.
FULL PAPER
δ = 143.6, 139.4, 138.5, 137.1, 132.0, 130.0, 129.4, 129.3, 128.6,
127.3, 126.7, 124.0, 110.1, 50.7 (CH2), 48.8 (CH2), 21.7 (CH3) ppm.
127.4, 119.8, 98.2 (Ar-CI), 55.6 (CH2), 51.1 (CH2), 21.7 IR (KBr): ν
= 1346 [asymmetric S(=O)2], 1166 [symmetric
˜
max
(CH3) ppm. MS (EI+): m/z (%) = 426.9 (31) [M]+, 300.0 (41) [M –
S(=O)2], 1090 cm–1. MS (EI+): m/z (%) = 299.0 (10) [M]+, 262.0
(13), 144.0 (83) [M – SO2C6H4CH3]+, 143.0 (100). HRMS (EI+):
calcd. for C17H17NO2S [M]+ 299.0980; found 299.0983.
I]+, 271.9 (100) [M – SO2C6H4CH3].
N-Benzyl-N-(2-iodobenzyl)prop-2-en-1-amine (22): NaH (13 mg,
60% dispersed in mineral oil, 0.33 mmol) was added in one portion
to a magnetically stirred solution of the benzylamine 28 (98 mg,
0.304 mmol) in DMF (2 mL). The resulting mixture was stirred
for 5 min, treated with allyl bromide (53 μL, 0.608 mmol) and then
stirred at room temperature for 6 h, before being concentrated un-
der reduced pressure. The resulting residue was subjected to col-
umn chromatography (EtOAc/hexane 1:19) to give the alkene 22 as
a colourless oil (85 mg, 0.234 mmol, 77%). Rf = 0.64 (EtOAc/hex-
Selected Reaction Procedures for Table 3
Entry 2: The Herrmann–Beller catalyst 19 (12 mg, 0.013 mmol) was
added to a magnetically stirred solution of Cs2CO3 (252 mg,
0.775 mmol), the aryl iodide 26 (100 mg, 0.258 mmol) and allyl
bromide (45 μL, 0.516 mmol) in DMF (2 mL). The resulting reac-
tion mixture was then heated to 100 °C and stirred overnight. The
mixture was concentrated under reduced pressure and the residue
was purified by column chromatography (EtOAc/hexane 1:19 Ǟ
EtOAc/hexane 1:4) to give the olefin 21 (53 mg, 48%) as a colour-
less oil [Rf = 0.18 (EtOAc/hexane 1:19)] and the tetrahydroisoquin-
oline 24 (18 mg, 23%) as a white solid [Rf = 0.38 (EtOAc/hexane
1:4)].
1
ane 1:19). H NMR (500 MHz, CDCl3): δ = 7.83 (m, 1 H, ArH)
7.62 (m, 1 H, ArH), 7.40 (m, 2 H, ArH), 7.34 (m, 2 H, ArH), 7.33
(m, 1 H, ArH), 7.25 (m, 1 H, ArH), 6.95 (m, 1 H, ArH), 5.97 (m,
1 H, CH=CH2), 5.25 (m, 1 H, C=CH2), 5.19 (m, J = 10.0 Hz, 1
H, C=CH2), 3.66 (s, 4 H, Ar-CH2), 3.13 (d, J = 6.0 Hz, H2C=CH-
CH2) ppm. 13C NMR: δ = (125.8 MHz, CDCl3) 141.8, 139.5, 139.4,
135.6, 130.2, 128.9, 128.6, 128.3, 128.2, 127.0, 117.7, 100.2 (Ar-I),
Entry 7: Pd(PPh3)4 (30 mg, 0.0258 mmol) was added to a magneti-
cally stirred solution of NEt3 (108 μL, 0.775 mmol), the aryl iodide
26 (100 mg, 0.258 mmol) and allyl chloride (42 μL, 0.516 mmol) in
DMF (2 mL). The resulting reaction mixture was heated to 80 °C
and stirred for 16 h. The mixture was concentrated under reduced
pressure and the residue was purified by column chromatography
(EtOAc/hexane 1:19 Ǟ EtOAc/hexane 1:4) to give the olefin 21
(53 mg, 0.124 mmol, 48%) as a colourless oil [Rf = 0.18 (EtOAc/
hexane 1:19)] and the aryl iodide 26 (33 mg, 33%).
62.3, 57.9, 56.5 ppm. IR (thin film): ν
= 3061 (C–H), 3027 (C–
˜
max
H), 3005 (C–H), 2976 (C–H), 2921 (C–H), 2796 (C–H), 2712 (C–
H), 1698, 1642, 1562, 1494, 1454, 1455, 1258, 1012, 749 cm–1. MS
(EI+): m/z (%) = 364 (7) [M + H]+, 363 (33) [M]+, 336 (29), 286
(19) 272 (35) [M – Bn]+, 217 (62), 91 (100). HRMS (EI+): calcd.
363.0484 [M]+; found 363.0492.
2,2,2-Trifluoro-1-[4-methylene-3,4-dihydroisoquinolin-2(1H)-yl]-
ethanone (23): Pd(PPh3)4 (16 mg, 0.0135 mmol) was added to a
magnetically stirred solution of Cs2CO3 (88 mg, 0.27 mmol) and
the allyl amide 20 (50 mg, 0.135) in DMF (1 mL). After this ad-
dition, the reaction mixture was heated to 80 °C and stirred for
16 h. The mixture was concentrated under reduced pressure and
the residue was purified by flash chromatography (EtOAc/hexane
1:19) to give the isoquinoline 23 (9 mg, 29%) as a colourless oil.
Rf = 0.27 (EtOAc/hexane 1:19), Rf = 0.27 (EtOAc/hexane 1:24). 1H
NMR (500 MHz, CDCl3): δ = 7.66 (m, 1 H, ArH), 7.31 (m, 2 H,
ArH), 7.19 (m, 0.6 H, ArH) 7.15 (m, J = 1.0 Hz, 0.4 H, ArH), 5.68
(m, 0.4 H, =CH2) 5.66 (s, 0.6 H, =CH2), 5.27 (m, J = 1.0 Hz, 0.4
H, =CH2), 5.18 (s, 0.6 H, =CH2), 4.87 (s, 1.2 H, CH2), 4.78 (s, 0.8
H, CH2), 4.50 (s, 0.8 H, CH2), 4.40 (s, 1.2 H, CH2) ppm. 13C NMR:
δ = (125.8 MHz, CDCl3), 155.9 (C=O), 155.6 (C=O), 132.5, 131.8,
131.5, 131.6, 128.9, 128.8, 128.1, 127.6, 126.7, 126.1, 124.5, 124.4,
116.6 (q, J = 1145 Hz, CF3), 116.7 (q, J = 1145 Hz, CF3), 111.4,
110.6, 50.2 (CH2), 48.1 (CH2), 48.0 (CH2), 46.2 (CH2) ppm. IR
Entry 8: Pd(PPh3)4 (32 mg, 0.28 mmol) was added to a magneti-
cally stirred solution of triethylamine (0.05 mL, 0.7 mmol), allyl
acetate (0.06 mL, 0.56 mmol) and the aryl iodide 26 (100 mg,
0.26 mmol) in DMF (3 mL). The resulting reaction mixture was
heated to 60 °C and stirred overnight. The reaction mixture was
allowed to cool to room temperature, extracted with EtOAc
(20 mL) and then washed sequentially with water (5ϫ1 mL) and
brine. The organic layer was then dried (MgSO4), concentrated un-
der reduced pressure and fused to silica gel. Flash chromatography
(EtOAc/hexane 1:9) afforded the alkene 21 (16.4 mg, 14%) as a
colourless oil and the isoquinoline 24 (7 mg, 9%) as a yellow solid.
Selected Reaction Procedures for Table 4
Entry 1: Pd(PPh3)4 (35 mg, 0.034 mmol) was added to a magneti-
cally stirred solution of Cs2CO3 (297 mg, 0.912 mmol), the aryl io-
dide 27 (100 mg, 0.304 mmol) and allyl bromide (53 μL, 0.608) in
DMF (2 mL). The resulting reaction mixture was heated to 80 °C
and stirred for 16 h. The resulting mixture was concentrated under
reduced pressure and the residue was purified by column
chromatography (EtOAc/hexane 1:19) to give the tetrahydroiso-
quinoline 23 (36 mg, 49%) as a colourless oil. Rf = 0.27 (EtOAc/
hexane 1:19).
(thin film): ν
= 2927 (C–H), 1694 (C=O), 1452, 1260, 1201 (C–
˜
max
F), 1177 (C–F), 1142 (C–F), 1009 cm–1. MS (EI+): m/z (%) = 241
(5) [M]+, 219 (12), 131 (10), 86 (66). 84 (100). HRMS (EI+): calcd.
241.0714 [M]+; found 241.0720.
4-Methylene-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydroiso-
quinoline (24): Pd(PPh3)4 (26 mg, 0.023 mmol) was added to a mag-
netically stirred solution of Cs2CO3 (148 mg, 0.454 mmol) and the
sulfonamide 21 (97 mg, 0.227 mmol) in DMF (1 mL). After the
addition, the reaction mixture was heated to 80 °C and stirred over-
night. The mixture was concentrated under reduced pressure and
the residue was purified by column chromatography (EtOAc/hex-
ane 1:4) to give the isoquinoline 24 (31 mg, 59%) as a white solid.
Entry 5: Pd(PPh3)4 (3 mg, 0.003 mmol) was added to a magneti-
cally stirred solution of Cs2CO3 (297 mg, 0.912 mmol), the aryl io-
dide 27 (100 mg, 0.304 mmol) and allyl bromide (53 μL, 0.608) in
DMF (2 mL). After the addition, the reaction mixture was then
heated to 80 °C and stirred for 16 h. The mixture was concentrated
under reduced pressure and the residue was purified by column
chromatography (EtOAc/hexane 1:19) to give alkene 20 (13 mg,
12%) as a colourless oil [Rf = (EtOAc/hexane 1:19)] and the iso-
quinoline 23 (17 mg, 23%) as a colourless oil [Rf = 0.27 (EtOAc/
hexane 5%)].
1
Rf = 0.38 (EtOAc/hexane 2:8). H NMR (400 MHz, CDCl3): δ =
7.67 (AAЈ part of AAЈ XXЈ system, 2 H), 7.55 (dd, J = 7.2, 1.6 Hz,
1 H), 7.33 (m, 1 H), 7.24 (XXЈ part of AAЈ XXЈ system, 2 H), 7.19
(ddd, J = 7.2, 7.2, 1.6 Hz, 1 H), 7.05 (m, 1 H), 5.59 (s, 1 H), 5.1 (s,
Entry 6: Pd(PPh3)4 (35 mg, 0.034 mmol) was added to a magneti-
1 H), 4.36 (s, 2 H), 4.0 (s, 2 H), 2.39 (s, 3 H) ppm. 13C NMR cally stirred solution of Cs2CO3 (297 mg, 0.912 mmol), the aryl io-
(100 MHz, CDCl3): δ = 143.8, 136.6, 133.7, 129.7, 128.5, 128.1, dide 27 (100 mg, 0.304 mmol), PPh3 (80 mg, 0.304 mmol) and allyl
554
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 544–558

Domino Reactions Incorporating the Heck Reaction
bromide (53 μL, 0.608) in DMF (2 mL). The resulting reaction
mixture was then heated to 80 °C and stirred for 16 h. The resulting
mixture was concentrated under reduced pressure and the residue
was purified by column chromatography (EtOAc/hexane 1:19) to
Method B: (Bromomethyl)triphenylphosphonium bromide (8.28 g,
19.5 mmol) was added portionwise at –78 °C to a magnetically
stirred solution of tBuOK (2.13 g, 19.0 mmol) in THF (50 mL) and
the resulting mixture was stirred for 1.5 h. 2-Bromobenzaldehyde
give the isoquinoline 23 (38 mg, 52%) as a colourless oil [Rf = 0.27 (3.0 g, 16.3 mmol) was added dropwise and the reaction mixture
(EtOAc/hexane 1:19)].
was stirred for 16 h, during which time the solution was allowed to
warm from –78 °C to ambient temperature. The solution was di-
luted with hexane (30 mL) and filtered through a small celite pad
with washing with hexane (150 mL). The filtrate was concentrated
under reduced pressure and the resulting colourless oil was sub-
jected to flash chromatography (hexane). The fractions correspond-
ing to the olefinic product 29 were divided into three batches. Al-
though the Z and E geometrical isomers could not be differentiated
through visualisation by tlc the early fractions (Rf = 0.4) contained
a Z/E ratio of 9.5:1 whereas the worst ratio fractions were 4.5:1.
The combined mass was 3.1 g (72%). This method was a modifica-
tion of the original procedure reported by Willis.[36a]
Selected Reaction Procedures for Table 5
Entry 3: The Herrmann–Beller catalyst 19 (15 mg, 0.015 mmol) was
added to a magnetically stirred solution of Cs2CO3 (302 mg,
0.927 mmol), 28 (100 mg, 0.309 mmol) and allyl bromide (54 μL,
0.618 mmol) in DMF (2 mL). The resulting reaction mixture was
then heated at 40 °C for 1.5 h and then to 80 °C and stirred for
16 h. The resulting mixture was concentrated under reduced pres-
sure and the residue was purified by column chromatography
(EtOAc/hexane 1:19) to give the tetrahydroisoquinoline 25 (15 mg,
21%) as a colourless oil. The spectroscopic data for this compound
were identical to those previously reported.[58]
1-[(Z)-2-(2-Bromophenyl)vinyl]pyrrolidin-2-one [(Z)-32]: DavePhos
(7.5 mg, 19 μmol) and Pd2(dba)3·CHCl3 (20 mg, 19 μmol) were
added in a single portion to a magnetically stirred solution of the
dibromostyrene 29 (100 mg, 0.382 mmol), Cs2CO3 (414 mg,
1.14 mmol) and pyrrolidin-2-one (87 μL, 1.14 mmol) in toluene
(0.4 mL). The resulting mixture was heated at 100 °C for 20 h. The
resulting mixture was concentrated under reduced pressure and the
residue was purified by column chromatography (EtOAc/hexane
1:4) to afford the Z-enamine 32 (92 mg, 90%) as a pale brown
solid. Rf = 0.2 (ethyl acetate/hexane 20%). 1H NMR (300 MHz,
CDCl3): δ = 7.55 (m, 1 H, 3-H/6-H), 7.29 (m, 1 H, 3-H/4-4/5-H/6-
H), 7.18 (m, 1 H, 3-H/4-H/5-H/6-H), 7.11 (m, 1 H, 4-H/5-H), 6.93
(d, J = 9.9 Hz, 1 H, 2Ј-H), 5.83 (d, J = 9.9 Hz, 1 H, 1Ј-H), 3.08 (t,
J = 7.2 Hz, 2 H, 5ЈЈ-H), 2.39 (t, J = 8.1 Hz, 2 H, 3ЈЈ-H), 1.91 (m,
2 H, 4ЈЈ-H) ppm. Further characterisation was not achieved due to
rapid isomerisation to the E isomer 32 under ambient light; see
next procedure.
1-Bromo-2-[(Z)-2-bromovinyl]benzene (29)
Method A: A solution of PPh3 (9.07 g, 34.6 mmol) in CH2Cl2
(30 mL) was added dropwise over 15 min to a magnetically stirred
solution of CBr4 (5.73 g, 17.3 mmol) in CH2Cl2 (30 mL), main-
tained at 0 °C. The reaction mixture was then allowed to warm to
room temperature and stirred for 1 h before cooling to 0 °C. 2-
Bromobenzaldehyde (1.00 mL, 8.65 mmol) in CH2Cl2 (30 mL) was
added to the yellow-brown reaction mixture over 3 min and the
resulting solution was allowed to warm to room temperature and
stirred for a further 2 h. The resulting mixture was poured into
hexane (400 mL) and filtered, and the residue was washed with
hexane (2ϫ50 mL). The filtrate was concentrated and purified by
column chromatography (hexane) to afford 1-bromo-2-(2,2-dibro-
movinyl)benzene (2.69 g, 91%) as a pale yellow oil.[35] Rf = 0.66
(100% hexane). 1H NMR (300 MHz, CDCl3): δ = 7.60 (m, 1 H,
Ar-H), 7.58 (m, 1 H, Ar-H), 7.51 (s, 1 H, 1Ј-H), 7.33 (m, 1 H, Ar-
H), 7.20 (m, 1 H, Ar-H) ppm. 13C NMR (125.8 MHz): δ = 136.7,
136.1 (C-2), 132.7, 130.4, 129.9, 127.2, 123.1 (C-1), 92.9 (C-
1-[(E)-2-(2-Bromophenyl)vinyl]pyrrolidin-2-one [(E)-32]: A solution
of 1-[(Z)-2-(2-bromophenyl)vinyl]pyrrolidin-2-one [(Z)-32, 92 mg,
0.34 mmol] in CDCl3 was left under ambient light and temperature
for approximately 20 h. The solvent was removed under reduced
pressure to afford (E)-32 as a colourless solid, Rf = 0.16 (EtOAc/
hexane 1:4). 1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 14.8 Hz,
1 H, 2ЈЈ-H), 7.47 (m, 1 H, 3-H/6-H), 7.45 (m, 1 H, 3-H/6-H), 7.17
(“dt”, J = 8.6, 1.2 Hz, 1 H, 4-H/5-H), 6.97 (“dt”, J = 8.0, 1.6 Hz,
1 H, 4-H/5-H), 6.13 (d, J = 14.8 Hz, 1 H, 2ЈЈ-H), 3.64 (t, J = 7.6 Hz,
2 H, 5-HЈ), 2.49 (t, J = 8 Hz, 2 H, 3Ј-H), 2.10 (“tt”, J = 7.2 Hz, 2
H, 4Ј-H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 173.7 (C-2Ј),
136.3, 133.0, 128.0, 127.7, 126.0, 125.6, 123.4, 110.6 (C-1ЈЈ), 45.4
2Ј) ppm. IR (thin film): ν = 3067 (C–H), 3019 (C–H), 2974 (C–H),
˜
2863 (C–H), 1605, 1583, 1561, 1462, 2435, 1428, 1046, 1025 cm–1.
MS EI: m/z (%) = 344 (18) [M(81Br3)]+, 342 (54) [M(81Br279Br1)]+,
340 (55) [M(81Br179Br2)]+, 338 (18) [M(79Br3)]+, 263 (49)
[M – Br]+, 261 (100) [M – Br]+, 259 (51) [M – Br]+, 182 (72) [M –
2Br]+, 180 (73) [M – 2Br]+, 101 (34). HRMS EI: calculated for
C8H5Br3: 337.7941, found 337.7949.
nBu3SnH (approx. 50%, 13.6 mL, 26 mmol) was added portionwise
at room temperature over 5 h to a magnetically stirred solution
of (Z)-1-bromo-2-(2-bromovinyl)benzene (8.90 g, 26.1 mmol) and
Pd(PPh3)4 in toluene (150 mL), with monitoring of conversion by
1H NMR. The mixture was stirred at room temperature for 16 h.
The solvent was removed under reduced pressure and the resulting
residue was purified by column chromatography (silica, hexane) to
afford the (Z)-dibromostyrene 29 (4.22 g, 62%) as a colourless
(C-5Ј), 31.3 (C-3Ј), 17.5 (C-4Ј) ppm. IR (KBr): ν = 3074 (C–H),
˜
2962 (C–H), 2930 (C–H), 2891 (C–H), 1700, 1637 (C=O),
1399 cm–1. MS AP-CI: m/z (%) = 309 (90) [M(81Br) + H +
CH3CN]+, 307 (94) [M(79Br) + H + CH3CN]+, (97) [M + H]+, 268
(98) [M(81Br) + H]+, 266 (100) [M(81Br) + H]. 187 (70) [M – Br]+.
HRMS FAB calculated for C12H12N1O1Br1: 265.0102, found
265.0102.
1
oil.[59] Rf = 0.63 (hexane). H NMR (300 MHz, CDCl3): δ = 7.78
(dd, J = 8.1, 1.8 Hz, 1 H, 6-H/3-H), 7.60 (dd, J = 7.8, 0.9 Hz, 1 H,
6-H/3-H), 7.34 (“dt”, “J” = 7.8, 1.2 Hz, 1 H, 5-H/6-H), 7.21 (d, J
3-Acetyl-1-methylene-2,3-dihydro-1H-3-benzazepine (35): Pd(PPh3)4
= 8.1 Hz, 1 H, 1Ј-H), 7.19 (m, 1 H, 5-H/6-H), 6.59 (d, J = 8.1 Hz, (10 mg, 0.008 mmol) was added to a magnetically stirred solution
1 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.3 (C-2), of the amide 34 (25 mg, 0.09 mmol) and K2CO3 (31 mg,
132.8 (ArC), 132.5 (ArC), 130.7 (ArC), 127.7 (ArC), 127.0 (ArC), 0.22 mmol) in DMF (0.5 mL). The resulting mixture was degassed
123.9 (C-1), 109.5 (C-1Ј) ppm. IR (thin film): ν = 3070 (C–H), 3014
and was then heated at 120 °C for 16 h. The resulting black mixture
˜
(C–H), 2921 (C–H), 1617, 1587, 1561, 1463, 1437, 1428, 1317 cm–1. was diluted in ethyl acetate (5 mL) and washed with water
MS EI: m/z (%) = 262 (49) [M(81Br179Br1)]+, 260 (25) [M(79Br2)]+, (5ϫ0.5 mL). The organic layer was dried (MgSO4), filtered and
183 (94) [M – Br]+, 181 (98) [M – Br]+, 102 (81), 93 (86), 84 (100).
HRMS (EI) calculated for C8H6Br2: 259.8836, found 259.8835.
concentrated under reduced pressure. The crude mixture was sub-
jected to column chromatography (EtOAc/hexane 1:9) to give the
Eur. J. Org. Chem. 2012, 544–558
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
555

S. G. Stewart et al.
FULL PAPER
3-benzazepine 35 (13 mg, 73%) as a pale yellow oil; Rf = 0.17 (ethyl
acetate/hexane 1:9). H NMR (500 MHz, CDCl3): δ = 7.44 (m, J azepino[4,5-b]indole (37), 6-Methylene-3-(trifluoroacetyl)-2,3,4,
= 7.0 Hz, 1 H, H9), 7.25–7.22 (m, 2 H, 6-H, 7-H), 7.20 (m, 1 H, 4a,5,6-hexahydroazepino[3,4,5-hi]benz[b]indolizine (39), and 5-Meth-
6-Allyl-5-methylene-3-(trifluoroacetyl)-1,2,3,4,5,6-hexahydro-
1
8-H), 6.69 (d, J = 10.1 Hz, 1 H, 4-H), 5.74 (d, J = 10.1 Hz, 1 H,
ylene-3-(trifluoroacetyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
5-H), 5.54 (s, 1 H, 3Ј-H), 5.41 (s, 1 H, 3Ј-H), 4.40 (s, 2 H, 2-H), (38)
2.28 (s, 3 H, 4Ј-H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 168.2
(C=O), 143.8 (C-1), 139.4 (C-1Ј), 132.4 (C-2Ј), 131.7 (C6), 128.0
(C7), 127.8 (C9), 127.3 (C4), 126.9 (C8), 117.4 (C-3Ј), 112.6 (C5),
Entry 3: The aryl bromide 36 (112 mg, 0.27 mmol) was placed in a
flask fitted with a reflux condenser and containing a stirrer bar.
NBu4OAc (162 mg, 0.54 mmol) and Pd(PPh3)4 (31 mg,
0.027 mmol, 10 mol-%) were added and the flask was backfilled
thrice with argon. DMF (5 mL) was added and the mixture was
heated at 100 °C for 3 h, allowed to cool to room temperature and
concentrated under reduced pressure. The crude material was sub-
jected to flash chromatography (toluene/hexane 1:1Ǟtoluene).
46.6 (C-2), 22.4 (C-4Ј) ppm. IR (thin film): ν = 3059, 3010, 2925,
˜
2853, 1732, 1674 (C=O), 1632 (C=O), 1455, 1387, 1334, 1238 cm–1.
MS (EI): m/z (%) = 200 (20) [M + H]+, 199 (20) [M]+, 158 (100).
HRMS calculated for C13H13NO: 199.0997, found 199.0997.
Selected Reaction Procedures for Table 6
1
First to elute was an otherwise pure (1:0.21 by H NMR) mixture
3-Acetyl-1-methylene-2,3-dihydro-1H-3-benzazepine (35)
of compounds 37 and 39 (66 mg, 73% combined, Rf = 0.6 in ace-
tone/toluene 1:19). The mixture of the tricycle 37 and the tetracycle
39 could be separated by semipreparative HLPC (MeOH/H2O 4:1,
4 mLmin–1) to give pure samples of both compounds.[10a]
Entry 2: Pd2(dba)3·CHCl3 (28 mg, 27 mmol) was added to a mag-
netically stirred solution of the dibromostyrene 29 (143 mg,
0.545 mmol), the allyl acetamide 33 (108 mg, 1.09 mmol), Cs2CO3
(592 mg, 1.63 mmol) and DavePhos (10.7 mg, 27.3 μmol) in dry
toluene (1 mL), and the mixture was heated at 100 °C for 20 h. The
resulting mixture was concentrated under reduced pressure and the
remaining residue was purified by column chromatography
(EtOAc/hexane 1:10) to afford the 3-benzazepine 35 as a yellow oil
(37 mg, 34%).
Entry 5: The aryl bromide 36 (100 mg, 0.24 mmol) was placed in a
flask fitted with a reflux condenser and containing a stirrer bar.
Pd(PPh3)4 (28 mg, 0.024 mmol, 10 mol-%) was added and the flask
was backfilled thrice with argon. DMF (3 mL) was followed by
NEt3 (101 mg, 3 equiv.mmol–1) and the mixture was heated to
100 °C for 3 h. The reaction mixture was allowed to cool to room
temperature and concentrated under reduced pressure. The crude
material was subjected to flash chromatography (toluene/hexane
Entry 5: Pd2(dba)3·CHCl3 (20 mg, 19 mmol) was added to a mag-
netically stirred solution of the dibromostyrene 29 (100 mg,
0.382 mmol), the allyl acetamide 33 (227 mg, 2.29 mmol), Cs2CO3
(373 mg, 1.15 mmol) and DavePhos (7.5 mg, 1.9 μmol) in dry tolu-
ene (1 mL), and the mixture was heated at 100 °C for 20 h. The
resulting mixture was concentrated under reduced pressure and the
remaining residue was purified by column chromatography
(EtOAc/hexane 1:10) to afford the 3-benzazepine 35 as a yellow oil
(37 mg, 34%).
1
1:1 Ǟ toluene). First to elute was an otherwise pure (1:1.18 by H
NMR) mixture of compounds 37 and 39 (46 mg, 57% combined),
Rf 0.6 (acetone/toluene 1:19). Second to elute was a sample of the
indoleazepine 38 (10 mg, 14%). The mixture of the tricycle 37 and
the tetracycle 39 could be separated by semipreparative HLPC
(MeOH/H2O 4:1, 4 mLmin–1) to give pure samples of both com-
pounds.[10a]
Entry 23: Pd2(dba)3·CHCl3 (20 mg, 19 μmol) was added to a mag-
netically stirred solution of the dibromostyrene 29 (100 mg,
0.382 mmol), the allyl acetamide 33 (76 mg, 0.76 mmol), Cs2CO3
(375 mg, 1.15 mmol) and XantPhos (22 mg, 38 μmol) in toluene
(1 mL), and the mixture was heated at 100 °C for 20 h. The re-
sulting mixture was concentrated under reduced pressure and the
remaining residue was purified by column chromatography
(EtOAc/hexane 1:10) to afford the 3-benzazepine 35 as a yellow oil
(62 mg, 82%).
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR, 13C NMR data for compouds 20–24, 32 and 35.
Acknowledgments
The Alexander von Humboldt Foundation is gratefully acknowl-
edged for a return fellowship to S. G. S. The authors would like to
thank Prof. Emil Ghisalberti and Prof. George Koutsantonis for
helpful discussions and the use of laboratory equipment. J. E. R.
and C. H. H. are recipients of a University of Western Australia
Post Graduate Scholarship (UPA) and Australian Postgraduate
Scholarships (APA), respectively. The authors would also like to
thank Dr. Lindsay Byrne for NMR assistance, Dr. Gavin Flematti
for HPLC assistance and Dr. Tony Reeder for mass spectra acqui-
sition.
Entry 24: Pd2(dba)3·CHCl3 (20 mg, 19 μmol) was added to a mag-
netically stirred solution of the dibromostyrene 29 (100 mg,
0.382 mmol), the allyl acetamide 33 (76 mg, 0.76 mmol), Cs2CO3
(375 mg, 1.15 mmol) and XantPhos (44 mg, 76 μmol) in dry tolu-
ene (1 mL), and the mixture was heated at 100 °C for 20 h. The
resulting mixture was concentrated under reduced pressure and the
remaining residue was purified by column chromatography
(EtOAc/hexane 1:10) to afford the 3-benzazepine 35 as a yellow oil
(63 mg, 83%).
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Received: September 8, 2011
Published Online: November 30, 2011
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Eur. J. Org. Chem. 2012, 544–558