Microwave-assisted direct biaryl coupling: first application to the synthesis of aporphines

Article abstract of DOI:10.1016/j.tetlet.2009.03.029

We have investigated the use of microwaves in a direct biaryl coupling reaction for the synthesis of analogs of the aporphine alkaloid nantenine. Our study shows that the aporphine core may be rapidly accessed from benzyl-tetrahydroisoquinoline substrates

Full text of DOI:10.1016/j.tetlet.2009.03.029

Tetrahedron Letters 50 (2009) 2437–2439
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted direct biaryl coupling: first application to the synthesis
of aporphines
*
Sandeep Chaudhary, Stevan Pecic, Onica LeGendre, Wayne W. Harding
Department of Chemistry, Hunter College, and the Graduate Center of the City, University of New York, 695 Park Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have investigated the use of microwaves in a direct biaryl coupling reaction for the synthesis of ana-
logs of the aporphine alkaloid nantenine. Our study shows that the aporphine core may be rapidly
accessed from benzyl-tetrahydroisoquinoline substrates with this method. This is the first report of a
microwave-assisted direct biaryl coupling reaction in the synthesis of aporphine molecules.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 November 2008
Revised 2 March 2009
Accepted 5 March 2009
Available online 11 March 2009
Microwave irradiation is being increasingly utilized in organic
synthesis due often to superior reaction rates, selectivity, and
product yields as compared to standard thermal conditions.1–3
Microwave-assisted versions of biaryl coupling methodologies
such as the Suzuki, Heck, and Negishi reactions have been reported
extensively in the literature.4–9 However, there have been rela-
tively few reports on the use of microwave irradiation in direct
biaryl coupling procedures.
3
O
O
O
O
O
2
NMe
NMe
NR
1
6
RO
10
O
O
O
9
3
O
2
1
O
O
Figure 1. Structure of nantenine and target analogs.
Direct biaryl coupling is similar to the Heck reaction in terms of
substrates used. However, whereas the Heck reaction couples an
activated arene (such as an aryl halide or aryl triflate) and an al-
kene, direct biaryl coupling uses an activated arene and an aro-
matic ring as substrates.10 There is evidence that the Heck and
direct biaryl coupling reactions are mechanistically dissimilar,
with direct biaryl coupling likely proceeding via a concerted meta-
lation–deprotonation pathway.11–13
For the synthesis of N6 analogs we required compound 2b
(Fig. 2). We anticipated that 2b could be readily obtained from ben-
zyl-tetrahydroisoquinoline 4 via 2a. Synthesis of 2a via direct biar-
yl coupling under thermal conditions has been reported to occur in
high yield (Pd(OAc)2, ligand A, K2CO3, DMA, 130 °C, 99%).14,15 How-
ever, in our hands only a 48% yield of cyclized product was ob-
The direct biaryl coupling procedure is very useful for construc-
tion of biaryl bonds, in both inter- and intra-molecular reactions,
and has been used in the synthesis of a number of bioactive mole-
cules including aporphines.14,15 Recently, this methodology has
also been applied to synthesis of heterocyclic biaryl motifs.16–18
Aporphines are a diverse group of alkaloids found in several
plant species and have been found to show a range of interesting
biological activities such as antiserotonergic, dopaminergic, anti-
plasmoidal, antihelminthic, and anticancer activities.19–23 This
has led to several syntheses of this class of compounds.24,14,25
One of our current interests is in the synthesis of aporphine alka-
P
PPh2
P
Me2N
HBF4
Ligand B
Ligand C
Ligand A
O
O
loids related to the serotonergic 5-HT2A and a1 adrenergic receptor
antagonist nantenine (1, Fig. 1).26,21,27,28 We were particularly
interested in preparing N6 and C1 nantenine analogs (general
structures 2 and 3, respectively) for our structure–activity relation-
ship (SAR) studies and envisaged that the direct biaryl coupling
route would be a facile strategy for accessing the required analogs.
Pd(OAc)2, solvent,
ligand, base, heat
NBoc
NR
O
O
O
O
O
Br
4
2
O
2a R = Boc
2b
R = H
* Corresponding author. Tel.: +1 212 772 5359; fax: +1 212 772 5332.
E-mail address: whardi@hunter.cuny.edu (W.W. Harding).
Figure 2. Approach to synthesis of N6 nantenine analogs.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.029

2438
S. Chaudhary et al. / Tetrahedron Letters 50 (2009) 2437–2439
Table 1
Table 2
Thermal cyclizationa of 4 and 5
Microwave-assisted biaryl couplinga of 5 and 630
Entry
Substrate
Product
Solvent
Ligand
Yield (%)
Entry
Substrate
Product
Solvent
Ligand
Yield (%)
1
4
4
5
2b
2b
7
DMA
DMA
DMA
A
A
A
48
47
47
1
2
3
4
5
6
7
5
5
5
5
6
6
6
7
7
7
7
8
8
8
DMA
DMA
DMF
DMSO
DMA
DMA
DMA
A
B
B
B
B
A
C
15
72
82
88
87
82
78
2b
3
a
Conditions: Pd(OAc)2, K2CO3, DMA, ligand A, 130 °C, 24 h.
Pivalic acid added to the reaction.
b
a
Conditions: Pd(OAc)2, K2CO3, solvent, pivalic acid, ligand, microwaves, 5 min.
tained using the previously reported thermal conditions (Table 1,
entry 1). Addition of pivalic acid which has been reported to en-
hance some biaryl coupling reactions and overall yields, did not re-
sult in any improvement in the yield of 2a (Table 1, entry 2).29
Furthermore, attempts to remove the boc group of 2a under typical
acidic conditions (TFA/DCM) gave only a moderate yield (52%) of
2b. Given the apparent sensitivity of the aporphine nucleus to
acidic conditions, we decided to prepare the ethyl carbamate
derivative 7 (Scheme 1) since we envisaged that cleavage of the
ethyl carbamate group to give 2b could be readily effected under
basic conditions.
Table 3
Thermal and microwave-assisteda cyclization of 9
Entry
Substrate
Product
Solvent
Ligand
Yield (%)
1
9a
9a
9a
9a
9a
9b
10a
10a
10a
10a
10a
10b
DMA
DMA
DMA
DMA
DMA
DMA
A
A
A
A
B
B
40
58
51
81
90
82
2b
3a
4a,b
5a,b
6a,b
Following this approach, we prepared compound 5 (Scheme 1).
However, when the direct biaryl coupling procedure was at-
tempted under standard thermal conditions (Table 1, entry 3) we
only obtained a 47% yield of the aporphine 7. We observed that a
significant amount of starting material remained after reacting
for 24 h. Even after reacting for 48 h, the reaction did not proceed
to completion. At this juncture, we decided to attempt to improve
the yield of this biaryl cyclization and increase the overall effi-
ciency of our synthesis through the use of microwaves.
a
Conditions: Pd(OAc)2, K2CO3, solvent, ligand microwaves, 5 min.
Pivalic acid added to the reaction.
b
O
O
NCO2R Pd(OAc)2, DMA,
NCO2R
O
pivalic acid, ligand
O
K2CO3, microwaves
5 min
81%-90%
Br
In our first attempt at microwave-assisted direct biaryl cycliza-
tion of 5, we employed ligand A with DMA as solvent (Table 2, en-
try 1). Disappointingly, we found that the yield was significantly
reduced as compared to the analogous thermal conditions, there
being formed a significant amount of an unidentified by-product.
Nevertheless, to examine the effect of different ligands, we con-
ducted the microwave-assisted reaction with ligand B using DMA
as solvent (Table 2, entry 2) and were elated to find that there
was considerable improvement in the yield. With ligand B, other
polar, high boiling solvents (DMF and DMSO) also gave excellent
yields (Table 2, entries 3 and 4). We next decided to apply our
microwave conditions to the synthesis of 8 (Scheme 1). Compound
8 is a versatile intermediate for the synthesis of N6 as well as C1
nantenine analogs. With substrate 6 we obtained a high yield of cy-
clized product 8 with the ligand B/DMA combination (Table 2, en-
try 5). Ligands A and C were also effective in achieving biaryl
cyclization with DMA as solvent (Table 2, entries 6 and 7) in very
good yields. From compound 8 we were able to synthesize several
C1 and N6 nantenine analogs using standard synthetic
transformations.
9
10
10a R = Me
10b
9a R = Me
R = Et
9b
R = Et
Scheme 2. Direct biaryl cyclization of 9.
combination gave only a moderate yield of 10a under thermal con-
ditions.14 We also found this to be the case, although addition of
pivalic acid gave a slight improvement in yield (Table 3, entries 1
and 2) (see Scheme 2).
Using ligand A, in the absence of pivalic acid under microwave
conditions, gave a moderate yield (Table 3, entry 3); addition of
pivalic acid substantially improved the yield of the microwave-as-
sisted reaction to 81% (Table 3, entry 4). Ligand B gave a slightly
improved yield as compared to ligand A using otherwise identical
conditions (Table 3, entry 5). With the ethyl carbamate congener
9b, cyclization was effected in 82% yield with ligand B (Table 3, en-
try 6).
To further explore the substrate scope of the newly developed
microwave-assisted conditions, we decided to investigate cycliza-
tion of the less reactive arene substrate 9a which is devoid of elec-
tron-releasing groups in the haloarene component. Previous
attempts at cyclization of this compound with a ligand A/DMA
R2
R2
O
O
NCO2R3
NCO2R3
R1
R1
Pd(OAc)2, DMA,
pivalic acid, ligand
K2CO3, microwaves
R5
O
O
O
R4
5 min
79%-90%
R4
Br
11-15
R5
11a-15a
R
NCO2Et
R
NCO2Et
Pd(OAc)2, solvent,
O
O
pivalic acid, K2CO3, ligand
microwaves
11, 11a R1=OEt, R2=H, R3=Et, R4=R5=OCH2O
12, 12a R1=OPr, R2=H, R3=Et, R4=R5=OCH2O
13, 13a R1=H, R2=OMe, R3=Et, R4=H, R5=H
14, 14a R1=H, R2=OMe, R3=Et, R4=OMe, R5=H
15, 15a R1=OMe, R2=H, R3=t-butyl, R4=H, R5=H
O
5 min
15-88%
Br
O
5 R = Methyl
6 R = Benzyl
O
7 R = Methyl
8 R = Benzyl
Scheme 1. Microwave-assisted direct biaryl coupling.
Scheme 3. Microwave-assisted direct biaryl cyclization of 11–15.

S. Chaudhary et al. / Tetrahedron Letters 50 (2009) 2437–2439
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Microwave-assisted cyclization of 11–15
Entry
Substrate
Product
Solvent
Ligand
Yield (%)
1
2
3
4
5
11
12
13
14
15
11a
12a
13a
14a
15a
DMA
DMA
DMA
DMA
DMA
B
B
B
B
B
82
79
90
84
79
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To further explore the substrate diversity of the microwave
reaction, we then applied our optimized conditions for the synthe-
sis of aporphines 11a–15a (Scheme 3). These results which demon-
strate broader substrate applicability of the reaction conditions are
presented in Table 4.
In conclusion, our study demonstrates the utility of microwaves
for rapid direct biaryl coupling in the synthesis of aporphines.
Additionally, we found that the microwave method is operationally
simpler because no special precautions need to be taken to avoid
exposure of the reaction to air. This is the first report on micro-
wave-assisted direct biaryl coupling in the synthesis of aporphines.
We are continuing to examine substrate tolerance in this micro-
wave-enhanced reaction and will report our findings in due course.
23. Zhang, A.; Zhang, Y.; Branfman, A. R.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2007, 50, 171–181.
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28. Orallo, F. Planta Med. 2003, 69, 135–142.
29. Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015–6020.
30. Typical microwave-assisted biaryl coupling procedure (using 6 as an example): To
a solution of compound 6 (50.0 mg, 0.09 mmol), in DMA (4 ml) were added
Pd(OAc)2 (2.0 mg, 0.1 mmol), ligand A (6.9 mg, 0.2 mmol), K2CO3 (37.5 mg,
0.3 mmol), and pivalic acid (2.8 mg, 0.03 mmol). The mixture was irradiated in
a Smith Creator microwave reactor in a sealed vial for 5 min with the power
level at 150 W. After cooling to room temperature, the reaction mixture was
loaded onto a deactivated silica gel column and eluted with 40% ethyl acetate-
hexanes. This gave compound 8 (35.0 mg, 0.074 mmol, 82%). Compound 8,
white solid, 1H NMR (CDCl3, 500 MHz): d 1.27 (t, J = 5.6 Hz, 3H), 2.65 (d,
J = 13.8 Hz, 1H), 2.72 (d, J = 13.8 Hz, 1H), 2.87 (t, J = 12.6 Hz, 2H), 2.96 (t,
J = 12.6 Hz, 1H), 3.89 (s, 3H), 4.21 (q, J = 5.6 Hz, 2H), 4.51 (br s, 1H), 4.66 (d,
J = 10.2 Hz, 1H), 4.67 (1H, obscured), 4.81 (d, J = 10.2 Hz, 1H), 5.96 (s, 1H), 5.99
(s, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.31 (m, 3H), 7.37 (d, J = 6.6 Hz, 2H), 8.05 (s,
1H).
Acknowledgments
O.L. acknowledges the RISE program at Hunter College for
financial support. We also thank Dr. Robert Bittman at Queens Col-
lege, CUNY for providing access to the microwave reactor and other
general assistance. This publication was made possible by Grant
No. RR03037 from the National Center for Research Resources
(NCRR), a component of the National Institutes of Health.
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