Domino or single-step Tsuji-Trost/Heck reactions and their application in the synthesis of 3-benzazepines and azepino[4,5-b]indole ring systems

Article abstract of DOI:10.1002/ejoc.200900028

A series of methods for palladium-mediated single-step and domino Tsuji-Trost/Heck reactions are described. These methods are applied to the synthesis of both 3-benzazepines and azepino[4,5-b]indoles in the category of complex 6-7-6 and 6-0-7 ring heteroc

Full text of DOI:10.1002/ejoc.200900028

FULL PAPER
DOI: 10.1002/ejoc.200900028
Domino or Single-Step Tsuji–Trost/Heck Reactions and Their Application in
the Synthesis of 3-Benzazepines and Azepino[4,5-b]indole Ring Systems
Scott G. Stewart,*[a] Charles H. Heath,[a] and Emilio L. Ghisalberti[a]
Keywords: Domino reactions / Cross-coupling / Tsuji–Trost reaction / Heck reaction / N-Heterocycles
A series of methods for palladium-mediated single-step and
domino Tsuji–Trost/Heck reactions are described. These
methods are applied to the synthesis of both 3-benzazepines
and azepino[4,5-b]indoles in the category of complex 6-7-6
and 6-5-7 ring heterocycles. In addition, a domino Heck/
Heck sequence of reactions that produces the azepino-
benzindolizine tetracyclic ring system from N-diallylated
precursors is described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Also within these methodologies, the palladium-cata-
Alkaloids containing seven-membered rings have been lyzed intramolecular Heck reaction provides an efficient
isolated from several natural sources and form a significant route to the 3-benzazepine ring system from halogenated
series of medicinal agents. One class, the substituted 3- aromatic precursors.[10] However, exploitation of this meth-
benzazepines, have been explored as potential medicinal odology to incorporate additional non-aromatic rings has
agents in many instances such as the dopamine agonist yet to be fully explored.
SCH23390 (1)[1] and the 5-HT2C agonist/anti-obesity com-
To increase the efficiency of this ring-forming process, we
pound 2.[2] The use of 3-benzazepines as N-methyl--as- initially envisioned the synthesis of these seven-membered
partate (NMDA) antagonists has also recently been high- systems through a domino cross-coupling reaction, where
lighted in the literature.[3] The azepino[4,5-b]indole ring sys- the N-allylated Heck precursor is prepared in situ through
tem, containing a seven-membered C ring, has recently an initial Tsuji–Trost reaction. Domino reactions are de-
been found in several natural products such as arboflorine fined as “the execution of two or more bond-forming trans-
(3) and subincanadine F (4).[4,5] These natural products formations under identical reaction conditions, in which the
have attracted our interest because of their unique molecu- latter transformations take place at the functionalities
lar architecture and unexplored biological properties (Fig- formed by the preceding transformation”.[11] Domino reac-
ure 1). The preparation of both of these classes of com- tions are attractive to industry and research laboratories be-
pounds could, in theory, come from the same retrosynthetic cause of their potential to save solvents, reagents, time and
disconnection. Historically, 3-benzazepines have been pre- energy.[11,12] Palladium-mediated domino reactions have
pared through various methods including Friedel–Crafts- been used in a host of important total syntheses including
type approaches,[6] thermal-rearrangement-promoted cycli- various alkaloids, the steroid ring system, vitamin E, xesto-
sations[7] and radical cyclisations,[8] among others.[3,9]
quinone and scopadulcic acid.[13] The single-pot combina-
Figure 1. Structures of interesting 3-benzazepines and azepino[4,5-b]indoles natural products.
[a] The School of Biomedical, Biomolecular & Chemical Sciences,
tion of a Tsuji–Trost[14] and Heck[15] reaction, falling in the
The University of Western Australia,
Crawley, WA 6009, Australia
category of a palladium-mediated domino reaction,[11] has
advantages over other domino-type processes because of
the similar conditions, in which the two reactions can be
carried out. Domino Tsuji–Trost/Heck reactions have been
Fax: +61-8-6488-1005
E-mail: sgs@cyllene.uwa.edu.au
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1934
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1934–1943

3-Benzazepines and Azepino[4,5-b]indole Ring Systems
Scheme 1. Proposed domino Tsuji–Trost/Heck reaction.
used to construct complex ring systems, being more com- timised. Thus, treatment of the amide 10 with allyl acetate
monly applied when both the initial Tsuji–Trost and Heck and a series of palladium catalysts afforded 11 in moderate
reactions are carried out intramolecularly.[16] Examples, yields. To improve this transformation,[20] allyl bromide was
where the Tsuji–Trost reaction is intermolecular and the investigated as a reagent with and without a palladium cata-
Heck reaction is intramolecular, are extremely rare in the lyst present. The reactions mediated by palladium(0) and
literature,[17] and to the best of our knowledge none have allyl bromide were faster than their uncatalysed counter-
been reported with a free amine or amide as the nucleo- parts. It thus appears that the more favoured pathway in-
philic species. Because these domino reactions are assumed volved a preformed π-allylpalladium species as opposed to
to go through two catalytic cycles they have also been de- a simple SN2Ј-type reaction, although the SN2Ј pathway
scribed as pseudo-domino reactions.[16c]
The intermolecular Tsuji–Trost reaction planned between pathway.
could not be completely ruled out as a possible mechanistic
a tethered alkylamine 5 and a π-allylpalladium complex
In these allylation reactions, the combination of
provides the olefin 6 (Scheme 1). A palladium(0) oxidative Pd(PPh3)4 (8 mol-%), KOH and a phase-transfer catalyst
addition to the aryl–halide bond initiates the Heck cross- consistently produced the most reliable yields (68%). With
coupling reaction process, and an increase in temperature the allyl product 11 in hand, we set about optimising the
should promote the ring-forming process.
intramolecular Heck reaction, which in turn could also be
applied in the domino process. In this case, the combination
of Pd(OAc)2 (10 mol-%), PPh3 (20 mol-%) was optimum,
affording the exocyclic double-bond Heck product in 73%
Results and Discussion
The 3-benzazepine ring system was first targeted to ex- yield and none of the product resulting from the sterically
amine the possibility of a domino intermolecular Tsuji– more encumbered 8-endo-trig cyclisation.[21] Similar results
Trost reaction followed by an intramolecular Heck reaction. have been observed in pioneering work completed by the
Trifluoroacetate was chosen as a protecting group because Tietze group.[10d]
of its ability as a directing group for aryl iodination reac-
Having completed the single-step approach in good
tions and its application in intramolecular Heck reac- yields, we investigated the domino reaction with several
tions.[18,19] Thus, treatment of the arylamine 8 with tri- combinations of catalysts, bases and additives. The most
fluoroacetic anhydride furnished the protected amine 9 in efficient conversion to the 3-benzazepine 12 involved the
excellent yield (99%, Scheme 2). Treatment of this com- use of Pd(PPh3)4, NaH, Cs2CO3 and Bu4NHSO3 starting
pound with IPy2BF4 following the ortho-directing iodin- the reaction at 60 °C and increasing the temperature to
ation procedure of Barluenga et al.[19] afforded the aryl io- 100 °C. Fittingly, under these conditions the desired dom-
dide 10 in good yields (88%). This substrate was sub- ino product 12 was isolated in good yields (62%). In all of
sequently set up for a domino Tsuji–Trost/Heck reaction; the attempted domino reactions the choice of conditions
however, the allylated intermediate 11 was prepared so later depended on the use of a strong base (i.e. NaH or KOH)
domino reactions could be more closely monitored and op- for the deprotonation of the amide and a mild base (K2CO3
Scheme 2. Construction of the 3-benzazepine ring system through single-step or domino Tsuji–Trost/Heck reaction.
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S. G. Stewart, C. H. Heath, E. L. Ghisalberti
FULL PAPER
or Cs2CO3) for an efficient turnover of the Heck catalytic intramolecular Heck reactions through the C-2 position of
cycle. Furthermore, the use of a toluene/DMF (9:1) mixture the indole ring system. Functionalisation at this position,
was essential for consistently high yields. As expected, ad- through intermolecular cross coupling, has recently been
ditional attempts to exclude either of these aforementioned observed by Hsung[26] and Chu,[27] and compound 20, bear-
bases resulted in either the Heck or Tsuji–Trost reaction ing a bromine atom at C-2, was considered an ideal precur-
not functioning. Treatment of compound 12 with NaBH4 sor for such cross couplings. This compound was prepared
in EtOH resulted in the formation of the unprotected 3- from tryptamine (18) through protection and bromina-
benzazepine 13 (73%).
tion,[27] in 70 and 83% yield, respectively (Scheme 4). Un-
To test the effectiveness of this series of reactions in the fortunately, iodination following the previously described
formation of other 3-benzazepines, an alternative pathway procedure with IPy2BF4 failed to produce any of the equiv-
containing a cyclohexene attachment was also tried. This alent 2-iodo derivative. The indole nitrogen atom within
procedure would provide the extremely rare 6-7-6 ABC- compound 20 was initially protected, to stop unwanted al-
ring-fused alkaloid.[22] In the single-step procedure amide lylation of this group. Thus, treatment of 20 with (Boc)2O
10 was treated with 3-bromocyclohexene[23] to afford the under standard conditions afforded the tert-butyl carba-
cyclohexene-tethered amide 14 in moderate yields mate 21 in 78% yield. Indole 21 was subjected to similar
(Scheme 3). Under conditions that facilitated the intramo- Tsuji–Trost and Heck reaction conditions as outlined in
lecular Heck reaction described earlier, the required tetra- Scheme 4. In the stepwise procedure with allyl bromide,
hydrodibenzazepine ring system was produced as found in Pd(PPh3)4 and base, the allylated 22 was produced in 69%
the regioisomers 15 (37%) and 16 (18%).[24] In all reactions yield. Treatment of this compound, under similar Heck re-
the major regioisomer 15 resulting from initial β-hydride action conditions described previously [Pd(PPh3)4, K2CO3
elimination could be isolated by using standard chromatog- in DMF], provided the desired product, compound 23 re-
raphy conditions, whereas 16 was isolated as a mixture of sulting from 7-exo-trig cyclisation. Such a ring system is
regioisomers. The mixture 16 was presumed to be a result rare in the literature, and compounds similar to tricycle 23,
of additional hydropalladation followed by β-hydride elimi- containing a double bond at C-5, are yet undescribed.
nation. Several alternative catalytic conditions with and Again, no endocyclic product was isolated as seen in other
without silver salts were tried, the best conditions being intramolecular Heck reactions in the literature. Once again
Pd(OAc)2, PPh3 and Ag2CO3 in acetonitrile. As reported subjecting the Boc-protected amine 21 to conditions, which
by others,[25] in our example the addition of silver salts sup- favour the domino Tsuji–Trost/Heck reaction sequence,
pressed some of the double-bond migration; however, in all Pd(PPh3)4, NaH, Cs2CO3 in DMF, returned the desired
instances the mixture 16 was obtained. Clean chromato- product 23 in 69% yield. A careful choice of bases allows
graphic separation in many of the methods tried proved dif- the domino reaction to proceed.
ficult. However, to fully gauge how successful the intramo-
We also investigated the reactivity and behaviour of com-
lecular Heck cyclisation was, a reaction mixture of 15 and pounds unprotected at the indole nitrogen atom with the
16 was hydrogenated (Pd/C under H2) to afford compound intention of also allylating in this position and later func-
17 with the overall yield from compound 14 being a respect- tionalising to produce more complex ring systems. Thus,
able 57%. Given the moderate yields of the initial allylation treatment of amide 20 with allyl bromide, under Tsuji–Trost
and the complex double-bond migration products of the conditions as described before, afforded the diallylated
intramolecular Heck reaction, the domino reaction was not product in 56% yield.
attempted in this series.
Interestingly, when compound 24 is subjected to palla-
To further explore the utility of this reaction and form dium-mediated catalysis, Pd(PPh3)4 and K2CO3, the azep-
precursors that could be used in the construction of a inobenzindolizine derivative 25 resulting from a second
seven-membered ring within compounds like arbiflorine (3) Heck-type cross coupling is produced in 24% yield
or subincanadine F (4), we investigated the possibility of (Scheme 5).
Scheme 3. Construction of the octahydrodibenzazepine ring system through single-step Tsuji–Trost and Heck reactions.
1936
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3-Benzazepines and Azepino[4,5-b]indole Ring Systems
Scheme 4. Construction of the azepino[4,5-b]indole ring system through single-step or domino Tsuji–Trost/Heck reactions.
Scheme 5. Synthesis of allylazepino[4,5-b]indoles and azepinobenzindolizine ring systems through a Heck and domino Heck/Heck reac-
tion.
Two other compounds, 26 (24%) and 27 (40%), resulting Heck-type pathway has been explored by several groups
from Heck reactions were also isolated providing excellent towards the synthesis of complex natural products.[13d,31]
overall mass conversion. Compound 27 resulted from a The formation of the tetracycle 25 is extremely interesting,
concomitant deallylation of the secondary amine.[28] To the and further examination of this series of reactions with in-
best of our knowledge, derivative 25, containing a 6-5-7-6- dole precursors and substituted allyl halides are currently
membered ring system, has not been reported in the litera- underway in our laboratories.
ture, although some natural products, e.g. dippinine A, par-
As in the previous series, we investigated the treatment of
tially contain this ring framework.[29] It is assumed this compound 20 under the domino Tsuji–Trost/Heck reaction.
product 25 arises from an intermediate such as alkylpalla- Treatment of the indole 20 with Pd(PPh3)4, allyl bromide,
dium bromide 28 prior to β-hydride elimination. The stabi- KOH and K2CO3 resulted in a mixture of allylated and
lisation of such intermediates through a nitrogen atom Heck-reaction product, compounds 24, 25, 26 and 29
within close proximity may enhance the chance of a second (Scheme 6) in a 1:1:3:1 ratio, respectively. Unfortunately, at
Heck reaction over dehydropalladation.[30] The domino- this stage conditions that favoured significant amounts of
Eur. J. Org. Chem. 2009, 1934–1943
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S. G. Stewart, C. H. Heath, E. L. Ghisalberti
FULL PAPER
Scheme 6. Domino Tsuji–Trost/Heck cross-coupling to produce tricycle 26 and accompanying domino Tsuji–Trost/Heck/Heck reaction
to produce tetracycle 25.
25 °C. For 1H and 13C NMR spectra, CDCl3 and [D6]-
only tricycle 26 and tetracycle 25 were not found. Investiga-
acetone were used as solvents. Chemical shifts are reported on a δ
tion into a series of alkylation and Heck reactions in more
scale. Signals are quoted as s (singlet), d (doublet), t (triplet), q
substituted substrates to extend this domino process will be
(quartet), m (multiplet) and br. (broad). 13C NMR assignments
undertaken.
were aided by the use of DEPT135 analysis. Mass spectra were
acquired with a VG AutoSpec instrument through electron-impact
ionisation (EI). HRMS was performed with a resolution of approx-
Conclusions
imately 10000. IR spectra were recorded with a Perkin-Elmer Spec-
trum One Spectrometer FT-IR spectrometer. Samples were ana-
lysed as thin films on NaCl discs, CHCl3 solution between NaCl
plates or pressed KBr plates.
The results of this paper highlight the use of Tsuji–Trost
and Heck reactions as key steps to create seven-membered-
ring nitrogen heterocycles. In particular, we have reported
2,2,2-Trifluoro-N-(2-phenylethyl)acetamide (9): The preparation of
trifluoroacetamide 9 was carried out according to that described by
Barluenga et al.[19] All spectroscopic data matched those acquired
previously.
the application of this method to the synthesis of novel 3-
benzazepines and azepino[4,5-b]indole ring systems. In this
study we have also developed a new method for a single-
pot domino Tsuji–Trost/Heck reaction involving an initial
intermolecular amide allylation. We have also highlighted
the need for a particular specific set of palladium cross-
coupling conditions for these reactions with particular em-
phasis on the choice of base. In further exploration of N-
diallylated compounds, formed in the initial study, we have
discovered a domino Tsuji–Trost/Heck/Heck reaction pro-
cess, which leads to the preparation of the azepinobenz-
indolizines.
2,2,2-Trifluoro-N-[2-(2-iodophenyl)ethyl]acetamide (10): The prepa-
ration of trifluoroacetamide 10 was carried out according to that
described by Barluenga et al.[19] All spectroscopic data matched
those acquired previously.
N-Allyl-2,2,2-trifluoro-N-[2-(2-iodophenyl)ethyl]acetamide
(11):
Amide 10 (200 mg, 0.58 mmol) was added to a magnetically stirred
suspension of powdered KOH (100 mg, 1.8 mmol) and Bu4NHSO4
(20 mg, 0.06 mmol) in toluene (6 mL), and the solution was stirred
at room temperature for 10 min. The resulting mixture was treated
with allyl bromide (50 µL, 70 mg, 0.58 mmol) followed immediately
by Pd(PPh3)4 (54 mg, 8 mol-%) and the yellow suspension heated
at 60 °C for 5 min. The mixture was cooled to 0 °C and treated
dropwise with water (ca. 5 mL) with stirring. The phases were sepa-
rated, the aqueous layer was extracted with CH2Cl2 (3ϫ 5 mL),
and the organic fractions were combined, dried (MgSO4), filtered
and concentrated under reduced pressure. The resulting crude oil
was subjected to flash chromatography (hexane Ǟ toluene/hexane,
3:7) to afford compound 11 (150 mg, 68% yield) as a colourless oil
Experimental Section
General: All reactions were performed in flame-dried glassware un-
der argon unless stated otherwise. Solvents were dried and purified
according to the method defined by Armarego and Chai.[32] All
reactions involving heating were carried out by immediately placing
reaction vessel in an oil bath preheated to the specified temperature.
All palladium-mediated cross-coupling reactions were carried out
by using degassed solvents or by degassing according to the freeze-
pump-thaw method. Thin-layer chromatography (TLC) was per-
formed on Merck silica gel 60 F254 pre-coated aluminium sheets.
Visualisation of developed plates was achieved through the use of
a 254-nm or 365-nm UV lamp or staining with phosphomolybdic
acid. Column chromatography was performed by using silica gel
60 (0.063–0.200 mm), as supplied by Merck, with the eluents indi-
cated. HPLC was performed with a Grace-Apollo 250ϫ 10 mm,
5 micron, C18 semi-preparative column coupled to a UV detector.
1H and 13C NMR spectra were acquired with either a Bruker Av-
1
(Rf = 0.6, in EtOAc/hexane, 1:4). H NMR (500 MHz, CDCl3): δ
= 7.84–7.81 (m, 1 H, HAr), 7.33–7.28 (m, 1 H, HAr), 7.26–7.20
(m, 1 H, HAr), 6.97–6.92 (m, 1 H, HAr), 5.87–5.79 (m, 0.36 H,
CH=CH2), 5.74–5.67 (m, 0.64 H, CH=CH2), 5.32–5.22 (m, 2 H,
CH=CH2), 4.11 (d, J = 6.0 Hz, 0.36 H, CH2), 3.85 (d, J = 6.0 Hz,
0.64 H, CH2), 3.57–3.54 (m, 2 H, CH2), 3.07–3.03 (m, 2 H, CH2)
ppm. 13C NMR (125.8 MHz, CDCl3): δ = 157.1, 156.9 (q, J =
35.9 Hz, COCF3), 140.9, 140.3 (C), 139.9, 139.8 (CH), 131.8, 131.2
(CH), 130.6, 130.2 (CH), 129.1, 128.9, 128.8 (CH), 119.6, 119.1
(CH2), 116.5, 116.7 (q, J = 288.0 Hz, CF3), 50.8 (q, J = 3.3 Hz),
49.6, 47.2 (q, J = 3.0 Hz), 46.8 (2ϫ CH2), 40.2, 37.7 (CH2) ppm.
HR-EIMS: calcd. for C13H13IF3NO 382.9994; found 382.9996. IR
1
ance (AV) 500 spectrometer (500.13 MHz, 125.8 MHz, for H and
13C, respectively) at 25 °C or a Bruker Avance (AV) 600 spectrome-
ter (600.1 MHz and 150.9 MHz for 1H and 13C, respectively) at
(neat): ν = 2941, 1693, 1467, 1204, 1145, 1008, 932, 754 cm–1.
˜
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3-Benzazepines and Azepino[4,5-b]indole Ring Systems
1-Methylene-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benz-
azepine (12). Method A (Single-Step Procedure from Compound 11):
A mixture of iodide 11 (154 mg, 0.40 mmol), Pd(OAc)2 (9 mg,
10 mol-%), triphenylphosphane (21 mg, 20 mol-%), Pr4NBr
142.6 (C), 138.6 (C), 129.1 (CH-Ar), 128.4 (CH-Ar), 127.7 (CH-
Ar), 126.6 (CH-Ar), 114.6 (C=CH2), 53.4 (CH2), 47.5 (CH2), 39.3
(CH2) ppm. HR-EIMS: calcd. for C11H13N 159.1048; found
159.1053. IR (neat): ν = 3271, 2927, 2855, 1626, 1484, 1431, 1316,
˜
(117 mg, 0.44 mmol), KOAc (126 mg, 1.28 mmol) in DMF (8 mL) 1135, 909, 752 cm–1.
was degassed. The resulting mixture was stirred and heated to
N-(Cyclohex-2-en-1-yl)-2,2,2-trifluoro-N-[2-(2-iodophenyl)ethyl]-
80 °C for 1.75 h. The resulting solution was cooled and then poured
directly into a separatory funnel containing water and diethyl ether
(1:1, 40 mL). The ensuing solution was extracted with diethyl ether
(3ϫ 10 mL), the combined organic extracts dried (MgSO4) and
concentrated under reduced pressure to afford a pale oil. The crude
oil was subjected to flash chromatography (hexane Ǟ toluene/hex-
ane, 1:1) to afford compound 12 (75 mg, 73%) as colourless oil (Rf
= 0.45, in EtOAc/hexane, 1:4). 1H NMR (500 MHz, CDCl3): δ =
7.36–7.32 (m, 1 H, HAr), 7.29–7.23 (m, 2 H, HAr), 7.16–7.12 (m,
1 H, HAr), 5.44 (s, 0.55 H, C=CH2), 5.42 (s, 0.55 H, C=CH2), 5.39
(s, 0.45 H, C=CH2), 5.31 (s, 0.45 H, C=CH2), 4.46 (s, 0.9 H, CH2),
4.42 (s, 1.1 H, CH2), 3.88 (t, J = 6.1 Hz, 0.9 H, CH2), 3.83 (t, J =
5.7 Hz, 1.1 H, CH2), 3.05 (m, 2 H, CH2) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 156.9, 156.5 (q, J = 35.8 Hz, COCF3),
145.8, 145.2 (C), 140.0, 139.1 (C), 136.0, 135.4 (C), 129.5, 129.4
(CH-Ar), 128.8, 128.7, 128.7, 128.3 (CH-Ar), 127.6, 127.5 (CH-
Ar), 118.1, 116.1 (C=CH2), 116.6, 116.5 (q, J = 288.0 Hz, CF3),
51.1 (q, J = 3.4 Hz), 51.0, 46.9 (q, J = 3.3 Hz), 45.8 (2ϫ CH2),
35.5, 33.3 (CH2) ppm. HR-EIMS: calcd. for C13H12F3NO
acetamide (14): Amide 10 (1.00 g, 2.91 mmol) was added to a mag-
netically stirred suspension of Bu4NHSO4 (200 mg, 0.60 mmol) in
toluene (20 mL). NaH (154 mg, 60% in paraffin oil, 3.85 mmol)
was added and the solution stirred at ambient temperature for
10 min. Pd(PPh3)4 (200 mg, 6 mol-%) was added followed by 3-bro-
mocyclohexene (1.0 mL, 8.7 mmol) and the mixture heated to
65 °C for 4.5 h. The ensuing solution was cooled to 0 °C and
treated dropwise with water (20 mL) and the mixture stirred
rapidly. The phases were separated, the aqueous phase was ex-
tracted with CH2Cl2 (4ϫ 15 mL) and the organic fractions were
combined, dried (MgSO4), filtered and concentrated under reduced
pressure. The crude oil was subjected to flash chromatography
(hexane Ǟ toluene/hexane, 1:1) to afford compound 14 (540 mg,
43% yield) as a colourless oil (Rf = 0.63, in EtOAc/hexane, 3:7).
1H NMR (500 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 1 H, HAr),
7.31–7.2 (m, 2 H, HAr), 6.93–6.90 (m, 1 H, HAr), 6.05–5.96 (m, 1
H, CH=CH), 5.58 (d, J = 10.2 Hz, 0.1 H, CH=CH), 5.31 (d, J =
10.2 Hz, 0.9 H, CH=CH), 4.96 (br. s, 0.1 H, CH=CH), 4.55 (br. s,
0.9 H, CH=CH), 3.54 (t, J = 8.6 Hz, 0.2 H, CH2), 3.46–3.38 (m,
1.8 H, CH2), 3.16–2.99 (m, 2 H, CH2), 2.08–1.55 (m, 6 H, 3ϫ CH2)
ppm. 13C NMR (125.8 MHz, CDCl3): δ = 157.4 (q, J = 35.3 Hz,
COCF3), 142.0, 141.2 (C), 139.9, 139.6 (CH), 133.6, 132.2 (CH),
130.6, 130.0 (CH), 129.0, 128.9, 128.8, 128.6 (2ϫ CH), 126.9, 126.5
(CH), 116.7 (q, J = 287.5 Hz, CF3), 100.5, 100.1 (ArCI), 55.2 (q,
255.0871; found 255.0872. IR (neat): ν = 2931, 1693, 1460, 1202,
˜
1144, 754 cm–1.
2,2,2-Trifluoro-1-(1-methylidene-1,2,4,5-tetrahydro-3H-3-benz-
azepin-3-yl)ethanone (12). Method B (Domino Procedure from Com-
pound 10): Amide 10 (200 mg, 0.58 mmol) was added to a magneti-
cally stirred mixture of Cs2CO3 (575 mg, 1.76 mmol) and J = 3.6 Hz, CH), 45.5 (q, J = 3.1 Hz) 44.5, (CH2), 41.9, 38.5 (CH2),
Bu4NHSO4 (60 mg, 0.18 mmol) in toluene/DMF (9:1) (4 mL).
NaH (36 mg, 60% in oil, 0.9 mmol) was then added and the reac-
28.6, 26.7 (CH2), 24.7, 24.4 (CH2), 21.8, 21.6 (CH2) ppm. HR-
EIMS: calcd. for C16H17F3INO 423.0307; found 423.0301. IR
tion mixture stirred for 10 min. Pd(PPh3)4 (65 mg, 0.06 mmol, (neat): ν = 2936, 1685, 1434, 1211, 1181, 1143, 748, 696 cm–1.
˜
10 mol-%) was added followed by allyl bromide (0.1 mL, 140 mg,
5-(Trifluoroacetyl)-4,4a,5,6,7,11b-hexahydro-3H-dibenzo[b,d]-
1.15 mmol), and the mixture was heated to 60 °C for 30 min, after
azepine (15): Aryl iodide 14 (119 mg, 0.28 mmol) was transferred
which time additional NaH (11 mg, 60 % in oil, 0.3 mmol) was
to a flask equipped with a reflux condenser. Ag2CO3 (155 mg,
added, and the reaction mixture was heated to 100 °C for 22 h. The
0.56 mmol), PPh3 (15 mg, 0.057 mmol, 30 mol-%) and Pd(OAc)2
(6.0 mg, 0.026 mmol, 30 mol-%) were transferred to this flask, and
reaction mixture was cooled to 0 °C, and water (4 mL) was added
with stirring. The phases were separated, and the aqueous phase
the flask was backfilled with argon. Acetonitrile (5 mL) was added,
was extracted with dichloromethane (4ϫ 5 mL). The combined or-
and the resulting mixture was heated at reflux for 2.5 h. The mix-
ganic phases were dried (MgSO4), filtered and concentrated. The
ture was cooled to room temperature and then concentrated under
crude oil was subjected to flash chromatography (toluene/hexane,
reduced pressure. The crude material was subjected to flash
2:3 Ǟ toluene/hexane, 45:55) to afford compound 12 (93 mg, 62%)
chromatography (toluene/hexane, 2:3 Ǟ toluene/hexane, 1:1) to af-
as a yellow oil.
ford compound 15 (31 mg, 37% yield) as a colourless oil (Rf =
1-Methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (13): NaBH4
(57 mg, 1.50 mmol) was added to a solution containing amide 12
(95 mg, 0.37 mmol) in EtOH (7 mL) maintained at room tempera-
ture. The mixture was heated to 80 °C with stirring for 45 min be-
fore being cooled to room temperature and concentrated in vacuo.
The crude residue was dissolved in diethyl ether (10 mL), and 2 
HCl was added slowly with stirring. The layers were separated, and
the organic phase was extracted with HCl (4ϫ 5 mL of 2  solu-
tion). The combined aqueous phases were basified with NaOH
(2.5 ) and extracted with dichloromethane (5ϫ 10 mL). The com-
bined organic extracts were concentrated, the resulting oil was re-
dissolved in toluene (10 mL) and concentrated to remove any resid-
ual water. Amine 13 was obtained as a faint yellow oil (43 mg,
73 %). 1H NMR (600.1 MHz, CDCl3): δ = 7.27–7.24 (m, 1 H,
HAr), 7.22–7.18 (m, 2 H, HAr), 7.12–7.08 (m, 1 H, HAr), 5.2 (m,
0.63, in acetone/toluene, 5:95). This material is sufficiently pure for
most purposes; however, an analytical sample may be obtained by
semi-preparative HPLC (MeOH/H2O, 4:1, 4 mL/min). 1H NMR
(500 MHz, CDCl3): δ = 7.33–7.27 (m, 1 H, HAr), 7.23–7.16 (m, 2
H, HAr), 7.14–7.08 (m, 1 H, HAr), 6.00–5.88 (m, 2 H, CH=CH),
5.10–5.05 (m, 0.6 H, CH), 4.65–4.55 (m, 0.4 H, CH), 4.47–4.41 (m,
0.4 H, CH2), 4.03–3.06 (m, 0.6 H, CH2), 3.77 (br. s, 0.6 H, CH)
3.74 (br. s, 0.4 H, CH), 3.5–3.41 (m, 0.6 H, CH2), 3.10–2.92 (m,
2.4 H, CH2), 2.45–2.20 (m, 2 H, CH2), 1.93–1.82 (m, 1 H, CH2),
1.66–1.58 (m, 1 H, CH2) ppm. 13C NMR (125.8 MHz, CDCl3): δ
= 156.8, 156.7, (q, J = 34.8 Hz, COCF3), 140.3, 139.2, 139.1, 138.7
(2ϫ C), 131.8, 131.7 (CH) 130.2, 130.0 (CH), 129.72, 129.70, (CH),
128.0 (CH), 127.3, 127.2 (CH), 127.0, 126.8 (CH), 116.9, 117.1 (q,
J = 288.5 Hz, CF3), 55.5 (q, J = 3.6 Hz), 52.9 (CH), 44.9, 44.1
(CH), 43.0 (q, J = 3.3 Hz), 41.2 (CH2), 36.4, 35.7 (CH2), 25.8, 24.9
1 H, C=CH2), 5.13 (d, J = 1.6 Hz, 1 H, C=CH2), 3.57 (s, 2 H, (CH2), 24.3, 23.5 (CH2) ppm. HR-EIMS: calcd. for C16H16 F3NO
CH2C=CH2), 3.05 (m, 2 H, CH2), 2.90 (m, 2 H, CH2), 1.9 (br. s, 295.1184; found 295.1179. IR (CHCl ): ν = 3024, 2952, 1682, 1450,
˜
3
1 H, NH) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 153.2 (C),
1204, 1148 cm–1. The second fraction collected from the chomatog-
Eur. J. Org. Chem. 2009, 1934–1943
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1939

S. G. Stewart, C. H. Heath, E. L. Ghisalberti
FULL PAPER
raphy column contained an inseparable mixture of regioisomers 16
(15 mg) as indicated by H NMR spectroscopy.
THF (14 mL). The resulting solution was heated to 38 °C for
40 min. The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was re-dissolved
in CH2Cl2 (15 mL), and water (10 mL) was added. The phases were
separated, and the aqueous phase was extracted with CH2Cl2 (3ϫ
5 mL). The combined organic phases were dried (MgSO4), filtered
and concentrated under reduced pressure. The crude material was
subjected to flash chromatography (hexane Ǟ EtOAc/hexane, 1:9)
to afford compound 21 (553 mg, 85%) as a colourless solid (Rf =
0.55, in acetone/toluene, 1:19). M.p. 115–116 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.1 (d, J = 8.1 Hz, 1 H, ArH), 7.48 (d, J
= 7.7 Hz, 1 H, ArH), 7.32 (t, J = 7.7 Hz, 1 H, ArH), 7.25 (t, J =
7.2 Hz, 1 H, ArH), 6.50 (s, 1 H, NH), 3.64 (q, J = 6.3 Hz, 2 H, 1Ј-
H), 3.05 (t, J = 6.7 Hz, 2 H, 2Ј-H), 1.71 (s, 9 H, tBu) ppm. 13C
NMR (125.8 MHz, CDCl3): δ = 157.5 (q, J = 37.1 Hz, COCF3),
149.1 (C=O), 136.7 (C-Ar), 128.6 (C-Ar), 125.0 (CH-Ar), 123.4
(CH-Ar), 119.2 (C-Ar), 117.8 (CH-Ar), 115.8 (q, J = 287.9 Hz,
CF3), 115.6 (CH-Ar), 110.0 (C-Ar), 85.4 (C), 39.3 (CH2), 28.3
(CH3), 24.8 (CH2) ppm. HR-EIMS: calcd. for C17H18BrF3N2O3
434.0453 and 436.0432; found 434.0463 and 436.0438. IR (KBr):
1
5-(Trifluoroacetyl)-2,3,4,4a,5,6,7,11b-octahydro-1H-dibenzo[b,d]-
azepine (17): Iodide 14 (396 mg, 0.93 mmol) was transferred to a
flask equipped with a reflux condenser and stirrer bar. Pd(OAc)2
(21.0 mg, 0.09 mmol, 10 mol-%) was added followed by PPh3
(24.0 mg, 0.09 mmol, 10 mol-%) and Bu4NOAc (845 mg,
2.80 mmol). The apparatus was evacuated and thrice backfilled
with argon. DMF (15 mL) was added via syringe, and the mixture
was heated to 86 °C for 45 min. The black reaction mixture was
cooled to room temperature and concentrated in vacuo. The crude
material was subjected to flash chromatography (toluene/hexane,
2:3 Ǟ toluene/hexane, 7:3), fractions from Rf ≈ 0.6 to 0.5 (acetone/
toluene, 5:95) were combined to afford crude regioisomers 15 and
16 (237 mg). This material was dissolved in EtOH (20 mL), Pd/C
(35 mg) was added and the mixture stirred under H2 from a balloon
at room temperature for 18 h. The mixture was concentrated under
reduced pressure. Flash chromatography (toluene/hexane, 3:7 Ǟ
toluene/hexane, 1:1) afforded 17 (158 mg, 57%) as a colorless oil
(Rf = 0.73, in acetone/toluene, 5:95). 1H NMR (600.1 MHz,
CDCl3): δ = 7.45 (d, J = 7.9 Hz, 1 H, ArH), 7.25 (m, 1 H, ArH),
7.2–7.1 (m, 2 H, ArH), 4.92–4.97 (m, 0.6 H, CH), 4.60–4.55 (m,
0.4 H, CH2), 4.25–4.20 (m, 0.4 H, CH), 4.05–3.95 (m, 0.6 H, CH2),
3.35–3.30 (m, 1.6 H, CH, CH2), 3.05–2.85 (m, 2.4 H, CH2), 2.6–
2.45 (m, 1 H, CH2), 2.05–1.6 (m, 6 H, 3ϫ CH2), 1.5–1.35 (m, 1 H,
CH2) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 156.2, 156.1 (q, J
= 34.8 Hz, COCF3), 141.2, 140.2, 138.7, 138 (2ϫ C), 130.5, 130.3,
130.2, 130.0 (2ϫ CH-Ar), 127.0, 126.8, 126.78, 126.7 (2ϫ CH-Ar),
117.3, 117.1 (q, J = 288.4 Hz, CF3), 59.7 (q, J = 3.4 Hz), 56.5 (CH),
44.2, 43.0 (CH), 42.7 (q, J = 3.3 Hz), 40.5 (CH2), 38.7, 37.8 (CH2),
30.38, 30.37 (CH2), 27.5, 26.8, 26.7, 26.2 (2 ϫ CH2), 21.2, 20.7
(CH2) ppm. HR-EIMS: calcd. for C16H18F3NO 297.1340; found
ν = 3296, 2988, 1730, 1701, 1561, 1453, 1354, 1165, 1153, 1100,
˜
749 cm–1.
tert-Butyl 3-{2-[Allyl(trifluoroacetyl)amino]ethyl}-2-bromo-1H-in-
dole-1-carboxylate (22): Amide 21 (195 mg, 0.45 mmol) was added
to a magnetically stirred suspension of powdered KOH (101 mg,
1.8 mmol) and Bu4NHSO4 (30 mg, 0.09 mmol) in toluene (4 mL),
and the solution was stirred at room temperature for 10 min. The
resulting mixture was treated with allyl bromide (97 µL, 135 mg,
1.12 mmol) followed immediately by Pd(PPh3)4 (58 mg, 11 mol-%)
and the resulting yellow suspension heated at 60 °C for 1 h. The
mixture was cooled to 0 °C and treated dropwise with water
(ca.4 mL) with stirring. The phases were separated, and the aque-
ous phase was extracted with dichloromethane (4ϫ 2 mL). The
combined organic phases were dried (MgSO4), filtered and concen-
trated under reduced pressure. The crude material was subjected to
flash chromatography (toluene/hexane, 1:1 Ǟ toluene/hexane, 4:1)
to afford compound 22 (148 mg, 69%) as a colourless oil (Rf = 0.6,
in acetone/toluene, 1:19). 1H NMR (500 MHz, [D6]acetone): δ =
8.11 (t, J = 7.9 Hz, HAr), 7.67, (d, J = 7.7 Hz, 0.66 H, HAr), 7.59
(d, J = 7.7 Hz, 0.33 H, HAr), 7.35–7.27 (m, 2 H, ArH), 5.92–5.78
(m, 1 H, CH=CH2), 5.33–5.24 (m, 2 H, CH=CH2), 4.21 (d, J =
5.9 Hz, 0.33 H, CH2), 4.05 (d, J = 5.9 Hz, 0.66 H, CH2), 3.68–3.58
(m, 2 H, CH2), 3.17–3.05 (m, 2 H, CH2), 1.71 (m, 9 H, tBu) ppm.
13C NMR (125.8 MHz, [D6]acetone): δ = 156.8, 157.1 (q, J =
35.5 Hz, COCF3), 149.6, 149.5 (C=O), 137.5 (C), 133.4, 132.7
(CH), 129.5, 129.2 (C), 125.6, 125.5 (CH), 124.0, 123.9 (CH), 120.6,
119.7 (C), 119.3, 118.9 (C=CH2), 119.1, 118.7 (CH), 117.7, 117.5
(q, J = 287.8 Hz, CF3), 116.2, 116.0 (CH-Ar), 110.6, 110.3 (C-Ar),
85.9, 85.8 (C), 51.4 (q, J = 3.3 Hz), 50.0, 46.6, 46.4 (q, J = 3.0 Hz,
2ϫ CH2), 28.2 (CH3), 25.3, 23.3 (CH2) ppm. HR-EIMS: calcd.
for C20H22BrF3N2O3 474.0766 and 476.0745; found 474.0757 and
297.1338. IR (CHCl ): ν = 3020, 2945, 1679, 1449, 1215, 1145 cm–1.
˜
3
N-[2-(2-Bromo-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide (20):
Pyridinium tribromide (5.35 g, 0.016 mol) was added portionwise
to a magnetically stirred solution of amide 19 (3.96 g, 0.015 mol)
in THF/CHCl3 (1:1, 180 mL) at 0 °C over 1.25 h. The resulting
mixture was then stirred at this temperature for an additional
15 min and then treated with aqueous Na2S2O3 (100 mL, 0.5 )
under continuous stirring. The resulting mixture was treated with
NaHCO3 (50 mL, saturated), water (50 mL) and CH2Cl2 (50 mL)
and stirred. The phases were separated, and the aqueous phase was
extracted with CH2Cl2 (3ϫ 50 mL). The combined organic phases
were dried (MgSO4), filtered and concentrated under reduced pres-
sure. The material was subjected to flash chromatography (toluene
Ǟ acetone/toluene, 1:49) to afford compound 20 (4.43 g, 83%) as
an off-white solid (Rf = 0.35, in acetone/toluene, 5:95). M.p. 101–
103 °C. 1H NMR (500 MHz, [D6]acetone): δ = 10.6 (br. s, 1 H,
NH), 8.6 (br. s, 1 H, NH), 7.56 (d, J = 8.0 Hz, 1 H, ArH), 7.35 (d,
J = 8.0 Hz, 1 H, ArH), 7.12 (t, J = 7.7 Hz, 1 H, ArH), 7.05 (t, J
= 7.5 Hz, 1 H, ArH), 3.61 (q, J = 6.6 Hz, 2 H, CH2), 3.03 (t, J =
7.2 Hz, 2 H, CH2) ppm. 13C NMR (125.8 MHz, [D6]acetone): δ =
157.7 (q, J = 36.2 Hz, COCF3), 137.5 (C), 128.5 (C), 122.8 (CH),
120.5 (CH), 118.6 (CH), 117.1 (q, J = 287.7 Hz, CF3), 112.1 (C),
111.6 (CH), 109.6 (C), 40.4 (CH2), 24.9 (CH2) ppm. HR-EIMS:
calcd. for C12H10BrF3N2O 335.9908 and 333.9929; found 335.9898
476.0747. IR (neat): ν = 2982, 1736, 1692, 1448, 1351, 1253, 1152,
˜
757 cm–1.
tert-Butyl-5-methylene-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-
azepino[4,5-b]indole-6(1H)-carboxylate (23). Method A (Single-Step
Procedure from Compound 22): Bromide 22 (150 mg, 0.31 mmol)
was transferred to a flask equipped with a reflux condenser and
stirrer bar. DMF (9 mL) was added followed by K2CO3 (88 mg,
0.63 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol, 12 mol-%). The
flask was evacuated briefly with stirring and backfilled thrice with
and 333.9925. IR (CHCl ): ν = 3387, 3308, 1707, 1553, 1450, 1337,
˜
3
1211, 1177, 746 cm–1.
2-Bromo-tert-butyl-3-{2-[(trifluoroacetyl)amino]ethyl}-1H-indole-1-
carboxylate (21): Di-tert-butyl dicarbonate (357 mg, 1.63 mmol) argon and heated to 100 °C for 1.75 h. The reaction mixture was
was added in one portion to a magnetically stirred solution of in- cooled to room temperature and concentrated under reduced pres-
dole 19 (500 mg, 1.49 mmol) and DMAP (20 mg, 0.16 mmol) in sure. The crude material was subjected to flash chromatography
1940
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1934–1943

3-Benzazepines and Azepino[4,5-b]indole Ring Systems
(toluene/hexane, 7:3 Ǟ toluene/hexane, 9:1) to afford compound
23 (107 mg, 85%) as a light pink oil (Rf = 0.5, in acetone/toluene,
1:19). 1H NMR (500 MHz, [D6]acetone): δ = 8.05 (dd, J = 8.3 and
4.8 Hz, 1 H, HAr), 7.50 (t, J = 7.2 Hz, 1 H, HAr), 7.34 (t, J =
8.2 Hz, 1 H, HAr), 7.26–7.23 (m, 1 H, HAr), 5.72 (d, J = 0.9 Hz,
0.5 H, C=CH2), 5.68 (s, 0.5 H, C=CH2), 5.32 (s, 0.5 H, C=CH2),
5.28 (s, 0.5 H, C=CH2), 4.65 (s, 1 H, CH2), 4.53 (s, 1 H, CH2), 4.05
(t, J = 5.6 Hz, 1 H, CH2), 3.99 (t, J = 5.8 Hz, 1 H, CH2), 3.09 (m,
2 H, CH2), 1.58 (m, 9 H, tBu) ppm. 13C NMR (125.8 MHz, [D6]-
acetone): δ = 156.8, 156.7 (q, J = 35.6 Hz, COCF3), 150.8, 150.7
(C=O), 138.2, 138.1 (C), 136.6, 136.2 (C), 135.0, 133.2 (C), 130.0,
129.9 (C), 125.9, 125.8 (CH-Ar), 123.7, 123.6 (CH-Ar), 122.3,
120.78 (C=CH2), 119.7, 119.6 (CH-Ar), 119.65, 118.9 (C), 117.5,
117.7 (q, J = 288.0 Hz, CF3), 115.14, 115.1 (CH-Ar), 84.5, 84.4
(C), 55.4 (q, J = 3.7 Hz), 55.3, 45.5 (q, J = 3.0 Hz), 44.7 (2ϫ CH2),
28.3, 28.0 (CH3), 27.0, 24.1 (CH2) ppm. HR-EIMS: calcd. for
111.1, 110.9 (CH), 51.4 (q, J = 3.3 Hz), 50.0, 47.6, 47.5, 47.3, 47.2
(q, J = 3.1 Hz, 3ϫ CH2), 25.4, 23.4 (CH2) ppm. HR-EIMS: calcd.
for C18H18BrF3N2O 414.0588 and 416.0534; found 414.0575 and
416.0529. IR (neat): ν = 2929, 1692, 1457, 1333, 1203, 1146, 929,
˜
742 cm–1.
6-Allyl-5-methylene-3-(trifluoroacetyl)-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole (26), 6-Methylene-3-(trifluoroacetyl)-
2,3,4,4a,5,6-hexahydroazepino[3,4,5-hi]benz[b]indolizine (25), 5-
Methylene-3-trifluoroacetyl-1,2,3,4,5,6-hexahydroazepino[4,5-
b]indole (27): Bromide 24 (345 mg, 0.83 mmol) was transferred to
a flask equipped with a reflux condenser and stirrer bar. K2CO3
(115 mg, 0.83 mmol) and Pd(PPh3)4 (95 mg, 0.08 mmol, 10 mol-%)
were added, and the flask was backfilled thrice with argon. DMF
(15 mL) was added and the mixture heated to 100 °C for 3 h. The
reaction mixture was cooled to room temperature and concentrated
under reduced pressure. The crude material was subjected to flash
chromatography (toluene/hexane, 1:1 Ǟ toluene). First to elute was
C20H21F3N2O3 394.1504; found 394.1490. IR (CHCl ): ν = 3021,
˜
3
1731, 1689, 1456, 1370, 1323, 1215, 1153 cm–1.
1
an otherwise pure 1:1 (by H NMR) mixture of compounds 26/25
(135 mg, 49% combined, Rf = 0.6, in acetone/toluene, 1:19). Next
to elute (Rf = 0.4, in acetone/toluene, 1:19) was the tricycle 27
(98 mg, 40% yield) as an off-white solid. M.p. 131–134 °C. The 1:1
mixture of tricycle 25 and tetracycle 26 was separated by using
semi-preparative HLPC (MeOH/H2O, 4:1, 4 mL/min) to give pure
samples of both compounds.
tert-Butyl-5-methylene-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-
azepino[4,5-b]indole-6(1H)-carboxylate (23). Method B (Domino
Procedure from Compound 21): Amide 21 (200 mg, 0.46) was added
to a magnetically stirred mixture of Cs2CO3 (475 mg, 1.45 mmol)
and Bu4NHSO4 (50 mg, 0.15 mmol) in toluene/DMF (9:1; 4 mL).
NaH (60% in oil; 30.0 mg, 0.75 mmol) was then added and the
reaction mixture allowed stirred for 10 min. Pd(PPh3)4 (55 mg,
0.05 mmol, 10 mol-%) was added followed by allyl bromide (84 µL,
117 mg, 0.97 mmol), and the resulting mixture was heated to 60 °C
for 30 min, after which time additional NaH (60% in oil; 12 mg,
0.3 mmol) was added, and the reaction mixture was heated to
100 °C for 19 h. The reaction mixture was cooled to 0 °C, and water
(4 mL) was added with stirring. The phases were separated, and
the aqueous phase was extracted with dichloromethane (4ϫ 5 mL).
The combined organic phases were dried (MgSO4), filtered and
concentrated. The crude oil was subjected to flash chromatography
(toluene/hexane, 1:1 Ǟ toluene/hexane, 65:35) to afford compound
22 (132 mg, 69%) as yellow oil.
6-Allyl-5-methylene-3-(trifluoroacetyl)-1,2,3,4,5,6-hexahydro-
1
azepino[4,5-b]indole (26): Colorless oil (31 mg). Rt = 18.3 min. H
NMR (500 MHz, [D6]acetone): δ = 7.54 (d, J = 7.9 Hz, 1 H, HAr),
7.34 (d, J = 8.3 Hz, 1 H, HAr), 7.20 (t, J = 7.6 Hz, 1 H, HAr),
7.09 (t, J = 7.0 Hz, 1 H, HAr), 6.07–5.96 (m, 1 H, CH=CH2), 5.74
(s, 0.6 H, C=CH2), 5.68 (s, 0.4 H, C=CH2), 5.45 (s, 0.6 H, C=CH2),
5.41 (s, 0.4 H, C=CH2), 5.15–5.10 (m, 1 H, CH=CH2), 4.87–4.78
(m, 3 H, CH2 and CH=CH2), 4.60 (s, 0.8 H, CH2), 4.45 (s, 1.2 H,
CH2), 4.02–3.96 (m, 2 H, CH2), 3.17 (t, J = 5.8 Hz, CH2) ppm. 13
C
NMR (125.8 MHz, [D6]acetone): δ = 156.7, 156.6 (q, J = 35.2 Hz,
COCF3), 139.1, 138.8 (C), 136.5, 136.3 (C), 135.8, 135.1 (C),
135.65, 135.6 (CH), 128.4, 128.3 (C), 123.5, 123.4 (CH), 121.0,
119.6 (C=CH2), 120.5 (CH), 119.5, 119.3 (CH), 117.7, 117.5 (q, J
= 287.7 Hz, CF3), 116.2, 116.1 (=CH2), 113.3, 112.4 (C-Ar),
111.35, 111.3 (CH), 55.3, 55.0 (q, J = 3.5 Hz), 47.6 (q, J = 3.5 Hz),
46.9, 46.8, 46.3 (3ϫ CH2) 26.6, 23.9 (CH2) ppm. HR-EIMS: calcd.
N-Allyl-N-[2-(1-allyl-2-bromo-1H-indol-3-yl)ethyl]-2,2,2-trifluoro-
acetamide (24): Amide 20 (500 mg, 1.49 mmol) was added to a
magnetically stirred suspension of powdered KOH (675 mg,
12 mmol) and Bu4NHSO4 (75 mg, 0.22 mmol) in toluene (10 mL),
and the solution was stirred at room temperature for 10 min. The
resulting mixture was treated with allyl bromide (650 µL, 908 mg,
7.51 mmol) followed immediately by Pd(PPh3)4 (175 mg, 10 mol-
%) and the resulting yellow suspension heated at 60 °C for 2.5 h.
The mixture was cooled to 0 °C and treated dropwise with water
(ca.10 mL) with stirring. The phases were separated, the aqueous
phase was extracted with dichloromethane (3ϫ 10 mL), and the
combined organic phases were dried (MgSO4), filtered and concen-
trated under reduced pressure. The crude material was subjected to
flash chromatography (toluene/hexane, 1:1 Ǟ toluene/hexane, 4:1)
to afford compound 24 (348 mg, 56%) as a colourless oil (Rf = 0.7,
in acetone/toluene, 1:19). 1H NMR (500 MHz, [D6]acetone): δ =
7.65 (d, J = 7.7 Hz, 0.6 H, HAr), 7.58 (d, J = 7.7 Hz, 0.4 H, HAr),
7.18 (m, 1 H, HAr), 7.11 (m, 1 H, HAr), 7.40 (m, 1 H, HAr), 6.00–
5.90 (m, 1 H, CH=CH2), 5.90–5.73 (m, 1 H, CH=CH2), 5.30–5.17
(m, 2 H, CH=CH2), 5.13–5.07 (m, 1 H, CH=CH2), 4.92–4.80 (m,
3 H, CH2 and CH=CH2), 4.87 (d, J = 6.0 Hz, 0.8 H, CH2), 3.95
(d, J = 6.0 Hz, 1.2 H, CH2), 3.64 (m, 2 H, CH2), 3.17–3.06 (m, 2
H, CH2) ppm. 13C NMR (125.8 MHz, [D6]acetone): δ = 157.0,
156.8 (q, J = 35.4 Hz, COCF3), 137.4, (C) 134.1, 134.0, 133.4, 132.7
(CH), 128.1, 127.8 (C), 123.1, 123.0 (CH), 121.0, 120.8 (CH), 119.1,
118.8 (CH=CH2), 118.9, 118.6 (CH), 117.8, 117.6 (q, J = 287.0 Hz,
for C H F N O 334.1293; found 334.1288. IR (CHCl ): ν = 3019,
˜
18 17
3
2
3
1686, 1463, 1215, 1149, 927 cm–1.
6-Methylene-3-(trifluoroacetyl)-2,3,4,4a,5,6-hexahydroazepino-
[3,4,5-hi]benz[b]indolizine (25): Colorless oil (31 mg). Rt = 23 min.
1H NMR (500 MHz, [D6]acetone): δ = 7.48 (t, J = 8.8 Hz, 1 H,
HAr), 7.33, (d, J = 8.1 Hz, 1 H, HAr), 7.15 (t, J = 7.1 Hz, 1 H,
HAr), 7.06 (t, J = 7.1 Hz, 1 H, HAr), 5.24–5.20 (m, 2 H, C=CH2),
4.76 (m, 1 H, 7-H), 4.69 (dt, J = 13.2 and 3.3 Hz, 0.4 H, 2-H), 4.63
(m, 1 H, 7-H), 4.50 (dd, J = 13.0 and 3.1 Hz, 0.6 H, 4-H), 4.33 (m,
0.6 H, 2-H), 4.16 (m, 0.4 H, 4-H), 3.55–3.48 (m, 0.6 H, 2-H), 3.45–
3.39 (m, 0.4 H, 4-H), 3.29–3.02 (m, 3 H, 1-H, 4a-H, 2-H, 4-H),
2.92–2.74 (m, 1 H, 1-H), 2.76–2.73 (m, 1 H, 5-H), 2.37–2.29 (m, 1
H, 5-H) ppm. 13C NMR (125.8 MHz, [D6]acetone): δ = 156.6 (q,
J = 35.4 Hz, COCF3), 140.8, 140.7 (C), 136.2, 135.8, 135.5 (2ϫ C),
129.0, 128.9 (C), 122.0, 121.9 (CH-Ar), 120.2 (CH-Ar), 118.7, 118.6
(CH-Ar), 117.8 (q, J = 287.7 Hz, CF3), 112.4, 112.3 (C=CH2),
110.6, 109.4 (C), 109.65, 109.60 (CH-Ar), 54.7 (q, J = 2.7 Hz), 54.5
(C-4), 50.4 (q, J = 2.8 Hz), 50.1 (C-2), 48.7, 48.6 (C-7), 40.6, 38.2
(C-4a), 35.0, 34.7 (C-5), 27.1, 24.9 (C-1) ppm. HR-EIMS: calcd.
for C H F N O 334.1293; found 334.1296. IR (CHCl ): ν = 3020,
˜
18 17
3
2
3
1687, 1472, 1458, 1215, 1168, 1147 cm–1.
5-Methylene-3-(trifluoroacetyl)-1,2,3,4,5,6-hexahydroazepino[4,5-
1
CF3), 116.8, 116.7 (CH=CH2), 113.9, 113.7 (C), 112.3, 111.4 (C), b]indole (27): H NMR (500 MHz, [D6]acetone): δ = 10.30 (s, 1 H,
Eur. J. Org. Chem. 2009, 1934–1943
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1941

S. G. Stewart, C. H. Heath, E. L. Ghisalberti
FULL PAPER
NH), 7.54 (dd, J = 4.2 and 8.0 Hz, 1 H, HAr), 7.33 (m, 1 H, HAr),
award of a Seeding Research Grant. C. H. H. is the recipient of an
7.14 (m, 1 H, HAr), 7.03, (t, J = 8.0 Hz, 1 H, HAr), 5.62 (m, 1 H, Australian Postgraduate Award. The authors would also like to
C=CH2), 5.32 (s, 1 H, C=CH2), 5.27 (s, 1 H, C=CH2), 4.64 (s, 1 thank Dr. Lindsay Byrne for NMR assistance, Dr. Gavin Flematti
H, CH2), 4.58 (s, 1 H, CH2), 4.02 (t, J = 5.8 Hz, 1 H, CH2), 3.95
(t, J = 6.1 Hz, 1 H, CH2), 3.28 (t, J = 6.1 Hz, 1 H, CH2), 3.24 (t,
J = 6.1 Hz, 1 H, CH2) ppm. 13C NMR (125.8 MHz, [D6]acetone):
δ = 156.9, 156.8 (q, J = 35.3 Hz, COCF3), 138.2, 137.9, 137.6, 137.4
(2 ϫ C), 134.2, 133.4 (C), 129.35, 129.3 (C) 123.8, 123.7 (CH),
120.05, 120.02 (CH) 117.7, 117.5 (q, J = 287.8 Hz, CF3), 113.7,
112.3 (C), 112.8, 111.7 (C=CH2), 111.8, 111.7 (CH), 52.6 (q, J =
3.5 Hz), 52.0, 50.0, 49.0 (q, J = 3.4 Hz, 2ϫ CH2), 24.5, 22.8 (CH2)
ppm. HR-EIMS: calcd. for C15H13F3N2O 294.0980; found
for HPLC assistance and Dr. Tony Reeder for mass spectra acqui-
sition.
[1]
[2]
[3]
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294.0984. IR (KBr): ν = 3357, 2936, 1668, 1453, 1329, 1207, 1188,
˜
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1142, 736 cm–1.
N-Allyl-N-[2-(1-allyl-2-bromo-1H-indol-3-yl)ethyl]-2,2,2-trifluoro-
acetamide (24), 6-Allyl-5-methylene-3-(trifluoroacetyl)-1,2,3,4,5,6-
hexahydroazepino[4,5-b]indole (26), 6-Methylene-3-(trifluoroacetyl)-
2,3,4,4a,5,6-hexahydroazepino[3,4,5-hi]benz[b]indolizine (25); N-Al-
lyl-N-[2-(1-allyl-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide (29):
Amide 20 (200 mg, 0.59 mmol) was added to a magnetically stirred
suspension of powdered KOH (267 mg, 4.76 mmol), K2CO3
(245 mg, 1.77 mmol) and Bu4NHSO4 (33 mg, 0.1 mmol) in toluene
(6 mL), and the solution was stirred at room temperature for
10 min. The resulting mixture was treated with allyl bromide
(320 µL, 447 mg, 3.7 mmol) followed immediately by Pd(PPh3)4
(104 mg, 0.09 mmol, 15 mol-%) and the resulting yellow suspension
heated at 60 °C for 40 min. The mixture was cooled to 0 °C and
treated dropwise with water (ca. 6 mL) with stirring. The phases
were separated, the aqueous phase was extracted with dichloro-
methane (4ϫ 4 mL) and the combined organic phases were dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude material was subjected to flash chromatography (toluene/
hexane, 2:3 Ǟ toluene/hexane, 55:45). First to elute was amide 24
(12 mg, 5% yield). Second to elute was a mixture of compounds
26/25/29 (61 mg) in a ratio (by 1H NMR) of 63:20:17 (colourless
oil). Compound 25 was separated by HPLC (MeOH/H2O, 4:1). Rt
= 23 min. Compounds 26 and 29 were separated by HPLC
(CH3CN/H2O, 7:3). Spectroscopic data for compounds 25, 26, and
24 matched those reported previously. Amide 29 (colourless oil):
1H NMR (600.1 MHz, [D6]acetone): δ = 7.67 (d, J = 7.8 Hz, 0.6
H, HAr), 7.59 (d, J = 7.9 Hz, 0.4 H, HAr), 7.38 (t, J = 8.2 Hz, 1
H, HAr), 7.19–7.15 (m, 1.4 H, HAr), 7.11 (s, 0.6 H, HAr), 7.09–
7.05 (m, 1 H, HAr), 6.05–5.97 (m, 1 H, CH=CHR2R), 5.90–5.80
(m, 1 H, CH=CH2), 5.30–5.21 (m, 2 H, CH=CH2), 5.15–5.12 (m,
1 H, CH=CH2), 5.07–5.02 (m, 1 H, CH=CH2), 4.80–4.76 (m, 2 H,
CH2), 4.19 (d, J = 5.9 Hz, 0.8 H, CH2), 4.01 (d, J = 5.9 Hz, 1.2 H,
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[15]
CH2), 3.73–3.65 (m, 2 H, CH2), 3.15–3.05 (m, 2 H, CH2) ppm. 13
C
NMR (125.8 MHz, [D6]acetone): δ = 156.9, 156.8 (q, J = 35.3 Hz,
COCF3), 137.53, 137.50 (C) 135.22, 135.18, 133.6, 132.9 (CH),
128.9, 128.7 (C), 127.2, 127.1 (CH), 122.4, 122.35 (CH), 119.8,
119.7, 119.6, 119.3 (2ϫCH), 118.8, 118.5 (CH=CH2), 117.8, 117.6
(q, J = 287.6 Hz, CF3), 117.0, 116.9 (CH=CH2), 112.0, 111.3 (C),
110.8, 110.7 (CH), 111.1, 110.9 (CH), 51.0 (q, J = 3.2 Hz), 49.9,
49.05, 49.00, 48.8 (q, J = 3.1 Hz), 48.6 (3ϫ CH2), 25.4, 23.2 (CH2)
ppm. HR-EIMS: calcd. for C18H19F3N2O 336.1449; found
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[19]
336.1443. IR (CHCl ): ν = 3020, 1686, 1467, 1215, 1148, 930 cm–1.
˜
3
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for new compounds.
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Acknowledgments
The authors would like to thank the Faculty of Medicine, Dentistry
and Health Sciences at the University of Western Australia for the
1942
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1934–1943

3-Benzazepines and Azepino[4,5-b]indole Ring Systems
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double-bond character within the amide protecting group. Due
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1
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Received: January 12, 2009
Published Online: February 23, 2009
Eur. J. Org. Chem. 2009, 1934–1943
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1943