Diversity-oriented synthesis of dibenzoazocines and dibenzoazepines via a microwave-assisted intramolecular A3-coupling reaction

Article abstract of DOI:10.1021/ol1008729

(Figure presented) An unprecedented, diversity-oriented strategy for the generation of 6,7-dihydro-5H-dibenzo[c,e]azepines and 5,6,7,8- tetrahydrodibenzo[c,e]azocines by a microwave-assisted copper-catalyzed intramolecular A³-coupling reaction is presented.

Full text of DOI:10.1021/ol1008729

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2774-2777
Diversity-Oriented Synthesis of
Dibenzoazocines and Dibenzoazepines
via a Microwave-Assisted Intramolecular
A3-Coupling Reaction
Jitender B. Bariwal,† Denis S. Ermolat’ev,† Toma N. Glasnov,§ Kristof
Van Hecke,‡ Vaibhav P. Mehta,† Luc Van Meervelt,‡ C. Oliver Kappe,§ and Erik
V. Van der Eycken*,†
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC) and Biomolecular
Architecture, Department of Chemistry, Katholieke UniVersiteit LeuVen,
Celestijnenlaan 200F, B-3001 LeuVen, Belgium, and Christian Doppler Laboratory for
MicrowaVe Chemistry, Institute of Chemistry, Karl-Franzens-UniVersity Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
erik.Vandereycken@chem.kuleuVen.be
Received April 16, 2010
ABSTRACT
An unprecedented, diversity-oriented strategy for the generation of 6,7-dihydro-5H-dibenzo[c,e]azepines and 5,6,7,8-tetrahydrodibenzo[c,e]azocines
by a microwave-assisted copper-catalyzed intramolecular A3-coupling reaction is presented.
In light of the increased demand for the diversity-oriented1
generation of biaryl-containing medium-sized rings,2 different
approaches have been developed for these biologically
interesting classes of compounds. As an example, the
apogalanthamine analogues (1)3 (Figure 1) belonging to the
Amaryllidaceae alkaloid family feature a rare 5,6,7,8-
tetrahydrodibenzo[c,e]azocine skeleton which comprises a
biaryl ring system linked with an eight-membered N-
heterocyclic ring. Buflavine4 (2) (Figure 1), isolated from
Boophane flaVa, an endemic Amaryllidaceae alkaloid species
from South Africa, is a typical member of this family,
exhibiting interesting biological activities such as R-adre-
nolytic and antiserotonin activities.3a-c,5 Five total syntheses
of buflavine have been reported in the literature6 to date,
while minor efforts have been done for the synthesis of
apogalanthamines and their structural analogues (6,7-dihydro-
5H-dibenzo[c,e]azepines and 5,6,7,8-tetrahydrodibenzo[c,e]azo-
cines (compounds 3 in Figure 1) after the pioneering work
of Kobayashi et al.7 While the biaryl moiety can be directly
† Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Katholieke Universiteit Leuven.
‡ Biomolecular Architecture, Department of Chemistry, Katholieke
Universiteit Leuven.
§ Institute of Chemistry, Karl-Franzens-University Graz.
(1) (a) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302,
613. (b) Burke, M. D.; Lalic, G. Chem. Biol. 2002, 9, 535. (c) Schreiber,
S. L. Science 2000, 287, 1964.
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G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(4) Viladomat, F.; Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee,
S. Phytochemistry 1995, 40, 307.
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biodyn. 1985, 8, 917. (b) Ishida, Y.; Sadamune, K.; Kobayashi, S.; Kihara,
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Org. Chem. 2008, 5867.
.
10.1021/ol1008729  2010 American Chemical Society
Published on Web 05/18/2010

accessed via Ullmann-type coupling, (asymmetric) Suzuki-
Miyaura cross-coupling reaction8a-c or intramolecular oxida-
tive coupling,8d,e the construction of the medium-sized ring
is still a major challenge for the construction of such
structures.
the applicability of the A3-coupling reaction for the synthesis
of (-)-steganacin and (-)-steganone aza analogues, and very
recently, we reported a new method to access polyalkyl-
substituted secondary propargylamine via A3-coupling using
scarcely explored primary aliphatic amines.14
As a part of our ongoing interest in the synthesis of
buflavine analogues8f-h in particular and of medium-sized
rings in general9 via the application of microwave irradiation,
In this report, we describe the first application of an
intramolecular A3-coupling reaction for the construction of
medium-sized rings. Our approach gives access to 6,7-
dihydro-5H-dibenzo[c,e]azepines as well as to 5,6,7,8-
tetrahydrodibenzo[c,e]azocines, thus allowing the introduc-
tion of five points of diversity (Scheme 1).
Scheme 1. Retrosynthesis for the Generation of the
6,7-Dihydro-5H-dibenzo[c,e]azepine and the
5,6,7,8-Tetrahydrodibenzo[c,e]azocine Skeleton via an
Intramolecular A3-Coupling Reaction
Figure 1. Structure of the apogalanthamine analogues (1), buflavine
(2), and the proposed new analogues 3.
we became interested in the development of an alternative
route for these compounds via an intramolecular A3-coupling
reaction. This multicomponent reaction has attracted much
attention in recent years10 as it easily allows for the
introduction of diversity in a single step under mild condi-
tions using inexpensive transition-metal catalysts. This A3-
coupling reaction can be performed in, e.g., an ionic liquid11
or water12 as reaction medium, and high enantioselectivities
could be achieved using QUINAP or Pybox chiral
ligands.10b,f Moreover, it has been recently demonstrated that
the process is suited for scale up using microwave-assisted
continuous flow conditions.13 We have already demonstrated
In our approach to construct medium-sized ring deriva-
tives, the required biaryl moiety was obtained via a
Suzuki-Miyaura cross-coupling reaction of a suitable o-
bromobenzylamine or an o-bromophenethylamine 4 and an
electron-poor o-formyl(hetero)arylboronic acid 6 (Scheme
1). We have previously demonstrated that this kind of
electronically unfavorable combination of binding partners
highly benefits from the application of microwave
irradiation.8f-h,9d For our optimization study, the starting
biaryl compound 7a was synthesized according to our
optimized microwave-assisted procedure.9b In continuation
of our research regarding A3 couplings, we investigated the
intramolecular reaction of biaryl compound 8a that was in
situ formed via Boc deprotection of the generated 7a upon
treatment with TFA/DCM (1:3) at 0 °C. The latter intermedi-
ate delivers both the aldehyde and the amine moiety, which
were reacted with p-tolylacetylene using CuBr (20 mol %)
as the catalyst in toluene under microwave irradiation at a
ceiling temperature of 100 °C and a maximum power of 80
W for 25 min (Table 1, entry 1). The desired compound 3a
was obtained in a high yield of 95%. Other copper salts such
as CuI and CuCl also worked equally well (Table 1, entries
2 and 3). The yield remained high even when the reaction
time was decreased to 15 min (Table 1, entry 4). The amount
of CuBr catalyst could be reduced to 10 mol % without
affecting the yield of 3a (Table 1, entries 5 and 7). Further
(7) (a) Kobayashi, S.; Kihara, M.; Shizu, S.; Katayama, S.; Ikeda, H.;
Kitahiro, K.; Matsumoto, H. Chem. Pharm. Bull. 1977, 25, 3312. (b) Kihara,
M.; Vangveravong, S.; Ohnishi, K.; Imakura, Y.; Kobayashi, S. Chem.
Pharm. Bull. 1989, 37, 1744.
(8) (a) Joncour, A.; Decor, A.; Liu, J. M.; Dau, M.; Baudoin, O.
Chem.sEur. J. 2007, 13, 5450. (b) Joncour, A.; Decor, A.; Thoret, S.;
Chiaroni, A.; Baudoin, O. Angew. Chem., Int. Ed. 2006, 45, 4149. (c)
Baudoin, O. Eur. J. Org. Chem. 2005, 4223. (d) Hamamoto, H.; Anilkumar,
G.; Tohma, H.; Kita, Y. Chem. Commun. 2002, 450. (e) Takada, T.; Arisawa,
M.; Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998, 63,
7698. (f) Appukkuttan, P; Dehaen, W; Van der Eycken, E. Chem.sEur. J.
2007, 13, 6452. (g) Appukkuttan, P.; Van der Eycken, E. Microwave-
Assisted Natural Product Chemistry. In Topics in Current Chemistry;
Microwave Methods in Organic Synthesis; Springer: New York, 2006; Vol.
266, p 1. (h) Appukkuttan, P; Dehaen, W; Van der Eycken, E. Comb. Chem.
High Throughput Screening 2007, 10, 790.
(9) (a) Mont, N; Mehta, V. P; Appukkuttan, P; Beryozkina, T; Toppet,
S; Van Hecke, K; Van Meervelt, L; Voet, A; De Maeyer, M; Van der
Eycken, E. J. Org. Chem. 2008, 73, 7509. (b) Donets, P; Van der Eycken,
E. V. QSAR Comb. Sci 2007, 26, 1239. (c) Beryozkina, T; Appukkuttan,
P; Mont, N; Van der Eycken, E Org. Lett. 2006, 8, 487. (d) Appukkuttan,
P.; Orts, A. B.; Chandran, R. P.; Goeman, J. L.; Van der Eycken, J.; Dehaen,
W.; Van der Eycken, E. Eur. J. Org. Chem. 2004, 3277.
(10) (a) Gommermann, N.; Knochel, P. Chem.sEur. J. 2006, 12, 4380.
(b) Gommermann, N; Knochel, P. Chem. Commun. 2005, 4174. (c) Wei,
C. M.; Mague, J. T.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5749. (d) Wei, C. M.; Li, Z. G.; Li, C. J. Synlett 2004, 1472. (e)
Gommermann, N.; Koradin, K.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2003, 42, 5763. (f) Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2002,
124, 5638. (g) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263.
(11) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358.
(12) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A. Org. Lett.
2004, 6, 1001.
(13) Shore, G.; Yoo, W.-J.; Li, C.-J.; Organ, M. G. Chem.sEur. J. 2010,
16, 126.
(14) Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V.
Chem.sEur. J. 2010, 16, 3281.
Org. Lett., Vol. 12, No. 12, 2010
2775

lowering the catalyst concentration resulted in a prolonged
reaction time to reach completion. The same was noticed
when the ceiling temperature was decreased to 80 °C. When
the solvent was changed from toluene to dioxane an
important drop of the yield was observed (Table 1, entry 6).
Best conditions were found when the reaction was run with
10 mol % of CuBr catalyst for 15 min under microwave
irradiation as described above (Table 1, entry 7).
Scheme 2
.
Investigation of the Scope of the Intramolecular
A3-Coupling Reaction
Table 1. Investigation of the Reaction Parameters for the
Intramolecular A3-Coupling Reaction
entry
catalyst (mol %)
time (min)
yieldb (%)
1
2
3
4
5
6
7
8
9
CuBr (20)
CuI (20)
25
25
25
15
25
25
15
25
25
95
96
93
94
94
78c
95
82
80
CuCl (20)
CuBr (20)
CuBr (10)
CuBr (20)
CuBr (10)
Cu/C (20)
Cu/C (10)
a Reaction conditions: compound 7a (1.0 mmol), p-tolylacetylene (1.5
mmol), dry toluene (1.0 mL), MW, 80 W, 100 °C. b Yields obtained for
the diastereomeric mixture calculated over two steps. c Dioxane was used
as solvent.
Interestingly, this intramolecular A3 coupling could also
be run using copper-in-charcoal as catalyst15 (Cu ≈ 15% by
weight). In this case, compound 3a could be isolated in a
slightly decreased yield of 80-82% (Table 1, entries 8 and
9). The possibility to apply heterogeneous catalysis opens
the way for performing the reaction as a flow process, as
will be further demonstrated. It has been observed that the
target compound 3a appeared at rt as a diastereomeric
mixture (≈55:45; determined by HPLC and NMR) that could
not be separated by column chromatography due to rapid
interconversion via rotation along the biaryl axis.
However, attempts to crystallize the diastereomeric mixture
provided single diastereomers of 3a in crystalline form. The
structures of these crystalline diastereomers were unequivo-
cally confirmed by X-ray crystallography. Compound 3a
crystallized in the centrosymmetric space group P21/c; hence,
both enantiomers are present in the structure.16 Using the
optimized conditions for our intramolecular A3 coupling
(Table 1,entry 7), we further investigated the scope of this
reaction evaluating different substrates (Scheme 2). To our
delight, all compounds were obtained in fairly good to
excellent yields.
The A3-coupling reaction seemed to work equally well
for the formation of a 5,6,7,8-tetrahydrodibenzo[c,e]azocine
(Scheme 2, 3b-h) as for a 6,7-dihydro-5H-dibenz-
o[c,e]azepine (Scheme 2, 3i-q) skeleton. Also, the incor-
poration of a thiophene ring in the biaryl axis does not seem
to hamper the medium-sized ring formation (Scheme 2,
3g,h). All of the eight-membered ring derivatives 3a-f,
where ring B is phenyl, appeared as an interconvertable
diastereomeric mixture (∼1:1) according to their NMR
spectra.
(15) Lipshutz, B. H.; Taft, B. R. Angew. Chem. 2006, 118, 8415; Angew.
Chem. Int. Ed. 2006, 45, 8235.
(16) CCDC 772382 (3a) and CCDC 772381 (3g) contain the supple-
mentary crystallographic data for these structures. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/conts/retrieving.html. (See the Supporting Information
for crystal structures of compound 3a and 3g and two enantiomers
overlapped for compound 3a).
However, for compounds 3g,h where ring B is replaced
by a thiophene ring, a diastereomeric ratio of ∼20:80 was
Org. Lett., Vol. 12, No. 12, 2010
2776

observed. The structure of the major (aR,5S) diastereoisomer
of compound 3g was unequivocally proven by X-ray
crystallography. The compound 3g crystallized in the chiral
space group P21; hence, only one enantiomer is present in
the structure.16 Interestingly, the seven-membered com-
pounds 2a-i were obtained as single diastereoisomers.17
The possibility to catalyze this intramolecular A3-coupling
process with copper-in-charcoal (Cu/C) (Table 1, entries 8
and 9) opens the way to perform this reaction under
continuous flow conditions. We have recently reported Cu(I)-
catalyzed azide-alkyne cycloaddition reactions (CuAAC)
using a high-temperature/pressure continuous flow reactor
incorporating immobilized Cu/C as a catalyst.18 For the A3
coupling 8a to 3a the initially optimized batch conditions
(100 °C, 25 min, Table 1) were not transferrable to a flow
experiment, due to the long reaction time, i.e., residence time,
in the reactor. For this reason, the reaction temperature was
increased to 150 °C and the reaction time thereby decreased
to 5 min, providing a similar isolated product yield (79%)
of 3a. Transferring the conditions from the microwave batch
experiment to continuous flow (X-Cube reactor),16 we found
that at a flow rate of 1.5 mL/min were able to obtain a good
yield of the desired intramolecular A3-coupling product 3a
(67%) (Scheme 3). It has to be noted that lower flow rates
lead to significant amounts of homocoupling of the terminal
alkyne (Glaser coupling), which can be rationalized by the
stoichiometric amounts of Cu under flow conditions.19
In summary, we have developed an unprecedented strategy
for the construction of 6,7-dihydro-5H-dibenzo[c,e]azepines
Scheme 3
.
Intramolecular A3-Coupling Reaction Performed As
a Continuous Flow Process
and 5,6,7,8-tetrahydrodibenzo[c,e]azocines via a microwave-
assisted copper-catalyzed intramolecular A3-coupling reac-
tion. This method allows the introduction of five different
points of diversity in the azepine and azocine skeleton in a
short and concise way. All compounds were obtained in good
yields and purities over two synthetic steps. Furthermore,
we proved that this reaction could easily be performed in a
microwave-assisted continuous flow process opening the way
for the generation of these compounds on a larger scale.
Acknowledgment. Support was provided by the Research
Fund of the University of Leuven and by the FWO (Fund
for Scientific Research - Flanders (Belgium)). D.S.E. and
J.B.B. are grateful to the University of Leuven for obtaining
a postdoctoral fellowship. V.P.M. is grateful to the IRO
(Interfacultaire Raad voor Ontwikkelingssamenwerking) for
obtaining a doctoral scholarship. This work was also sup-
ported by the Christian Doppler Research Foundation (CDG).
Supporting Information Available: Experimental pro-
cedures and characterizations of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Pira, S. L.; Wallace, T. W.; Graham, J. P. Org. Lett. 2009, 11,
1663.
(18) Fuchs, M; Goessler, W; Pilger, C; Kappe, C. O AdV. Synth. Catal
2010, 352, 323.
(19) Similar changes in selectivity have been observed in Pd-catalyzed
Heck reactions under continuous flow conditions. Glasnov, T. N; Findenig,
S; Kappe, C. O Chem.sEur. J. 2009, 15, 1001.
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