Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues

Article abstract of DOI:10.1002/chem.200700177

Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.

Full text of DOI:10.1002/chem.200700177

DOI: 10.1002/chem.200700177
Microwave-Assisted Transition-Metal-Catalyzed Synthesis of N-Shifted and
Ring-Expanded Buflavine Analogues
Prasad Appukkuttan,[a, b] Wim Dehaen,[a] and Erik Van der Eycken*[a]
Abstract: Two novel and efficient strat-
egies for the synthesis of hitherto un-
known N-shifted and ring-expanded
buflavine analogues are presented.
Construction of the medium-sized ring
system of the title molecules, a difficult
taskdue to the high activation energy
needed for the ring-closure with the
additional rigidity imposed by the
biaryl skeleton, was achieved by using
Suzuki–Miyaura biaryl coupling and a
ring-closing metathesis reaction as the
key steps. The combination of
a
second-generation Grubbs catalyst and
microwave irradiation proved to be
highly useful in generating the other-
wise difficult to obtain medium-sized
ring system of the buflavine analogues.
Keywords: buflavine
pling medium-sized rings
metathesis · microwave irradiation
· cross-cou-
·
·
Introduction
The apogalanthamine ana-
logues[1] feature
a
unique
5,6,7,8-tetrahydrodibenzo-
[c,e]azocine skeleton com-
ACHTREUNG
posed of a biaryl-fused eight-
membered N-heterocyclic ring
system. Isolated from an en-
demic amaryllidaceae alkaloid
species Boophane flava, bufla-
Scheme 1. The 5,6,7,8-tetrahydrodibenzo[c,e]azocines and buflavine (1).
A
vine[2] (1), a typical member of this family, exhibits interest-
ing a-adrenolytic and anti-serotonin activities (Scheme 1).[3]
Despite the intriguing biological potential of this class of
natural products, few efforts have been made towards the
synthesis of analogues since the pioneering workof Kobaya-
shi et al.[4] Their approaches were mainly based on Ullmann-
type[5] or photochemical[6] coupling reactions for the key
biaryl-forming step. However, as these protocols are associ-
ated with rather low yields, long reaction times, and a strong
dependence on the nature of the substituents on the aryl
components, they are not efficient for the generation of
structurally diverse libraries for screening purposes. To date,
only four total syntheses of buflavine (1) have been report-
ed,[7] based on various biaryl formation strategies, while
little effort has been made towards an efficient and general
protocol for the generation of structurally diverse analogues.
We have previously demonstrated[8] the usefulness of mi-
crowave irradiation in promoting difficult Suzuki–Miyaura
cross-coupling reactions of highly electron-rich aryl halides,
en route to the synthesis of apogalanthamine analogues. As
part of our ongoing research on the synthesis of difficult to
obtain natural product analogues possessing a biaryl-fused
medium-sized ring, we have devised a novel and efficient
strategy for the generation of N-shifted and ring-expanded
buflavine (1) analogues.[9] This strategy relies on the combi-
nation of a Suzuki–Miyaura reaction[10] of highly electron-
rich aryl halides, to generate the biaryl axes, followed by
ring-closing metathesis (RCM)[11] to construct the medium-
sized ring. The formation of the medium-sized ring systems
by RCM is rather difficult due to the high activation energy
needed for the ring-closure, and the additional rigidity im-
[a] Dr. P. Appukkuttan, Prof. W. Dehaen, Prof. Dr. E. Van der Eycken
Department of Chemistry, University of Leuven
Celestijnenlaan 200F, 3001 Leuven (Belgium)
Fax : (+32)16-327990
E-mail: Erik.Vandereycken@chem.kuleuven.be
[b] Dr. P. Appukkuttan
Current Address: Department of Medicinal Chemistry
Uppsala Biomedical Centre (BMC), Uppsala University
P.O. Box 574, 75123 Uppsala (Sweden)
6452
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FULL PAPER
posed by the stiff biaryl backbone presented a considerable
challenge to our methodology. We have previously demon-
strated that both reactions benefit greatly from microwave
irradiation.[9] Herein, we discuss the application of our meth-
odology in full detail.
urea at À158C for 3 h.[14] The desired product 2a was ob-
tained in a good yield of 63% with excellent regioselectivity
(ortho:para 96:4) (Scheme 3).
Results and Discussion
Synthesis of N-shifted buflavine analogues: As is apparent
from the retrosynthetic scheme (Scheme 2), the success of
Scheme 3. Synthesis of 2-nitrophenylboronic acid (2a): i) HNO3 (100%),
Ac2O, urea (cat.), À158C, 3 h, 63% combined yield (ortho:para 96:4).
A detailed study aimed at tuning the selectivity of the ni-
tration revealed that the temperature was critical. When the
reaction was performed at À258C, a period of 7 h was re-
quired to reach completion. However, at 08C, the reaction
was found to proceed too vigorously, resulting in decomposi-
tion of the boronic acid to a darkand tarry mass. The addi-
tion of a catalytic amount of urea seemed to be essential for
obtaining high regioselectivity, as, in the absence of urea, a
lower yield of 58% with predominant para-selectivity (or-
tho:para 36:64) was obtained. Although we are unaware of
any literature precedent for this kind of ate-formation of
urea and boronic acids, the experimental results lead us to
believe that the mechanism of nitration most likely involves
the attachment of one of the urea nitrogen atoms to the
boron, such that it might act as a handle capable of directing
the reactive nitronium ion to the ortho position (Scheme 4).
Scheme 2. Retrosynthetic analysis for N-shifted buflavine analogues.
our strategy depends on two key steps: a Suzuki–Miyaura
coupling to generate the required biaryl intermediates and
an RCM reaction to generate the medium-sized ring system
of the title molecules.
The required intermediates for the cross-coupling, a suita-
bly functionalized o-bromostyrene and o-nitrophenylboronic
acid, could be easily generated from inexpensive and com-
mercially available starting materials. We chose to incorpo-
rate electron-rich substituents in the biaryl skeleton, with a
view to keeping semblance with buflavine (1). Furthermore,
the combination of a highly electron-rich aryl bromide with
a boronic acid bearing an electron-withdrawing group at the
ortho position poses an interesting challenge to the Suzuki–
Miyaura cross-coupling, owing to the slow oxidative addi-
Scheme 4. Regioselective nitration of phenylboronic acid.
À
tion of the catalyst to the C Br bond as well as the possibili-
The methoxylated ortho-bromostyrenes 5a,b, needed for
the Suzuki–Miyaura cross-coupling, were generated in yields
of 89 and 86%, respectively, starting from commercially
available 3,4-dimethoxybenzaldehyde (3a) and 3,4,5-trime-
thoxybenzaldehyde (3b), by way of regioselective bromina-
tion using bromine in methanol (Scheme 5).[15]
ty of proto-deboronation of the boronic acid. We envisaged
that our microwave-assisted cross-coupling protocol could
be highly beneficial in circumventing these problems.[8,9,12]
We also envisaged that the possibility of a competing Heck
reaction,[13] promoted by complexation of the p-electrons of
the double bond to the transition-metal catalyst, would
make it an interesting challenge to our previously establish-
ed cross-coupling strategy.
To achieve Wittig olefination,[16] aldehydes 4a,b were
treated with methyl(triphenyl)phosphonium bromide in
THF, using nBuLi as the base at room temperature. The re-
actions proceeded smoothly, furnishing the corresponding
To evaluate our strategy, we decided to investigate the
biaryl coupling by applying the
unsubstituted
2-nitrophenyl-
boronic acid (2a). This could
be generated by regioselective
nitration of the inexpensive
and commercially available
phenylboronic
acid
using
100% nitric acid in the pres-
ence of a catalytic amount of
Scheme 5. Synthesis of bromostyrenes 5a,b: i) Br2, MeOH, RT, 1–3 h, 89% (4a), 86% (4b); ii) MePPh3Br,
nBuLi, THF, RT, 3 h, 89% (5a), 93% (5b).
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E. Van der Eycken et al.
styrenes 5a,b in good yields of 89 and 93%, respective-
ly.[17]
We therefore decided to redesign our retrosynthetic
scheme, starting directly from a suitably protected aniline,
thereby avoiding the problematic reduction of the nitro
Having the required Suzuki counterparts at hand, we en-
visaged the cross-coupling reaction to generate the required
biaryl intermediates 6a,b (Scheme 6). From previous re-
search,[8,18] we knew already that this coupling of electron-
rich aryl bromides with a boronic acid, which is prone to
proto-deboronation, would be difficult to achieve by apply-
ing conventional heating conditions. We therefore decided
to directly investigate this cross-coupling reaction under mi-
crowave irradiation conditions. According to our optimized
protocol,[17] boronic acid 2a and styrene 5a were reacted
with NaHCO3 as base and [Pd(PPh3)4] as catalyst in a 1:1
A
Scheme 7. Alternative retrosynthetic analysis for the synthesis of N-shift-
ed analogues.
mixture of DMF and water, using a pre-selected maximum
temperature of 1508C and a maximum irradiation power of
150 W. To our satisfaction, the reaction was completed in
compound (Scheme 7). We en-
visaged that the required
biaryl skeleton could be
reached by way of a cross-cou-
pling reaction between an o-
bromostyrene and a suitable
aniline-derived boronic acid,
which might be generated in
two steps from a commercially
available aniline according to a
directed ortho-metalation pro-
tocol (DoM).[20]
2-Pivaloylaminophenylbor-
Scheme 6. Attempts to generate the biaryl anilines 7a,b: i) NaHCO3 (3.0 equiv), [Pd(PPh3)4] (5 mol%), DMF/
A
onic acid (8) was generated
from the corresponding pivala-
mide, following the procedure
reported by Rocca et al.[21]
Subsequently, this boronic acid
H2O (1:1), 150 W, 1508C, 15 min, 84% (6a), 82% (6b); ii) SnCl2, HCl (aq.), reflux, 12 h; iii) Sn, HCl (aq.),
EtOH, reflux, 12 h; iv) Sn, NH4OH (aq.), EtOH, reflux, 12 h; v) Fe, HCl (aq.), EtOH, reflux, 3 h; vi) Fe,
NH4OH (aq.), EtOH, reflux, 3 h; vii) Pd/C (10%), H2, MeOH, RT, 2 h.
15 min and biaryl compound 6a was isolated in an excellent
yield of 84% with a negligible degree of proto-deborona-
tion, and no homo-coupling products were observed. Fol-
lowing the same procedure, the trimethoxy analogue 6b was
synthesized in 82% yield, starting from boronic acid 2a and
styrene 5b.
8 was cross-coupled with the bromostyrenes 5a,b to gener-
ate the required biaryl intermediates 9a,b in excellent yields
of 93 and 91%, respectively (Scheme 8). These microwave-
assisted Suzuki couplings were run in a DMF/water (1:1)
mixture at a ceiling temperature of 1508C in 15 min, using
NaHCO3 as base and [Pd(PPh3)4] as catalyst. Finally, the
A
However, the subsequent reduction of the nitro group of
6a,b turned out to be problematic as all attempted common
reduction protocols,[19] using either SnCl2 or granular tin,
failed, even after prolonged heating (Scheme 6). Invariably,
the starting compounds 6a,b were recovered. Although the
use of iron in refluxing EtOH
second allyl handle, required for the subsequent RCM, was
introduced by allylation of the aniline nitrogen by refluxing
9a,b with allyl bromide in THF using NaH as base. The
products 10a,b were isolated in very high yields of 96 and
94%, respectively (Scheme 8).
with either 6n HCl or with
NH4OH was found to reduce
the nitro group,
a complex
mixture was obtained, contain-
ing, for example, the phenan-
thridines 7c,d. Attempts to
perform catalytic hydrogena-
tion, using Pd/C (10%) in
MeOH, failed to furnish any
substantial amount of the
target anilines 7a,b.
Scheme 8. Synthesis of biaryl anilines 10a,b: i) NaHCO3, [Pd(PPh3)4], DMF/H2O (1:1), MW, 150 W, 1508C,
15 min, 93% (9a), 91% (9b); ii) NaH (80% in mineral oil), allyl bromide, THF, reflux, 6 h, 96% (10a), 94%
(10b).
A
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Syntheses of Buflavine Analogues
FULL PAPER
Having the required intermediates 10a,b at hand, our
next goal was to evaluate the RCM reaction for the genera-
tion of the required biaryl-fused medium-sized rings in com-
pounds 11a,b (Scheme 9). As expected, this conversion was
rather troublesome. In a first run, 10a (0.25 mmol) was
tion. When a sample of 10a was irradiated in toluene, at
1508C, applying a maximum power level of 150 W, the yield
of 11a increased to 69% in a mere 5 min of irradiation time
(Table 1, entry 7). As expected, only the cis isomer was gen-
erated in this RCM, owing to the high conformational rigidi-
ty of the ring system. Applying
the same conditions, the trime-
thoxy analogue 11b was syn-
thesized in 55% yield under
conventional heating condi-
tions (Table 1, entry 8), but in
a much better yield of 68%
under microwave irradiation
(Table 1, entry 9). To generate
the target molecules 12a,b and
complete the synthesis, the
ring-closed compounds 11a,b
were subjected to palladium-
Scheme 9. Synthesis of N-shifted buflavine analogues 12a,b: i) see Table 1; ii) Pd/C (10%), H2 (30 atm),
MeOH, 8 h, 94% (12a), 91% (12b).
catalyzed
hydrogenation
stirred with
a
Grubbs first-generation (G-1) catalyst
(Scheme 9). Thereby, the N-shifted buflavine analogues
12a,b were isolated in excellent yields of 94 and 91%, re-
spectively.
(3 mol%) in dry, degassed CH2Cl2 at room temperature.
Unfortunately, no reaction tookplace even after 24 h and
the starting material 10a was fully recovered.[9] On the con-
trary, when the reaction was carried out at reflux tempera-
ture in CH2Cl2 for 3 h with G-1 (3 mol%) as the catalyst,
the product 11a was isolated in 17% yield, together with
unreacted starting material 10a (Table 1, entry 1). Increasing
the reaction time to 12 h failed to improve the outcome. We
Synthesis of ring-expanded buflavine analogues: After the
successful synthesis of N-shifted buflavine analogues 12a,b
by applying Suzuki biaryl coupling followed by an RCM re-
action, we turned our attention to the synthesis of ring-ex-
panded buflavine analogues possessing a nine-membered
medium-sized ring (Scheme 10). It was envisaged that the
Table 1. Ring-closing metathesis to generate targets 11a,b.[a]
Entry Alkene Product Catalyst
t
Solvent
T
[8C]
Yield
[%][b]
[h]
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10a
10b
10b
11a
11a
11a
11a
11a
11a
11a
11b
11b
G-1
G-2
G-2
G-2
G-2
G-1
3
3
3
3
3
3
CH2Cl2 reflux
CHCl3 reflux
PhMe reflux
CH2Cl2 reflux
CHCl3 reflux
PhMe reflux
17
22
28
32
42
58
69
55
68
G-1 5 min[c]
G-2
G-2 5 min[c]
PhMe
PhMe reflux
PhMe 150
150
3
Scheme 10. Retrosynthetic analysis for ring-expanded buflavine ana-
logues.
[a] All reactions were carried out on a 0.25 mmol scale with 3.0 mol% of
catalyst in 5.0 mL of solvent. [b] Yield of isolated product. [c] Reactions
were carried out under microwave irradiation in 3.0 mL of solvent at a
maximum power level of 150 W.
desired biaryl skeleton could be generated from the corre-
sponding suitably functionalized styrene derivatives and
ortho-formyl-phenylboronic acid by means of a Suzuki–
Miyaura cross-coupling reaction. After introduction of the
required double bond, the targeted nine-membered ring
might then be constructed by an RCM reaction. It has to be
stressed that, as the application of RCM for the generation
of nine-membered ring systems has been scarcely document-
ed in the literature,[22] the proposed strategy represents a
real challenge.
To evaluate the usefulness of our previously optimized
microwave-assisted Suzuki–Miyaura cross-coupling,[8] we
chose to investigate the reaction of 2-formylphenylboronic
acid (13) with the electron-rich ortho-bromostyrenes 5a,b
(Scheme 11). In a typical run, a mixture of 5a (1.0 mmol),
therefore decided to perform the reaction at higher temper-
ature in refluxing CHCl3. This resulted in a slightly higher
yield of 22%. Carrying out the reaction in refluxing toluene,
a moderate 28% yield was obtained (Table 1, entries 2 and
3).
However, the use of catalyst G-2 was found to increase
the yield substantially, and compound 11a was isolated in an
improved yield of 32% when the reaction was run in reflux-
ing CH2Cl2. Switching to CHCl3 or toluene raised the yield
to 42 and 58%, respectively (Table 1, entries 4–6). As higher
temperature seemed to be advantageous for the RCM, we
decided to investigate the reaction upon microwave irradia-
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E. Van der Eycken et al.
the aldehyde 14a. Following
the same procedure, the trime-
thoxy analogue 15b was syn-
thesized
in
74%
yield
(Scheme 11).
Having obtained the neces-
sary biaryl-amine intermedi-
ates 15a,b, we proceeded to
the crucial RCM reaction to
generate the nine-membered
ring system (Scheme 12). Al-
though the use of Grubbs and
Hoveyda first-generation cata-
Scheme 11. Microwave-assisted Suzuki–Miyaura reaction: i) NaHCO3 (3.0 equiv), [Pd(PPh3)4] (5 mol%),
A
DMF/H2O (1:1), MW, 150 W, 1508C, 15 min, 92% (14a), 90% (14b); ii) a) allylamine, toluene/TFA (20:1),
MW, 1758C, 3 min; b) Na(CN)BH3 (5.0 mmol), MeOH, RT, 1.5 h; iii) HCHO (37% solution), RT, 1.5 h, 76%
(15a), 74% (15b).
boronic acid 13 (1.3 mmol),
NaHCO3 (3.0 equiv), and [Pd-
A
H2O (1:1; 1.5 mL each) was
sealed in a 10 mL glass vial.
The mixture was then irradiat-
ed at a pre-selected ceiling
temperature of 1508C for
15 min. The reaction was
found to proceed smoothly,
and compound 14a was isolat-
ed in an excellent yield of
92% (Scheme 11). Applying
the same conditions, we suc-
Scheme 12. Synthesis of ring-expanded buflavine analogues 17a,b: i) RCM, see Table 1; ii) Pd/C (10%),
MeOH, H2 (30 atm.), 8 h, 94% (17a), 93% (17b).
ceeded in synthesizing the trimethoxy analogue 14b in 90%
yield (Scheme 11).
lysts (G-1 and H-1) was found to be inadequate for effecting
the conversion, both under conventional heating conditions
as well as under microwave irradiation (Table 2, entries 1–
4), a Grubbs second-generation catalyst (G-2) was found to
promote the reaction under conventional heating conditions,
albeit in a low yield of 15% (Table 2, entry 5).
The situation improved dramatically upon microwave ir-
radiation of the reaction mixture. Thus, irradiating a sample
of the biaryl-amine 15a with G-2 (3 mol%) in toluene at a
Our next aim was to perform reductive aminations of the
respective biaryl aldehydes 14a,b with allylamine, followed
by N-alkylations of the thus formed amines, to generate the
key biaryl intermediates for RCM (Scheme 11). These con-
versions were tested with the least substituted aldehyde 14a.
Imination was carried out in refluxing toluene in the pres-
ence of 5% trifluoroacetic acid. When a Dean–Starktrap
was used for the azeotropic removal of water, the reaction
was found to be complete in 3 h. The imine, which was not
isolated, was identified as the sole product of the reaction
when the crude mixture was analyzed by CI-MS. Microwave
irradiation was found to be extremely valuable in this
regard, and the reaction was completed in a mere 3 min
when the mixture was irradiated in a sealed reaction vessel
at a ceiling temperature of 1758C. The presence of highly
microwave-absorbing trifluoroacetic acid in the reaction
mixture was useful not only for the condensation process,
but also for enabling attainment of the high ceiling tempera-
ture in the reaction medium when using an almost micro-
wave-transparent solvent such as toluene. The crude imine
was reduced with an excess of Na(CN)BH3 in MeOH at
room temperature for 1.5 h under an inert atmosphere.
Once the conversion to the corresponding amine was com-
plete, an excess of formaldehyde was added to effect N-
methylation. The reaction was completed after stirring for a
further 1.5 h at room temperature, and the N-methylated
amine 15a was isolated in 76% overall yield starting from
Table 2. Ring-closing metathesis to generate the nine-membered ring in
16a,b.[a]
Entry
Starting
material
Product
Catalyst
t
T [8C]
Yield [%][b]
AHCTREUNG
1
2
3
4
5
6
7
8
9
10
11
12
13
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15b
15b
15b
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16b
16b
16b
G-1
G-1
H-1
H-1
G-2
G-2
G-2
G-2
G-2
H-2
G-2
G-2
H-2
720[c]
15
110[c]
125
0
0
0
0
15
38
44
49
55
41
42
54
39
720[c]
15
110[c]
125
720[c]
5
10
15
15
15
15
15
15
110[c]
125
125
125
150
150
125
150
150
[a] All reactions were carried out on a 0.2 mmol scale with 3.0 mol% of
the catalyst in 3 mL of PhMe under microwave irradiation. [b] Yield of
isolated product. [c] Experiments were carried out under conventional
heating conditions in 5 mL of PhMe.
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Syntheses of Buflavine Analogues
FULL PAPER
mercially available compounds were purchased from Aldrich and were
used without further purification.
pre-selected temperature of 1258C for 5 min was found to
effect the conversion and the desired product 16a was iso-
lated in a moderate yield of 38% (Table 2, entry 6). Increas-
ing the reaction time to 10 and 15 min was found to furnish
better yields of 44 and 49%, respectively (Table 2, entries 7
and 8). The yield was further improved to 55% when the re-
action temperature was elevated to 1508C (Table 2, entry 9).
As expected, the cis-isomer was the only product generated
by the RCM, owing to the high conformational rigidity of
the ring system. Further increase of the reaction time and/or
temperature was found to be ineffective. Changing the cata-
lyst from G-2 to H-2 resulted in a decrease in the yield to
41% (Table 2, entry 10). The trimethoxy analogue 16b was
likewise synthesized in a good yield of 54% under the same
microwave-assisted conditions (Table 2, entry 12).
Microwave irradiation experiments: All microwave irradiation experi-
ments were carried out in a dedicated CEM-Discover mono-mode micro-
wave apparatus, operating at a frequency of 2.45 GHz with continuous ir-
radiation power from 0 to 300 W, utilizing the standard absorbance level
of 300 W maximum power. The reactions were carried out in 10 mL
sealed glass tubes capable of withstanding exposure to 2508C and 20 bar
internal pressure. The temperature was measured with an IR sensor on
the outer surface of the process vial. After the irradiation period, the re-
action vessel was rapidly cooled (60–120 s) to ambient temperature by
air-jet cooling.
Representative procedure for the bromination of aldehydes 3a,b
2-Bromo-4,5-dimethoxybenzaldehyde[23]
(4a): 3,4-Dimethoxybenzalde-
G
hyde 3a (1.66 g, 10.0 mmol) was dissolved in dry, degassed MeOH
(50 mL) and the resulting solution was stirred under argon. Bromine
(0.52 mL, 10.5 mmol) was added and the reaction mixture was stirred at
room temperature for 3 h. After completion of the reaction, as evidenced
by TLC and CI-MS analyses, the solvent was evaporated and the residual
mixture was partitioned between DCM (50 mL) and saturated aqueous
Na2S2O3 solution (50 mL). The aqueous layer was extracted once with
DCM (50 mL), and the combined organic layers were washed sequential-
ly with brine (25 mL) and water (25 mL). The solvent was removed
under reduced pressure to furnish the bromoaldehyde 4a, which was
used without further purification.
To complete the sequence, the dihydrodibenzo-
ACHTREUNG
ACHTREUNG
um-catalyzed hydrogenation protocol (Scheme 12) using a
high-pressure Parr hydrogenation apparatus. The reactions
were run in MeOH at a hydrogen pressure of 30 atm for 8 h.
The products 17a,b were isolated in yields of 94 and 93%,
respectively.
Representative procedure: Wittig reaction in the synthesis of alkenes
5a,b
1-Bromo-4,5-dimethoxy-2-vinylbenzene[24]
(5a): nBuLi (2.5m in hexanes,
C
1 mL) was slowly added to a stirred solution of methyl(triphenyl)phos-
phonium bromide (0.89 g, 2.5 mmol) in dry, degassed THF (20 mL) at
room temperature under an argon atmosphere. The resultant yellowish
solution was stirred for an additional 15 min until the deep yellow color
of the ylide developed. A solution of 2-bromo-4,5-dimethoxybenzalde-
hyde (4a, 0.61 g, 2.5 mmol) in dry THF (10 mL) was then added by
means of a hypodermic syringe, whereupon the color of the reaction mix-
ture soon started to fade. The resultant off-white solution was stirred at
room temperature for an additional 3 h, whereupon TLC and CI-MS
analyses indicated completion of the reaction. After NH4Cl work-up, the
organic components were extracted with DCM (3”25 mL) and the com-
bined organic layers were washed with brine (25 mL) and water (25 mL)
and finally dried over MgSO4. Removal of the solvents under reduced
pressure left the styrene 5a as a thickyellow oil, which was further puri-
fied by column chromatography (silica gel; heptane/diethyl ether 3:2) to
furnish the pure product (0.54 g, 89%).
Conclusion
We have developed two novel, flexible, and efficient strat-
egies for the synthesis of N-shifted and ring-expanded bufla-
vine analogues based on a Suzuki–Miyaura biaryl coupling
followed by a ring-closing metathesis reaction for the con-
struction of the medium-sized ring. The Suzuki–Miyaura re-
action, which is often problematic in instances of cross-cou-
pling between an electron-rich aryl halide and an electron-
poor boronic acid, has been successfully applied under con-
ditions of microwave irradiation. The combination of a
second-generation Grubbs catalyst and microwave irradia-
tion has proved to be highly useful in generating the other-
wise difficult to synthesize eight- and nine-membered ring
systems.
General procedure: microwave-assisted Suzuki–Miyaura reaction for the
synthesis of 2-nitro-biaryls 6a,b: Aryl bromide 5a,b (0.25 mmol), boronic
acid 2a (0.325 mmol, 1.30 equiv), NaHCO3 (0.75 mmol, 3.0 equiv), and
[Pd(PPh3)4] (5 mol%) were suspended in DMF (1.5 mL) and water
A
(1.5 mL) and the vial was tightly sealed. The mixture was irradiated for
15 min at a pre-selected temperature of 1508C, using a maximum irradia-
tion power of 100 W. After the reaction, the vial was cooled to 608C by
air-jet cooling. The crude mixture was partitioned between diethyl ether
(25 mL) and water (25 mL) and the aqueous layer was extracted with di-
ethyl ether (3”20 mL). The combined organic layers were dried over
magnesium sulfate and the solvents were removed under reduced pres-
sure to yield the crude product as a yellow oil. Column chromatography
(silica gel; heptane/diethyl ether 3:2) afforded the 2-nitro-biaryls 6a,b as
yellowish oily materials.
Experimental Section
General remarks: 1H and 13C NMR spectra were recorded on a Bruker
AMX 400 or Bruker 300 Avance instrument. The 1H chemical shifts are
reported in ppm relative to tetramethylsilane, using the residual solvent
signal as an internal reference. 13C chemical shifts are referenced to
CDCl3 as an internal standard, unless otherwise stated. Low-resolution
mass spectra were obtained with a Hewlett–Packard MS Engine 5989A
Synthesis of biaryl 6a by Suzuki–Miyaura reaction: Biaryl 6a was synthe-
sized according to the general procedure for
Suzuki–Miyaura reaction from styrene 5a (0.48 g, 2.0 mmol), boronic
acid 2a (0.43 g, 2.6 mmol), NaHCO3 (0.5 g, 6.0 mmol), and [Pd(PPh3)4]
a microwave-assisted
instrument. High-resolution mass spectra were recorded by using
a
Kratos MS50TC (ionization energy 70 eV) and a Kratos Mach III data
system. The ion source temperature was 150–3008C as required. High-
resolution EI-mass spectra were measured with a resolution of 10000.
For thin-layer chromatography, Alugram SIL G/UV254 analytical TLC
plates (E. M. Merck) were used. Column chromatography was carried
out using 70–230 mesh silica gel 60 (E. M. Merck). All compounds were
ACHTREUNG
(0.12 g, 5 mol%), using a maximum irradiation power of 150 W. After
chromatographic purification (silica gel; heptane/diethyl ether 3:2), ana-
lytically pure product 6a was isolated as a yellow oily material (0.48 g,
1
84%). H NMR (400 MHz, CDCl3): d=7.81 (d, J=8.2 Hz, 1H), 7.38 (dd,
J=7.8, 0.4 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J=7.1 Hz, 1H), 7.01 (s, 1H),
7.00 (dd, J=7.0, 0.4 Hz, 1H), 6.85 (dd, J=11.1, 17.3 Hz, 1H), 5.60 (dd,
characterized by H, 13C, and DEPT NMR, as well as by EI-MS. All com-
1
Chem. Eur. J. 2007, 13, 6452 – 6460
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www.chemeurj.org
6457

E. Van der Eycken et al.
J=17.3, 1.7 Hz, 1H), 5.20 (dd, J=11.1, 1.7 Hz, 1H), 3.87 (s, 3H),
3.81 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=149.1, 147.7, 147.3,
137.0, 136.8, 136.1, 134.5, 134.5, 133.6, 131.4, 129.0, 127.5, 115.6, 112.7,
56.0, 55.9 ppm; DEPT (100 MHz, CDCl3): d=137.0, 133.6, 129.0, 127.5,
115.6, 115.2, 112.7, 56.0, 55.9 ppm; MS (EI): m/z (%): 285 (100), 244, 239,
198.
rous evolution of H2 gas was observed and the solution tookon a pale-
yellow hue. Stirring was continued for a further 1.5 h, whereupon TLC
and CI-MS analyses indicated completion of the reaction. HCHO (37%
aqueous solution, 0.15 mL) was then added by means of a hypodermic sy-
ringe and stirring was continued for a further 1.5 h, whereupon the reac-
tion was found to be complete. The solvents were then removed under
reduced pressure and the residue was redissolved in EtOAc (50 mL). The
resulting solution was stirred at room temperature for 30 min with an
excess of K2CO3 (2.5 g). The mixture was then filtered through a small
pad of silica and the pad was repeatedly washed with EtOAc (3”10 mL)
and DCM (2”10 mL). The organic layers were combined and the sol-
vents were removed under reduced pressure. The crude residue was puri-
fied by column chromatography (silica gel; DCM/MeOH 9:1) to afford
the analytically pure product 15a (0.12 g, 76% from 14a) as a deep
yellow oil. 1H NMR (400 MHz, MeOD): d=8.52 (dd, J=17.8, 11.3 Hz,
1H), 7.59 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.21
(t, J=7.5 Hz, 1H), 7.09 (s, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.71–5.83 (m,
1H), 5.56 (dd, J=17.8, 1.7 Hz, 1H), 5.20 (dd, J=11.3, 1.3 Hz, 1H), 5.05
(dd, J=16.4, 1.3 Hz, 1H), 5.00 (dd, J=10.3, 1.3 Hz, 1H), 3.87 (s, 3H),
3.85 (s, 2H), 3.81 (s, 3H), 3.11 (d, J=5.3 Hz, 1H), 2.28 ppm (s, 3H); 13C
NMR (100 MHz, MeOD): d=151.6, 144.9, 142.3, 134.7, 133.9, 133.6,
131.6, 131.3, 131.0, 129.2, 127.8, 126.4, 117.4, 116.5, 115.2, 115.1, 57.7,
56.5, 56.0, 55.9, 43.8 ppm; DEPT (100 MHz, MeOD): d=133.9, 133.6,
131.6, 129.2, 126.4, 117.4, 116.5, 115.2, 115.1, 57.7, 56.5, 56.0, 55.9,
43.8 ppm; MS (EI): m/z (%): 323 (100%), 282, 267, 253, 226; HRMS
(EI): m/z (%): calcd for C21H25NO2: 323.18853; found: 323.18856.
Synthesis of biaryl 6b by a Suzuki–Miyaura reaction: Biaryl 6b was syn-
thesized according to the general procedure for a microwave-assisted
Suzuki–Miyaura reaction from styrene 5b (0.54 g, 2.0 mmol), boronic
acid 2a (0.43 g, 2.6 mmol), NaHCO3 (0.5 g, 6.0 mmol), and [Pd(Ph3P)4]
N
(0.12 g, 5 mol%), using a maximum irradiation power of 150 W. After
chromatographic purification (silica gel; heptane/diethyl ether 3:2), ana-
lytically pure product 6b was isolated as a yellow oily material (0.52 g,
1
82%). H NMR (400 MHz, CDCl3): d=7.89 (d, J=8.2 Hz, 1H), 7.39 (dd,
J=7.5, 0.3 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.96 (dd, J=7.5, 0.7 Hz,
1H), 6.85 (s, 1H), 6.83 (dd, J=11.0, 17.3 Hz, 1H), 5.56 (dd, J=17.3,
1.7 Hz, 1H), 5.24 (dd, J=11.0, 1.7 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H),
3.79 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=152.9, 149.6, 143.3,
140.1, 136.4, 136.1, 134.7, 133.6, 132.6, 129.6, 128.9, 124.6, 115.1, 103.2,
61.1, 60.9, 56.2 ppm; DEPT (100 MHz, CDCl3): d=136.4, 134.7, 132.6,
129.6, 128.9, 115.1, 103.2, 61.1, 60.9, 56.2 ppm; MS (EI): m/z (%): 315
(100%), 274, 269, 228.
Synthesis of 4’,5’-dimethoxy-2’-vinyl-1,1’-biphenyl-2-carbaldehyde (14a):
The biphenyl carbaldehyde 14a was synthesized from bromostyrene 5a
(0.24 g, 1 mmol), boronic acid 13 (0.20 g, 1.3 mmol), NaHCO3 (0.25 g,
3.0 mmol), and [Pd(PPh3)4] (0.6 g, 5 mol%) according to the general pro-
U
Synthesis of N-methyl-N-[{2’,3’,4’-trimethoxy-6’-vinyl-(1,1’-biphenyl)-2-
yl}methyl]-2-propen-1-amine (15b) under microwave irradiation: Amine
15b was synthesized from the biaryl aldehyde 14b (0.15 g, 0.5 mmol) fol-
lowing the procedure for the synthesis of 15a. Column chromatography
(silica gel; DCM/MeOH 9:1) afforded the analytically pure product 15b
(0.13 g, 76% from 14b) as a deep yellow oil. 1H NMR (400 MHz,
MeOD): d=7.23 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.83 (dd,
J=17.3, 11.30 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 6.64 (s, 1H), 6.58 (t, J=
7.5 Hz, 1H), 6.28 (t, J=8.1 Hz, 1H), 5.80–5.92 (m, 1H), 5.56 (dd, J=
17.3, 1.6 Hz, 1H), 5.09–5.22 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.80 (s,
2H), 3.79 (s, 3H), 3.10 (d, J=4.95 Hz, 1H), 2.29 ppm (s, 3H); 13C NMR
(100 MHz, MeOD): d=150.5, 148.8, 142.6, 136.9, 134.7, 134.3, 133.3,
131.8, 131.0, 129.3, 127.4, 126.3, 117.4, 116.2, 115.1, 105.7, 61.1, 60.9, 60.5,
58.5, 56.2, 46.0 ppm; DEPT (100 MHz, MeOD): d=134.7, 134.3, 133.3,
131.0, 127.4, 126.3, 117.4, 115.1, 105.7, 61.1, 60.9, 60.5, 58.5, 56.2,
46.0 ppm; MS (EI): m/z (%): 353 (100%), 312, 297, 283, 256; HRMS
(EI): m/z (%): calcd for C22H27NO3: 353.19909; found: 353.19916.
cedure for a microwave-assisted Suzuki–Miyaura reaction, using a maxi-
mum power level of 100 W. Column chromatography (silica gel; heptane/
diethyl ether 3:2) afforded the analytically pure product 14a (0.25 g,
92%) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3): d=9.21 (s, 1H),
8.53 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.12 (s,
1H), 6.86 (dd, J=17.3, 11.0 Hz, 1H), 6.76 (t, J=8.1 Hz, 1H), 6.50 (t, J=
8.1 Hz, 1H), 5.56 (dd, J=17.3, 1.7 Hz, 1H), 5.20 (dd, J=11.0, 1.7 Hz,
1H), 3.87 (s, 3H), 3.81 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
190.9, 149.3, 148.7, 148.3, 141.9, 136.8, 133.6, 131.6, 130.4, 127.9, 127.1,
122.9, 121.4, 115.2, 111.9, 56.0, 55.9 ppm; DEPT (75 MHz, CDCl3): d=
190.9, 136.8, 133.6, 130.4, 127.9, 122.9, 121.4, 115.2, 111.9, 56.0, 55.9 ppm;
MS (EI): m/z (%): 268 (100%), 239, 198; HRMS (EI): m/z (%): calcd
for C17H16O3: 268.10994; found: 268.10991.
Synthesis
of
2’,3’,4’-trimethoxy-6’-vinyl-1,1’-biphenyl-2-carbaldehyde
(14b): The biphenyl carbaldehyde 14b was synthesized from bromostyr-
ene 5b (0.27 g, 1.0 mmol), boronic acid 13a (0.20 g, 1.3 mmol), NaHCO3
(0.25 g, 3.0 mmol), and [Pd(PPh3)4] (0.6 g, 5 mol%) according to the gen-
G
General procedure for the synthesis of dihydrodibenzo[c,e]azonines
A
eral procedure for a microwave-assisted Suzuki–Miyaura reaction, using
a maximum power level of 100 W. Column chromatography (silica gel;
heptane/diethyl ether 3:2) afforded the analytically pure product 14b
(0.27 g, 90%) as a yellowish oily material. 1H NMR (300 MHz, CDCl3):
d=9.97 (s, 1H), 8.57 (dd, J=17.8, 11.3 Hz, 1H), 8.30 (d, J=7.7 Hz, 1H),
7.95 (s, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.54 (t, J=
8.1 Hz, 1H), 5.48 (dd, J=17.8, 1.7 Hz, 1H), 5.21 (dd, J=11.3, 1.7 Hz,
1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.77 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=191.0, 154.3, 154.1, 144.5, 139.3, 138.8, 135.2, 134.7, 129.0,
128.9, 127.2, 121.2, 115.8, 115.1, 102.4, 61.1, 60.9, 56.2 ppm; DEPT
(75 MHz, CDCl3): d=191.0, 138.8, 134.7, 129.0, 127.2, 121.2, 115.1, 102.4,
61.1, 60.9, 56.2 ppm; MS (EI): m/z (%): 298 (100%), 269, 228; HRMS
(EI): m/z (%): calcd for C18H18O4: 298.12051; found: 298.12055.
16a,b by ring-closing metathesis under microwave irradiation: The N-
allyl derivative 15a,b (0.25 mmol) was dissolved in dry, degassed solvent
(Table 1, 3 mL) and then the catalyst (Table 1, 3 mol%) was added to
this solution. The vial was tightly sealed and the mixture was irradiated
at a maximum power level of 150 W, for the time and at the temperature
indicated in Table 1. The mixture was then diluted with DCM (25 mL)
and washed with brine (10 mL), saturated NaHCO3 solution (10 mL),
and H2O (10 mL), and dried over MgSO4. After removal of the solvent,
the crude mixture was purified by column chromatography (silica gel;
DCM/MeOH 9:1) to furnish pure products 16a,b in the yields noted in
Table 1.
11,12-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo
[c,e]azonine (16a): 1H
G
NMR (400 MHz, MeOD): d=7.52 (d, J=8.1 Hz, 1H), 7.41 (s, 1H), 7.30–
7.38 (m, 3H), 6.85 (s, 1H), 6.53–6.60 (m, 1H), 6.56 (d, J=11.4 Hz, 1H),
5.79 (dt, J=11.4, 1.9 Hz, 1H), 4.71 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H),
3.29 (d, J=1.9 Hz, 1H), 2.28 ppm (s, 3H); 13C NMR (100 MHz, MeOD):
d=154.8, 150.3, 142.6, 142.1, 139.8, 134.2, 131.8, 131.7, 129.8, 129.2, 127.5,
124.9, 115.8, 114.7, 61.4, 56.0, 55.9, 55.9, 55.4, 42.2 ppm; DEPT (100 MHz,
MeOD): d=131.8, 131.7, 129.8, 129.2, 127.5, 124.9, 115.8, 114.7, 61.4,
56.0, 55.9, 55.4, 42.2 ppm; MS (EI): m/z (%): 295 (100%), 280, 214;
HRMS (EI): m/z (%): calcd for C19H21NO2: 295.15723; found: 295.15724.
Synthesis of N-[{4’,5’-dimethoxy-2’-vinyl-(1,1’-biphenyl)-2-yl}methyl]-N-
methyl-2-propen-1-amine (15a) under microwave irradiation: Biaryl al-
dehyde 14a (0.13 g, 0.5 mmol) was dissolved in PhMe (2.85 mL) and the
solution was transferred to a 10 mL glass vial equipped with a small stir-
ring magnet. TFA (0.15 mL) was then added, which led to an immediate
darkening of the golden-yellow solution. The vial was tightly sealed and
irradiated at a pre-selected temperature of 1758C for 3 min, using a maxi-
mum power level of 150 W. It was then returned to room temperature by
air-jet cooling and the contents were transferred to a 50 mL round-bot-
tomed flaskby rinsing with dry, degassed MeOH (3”5 mL). The result-
ing methanolic solution was thoroughly flushed with argon, and then
Na(CN)BH3 (0.32 g, 5.0 mmol) was added in a portionwise manner. Vigo-
11,12,13-Trimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azonine (16b):
A
1H NMR (400 MHz, MeOD): d=8.00 (d, J=8.0 Hz, 1H), 7.65 (t, J=
8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.99 (s,
6458
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Chem. Eur. J. 2007, 13, 6452 – 6460

Syntheses of Buflavine Analogues
FULL PAPER
1H), 6.52 (d, J=11.4 Hz, 1H), 5.82 (dt, J=11.4, 1.9 Hz, 1H), 4.61 (s,
2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.27 (d, J=1.9 Hz, 1H),
2.29 ppm (s, 3H); 13C NMR (100 MHz, MeOD): d=152.1, 150.6, 142.9,
139.1, 134.2, 133.7, 131.8, 131.7, 131.0, 127.4, 127.3, 125.9, 118.1, 104.4,
60.9, 60.4, 59.5, 56.0, 55.4, 42.2 ppm; DEPT (100 MHz, MeOD): d=
131.8, 131.7, 131.0, 127.4, 127.3, 125.9, 104.4, 60.9, 60.4, 59.5, 55.4,
42.2 ppm; MS (EI): m/z (%): 325 (100%), 310, 244; HRMS (EI): m/z
(%): calcd for C20H23NO3: 325.16779; found: 325.16781.
S. M. Weinreb, J. Am. Chem. Soc. 1997, 119, 5773; i) E. E. Elgorashi,
S. Zschocke, J. S. Van Staden, S. Afr. J. Bot. 2003, 69, 448; j) Z. Jin,
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bedahunsi, A. Adegbulugbe, Phytochemistry 2004, 65, 2893.
[2] F. Viladomat, J. E. Bastida, C. Codina, W. E. Campbell, S. Mathee,
Phytochemistry 1995, 40, 307.
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Bull. 1977, 25, 1851; b) S. Ishida, Y. Sasaki, Y. Kimura, K. Watanabe,
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Imakura, M. Kihara, S. Kobayashi, Res. Virol. 1989, 140, 115.
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161.
[5] See: a) P. E. Fanta, Chem. Rev. 1946, 46, 139; b) P. E. Fanta, Chem.
Rev. 1964, 64, 613; c) P. E. Fanta, Synthesis 1974, 9; d) G. H. Posner,
An Introduction to Synthesis using Organocopper Reagents, Wiley,
New York, 1980; e) G. Bringmann, R. Walter, R. Weirich, Angew.
Chem. Int. Ed. Engl. 1990, 29, 977.
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159.
General procedure: synthesis of dihydrodibenzo[c,e]azonines 17a,b: The
A
cyclized compound 16a,b (0.25 mmol) was dissolved in dry, degassed
MeOH (25 mL) and the solution was transferred to a high-pressure Parr
hydrogenation bottle. 10% Pd/C (10 mol%) was added and the vessel
was repeatedly evacuated and flushed with hydrogen (4”). The mixture
was then kept under hydrogen pressure (30 atm) for 8 h, whereupon TLC
and CI-MS analyses showed completion of the reaction. The contents of
the vessel were then filtered though a small pad of Celite and the pad
was repeatedly washed with DCM (3”25 mL). The solvents were re-
moved under reduced pressure to furnish the crude products 17a,b,
which were further purified by column chromatography (silica gel; DCM/
MeOH 9:1) to furnish the pure products as pale-yellow oils.
11,12-Dimethoxy-6-methyl-6,7,8,9-tetrahydro-5H-dibenzo[c,e]azonine
N
[7] a) P. A. Patil, V. Snieckus, Tetrahedron Lett. 1998, 39, 1325; b) C.
Hoarau, A. Couture, E. C. Deniau, P. Grandclaudon, J. Org. Chem.
2002, 67, 5846; c) P. Sahakitpichan, S. Ruchirawat, Tetrahedron Lett.
2003, 44, 5239; d) S. Kodama, H. Takita, T. Kajimoto, K. Nishide, M.
Node, Tetrahedron 2004, 60, 4901.
[8] P. Appukkuttan, A. B. Orts, R. P. Chandran, J. L. Goeman, J. van der
Eycken, W. Dehaen, E. van der Eycken, Eur. J. Org. Chem. 2004,
3277.
(17a): Compound 17a was synthesized from the cyclized compound 16a
(0.25 mmol) according to the general procedure. Column chromatogra-
phy (silica gel; DCM/MeOH 9:1) afforded the pure product 17a (0.07 g,
1
94%) as a pale yellow oil. H NMR (400 MHz, MeOD): d=7.84 (s, 1H),
7.40 (d, J=8.3 Hz, 1H), 7.29–7.36 (m, 2H), 6.61 (d, J=8.5 Hz, 1H), 6.34
(s, 1H), 4.31 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.79 (t, J=7.0 Hz, 2H),
2.32 (s, 3H), 2.26 (dt, J=7.0, 0.8 Hz, 2H), 1.46 ppm (m, 2H); 13C NMR
(100 MHz, MeOD): d=153.9, 151.4, 141.9, 140.3, 138.2, 135.7, 129.0,
127.9, 127.5, 126.0, 117.7, 112.8, 60.4, 60.3, 56.0, 55.8, 47.1, 34.3, 29.7 ppm;
DEPT (100 MHz, MeOD): d=129.0, 127.9, 127.5, 126.0, 117.7, 112.8,
60.4, 60.3, 56.0, 55.8, 47.1, 34.3, 29.7 ppm; MS (EI): m/z (%): 297
(100%), 282, 214; HRMS (EI): m/z (%): calcd for C19H23NO2:
297.17288; found: 297.17294.
[9] For our preliminary communication on microwave-assisted synthesis
of N-shifted buflavine analogues, see: P. Appukkuttan, W. Dehaen,
E. van der Eycken, Org. Lett. 2005, 7, 2723.
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in Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich,
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Organomet. Chem. 1999, 576, 147; d) S. Kotha, K. Lahiri, D. Kashi-
nath, Tetrahedron 2002, 58, 9633, and references therein. For micro-
wave-assisted Suzuki–Miyaura reactions, see: e) M. Larhed, G. Lin-
deberg, A. Hallberg, Tetrahedron Lett. 1996, 37, 8219; f) N. E. Lead-
beater, M. Marco, Angew. Chem. Int. Ed. 2003, 42, 1407; g) C. O.
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2981; j) J. Hashim, T. N. Glasnov, J. M. Kremsner, C. O. Kappe, J.
Org. Chem. 2006, 71, 1707; k) E. F. DiMauro, J. R. Vitullo, J. Org.
Chem. 2006, 71, 3959; l) C. O. Kappe, D. Dallinger, Nature Rev.
Drug. Discov. 2006, 5, 51, and references therein; m) R. L. Harker,
R. D. Crouch, Synthesis 2007, 25.
[11] a) M. Schuster, S. Blechert, Angew. Chem. Int. Ed. Engl. 1997, 36,
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11,12,13-Trimethoxy-6-methyl-6,7,8,9-tetrahydro-5H-dibenzo[c,e]azonine
G
(17b): Compound 17b was synthesized from the cyclized compound 16b
(0.25 mmol) according to the general procedure. Column chromatogra-
phy (silica gel; DCM/MeOH 9:1) afforded the pure product 17b (0.08 g,
93%) as a pale yellow oil. 1H NMR (400 MHz, MeOD): d=7.72 (d, J=
8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.79 (t, J=8.1 Hz, 1H), 6.58 (t, J=
8.1 Hz, 1H), 6.54 (s, 1H), 4.35 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.44 (t,
J=7.0 Hz, 2H), 3.42 (s, 3H), 2.31 (s, 3H), 2.28 (dt, J=7.0, 0.8 Hz, 2H),
1.49 ppm (m, 2H); 13C NMR (100 MHz, MeOD): d=154.0, 151.6, 144.0,
138.4, 134.3, 129.8, 128.2, 127.8, 127.4, 124.0, 108.0, 61.1, 60.9, 60.4, 60.3,
56.1, 47.1, 34.7, 29.7 ppm; DEPT (100 MHz, MeOD): d=129.8, 127.8,
127.4, 124.0, 108.0, 61.1, 60.9, 60.4, 60.3, 56.1, 47.1, 34.7, 29.7 ppm; MS
(EI): m/z (%): 327 (100%), 312, 244; HRMS (EI): m/z (%): calcd for
C20H25NO3: 327.18344; found: 327.18340.
Acknowledgements
The authors wish to thankthe F.W.O. [Fund for Scientific Research -
Flanders (Belgium)] and the Research Fund of the University of Leuven
for financial support. P.A. is grateful to the University of Leuven for
granting a postdoctoral fellowship. We also wish to thankProf. Dr. S.
Toppet for her valuable help with the NMR experiments.
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6460
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Chem. Eur. J. 2007, 13, 6452 – 6460