Palladium-catalyzed intramolecular C-H activation: A synthetic approach towards polycyclic aromatic hydrocarbons

Article abstract of DOI:10.1055/s-0029-1220070

A simple and convenient synthetic protocol for the construction of polycyclic aromatic hydrocarbons has been developed. A variety of phenanthrene, benzo[c]phenanthrene and chrysene derivatives was synthesized via Pd-catalyzed intramolecular C-H activation followed by acid-catalyzed water elimination.

Full text of DOI:10.1055/s-0029-1220070

LETTER
1463
Palladium-Catalyzed Intramolecular C–H Activation: A Synthetic Approach
towards Polycyclic Aromatic Hydrocarbons
P
alladium-Cat
u
alyze
d
Intram
n
olecular C–
a
H Activatio
n
n
da Paul, Rathin Jana, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: jkray@chem.iitkgp.ernet.in
Received 1 February 2010
tion.13 Fagnou et al. have reported the intramolecular for-
Abstract: A simple and convenient synthetic protocol for the con-
struction of polycyclic aromatic hydrocarbons has been developed.
A variety of phenanthrene, benzo[c]phenanthrene and chrysene de-
rivatives was synthesized via Pd-catalyzed intramolecular C–H ac-
tivation followed by acid-catalyzed water elimination.
mation of biaryl compounds via palladium-catalyzed
direct C–H arylation.14 Our continued interest in the de-
velopment of carbocycles and heterocycles based on pal-
ladium chemistry15 prompted us to develop a new route
for the synthesis of aromatic hydrocarbons via a palladi-
um-catalyzed intramolecular coupling reaction.
Key words: benzyl Grignard, Pd catalyst, C–H activation, polycy-
clic aromatic hydrocarbons
For this purpose the required precursors 3a–p (Scheme 1)
were efficiently prepared in 75–80% yield by treating the
o-bromoaromatic aldehydes 2a–h with benzyl magne-
sium chloride in diethyl ether at 0 °C for 30 minutes.16
The o-bromoaromatic aldehydes 2a–f were in turn pre-
pared in excellent yield by the Vilsmeier–Haack-type re-
action from the corresponding tetralone derivatives17
followed by the aromatization with 2,3-dichloro-5,6-dicy-
anobenzoquinone (DDQ).
Polycyclic aromatic hydrocarbons (PAH) form a large
class of compounds found mainly in petrochemical sourc-
es.1 The unique properties of PAH in producing the tumor
growth have made these compounds a focal point of con-
siderable synthetic importance. The utility of PAH as base
molecules for electronic devices such as field-effect tran-
sistors or light-emitting diodes is also important. There
are also large numbers of aromatic and polycyclic aromat-
ic hydrocarbons that find use as ligands in transition-
metal-catalyzed asymmetric synthesis.2 Thus develop-
ment of new efficient methods for synthesis of this class
of compound is still an active area of research.
Table 1 Optimization Studiesa
Br
Many synthetic approaches for the preparation of PAH
have been reported by different groups, of which the most
common procedure involves classical oxidative photocy-
clization of stilbene derivatives.3 Among other methods,
OH
OH
3a
4
the intramolecular Diels–Alder reaction,4 flash vacuum Entry Catalyst
pyrolysis,5 olefin metathesis,6 Friedel–Crafts-type cy-
Base
Solvent Temp (°C) Yield (%)b
1
2
Pd(OAc)2
Cs2CO3 DMF
NaOAc DMA
Cs2CO3 DMF
135
135
100
135
135
100
110
120
135
135
135
dec.
dec.
n.r.
n.r.
30
clization,7 dimerization or trimerization of acetylenes and
arynes,8 transition-metal-catalyzed cycloisomerization9
have been used as the key step for construction of a ben-
zene ring for the synthesis of PAH. We have contributed
in this field by synthesizing trisubstituted benzene deriva-
tives via base-catalyzed condensation and aromatization
of various bromoaldehydes with active methylene com-
pounds.10
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
3
4
Et3N
DMA
5
NaOAc DMA
6
Pd(PPh3)2Cl2 NaOAc DMA
Pd(PPh3)2Cl2 NaOAc DMA
Pd(PPh3)2Cl2 NaOAc DMA
Pd(PPh3)2Cl2 NaOAc DMA
Pd(PPh3)2Cl2 Cs2CO3 DMA
<20
20
Palladium-catalyzed activation of aromatic C–H bonds
has been extensively used for the construction of carbo-
and heterocycles from the corresponding halides and tri-
flates.11 Larock et al. have developed a novel palladium-
catalyzed migration/C–H activation methodology for the
synthesis of complex fused polycycles.12 De Meijere et al.
have synthesized phenanthrene molecules from o-bromo-
cis-stilbene via palladium-catalyzed intramolecular aryla-
7
8
42
9
73
10
11
n.r.
<10
PdCl2
NaOAc DMA
a All the reactions were carried out with 3a (1 mmol) in presence of
catalyst (5 mol%), base (1.5 mmol) in solvent (5 mL) at the indicated
temperature for 2 h.
SYNLETT 2010, No. 10, pp 1463–1468
x
x
.x
x
.2
0
1
0
b Yields refer to the isolated yield of 4 after purification; n.r. = no
reaction.
Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1220070; Art ID: D03110ST
© Georg Thieme Verlag Stuttgart · New York

1464
S. Paul et al.
LETTER
R2
a) PBr3, DMF,
CHCl3, 25 °C,
12 h
Br
X
O
X
Br
X
CHO
c) Ar
Et2O, 0 °C,
MgCl
OH
b) DDQ,
benzene
reflux, 12 h
30 min
R1
R1
R1
R1 = H, OMe
X = CH, CMe
2 = H, Me
1a–e
2a–e
3a–j
R1 = H, OMe
R
X = CH2, CHMe
R2
HO
CHO
Br
O
Br
c
a, b
1f
2f
3k–m
R2 = H, Me
R2
Br
Br
CHO
c
OH
R3
2g–h
R3
3n–p
R2 = H, Me
3 = H, F
R
Scheme 1 Synthesis of precursors
After a thorough screening of different combinations of Therefore, after the C–H arylation step, no attempt was
reagent, solvent, and temperature, the optimized reaction made to isolate the cyclized alcohol and instead the crude
conditions were found when substrate 3a (1 mmol), reaction mixture was treated with 6 M hydrochloric acid
Pd(PPh3)2Cl2 (5 mol%), and NaOAc (1.5 mmol) in N,N- to obtain the fully aromatized hydrocarbon. Thus an im-
dimethylacetamide (DMA, 5 mL) were heated at 130– portant feature of this methodology for the preparation of
140 °C for two hours to obtain the cyclized product 4. aromatic hydrocarbon is the ability to conduct the two-
When this reaction was carried out with the same combi- step operation (cyclization via C–H activation and elimi-
nation of catalyst, base, and solvent at the temperature of nation of water) in one pot without purification of the in-
100–120 °C a poor yield was obtained. The optimization termediate cyclized alcohol. The yields of aromatic
studies are summarized in Table 1.
hydrocarbons are tabulated in the Table 2.
The cyclized alcohol 4 thus obtained in the carbopallada- It is important to note that substrates 3d,g,l,n bearing an
tion reaction, on treatment with 6 M hydrochloric acid un- ortho substituent in the aryl ring gave slightly lower yields
derwent elimination of water to afford the aromatic which may be due to steric hindrance. A relatively poor
hydrocarbon 5a (Scheme 2).
yield of the phenanthrene 5p was obtained.
A possible mechanistic pathway of Pd-catalyzed intramo-
lecular C–H activation25 is depicted in Scheme 3. Initially
oxidative insertion of palladium to the carbon–halogen
bond occurs to form an aryl–palladium intermediate 6
which undergoes palladation–deprotonation in either of
the two alternative pathways shown to give the Pd(II) in-
termediate 9. This species then undergoes reductive elim-
ination to form the cyclized alcohol 4, and the catalyst is
regenerated.
Pd(PPh3)2Cl2, NaOAc
Br
DMA, 130–140 °C, 2 h
OH
OH
3a
4
H+
In conclusion we have developed a new efficient and con-
venient route to a various isomers of tri- and tetracyclic
polycondensed aromatic compound in good yields from
readily available starting materials via palladium-cata-
lyzed intramolecular C–C coupling followed by acid-cat-
alyzed dehydration.26,27
5a
Scheme 2 Synthesis of polycyclic aromatic hydrocarbon
Synlett 2010, No. 10, 1463–1468 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Intramolecular C–H Activation
1465
Br
OH
OH
Pd(PPh3)n
4
3a
#
O
Br
Me
O
Ph3P
Ph3P
Pd
Pd
NaOAc
H
Br
Ph3P
OH
OH
Pd
AcOH
NaBr
9
6
OH
NaOAc
AcOH
10
NaBr
O
#
H
O
O
PPh3
Pd
O
Pd
Ph3P
OH
OH
8
7
Scheme 3 Plausible reaction mechanism
Table 2 Polycyclic Aromatic Hydrocarbonsa
Entry
Substrate
Product
Yield (%)b
Br
1
71
OH
OH
OH
5a18
3a
3b
Br
2
3
71
72
5b19
Br
5c19
3c
Synlett 2010, No. 10, 1463–1468 © Thieme Stuttgart · New York

1466
S. Paul et al.
Table 2 Polycyclic Aromatic Hydrocarbonsa (continued)
Entry Substrate
LETTER
Product
Yield (%)b
Br
OMe
4
69
OH
5d
OMe
3d
Br
OMe
5
75
OH
OMe
5e
3e
Br
Br
Br
6
7
8
9
74
68
75
74
OH
OH
OH
OMe
5f20
MeO
3f
OMe
MeO
5g
3g
OMe
MeO
5h
3h
Br
MeO
OH
OMe
5i20
3i
Br
10
11
74
70
MeO
OH
OMe
5j
3j
OH
Br
5k4
3k
Synlett 2010, No. 10, 1463–1468 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Intramolecular C–H Activation
1467
Table 2 Polycyclic Aromatic Hydrocarbonsa (continued)
Entry
12
Substrate
Product
Yield (%)b
OH
65
Br
3l
5l21
OH
13
14
71
67
Br
5m22
3m
Br
OH
Br
5n23
3n
3o
15
16
72
58
OH
5o13
Br
F
OH
F
3p
5p24
a Reaction conditions: All the reactions were carried out with substrate (1 mmol) in presence of Pd(PPh3)2Cl2 (5 mol%), NaOAc (1.5 mmol) in
DMA (5 mL) at 130–140 °C for 2 h.
b Yields refer to the isolated yield after purification.
(5) (a) Scott, L. T.; Hashemi, M. M.; Meyer, D. T.; Warren,
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Acknowledgment
(6) Bonifacio, M. C.; Robertson, C. R.; Jung, J. Y.; King, B. T.
We thank DST, New Delhi for financial support. S.P. and R.J.
thanks CSIR, New Delhi for fellowships.
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Synlett 2010, No. 10, 1463–1468 © Thieme Stuttgart · New York

1468
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LETTER
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(26) General Procedure for the Grignard Reaction
Benzyl chloride (1.4 mmol) in anhyd Et2O (3 mL) was added
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magnesium turnings (4.3 mmol) in anhyd Et2O (4 mL). The
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dropwise to the o-bromoaromatic aldehyde (0.8 mmol) in
anhyd Et2O (5 mL) at 0 °C, and the mixture was stirred at
that temperature for 30 min. The reaction was quenched with
sat. aq NH4Cl solution, and the aqueous phase was extracted
with Et2O (3 × 15 mL). The combined organic phases were
washed with brine, dried over anhyd Na2SO4, filtered, and
evaporated to give the crude product which was purified by
silica gel (60–120 mesh) column chromatography using PE–
EtOAc as the eluent.
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(27) General Procedure for Pd-Catalyzed C–H Activation
The precursor (1 mmol) and dry NaOAc (1.5 mmol) were
flushed with argon and DMA (5 mL) was added to it. After
degasification, Pd(PPh3)2Cl2 (5 mol%) was added, and the
reaction mixture was heated at 130–140 °C for 2 h. This was
then cooled and stirred with 2–3 mL of 6 N HCl for 5–10 min
at r.t. The mixture was diluted with H2O and extracted with
EtOAc (3 × 15 mL). After drying over anhyd Na2SO4 and
filtering, the solvent was evaporated in vacuo to give the
crude product which was purified by silica gel (60–120
mesh) column chromatography using PE as the eluent.
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