A domino palladium catalysis: Synthesis of 7-methyl-5 H -dibenzo[ a, c ][7] annulen-5-ones

Article abstract of DOI:10.1055/s-0033-1338438

A domino Pd-catalyzed reaction of 1-(2-bromophenyl)ethanones for the synthesis of novel 7-methyl-5H-dibenzo[a,c][7]annulen-5-ones, a carbon core structure present in colchicinoid natural products, is presented. The reaction is proposed to proceed via intermolecular homobiaryl coupling and intramolecular aldol condensation. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1338438

LETTER
▌967
lAetteDr omino Palladium Catalysis: Synthesis of 7-Methyl-5H-dibenzo[a,c][7]
annulen-5-ones
7-Methyl-5H-dibenzo[a,c][7]annulen-5-ones
Jonnada Krishna, Alavala Gopi Krishna Reddy, Gedu Satyanarayana*
Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram – 502 205, Medak District, Andhra Pradesh,
India
Fax +91(40)23016032; E-mail: gvsatya@iith.ac.in
Received: 18.01.2013; Accepted after revision: 03.04.2013
This paper is affectionately dedicated to Professor Kavirayani R. Prasad, Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
dative coupling,10 and Lewis acid mediated Nicholas
Abstract: A domino Pd-catalyzed reaction of 1-(2-bromophe-
cyclization11 that facilitate the biaryl tricyclic systems in a
nyl)ethanones for the synthesis of novel 7-methyl-5H-diben-
step-wise manner.
zo[a,c][7]annulen-5-ones, a carbon core structure present in
colchicinoid natural products, is presented. The reaction is proposed
to proceed via intermolecular homobiaryl coupling and intramolec-
ular aldol condensation.
HO
OH
MeO
OH
Key words: Pd catalysis, homobiaryl coupling, domino reaction,
aldol condensation, 2-bromoacetophenones
O
OH
O
HO
subamol
reticuol
The invention of efficient and viable synthetic methods to
accomplish complex molecules by employing one-pot
processes is a significant area in synthetic organic chem-
istry.1 In this regard, transition-metal catalysis is consid-
ered to be a powerful technique for constructing C–C
bonds efficiently and palladium, in particular, has been
used to develop such novel interconversions.2,3 Generally,
it has been observed that, in the presence of inherent intra-
molecular ring constraints, the initially formed Pd inter-
mediates prefer to undergo intermolecular homo- or
heterocoupling rather than intramolecular reaction.4,5 For
example, when we recently subjected α,α-disubstituted
(2-haloaryl)methanols to Pd(0) catalysis, the reaction did
not proceed via intramolecular coupling to yield the ex-
pected 8,8-dialkyl-7-oxabicyclo[4.2.0]octa-1,3,5-trienes,
but rather furnished 6,6-dialkyl-6H-benzo[c]chromenes
via an efficient homobiaryl coupling.5h
NHAc
R
MeO
OMe
MeO
R = CO2Me; allocolchicine
R = OH; N-acetylcolchinol
Figure 1
The required 1-(2-bromophenyl)ethanones 1 for this
study were prepared from the corresponding ortho-halo-
benzaldehydes using an alkyl Grignard addition and oxi-
dation protocol (see Supporting Information). Having
obtained the requisite 1-(2-bromophenyl)ethanones 1, the
Pd-mediated transformation of the 1-(2-bromophe-
nyl)ethanone 1c was subjected to numerous conditions
(for complete details see Supporting Information). Treat-
ment of 1c in the presence of Pd(OAc)2 (5 mol%), dppf
(10 mol%), and base K3PO4 (4 equiv) in hot DMF at
100 °C for 10 hours gave the product 3c, in poor yield
(26%, Table 1, entry 1). The reaction with the ligand L1
further decreased the yield (8%, Table 1, entry 2), whereas
ligand L2 returned it to 25% (Table 1, entry 3). Other li-
gands L3, L4, PCy3, and Pd(PPh3)4 also proved ineffec-
tive (Table 1, entries 4–7). Interestingly, the use of
different catalysts improved the yield (Table 1, entries 8
and 9). Gratifyingly, the reaction in the presence of ligand
L5 improved the yield to 50% (Table 1, entry 10). Disap-
pointingly, addition of various additives was unsuccessful
in improving the yield further (Table 1, entries 11–14).
In continuation of our interest in transition-metal cataly-
sis,6 we present herein a novel one-pot process based on a
hitherto unexplored domino palladium catalysis of 1-(2-
bromophenyl)ethanones 1 for the effective construction
of 7-methyl-5H-dibenzo[a,c][7]annulen-5-ones 3. This
process involves an unprecedented mechanistic pathway
to yield structures present as the carbon core of biological-
ly active natural products such as the colchicinoids (Fig-
ure 1).7 It is worth mentioning that this method delivers
these systems via a novel domino C–C σ-bond and C=C
π-bond-forming process, using simple 1-(2-bromophe-
nyl)ethanones 1, unlike the usual methods, such as inter-
molecular Suzuki–Miyaura coupling followed by aldol
condensation,8 intramolecular Heck reaction,9 biaryl oxi-
SYNLETT 2013, 24, 0967–0972
Advanced online publication: 11.04.2013
Although the yield of 3c is moderate, it is still in an ac-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338438; Art ID: ST-2013-D0061-L
© Georg Thieme Verlag Stuttgart · New York
ceptable range because each individual step (i.e., biphenyl

968
J. Krishna et al.
LETTER
coupling and aldol condensation) accounts for nearly 70% aryl-cyclized products 3a–g in comparable yields
yield. Moreover, the present method compares well with (Scheme 1).
previous reports, which involve not less than four steps
The chemical structures of 3a–g have been further unam-
with poor overall yield,12 for the synthesis of such struc-
biguously confirmed by the single-crystal X-ray diffrac-
turally relevant compounds.
tion analysis of 3g13 (Figure 2 and Supporting
Thus, to study the scope and limitations of the present Information).
method, these optimized conditions were applied to other
1-(2-bromophenyl)ethanones 1. Pleasingly, the reaction
progressed well with the other substrates and gave the bi-
tions of the methodology by changing the alkyl group of
After the accomplishment of one-pot synthesis of 3a–g,
we became interested in looking at the scope and limita-
Table 1 Optimization Reaction Conditions for the Synthesis of 3,9-Dimethoxy-7-methyl-5H-dibenzo[a,c][7]annulen-5-one (3c)
O
MeO
O
Me
MeO
[Pd]/ligand
Me
base
solvent
Δ
Br
OMe
1c
3c
Entrya,b
[Pd] (mol%)
Ligand (mol%)
Base (equiv)
Time (h)
Yield of 3c (%)c
1
2
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (5)
Pd(PPh3)4 (2)
Pd(dppf)Cl2 (2)
dppf (10)
L1 (4)
L2 (4)
L3 (4)
L4 (4)
P(Cy)3 (10)
–
K3PO4 (4)
K3PO4 (4)
K3PO4 (4)
K3PO4 (4)
K3PO4 (4)
K3PO4 (4)
Cs2CO3 (4)
Cs2CO3 (2)
K3PO4 (4)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
10
3
26
8
3
3
25
15
16
16
11
32
30
50
45d
23e
36f
25g
4
3
5
3
6
3
7
34
18
3
8
–
9
Pd(PPh3)2Cl2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
–
10
11
12
13
14
L5 (4)
L5 (4)
L5 (4)
L5 (4)
L5 (4)
2
2
12
2
3
PPh2
PPh2
O
P(t-Bu)2
PCy2
PCy2
P(t-Bu)2
i-Pr
Me2N
i-Pr
Me Me
i-Pr
L4: tert-Butyl XPhos
L1: JohnPhos
L2: Cyclohexyl
L3: DavePhos
L5: Xantphos
JohnPhos
a All reactions were performed on 100 mg (0.44 mmol) scale of 1c at 0.22 M concentration, in DMF (2 mL).
b All reactions were heated to 150 °C except in entries 1 (100 °C) and 7 (120 °C).
c Isolated yields of chromatographically pure products.
d 4 Å MS (100 mg) were used as additive.
e H2O (40 equiv) was used as additive.
f ZnCl2 (0.2 equiv) was used as additive.
g n-Bu4NBr (0.2) was used as additive.
Synlett 2013, 24, 967–972
© Georg Thieme Verlag Stuttgart · New York

LETTER
7-Methyl-5H-dibenzo[a,c][7]annulen-5-ones
969
O
O
R2
R1
Pd(OAc)2 (2 mol%)
Xantphos (4 mol%)
R2
Me
Me
K3PO4 (2 equiv)
DMF (2 mL)
R1
Br
150 °C, 0.75–2 h
R2
1a–g
R1
3a–g
O
O
BnO
Me
Me
OBn
3a (45%)
3b (41%)
O
O
BnO
MeO
MeO
Figure 2 X-ray crystal structure of 3g. Thermal ellipsoids are drawn
at 50% probability level.
Me
Me
OBn
OMe
MeO
O
Me
3c (50%)
3d (43%)
O
MeO
Pd(OAc)2
Xantphos
X
K3PO4
DMF,150 °C
O
O
MeO
Et
Et
MeO
BnO
O
O
Me
Me
Br
OMe
4c
5c
Scheme 2
OMe
O
BnO
O
3e (41%)
3f (41%)
Furthermore, Pd catalysis of 1c with the simple haloben-
zenes 6a was also explored, in order to achieve a hetero-
biaryl variant of the reaction. However, performing the Pd
catalysis under a range of different conditions, neither al-
lowed us to recover back the starting material nor gave the
expected product 7a as depicted in Scheme 3.
O
MeO
MeO
Me
OMe
MeO
O
O
Br
3g (44%)
MeO
MeO
[Pd]/ligand
Me
Scheme 1 Scope of one-pot Pd-catalyzed homobiaryl coupling.
Reagents and conditions: 1a–g (100–150 mg, 0.30–0.58 mmol),
0.15–0.25 M in DMF. Yields in the parentheses are isolated yields of
chromatographically pure products.
+
X
base
Br
solvent
Δ
1c
6a
7a
Scheme 3
the ketone. Unpromisingly, Pd catalysis of 1-(2-bromo-
phenyl)propan-1-one 5ac was sluggish (Scheme 2). This
can be reasoned to be based on the availability of the β-hy-
drogen to initially formed aryl Pd-five membered species,
which in turn may collapse quickly by preferring intramo-
lecular syn elimination rather than the intermolecular bi-
aryl coupling.
Since, the formation of heterobiaryl system 7a was not
successful, we turned to our attention to modify the meth-
od to generate such biaryls via a preferential α-arylation of
2-bromoacetophenone 1c with a more reactive iodoarene
followed by intramolecular Heck reaction. However,
treatment of 1c with iodoarenes 8a and 8b did not furnish
the desired products, but gave only α-arylation products
9a and 9b, respectively (Scheme 4). This parallels previ-
ously reported α-arylations.14
A plausible mechanism for the formation of 3a is similar
to that reported in our earlier work.5h The five-membered
palladacycle B could be formed via the insertion of the
initially formed aryl-palladium(II) species A, into the sp3
C–H bond of the ketone (Scheme 5). The Pd(IV) interme-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 967–972

970
J. Krishna et al.
LETTER
O
MeO
I
X
R
7a
7b
O
8a
8b
R
MeO
Me
Pd(OAc)2 (2 mol%)
Xantphos (4 mol%)
t-BuOK, toluene
80 °C, 12 h
R
Br
O
1c
MeO
Br
9a; R = H (72%)
9b; R = COOMe (75%)
Scheme 4 α-Arylation of 1c with 8a and 8b
O
O
O
O
Ln–2
HBr
Me
Me
Pd(0)Ln
Pd(II)L2
Br
Pd(II)BrL2
Pd(IV)L2
1a
A
B
C
Br
H
Ln–2
1a
Pd(II)Br(K2PO4)L2
O
O
O
Me
OK
Me
3a
Pd(IV)L2
OPd(II)BrL2
Br
O
K3PO4
Me
D
F
E
Scheme 5 Plausible catalytic cycle for the formation of 3a
diate B converts into the reactive Pd(II) species C through
HBr elimination. The key Pd cyclic species C combines
with a second molecule 1a via C–Br bond insertion and
generates Pd(IV) complex D.2b,15 Biaryl coupling leads to
the Pd(II) intermediate, which on nucleophilic addition to
keto group of second aromatic ring furnishes Pd(II) spe-
cies E. Expulsion of Pd complex E16 by base yields tertia-
ry alkoxide F and a Pd(II) species. Finally, F transforms
into the product 3a by elimination, and Pd(II) returning to
Pd(0) completes the catalytic cycle (Scheme 5).
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI: 10.4125/pd0045th. mPirDayramPtirDayra1t0.421p5d0/04mhP5itrD.yraZateanh1l01
C
h
yemrsti
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m
iotSrat
ungIifoop
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Synlett 2013, 24, 967–972
© Georg Thieme Verlag Stuttgart · New York

LETTER
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(10) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma,
H.; Kita, Y. J. Org. Chem. 1999, 63, 7698.
(17) General Procedure-1 for the Pd-Mediated Cyclization
(GP-1)
In an oven-dried Schlenk tube under nitrogen atmosphere
were added ortho-bromoacetophenone 1a–g (100–150 mg,
0.30–0.58 mmol), Pd(OAc)2 (2 mol%), Xantphos (4 mol%),
and K3PO4 (0.60–1.16 mmol) followed by addition of dry
DMF (2 mL). The resulted reaction mixture was stirred at
150 °C for 0.75–2 h. Progress of the reaction was monitored
by TLC until the reaction was completed. The reaction
mixture was then quenched with sat. aq NH4Cl, and the
aqueous layer was extracted with EtOAC (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude product 3a–g was purified
by column chromatography on silica gel using PE–EtOAc as
eluent.
Representative Analytical Data
7-Methyl-5H-dibenzo[a,c][7]annulen-5-one (3a)
Yield: 25 mg, 45%; viscous liquid. IR (MIR-ATR, 4000–
600 cm–1): νmax = 3062, 2957, 2853, 1652, 1593, 1439, 1377,
1356, 1307, 1250, 1121, 1003, 850, 771, 735, 621 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.79 (dd, 2 H, J = 7.6, 5.3 Hz,
ArH), 7.74 (m, 2 H, ArH), 7.63 (ddd, 1 H, J = 8.7, 7.4, 1.3
Hz, ArH), 7.53 (dd, 1 H, J = 7.7, 7.6 Hz, ArH), 7.48 (2 H,
J = Hz, ArH), 6.62 (s, 1 H, ArH), 2.44 (s, 3 H, CH=CCH3).
13C NMR (100 MHz, CDCl3): δ = 194.0 (s, ArC=O), 144.8
(s, CH=CCH3), 142.0 (s, ArC), 137.5 (s, ArC), 137.3 (s,
ArC), 135.7 (s, ArC), 133.2 (d, ArCH), 131.9 (d, CH=CCH3),
131.2 (d, ArCH), 130.8 (d, ArCH), 128.6 (d, ArCH), 128.1
(d, ArCH), 127.8 (d, ArCH), 127.3 (d, ArCH), 127.1 (d,
ArCH), 24.4 (q, CH=CCH3). HRMS (ESI+): m/z calcd for
[C32H25O2]+ = [2 (M + H)]+: 441.1849; found: 441.1836.
(11) Djurdjevic, S.; Green, R. R. Org. Lett. 2007, 9, 5505.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 967–972

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J. Krishna et al.
LETTER
3,9-Dimethoxy-7-methyl-5H-dibenzo[a,c][7]annulen-5-
one (3c)
3.89 (s, 3 H, ArOCH3), 2.43 (d, 3 H, J = 0.9 Hz, CH=CCH3).
13C NMR (100 MHz, CDCl3): δ = 193.6 (s, ArC=O), 159.0
(s, ArC), 158.4 (s, ArC), 144.8 (s, CH=CCH3), 142.3 (s,
ArC), 136.3 (s, ArC), 132.9 (d, CH=CCH3),132.8 (d, ArCH),
131.3 (d, ArCH), 130.5 (s, ArC), 130.4 (s, ArC), 119.4 (d,
ArCH), 114.5 (d, ArCH), 112.2 (d, ArCH), 109.7 (d, ArCH),
55.6 (q, ArOCH3), 55.4 (q, ArOCH3), 24.6 (q, CH=CCH3).
HRMS (ESI+): m/z calcd for [C18H17O3]+ = [M + H]+:
281.1172; found: 281.1161.
Yield: 31 mg, 50%; white solid; mp 125–127 °C. IR (MIR-
ATR, 4000–600 cm–1): νmax = 3001, 2934, 2837, 1643, 1603,
1571, 1484, 1408, 1337, 1281, 1240, 1174, 1039, 814, 753,
722, 614 cm–1. 1H NMR (400 MHz CDCl3): δ = 7.69 (d,
J = 8.9 Hz, ArH), 7.66 (d, J = 8.9 Hz, ArH), 7.28 (d, 1 H,
J = 2.9 Hz, ArH), 7.20 (d, 1 H, J = 2.8 Hz, ArH), 7.18 (dd, 1
H, J = 8.9, 2.9 Hz, ArH), 7.04 (dd, 1 H, J = 8.9, 2.8 Hz,
ArH), 6.61 (d, 1 H, J = 0.9 Hz, ArH), 3.89 (s, 3 H, ArOCH3),
Synlett 2013, 24, 967–972
© Georg Thieme Verlag Stuttgart · New York

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