Microwave-enhanced synthesis of N-shifted buflavine analogues via a Suzuki-ring-closing metathesis protocol

Article abstract of DOI:10.1021/ol050806+

(Chemical Equation Presented) A novel, microwave-enhanced six-step synthesis was devised for the synthesis of N-shifted buflavine analogues. Microwave-enhanced Suzuki-Miyaura cross-coupling and ring-closing metathesis reactions were used as the key steps. Microwave irradiation was found to enhance the ring-closing metathesis reaction to generate the otherwise difficultly obtainable medium-sized ring system of the target molecules.

Full text of DOI:10.1021/ol050806+

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2723-2726
Microwave-Enhanced Synthesis of
N-Shifted Buflavine Analogues via a
Suzuki
−Ring-Closing Metathesis
Protocol
Prasad Appukkuttan, Wim Dehaen, and Erik Van der Eycken*
Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F,
B-3001 LeuVen, Belgium
erik.Vandereycken@chem.kuleuVen.ac.be
Received April 13, 2005
ABSTRACT
A novel, microwave-enhanced six-step synthesis was devised for the synthesis of N-shifted buflavine analogues. Microwave-enhanced Suzuki
−
Miyaura cross-coupling and ring-closing metathesis reactions were used as the key steps. Microwave irradiation was found to enhance the
ring-closing metathesis reaction to generate the otherwise difficultly obtainable medium-sized ring system of the target molecules.
The apogalanthamine analogues represent an intriguing class
of natural products belonging to the Amaryllidaceae alkaloid
family.1 They feature a rare 5,6,7,8-tetrahydrobenzo[c,e]-
azocine skeleton composed of a biaryl-incorporated eight-
membered N-heterocyclic ring. Buflavine (1) (Figure 1),
isolated from Boophane flaVa,2 an endemic Amaryllidaceae
alkaloid species from South Africa, is a typical member of
this family, exhibiting interesting biological activities such
as R-adrenolytic and anti-serotonin activities.3 However, after
the pioneering work of Kobayashi,4 little work has been
published regarding the synthesis of apogalanthamine ana-
logues (Figure 1). Only three total syntheses of buflavine
have been reported,5 while minor efforts have been made to
generate structural analogues of these molecules for the
purpose of biological and pharmacological screening.6
* To whom correspondence should be addressed. Tel: + 32 16 327406.
Fax: + 32 16 327990.
(1) Ueyo, S.; Kobayashi, S. Chem. Pharm. Bull. 1953, 1, 139. Kobayashi,
S.; Uyeo, S. J. Chem. Soc. 1957, 638. Ishida, Y.; Sadamune, K.; Kobayashi,
S.; Kihara, M. J. Pharmacobiodyn. 1983, 6, 391. Kihara, M.; Miyake, Y.;
Iitomi, M.; Kobayashi, S. Chem. Pharm. Bull. 1985, 33, 1260.
(2) Viladomat, F.; Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee,
S. Phytochemistry 1995, 40, 307.
Figure 1. 5,6,7,8-Tetrahydrobenzo[c,e]azocines.
(3) Ishida, S.; Sasaki, Y.; Kimura, Y.; Watanabe, K. J. Pharmacobiodyn.
1985, 8, 917. Ishida, K.; Watanabe, K.; Kobayashi, S.; Kihara, M. Chem.
Pharm. Bull. 1977, 25, 1851. Renard-Nozaki, J.; Kim, T.; Imakura, Y.;
Kihara, M.; Kobayashi, S. Res. Virol. 1989, 140, 115.
We have recently demonstrated the usefulness of micro-
wave-irradiation in promoting Suzuki-Miyaura reactions7
of highly electron-rich substrates8 en route toward the
10.1021/ol050806+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/20/2005

synthesis of apogalanthamine analogues. As a part of our
ongoing research on microwave-enhanced transition-metal-
catalyzed synthesis9 of difficultly obtainable medium-sized-
ring natural product analogues, we devised a novel strategy
for the synthesis of the hitherto unknown N-shifted buflavine
analogues (Figure 1), which we wish to delineate herein.
incorporate electron-rich methoxy substituents in the biaryl
unit in order to keep a maximum resemblance with bufalvine
(1). Furthermore, these electron-rich substituents will tend
to slow the oxidative addition of the palladium catalyst to
the C-Br bond,7,8 making it a challenge to our cross-coupling
strategy. Commercially available 3,4-dimethoxybenzaldehyde
(2a) and 3,4,5-trimethoxybenz aldehyde (2b) were bromi-
nated regioselectively using bromine in methanol (Scheme
2).
Our approach comprises a microwave-assisted Suzuki-
Miyaura cross-coupling reaction followed by a ring-closing
metathesis10 (RCM) reaction (Scheme 1). The required biaryl
Scheme 2. Synthesis of o-Bromostyrenes 4a,b
Scheme 1. Retrosynthetic Analysis
The reactions were completed in 1-3 h at rt, and the
products 3a and 3b were isolated in high yields of 89% and
86%, respectively. The aldehydes were then converted to
the corresponding styrenes 4a and 4b via Wittig reaction
(Scheme 2) with methyl(triphenyl)phosphonium bromide in
THF at rt, using n-BuLi as the base. The reactions were found
to proceed smoothly, and the corresponding styrenes 4a,b
were isolated in excellent yields of 89% and 93%, respec-
tively.
skeleton can easily be generated from the corresponding
suitably functionalized styrene derivatives and anilines. After
Suzuki-Miyaura cross-coupling reaction, the obtained biaryl
system might be converted to the corresponding ring-closed
targets by an RCM reaction. However, there is scarce
literature precedent using the RCM for the generation of such
medium-sized rings.11 The increased ring strain of the target
molecule, moreover reinforced by the incorporated biaryl
unit, will impose severe challenges to perform this RCM.
To explore the Suzuki-Miyaura reaction, we chose
2-pivaloylaminophenylboronic acid 5 as the coupling partner
(Scheme 3). The boronic acid was synthesized in two steps
Our initial goal was to synthesize the o-bromostyrenes
needed for the biaryl coupling protocol. We decided to
Scheme 3. Suzuki-Miyaura Reaction in the Synthesis of
Biaryl Amines 7a,b
(4) Kobayashi, S.; Kihara, M.; Yamasaki, K.; Ishida, Y.; Watanabe, K.
Chem. Pharm. Bull. 1975, 23, 3036. Kobayashi, S.; Kihara, M.; Shizu, S.;
Katayama, S.; Ikeda, H.; Kitahiro, K.; Matsumoto, H. Chem. Pharm. Bull.
1977, 25, 3312. Kihara, M.; Kobayashi, S. Yakugaku Zasshi. 1978, 26, 155.
Kihara, M.; Ohnishi, K.; Kobayashi, S. J. Heterocycl. Chem. 1988, 25, 161.
Kobayashi, S.; Kihara, M.; Shingu, T. Yakugaku Zasshi. 1980, 100, 302.
Kobayashi, S.; Kihara, M.; Miyake, Y. Heterocycles 1985, 23, 159.
(5) Patil, P. A.; Snieckus, V. Tetrahedron Lett. 1998, 39, 1325. Hoarau,
C.; Couture, A.; Deniau, E. c.; Grandclaudon, P. J. Org. Chem. 2002, 67,
5846. Sahakitpichan, P.; Ruchirawat, S. Tetrahedron Lett. 2003, 44, 5239.
(6) Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem.
2002, 67, 1199. Herrbach, A.; Marinetti, A.; Baudoin, O.; Guenard, D.;
Gueritte, F. J. Org. Chem. 2003, 68, 4897.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. Suzuki, A. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; p 49. Suzuki, A. J. Organomet. Chem. 1999,
576, 147; Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633,
and references therein.
(8) 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. Appukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett 2005, 127.
(9) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225. Lidstro¨m, P.; Westman, J.; Lewis, A. Comb. Chem. High
Throughput Screening 2002, 6, 441. Larhed, M.; Moberg, C.; Hallberg, A.
Acc. Chem. Res. 2002, 35, 717. Loupy, A. MicrowaVes in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2002; and references therein. Kappe,
C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. Hayes, B. L. Aldrichim. Acta
2004, 37, 66.
from aniline following the literature procedure,12 via directed
ortho metalation.13 Following our previous experience with
(11) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C.
W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061. Banfi, L.; Basso, A.;
Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655. Rodriguez, C.;
Ravelo, J. L.; Martin, V. S. Org. Lett. 2004, 6, 4787. Kim, Y. J.; Lee, D.
Org. Lett. 2004, 6, 4351. Vassilikogiannakis, G.; Margaros, I.; Tofi, M.
Org. Lett. 2004, 6, 205. Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall,
N.; White, A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org.
Chem. 2005, 70, 1545. Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.;
White, A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem.
2005, 70, 1552.
(12) Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Queguiner, G.;
Siddiqui, M. A.; Snieckus, V. J. Org. Chem. 1995, 60, 292. Rocca, P.;
Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1993, 49, 49.
(13) Snieckus, V. Chem. ReV. 1990, 90, 879. Snieckus, V. Pure Appl.
Chem. 1990, 62, 671. Chauder, B.; Green, L.; Snieckus, V. Pure Appl. Chem.
1999, 71, 1521. Hartung, C. G.; Snieckus, V. Mod. Arene Chem. 2002,
330. Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
(10) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036. Grubbs, R. H.; Blackwell, H. E. Angew. Chem., Int. Ed. 1998, 37,
3281. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3812. Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18. Grubbs, R. H. Tetrahedron 2004, 60, 7117. Deiters,
A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
2724
Org. Lett., Vol. 7, No. 13, 2005

the Suzuki-Miyaura cross-coupling reaction between an
electron-rich aryl halide and ortho-substituted boronic acids,8
we decided to carry out the reaction under microwave
irradiation. Thus, styrene 4a and boronic acid 5 (1.3 equiv)
were suspended in a 1:1 mixture of DMF and H2O (3 mL)
together with NaHCO3 as the base (3.0 equiv) and Pd(Ph3P)4
as the catalyst (5 mol %) in a 10 mL sealed glass vial. The
mixture was irradiated at 150 °C for 15 min, using a
maximum power level of 150 W. The cross-coupling was
found to proceed smoothly, and the product 6a was isolated
in an excellent yield of 93% (Scheme 3).
Table 1. Ring-Closing Metathesis To Generate Targets 8a,ba
starting
time
(h)
T
yield
(%)
entry material product catalyst
solvent (°C)
1
2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
G-1
G-2
H-2
G-1
G-1
G-1
G-1
G-1
G-2
G-2
G-2
H-1
H-2
G-2
G-1
G-2
H-2
G-2
24
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
0
0
0
24
24
3
3
4
CH2Cl2 reflux 17
CH2Cl2 reflux 17
CH2Cl2 reflux 17
CHCl3 reflux 22
5
6
6
12
3
7
8
3
PhMe
reflux 28
9
3
CH2Cl2 reflux 32
CHCl3 reflux 42
10
11
12
13
14
15
16
17
18
3
Following the same procedure, the cross-coupling between
styrene 4b and boronic acid 5 was carried out under
microwave irradiation and the product 6b was isolated in
an excellent yield of 91% (Scheme 3). To generate the
intermediate for the RCM, the remaining task was the
creation of the N-allyl handle by allylating the aniline
nitrogen (Scheme 3). Refluxing the intermediates 6a,b with
NaH and allylbromide in dry THF for 6 h was found to drive
the allylation to completion, and the biaryl compounds 7a,b
were isolated in excellent yields of 96% and 94%, respec-
tively.
3
PhMe
PhMe
PhMe
reflux 58
reflux 29
reflux 43
3
3
5 minb PhMe
150
69a
3
3
3
PhMe
PhMe
PhMe
reflux 41
reflux 55
reflux 43
5 minb PhMe
150
68a
a All reactions were carried out in a 0.25 mmol scale with 3 mol % of
catalyst in 5 mL of solvent. b Reactions were carried out under microwave
irradiation in 3 mL of solvent at a maximum power level of 150 W. All
yields correspond to the isolated pure compounds, as determined by the
NMR experiments.
Our next goal was to carry out the RCM reaction to
generate the required biaryl-incorporated medium-sized rings
8a,b (Scheme 4). As expected, this conversion was rather
of 32% when the reaction was carried out with G-2 in
refluxing CH2Cl2, 42% in refluxing CHCl3, and a good yield
of 58% in refluxing toluene each upon stirring for 3 h (Table
1, entries 9-11, respectively). Changing the catalytic system
to the Hoveyda catalyst, the product was isolated in slightly
lower yields of 29% in the case of using H-1 and 43% in
the case of H-2, in refluxing toluene (Table 1, entries 12
and 13). As it seemed to be advantageous to perform the
RCM at higher temperature, we decided to investigate the
reaction upon microwave irradiation. When a sample of 7a
was irradiated in toluene, at 150 °C and a maximum power
level of 150 W, the yield was found to increase to 69%,
while the reaction time could be decreased to a mere 5 min
(Table 1, entry 14). Applying the same conditions, the
trimethoxy analogue 8b was synthesized in 5 min under
microwave irradiation in a good yield of 68% (Scheme 4,
Table 1, entry 18) and under conventional heating conditions
in a 55% yield (Table 1, entry 16). To complete the sequence,
the dihydrodibenzo[b,d]azocines 8a,b were converted into
the corresponding tetrahydrodibenzo[b,d]azocines 9a,b via
a simple palladium-catalyzed hydrogenation protocol apply-
ing a high-pressure Parr hydrogenation apparatus (Scheme
4). The reactions were run for 8 h in MeOH at 30 atm of H2
pressure. The products 9a,b were isolated in excellent yields
of 94% and 91%, respectively.
Scheme 4. RCM of the Intermediates 7a,b and Further
Conversion to the Target Molecules 9a,b
troublesome. In a first run, 7a (0.1 mmol) was stirred with
Grubbs first-generation (G-1) catalyst (3 mol %) in dry and
degassed CH2Cl2 at rt. Unfortunately, no reaction was
observed even after 24 h, and the starting material was found
untouched (Table 1, entry 1). The use of Grubb’s second-
generation catalyst (G-2) as well as the Hoveyda second-
generation (H-2) catalyst also failed to provide any change
to the course of the reaction (Table 1, entries 2 and 3). On
the contrary, when the reaction was carried out at reflux
temperature in CH2Cl2 for 3 h with G-1 (3 mol %) as the
catalyst, the product 8a was isolated in 17% yield, together
with unreacted starting material 7a (Table 1, entry 4).
Increasing the reaction time to 6 or 12 h failed to improve
the outcome of the reaction (Table 1, entries 5 and 6).
Therefore, we decided to perform the reaction at elevated
temperature in CHCl3, resulting in a slightly higher yield of
22%, while in refluxing toluene a moderate 28% was
obtained (Table 1, entries 7-8).
In conclusion, we have developed a novel microwave-
enhanced, transition-metal-mediated protocol for the syn-
thesis of hitherto unknown N-shifted buflavine analogues.
The key biaryl generating step was performed via a pal-
ladium-catalyzed Suzuki-Miyaura reaction upon focused
microwave irradiation. RCM reactions were successfully
employed in generating the rigid, medium-sized ring system
of the target molecules. Again, microwave irradiation was
found to be highly beneficial in overcoming the high
activation barrier of the reaction. The synthesis of a small
However, the use of G-2 was found to increase the yields
substantially, and we could isolate 8a in a moderate yield
Org. Lett., Vol. 7, No. 13, 2005
2725

library of the title molecules as well as attempts to vary the
ring size is under current investigation.
Supporting Information Available: Complete experi-
mental procedures, both under conventional heating and
microwave irradiation, as well as full characterization data
(1H, 13C, and DEPT NMR, CI-MS, and HRMS (EI)) for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the F.W.O. (Fund for
Scientific Research - Flanders (Belgium)) and the Research
Fund of the University of Leuven for financial support to
the laboratory. P.A. is grateful to the University of Leuven
for a fellowship. We also thank Prof. Dr. S. Toppet and Mr.
K. Duerinckx for their valuable help with NMR experiments.
OL050806+
2726
Org. Lett., Vol. 7, No. 13, 2005