Palladium-catalyzed intramolecular oxidative heck cyclization and its application toward a synthesis of (±)-β-cuparenone derivatives supported by computational studies

Article abstract of DOI:10.1055/s-0032-1316884

A novel and efficient intramolecular oxidative cyclization of substituted homoallylic alcohols to form cyclic keto compounds under palladium-catalyzed conditions is described. The reaction has practical applications in the synthesis of sesquiterpenes. The

Full text of DOI:10.1055/s-0032-1316884

PAPER
▌1261
paper
Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization and Its
Application toward a Synthesis of (±)-β-Cuparenone Derivatives Supported by
Computational Studies
Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization
Devalina Ray, Yasmin Nasima, Mal K. Sajal, Priyanka Ray, Sharmistha Urinda, Anakuthil Anoop,* Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur, India
Fax +91(3222)282252; E-mail: jkray@chem.iitkgp.ernet.in
Received: 16.11.2012; Accepted after revision: 11.03.2013
the corresponding fused methyl-substituted cyclopenten-
Abstract: A novel and efficient intramolecular oxidative cycliza-
one derivatives 3 (Scheme 1).
tion of substituted homoallylic alcohols to form cyclic keto com-
pounds under palladium-catalyzed conditions is described. The
reaction has practical applications in the synthesis of sesquiter-
penes. The mechanism of cyclization, the key step in the tandem
reaction, was analyzed by using density functional theory calcula-
tions.
Br
Br
In(0), CH2=CHCH2Br
NaI, DMF, r.t.
Pd(OAc)2, Ph3P
HCO2Na, DMF
80 °C, 8 h
CHO
O
OH
3
2
1
Key words: palladium, Heck reaction, cyclizations, terpenoids,
ketones, alkenes, catalysis, oxidations, computational studies
Scheme 1 Synthesis of substituted cyclopentenones
Various cyclic bromovinyl aldehydes 1.11–1.16 (Table 1)
were subjected to an allylation protocol to assess the gen-
erality of our method. In all cases, we obtained the corre-
sponding 1-bromohexa-1,5-dien-3-ol derivatives 2 in
good-to-excellent yields.
The cyclization of unsaturated substrates by intramolecu-
lar Heck reactions promoted by organopalladium com-
plexes is of fundamental importance for the construction
of vast array of mono- and polycarbocyclic systems, and
is therefore a highly attractive technique for the synthesis
of cyclic natural products.1 Palladium(II) complexes are
extremely important in organopalladium chemistry. Palla-
dium(0) complexes are fairly nucleophilic, rather labile,
and easily oxidized, usually to the palladium(II) state. The
most synthetically useful chemistry of palladium(0) in-
volves the oxidative addition of aryl, vinylic, or allylic ha-
lides or triflates to palladium(0); such reactions can be
very useful in the synthesis of carbocycles or heterocy-
cles.2 Our investigations have focused mainly on possible
cycloannulations through an intramolecular Heck reaction
followed by oxidation of an alcohol group, most signifi-
cantly from a bromovinyl alcohol. In continuation of these
studies, we have examined the corresponding reactions of
homoallylic alcohol derivatives and we have inferred the
mechanism of this reaction.
Initially, we chose sodium formate as the base for the
Heck cyclization reaction. We subsequently examined the
effect on the yields of cyclopentenones of other bases, in-
cluding organic bases such as triethylamine, which was
not effective in promoting the reaction. Although many
factors could have effects under our reaction conditions, it
seemed logical to assume that the yield might be im-
proved by using an inorganic base. We found that inor-
ganic bases such as sodium carbonate, potassium
carbonate, or sodium acetate gave the cyclized products in
good-to-moderate yield. When we performed the Heck re-
action of 2.16 in the presence of these inorganic bases,
keeping other variables constant, we obtained the corre-
sponding product 3.16 in 59–69% yield (Table 2).
The cyclization reaction of the allylated substrates 2.11–
2.16 with sodium formate as the base gave the corre-
sponding cyclized products in moderate-to-good yields
(Table 3). The use of phase-transfer conditions with tetra-
butylammonium chloride (TBAC) improved the yield by
12% in the case of substrate 2.16. In this case, we believe
that the greater solubility of the reagents as a result of the
presence of TBAC might play a crucial role in determin-
ing the outcome of the reaction.
As part of our ongoing interest in palladium-catalyzed
Heck reactions,3 we developed a new method and we ex-
tended it to the synthesis of some precursors of sesquiter-
pene natural products. In the context of our general
interest in the chemistry of β-bromovinyl aldehydes4 and
our exploration of the sequential indium-mediated al-
lylation and palladium-catalyzed cyclization of such com-
pounds, we attempted to develop a general method for the
synthesis of 1-bromohexa-1,5-dien-3-ol derivatives 2 that
would undergo an intramolecular Heck reaction to form
A fundamental goal of chemical research is to understand
the mechanism of a reaction that leads to specific prod-
ucts. Because we could not isolate any intermediates from
these reaction, there were many plausible mechanisms.
We therefore performed some additional experiments to
obtain some clues as to the mechanism of the reaction. By
using the chiral agent (+)-(R)-1,1′-binaphthalene-2,2'-di-
SYNTHESIS 2013, 45, 1261–1269
Advanced online publication: 08.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316884; Art ID: SS-2012-Z0825-OP
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Table 1 Allylation of β-Bromovinyl Aldehydes
Table 2 Heck Reaction of Substrate 2.16 in the Presence of Various
Inorganic Bases
Entrya Substrate
Product
Time
(h)
Yieldb
(%)
Substrate
Basea
Yieldb (%)
Br
Br
Na2CO3
K2CO3
NaOAc
68
69
59
Br
OH
1
2
4.0
3.0
73
61
CHO
OH
1.11
1.12
2.11
Br
Br
a All the reactions were carried out with Pd(OAc)2 (10 mol%), Ph3P
(0.25 mmol), and base (1 mmol) in DMF at 80 °C for 8 h.
b Isolated yield after purification
CHO
OH
2.12
Br
Br
Table 3 Heck Reaction with 1-Bromohexa-1,5-dien-3-ol
CHO
Entrya
Substrate
Product
Yieldb (%)
3
4
5
3.5
4.5
3.5
72
76
76
OH
O
1.13
1.14
2.13
2.14
1
2.11
58
Br
Br
CHO
OH
2
3
4
2.12
2.13
2.14
61
60
63
HO
CHO
O
Br
Br
1.15
2.15
O
Br
CHO
Br
OH
6
4.0
81
O
O
1.16
2.16
5
6
2.15
2.16
62
71
a Reaction conditions: β-bromovinyl aldehyde (1 mmol), In metal (1.2
mmol), CH2=CHCH2Br (3 mmol), NaI (4 mmol), DMF, stirring, r.t.,
5 h.
O
b Isolated yields after purification.
ylbis(diphenylphosphine) [(+)-(R)-BINAP], we attempt-
ed to induce chirality at the tertiary center formed by
cyclization with the aim of determining whether a partic-
ular enantiomer would be formed in excess. However, we
obtained a racemic mixture of products, implying that
there no chiral induction had occurred (Scheme 2).
a All reactions were carried out with Pd(OAc)2 (10 mol%), Ph3P (0.25
mmol), and HCO2Na (1 mmol) in DMF at 80 °C for 8 h.
b Isolated yield after purification.
Our next experiment, however, led us to a probable mech-
anistic interpretation. The bromodienol O-methoxy deriv-
ative 2.16a underwent Heck cyclization to afford the
corresponding fused O-methoxycyclopentenol derivative
3.16a containing an exocyclic double bond. Substrate
2.16a was prepared in 67% yield by O-alkylation of 1-(2-
bromoacenaphthylen-1-yl)but-3-en-1-ol (2.16) with iodo-
H
Pd(OAC)2
(+)-(R)-BINAP
Br
H
+
HCO2Na, DMF
80 °C
O
O
OH
Scheme 2 Heck reaction in the presence of the (+)-(R)-BINAP li-
gand
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Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization
1263
methane in the presence of sodium hydride. Heck reaction (11.60 kcal/mol). The energies were also evaluated by
of this substrate in the presence of either sodium formate means of hybrid-density functional theory (DFT) B3LYP
or potassium carbonate as the base gave the tetracycle for BP86-optimized geometries. In B3LYP, the activation
3.16a (Scheme 3). In this case, the hydroxyl group is pro- energy was 114.6 kJ/mol (27.39 kcal/mol) and the reac-
tected, so a keto group cannot form through isomerization. tion energy was 35.02 kJ/mol (8.73 kcal/mol), in agree-
The isolation of the product with an exocyclic double ment with the usual energetic trends in DFT.
bond indicates that a hypothesis based on cyclization of
the homoallylic alcohol derivatives followed by β-hydride
elimination is logical.
OMe
Br
OMe
Br
OH
Pd(0)
base
NaH, MeI
THF, 0 °C
Figure 1 Optimized geometries (BP86/def2-SVP) of the species in-
volved in the migratory insertion step
2.16a
2.16
3.16a
Scheme 3 Heck reaction of the O-methoxy derivative of 1-(2-bro-
moacenaphthylen-1-yl)but-3-en-1-ol 3.16a
To examine whether the C1=C2 double bond plays any
role in the reaction, we synthesized the novel substrate
2.16b by indium-mediated allylation of bromovinyl alde-
hyde 1.16 with 1-bromo-3-methylbut-2-ene (Scheme 5).
Our proposed oxidative cyclization mechanism involves
an initial oxidative addition of palladium(0) to produce a
palladium(II) complex A; this is followed by intramolec-
ular ring closure to form the cyclic intermediate B, which
undergoes β-hydride elimination followed by isomeriza-
tion of the resulting intermediate C to give the thermody-
namically stable ketone (Scheme 4).
Br
1
1
Br
In(0), DMF
BrCH2CH=CMe2
63%
2
2
CHO
OH
1.16
2.16b
PdBr
Br
PdBr
OH
Scheme 5 Indium-mediated allylation of bromo aldehyde 1.16
Pd(0)
Pd(0)
n
n
n
Application of Heck reaction conditions with sodium for-
mate to substrate 2.16b gave a mixture of products 3.16b
and 3.16c in a 3:1 ratio (Scheme 6). It is possible that the
indenol compound containing an exocyclic double bond
3.16c was initially formed and that this readily isomerized
by a route involving C1–C2 to give the thermodynamical-
ly stable ketone 3.16b. Isomerization by the path involv-
ing C4–C5 is not possible because there are no available
hydrogen atoms at C4, which is substituted by two methyl
groups (Scheme 6).
OH
OH
A
B
n = 1,2,3
HPdBr
HPdBr
n
n
PdBr
OH
OH
C
D
n
O
Scheme 4 A plausible mechanism for the cyclization reaction
This observation was confirmed when we performed the
Heck reaction with the allylated bromo aldehyde deriva-
tive 2.17 (Scheme 7).5 In this case, inseparable mixtures
of products 3.17b and 3.17a, containing an exocyclic and
an endocyclic double bond, respectively, were obtained in
proportions that depended on the reaction conditions and
no keto product was isolated.
The existence of the cyclization step shown in Scheme 4
for the case of n = 3 was supported by a computational
study (see below for details). The geometry of the inter-
mediate after oxidative addition was modeled by using
PdL (L = Ph3P) as the catalyst. In the optimized structure
X (Figure 1), the palladium atom adopts a square-planar
geometry with coordination from carbon, bromine, and
phosphorus, and the double bond. The transition state TS
for the cyclization was located and characterized. The ac-
tivation energy for this process is 102.0 kJ/mol (24.37
kcal/mol) at the BP86/def2-SVP level of theory. In the cy-
clized intermediate Y, palladium is coordinated to the
double bond and has an agostic interaction with the β-hy-
drogen. The reaction energy for this step is 48. 53 kJ/mol
From these results, we can relate the reaction mechanism
for β-bromoallyl alcohol derivatives to that of their aro-
matic analogues. It is possible that in the case of β-bro-
moallyl alcohol derivatives of vinylic bromo aldehydes,
cyclization and β-elimination reactions of intermediate A
give intermediate C, which undergoes two consecutive
1,5-hydrogen shifts to form the product (Scheme 8). In the
case of the aromatic system, the exocyclic double bond
formed after cyclization cannot participate in isomeriza-
© Georg Thieme Verlag Stuttgart · New York
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D. Ray et al.
PAPER
Br
1
2
Pd(OAc)2
5
Ph3P, TBAC
HCO2Na
DMF, 80 °C, 8 h
4
3
OH
O
OH
2.16b
3.16b
3.16c
Scheme 6 Cyclization of substrate 2.16b under Heck reaction conditions
yields prompted us to investigate an unusual palladium-
catalyzed tandem Heck cyclization. We therefore exam-
ined the formation of gem-dimethyl cyclopentenone moi-
eties from 1-bromo-5-methyl-1-arylhexa-1,5-dien-3-ols
under palladium-catalyzed Heck reaction conditions
(Scheme 9).9
Br
Pd(OAc)2, Ph3P
+
HCO2Na, DMF
80 °C, 5 h
OH
OH
OH
2.17
3.17a
3.17b
Aware of the possibilities offered by this reaction, we ap-
plied the method to obtain two different products from a
common starting material by varying the reaction condi-
tions (Scheme 9). In this scheme lies the beauty of our
methodology. By applying our methodology, we aimed to
synthesize various sesquiterpene natural products by
changing the substituents in the aryl moiety. This conver-
gent approach involved the preparation of the cyclization
precursors 2.21–2.27, which were efficiently assembled
by indium-mediated methallylation of the corresponding
bromo aldehydes 1.21–1.27 with 3-bromo-2-methylprop-
1-ene in 80–90% yield (Scheme 10).
Scheme 7 Heck reaction of substrate 2.17
tion with the double bond of the aromatic ring system, and
therefore no keto compound is obtained. We therefore
speculate that the β-bromoallyl alcohol derivatives react
by the pathway shown in Scheme 8.
PdBr
PdBr
OH
Br
Pd(0)
HCO2Na
OH
OH
Br
B
R1
A
Br
CHO
In(0), CH2=C(Me)CH2Br
NaI, DMF
R1
R2
OH
R2
1.21–1.27
2.21–2.27
H
80–90%
O
H
O
OH
E
C
Scheme 10
Scheme 8
We then attempted to perform the cyclization reaction
with various bases, solvents, and catalysts to optimize the
reaction conditions. We found that when we carried out
the reaction with 2 mol% of palladium(II) acetate, 0.5
equivalents of triphenylphosphine, and 1.5 equivalents of
sodium carbonate in N,N-dimethylformamide at 80 °C for
five hours, the yield of 3.21 increased to 70% (Scheme 11
and Table 4). Compound 3.21 can be converted into (±)-
β-cuparenone in a single step.10
To examine the practical utility of our methodology, we
developed a new and efficient method related to the pre-
vious one, and we extended it to the synthesis of sesqui-
terpene natural products. Many multistep methods have
previously been developed for the synthesis of com-
pounds such as (±)-α- and (±)-β-cuparenone or (±)-her-
bertene, but these methods are lengthy, involve hazardous
materials, or give low yields.6–8 Our need to develop a
practical method involving fewer step and giving higher
Br
R1
R1
O
OH
R1
R2
OH
Pd(OAc)2, Ph3P
Pd(OAc)2, Ph3P
R2
Na2CO3, DMF
80 °C, 5 h
HCO2Na, DMF
80 °C, 3 h
R2
Scheme 9
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Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization
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Table 4 Synthesis of gem-Dimethylcyclopentenone Derivatives
3.21–3.27 by Palladium-Catalyzed Intramolecular Cyclization of
Dienols 2.21–2.27
Br
R1
R2
O
R1
R2
Pd(OAc)2, Ph3P
OH
Na2CO3, DMF
80 °C, 5 h
Entrya Substrate
Product
Yieldb
(%)
2.21–2.27
3.21–3.27
Scheme 11
Br
O
OH
1
70
75
As described above, we were able to obtain the methyl-
substituted fused cyclopentenone derivatives through a
1,5-hydrogen shift of the cyclized product containing an
exocyclic double bond, formed by intramolecular cycliza-
tion of the allylated and propargylated derivatives of vinyl
bromo aldehyde. In this case, the possibility of formation
of an exocyclic double bond could be eliminated because
of lack of availability of a β-hydrogen for elimination af-
ter cyclization through the 5-exo-trig pathway (Scheme
12).
In a recent communication,11 it was established that in the
absence of a terminating agent, this type of substrate un-
dergoes olefin insertion in the 6-endo mode. In our case,
5-exo-trig cyclization occurred, probably because of the
presence of the –CHOH group in the substrate, which do-
nates hydride for termination and is thereby converted
into a carbonyl group.
3.21
3.22
2.21
Br
O
OH
2
2.22
Br
O
OH
3
65
MeO
MeO
3.23
2.23
By changing the reaction conditions by using sodium for-
mate as the hydride donor in the absence of a base, we
were able to isolate the cyclized hydroxy derivative as an
isolable product. This may have occurred because, in the
absence of a base, no hydride transfer occurred; there was
therefore no proton abstraction to form the palladium hy-
dride intermediate, and the palladium bromide intermedi-
ate cyclized directly. This reaction, in turn, terminated
through capture of hydride from sodium formate to gener-
ate the nonoxidized gem-dimethyl cyclopentenol deriva-
tive 3.31–3.37 (Scheme 13 and Table 5).
OMe
Br
O
OH
4
60
78
MeO
3.24
2.24
Br
O
MeO
MeO
OH
5
In conclusion, we have developed a new method for the
synthesis of fused cyclopentenones and we have extended
it to obtain gem-dimethyl-substituted cyclopentenones,
useful in a convenient and efficient synthesis of sesquiter-
pene natural products. We were able to establish two dif-
ferent sets of reaction conditions that gave two
structurally and mechanistically different products, one of
which led directly to the required sesquiterpene precur-
sors.
MeO
MeO
2.25
3.25
Br
O
OH
6
75
80
3.26
2.26
Br
All the chemicals were purchased from Sigma-Aldrich and used di-
rectly. DMF was dried, distilled and stored over molecular sieves (4
Å). THF was freshly distilled over sodium–benzophenone. Chro-
matographic purification was done with either 60–120 or 100–200
mesh silica gel (SRL). For reaction monitoring, precoated silica gel
60 F254 TLC sheets (Merck) were used. Petroleum ether refers to the
fraction boiling in the range 60–80 °C. Melting points were deter-
mined on a Toshniwal electrical air heating instrument and are un-
corrected. IR spectra were recorded on Perkin–Elmer 883 and
O
OH
7
2.27
3.27
a Reaction conditions: Pd(OAc)2 (2 mol%), Ph3P (0.5 mmol), Na2CO3
(1.5 mmol), DMF, 80 °C, 5 h.
b Isolated yield after purification.
1
Shimadzu FTIR-8300 infrared spectrophotometers. H NMR (200
MHz) spectra were recorded on a Bruker AC 200 MHz spectrome-
© Georg Thieme Verlag Stuttgart · New York
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D. Ray et al.
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Br
R1
R2
R1
R2
O
OH
Pd(0)
PdBr
Pd
H
R1
R2
OH
R1
R2
O
I
IV
PdH
R1
O
R1
R2
PdH
OH
R1
R2
O
V
R2
II
III
Na2CO3
Scheme 12
Pd(0)
R1
Table 5 Synthesis of gem-Dimethyl Cyclopentenol Derivatives
Br
OH
Entrya Substrate
Product
Yieldb
(%)
R2
Br
PdBr
OH
R1
R2
OH
1
50
56
OH
HCO2Na
Pd
3.31
3.32
2.21
H
PdBr
Br
OH
OH
R1
OH
R1
R2
OH
2
R2
2.22
HCO2Na
R1
OH
Pd(0)
Br
Pd(0)
OH
R2
OH
3
60
58
Scheme 13
3.36
3.37
2.26
ter. Chemical shifts are reported in parts per million relative to tet-
ramethylsilane as the internal standard. 13C NMR (50 MHz) spectra
were recorded on the same spectrometer with complete proton de-
coupling. EIMS (70 eV) spectra were collected on a VG Autospec
M mass spectrometer and ESI-MS spectra were collected on a
Waters LCT mass spectrometer. Elemental analysis was carried out
on a Vario EL ElementalAnalyzer.
Br
OH
OH
4
2.27
a Reaction conditions: Pd(OAc)2 (2 mol%), Ph3P (0.5 mmol),
HCO2Na (1.2 mmol), DMF, 80 °C, 3 h.
b Isolated yield.
Homoallylic Alcohols 2; General Procedure
A mixture of CH2=CHCH2Br or CH2=C(Me)CH2Br (3 mmol), In
metal (1.2 mmol), and NaI (4 mmol) in DMF (3–4 mL) was stirred
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Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization
1267
at r.t. until the complex was completely formed. A soln of the ap-
propriate bromo aldehyde (1 mmol) in DMF (3 mL) was then added.
The reaction was monitored by TLC and after 5–6 h the reaction
was quenched with a few drops of 1 M aq HCl. The mixture was ex-
tracted with CH2Cl2 (3 × 15 mL), and the extracts were thoroughly
washed with 2 M aq Na2S2O3 (2 × 20 mL) and brine (2 × 20 mL).
Evaporation of the solvent gave a residue that was purified by col-
umn chromatography [silica gel (60–120 mesh), PE–EtOAc (1:1)].
IR (CHCl3): 3415, 3064, 2966, 2918, 1423, 1262, 1092, 1026, 865,
804 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.91 (br s, 1 H), 2.69–2.80 (m, 2
H), 5.14–5.26 (m, 3 H), 5.83–6.03 (m, 1 H), 7.47–7.65 (m, 3 H),
7.76–7.85 (m, 2 H), 7.97–8.00 (d, J = 6.9 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 41.9, 69.5, 117.2, 118.3, 123.0,
124.7, 127.1, 127.4, 127.5, 127.6, 127.7, 128.3, 134.2, 136.4, 137.4,
141.5.
1-(2-Bromocyclopent-1-en-1-yl)but-3-en-1-ol (2.11)
Anal. Calcd for C16H13BrO: C, 63.81; H, 4.35. Found: C, 63.99; H,
4.51.
Yellow liquid; yield: 182 mg (73%).
IR (CHCl3): 1646, 1439, 1023, 873 cm–1.
1-Bromo-2-(1-methoxybut-3-en-1-yl)acenaphthylene (2.16a)
A suspension of NaH (washed with pentane; 21 mg, 0.87 mmol) in
anhyd THF (5 mL) was cooled to 0 °C. A soln of alcohol 2.16 (240
mg, 0.79 mmol) in THF (5 mL) was added dropwise then the mix-
ture was warmed to r.t. and stirred for 20 min. MeI (123 mg, 0.87
mmol) was added, and the mixture was stirred at r.t. for 4 h. The re-
action was quenched with ice-water (10 g) and the mixture was di-
luted with Et2O (30 mL). The organic layer was washed with H2O
(2 × 20 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by chromatography [silica gel (60–
120 mesh), PE–EtOAc (4:1)] to give a yellow oil; yield: 168 mg
(67%).
1H NMR (200 MHz, CDCl3): δ = 2.57–2.71 (m, 1 H), 2.76–2.90 (m,
1 H), 3.33 (s, 3 H), 4.72 (t, J = 6.9 Hz, 1 H), 5.03–5.15 (m, 2 H),
5.79–5.96 (m, 1 H), 7.48–7.66 (m, 3 H), 7.72–7.92 (m, 2 H), 7.97
(d, J = 5.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 40.90, 57.32, 78.89, 117.52,
119.86, 123.15, 124.58, 127.73, 128.00, 128.17, 128.53, 129.03,
134.54, 136.60, 137.74, 140.30.
1H NMR (200 MHz, CDCl3): δ = 1.77–1.97 (m, 3 H), 2.00–2.49 (m,
4 H), 2.58–2.67 (m, 2 H), 4.60 (t, J = 7.1 Hz, 1 H), 5.01–5.26 (m, 2
H), 5.68–5.88 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 21.5, 29.5, 39.4, 40.1, 68.6, 117.0,
117.5, 134.0, 141.8.
Anal. Calcd for C9H13BrO: C, 49.79; H, 6.04. Found: C, 49.97; H,
6.12.
1-(2-Bromocyclohex-1-en-1-yl)but-3-en-1-ol (2.12)
Yellow liquid; yield: 153 mg (61%).
IR (CHCl3): 2927, 1666, 1454, 1375, 1261, 1022 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.69 (br s, 4 H), 2.02 (br s, 1 H,
OH), 2.29–2.36 (m, 4 H), 2.51 (br s, 2 H), 4.80 (t, J = 6.8 Hz, 1 H),
5.11–5.19 (m, 2 H), 5.76–5.89 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 22.1, 24.7, 25.3, 36.8, 38.9, 73.2,
117.9, 120.2, 134.3, 136.9.
Anal. Calcd for C10H15BrO: C, 51.97; H, 6.54. Found: C, 52.13; H,
6.39.
Anal. Calcd for C17H15BrO: C, 64.78; H, 4.80. Found: C, 64.91; H,
4.63.
1-(2-Bromocyclohept-1-en-1-yl)but-3-en-1-ol (2.13)
Yellow liquid; yield: 180 mg (72%).
1H NMR (200 MHz, CDCl3): δ = 1.21–1.41 (m, 6 H), 1.92–2.11 (m,
3 H), 2.18–2.24 (m, 2 H), 2.53–2.41 (m, 2 H), 4.76 (br s, 1 H), 4.91–
5.05 (m, 2 H), 5.79–5.89 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 25.3, 26.3, 27.3, 31.7, 39.0, 41.6,
74.6, 117.8, 123.3, 134.3, 142.2.
1-(2-Bromoacenaphthylen-1-yl)-2,2-dimethylbut-3-en-1-ol
(2.16b)
Yellow oil; yield: 158 mg (63%).
1H NMR (200 MHz, CDCl3): δ = 1.21 (s, 3 H), 1.23 (s, 3 H), 1.96
(br s, 1 H), 4.98 (s, 1 H), 5.19–5.21 (m, 1 H), 5.22 (s, 1 H), 5.97–
6.19 (m, 1 H), 7.56–8.05 (m, 4 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.33
(d, J = 6.9 Hz, 1 H).
Anal. Calcd for C11H17BrO: C, 53.89; H, 6.99. Found: C, 54.12; H,
6.86.
Anal. Calcd for C18H17BrO: C, 65.67; H, 5.20. Found: C, 65.78; H,
5.31.
1-(2-Bromocyclooct-1-en-1-yl)but-3-en-1-ol (2.14)
Yellow liquid; yield: 190 mg (76%).
1H NMR (200 MHz, CDCl3): δ = 1.49–1.76 (br s, 8 H), 1.90 (br s, 1
H, OH), 2.24–2.47 (m, 4 H), 2.66–2.72 (m, 2 H), 4.77–4.82 (dd,
J = 5.5 and 5.5 Hz, 1 H), 5.09–5.18 (m, 2 H), 5.74–5.91 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 25.5, 26.7, 27.2, 27.5, 31.3, 37.0,
39.6, 74.4, 117.8, 122.3, 134.7, 139.5.
Palladium-Catalyzed Heck Cyclization of Methallylated Deriv-
atives; General Procedure
A mixture of the appropriate methallylated derivative (1 mmol),
Pd(OAc)2 (2 mol%), Ph3P (0.5 mmol), and Na2CO3 (1.5 mmol) was
flashed with argon and then DMF (5 mL) was added. The mixture
was degassed with argon, heated to 80 °C for 5 h, cooled, and dilut-
ed with ice-water (10 g). The resulting mixture was extracted with
Et2O (3 × 20 mL) and the extracts were dried (Na2SO4) and concen-
trated. The residue was purified by column chromatography [silica
gel (60–120 mesh), PE–EtOAc (9:1)].
Anal. Calcd for C12H19BrO: C, 55.61; H, 7.39. Found: C, 55.93; H,
7.23.
1-(2-Bromo-3,4-dihydronaphthalen-1-yl)but-3-en-1-ol (2.15)
Palladium-Catalyzed Heck Reaction of Homoallylic Alcohols;
General Procedure
Yellow liquid; yield: 190 mg (76%).
IR (CHCl3): 3407, 2932, 1663, 1452, 1053 cm–1.
A two-necked round-bottom flask was charged with the appropriate
homoallylic alcohol (1 mmol), Pd(OAc)2, (10 mol%), Ph3P (0.25
mmol), HCO2Na (1 mmol), and DMF (6–8 mL). The mixture was
then degassed with N2 and heated to 80 °C for 8 h. The mixture was
then cooled, diluted with cold H2O (15 mL), and extracted with
Et2O (3 × 20 mL). The extracts were dried (Na2SO4) and concentrat-
ed under reduced pressure to give a residue that was purified by col-
umn chromatography [silica gel, PE–EtOAc (8:1)].
1H NMR (200 MHz, CDCl3): δ = 1.83 (br s, 1 H, OH), 2.50–2.63
(m, 4 H), 2.72–2.91 (m, 2 H), 5.10–5.30 (m, 3 H), 5.77–5.98 (m, 1
H), 7.09–7.24 (m, 3 H), 7.86–7.91 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 29.7, 36.1, 39.6, 74.0, 117.8, 124.8,
125.4, 126.2, 127.1, 127.5, 132.4, 134.6, 135.7, 135.8.
Anal. Calcd for C14H15OBr: C, 60.23; H, 5.42. Found: C, 60.48; H,
5.31.
3-Methyl-3,4,5,6-tetrahydropentalen-1(2H)-one (3.11)12
Yellow liquid; yield: 87 mg (58%).
1-(2-Bromoacenaphthylen-1-yl)but-3-en-1-ol (2.16)
Yellow liquid; yield: 202 mg (81%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1261–1269

1268
D. Ray et al.
PAPER
IR (CHCl3): 3391, 2927, 1679, 1633, 1438, 1263, 1170 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.16 (d, J = 6.9 Hz, 3 H), 1.93–
13C NMR (50 MHz, CDCl3): δ = 20.9, 31.5, 50.4, 124.6, 126.1,
127.6, 127.6, 128.2, 129.5, 130.6, 131.2, 133.1, 133.7, 142.8, 181.1,
200.2.
2.54 (m, 4 H), 2.56–2.95 (m, 4 H), 2.98–3.01 (m, 1 H).
MS (EI, 70 eV): m/z = 220, 205, 191, 181, 152.
Anal. Calcd for C9H12O: C, 79.37; H, 8.88. Found: C, 79.58; H,
8.67.
Anal. Calcd for C16H12O: C, 87.25, H, 5.49. Found: C, 87.54, H,
5.36.
3-Methyl-2,3,4,5,6,7-hexahydro-1H-inden-1-one (3.12)13
Yellow liquid: yield: 92 mg (61%).
IR (CHCl3): 1698, 1681, 1645, 1453, 1276 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.15 (d, J = 6.8 Hz, 3 H), 1.63–
1.76 (m, 5 H), 2.11–2.30 (m, 3 H), 2.37–2.58 (m, 2 H), 2.64–2.72
(m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 18.5, 19.7, 21.4, 22.3, 25.7, 36.1,
43.2, 137.8, 177.5, 208.3.
7-Methoxy-9-methylene-8,9-dihydro-7H-cyclopenta[a]ace-
naphthylene (3.16a)
Yellow oil; yield 81 mg (54%).
1H NMR (200 MHz, C6D6): δ = 2.99–3.16 (m, 2 H), 3.20 (s, 3 H),
4.83 (dd, J = 2.9, 2.9 Hz, 1 H), 5.02 (br s, 1 H), 5.49 (br s, 1 H),
7.20–7.31 (m, 2 H), 7.45–7.60 (m, 4 H).
MS (EI, 70 eV): m/z = 234, 219.
Anal. Calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 87.33; H,
5.88.
MS (EI, 70 eV): m/z = 150 (26) [M+], 69 (100).
Anal. Calcd for C10H14O: C, 79.96; H, 9.39. Found; C, 80.13; H,
9.21.
8,8,9-Trimethyl-8,9-dihydro-7H-cyclopenta[a]acenaphthylen-
7-one (3.16b)
Yellow solid; yield: 92 mg (61%).
IR (CHCl3): 1681 cm–1.
3-Methyl-3,4,5,6,7,8-hexahydroazulen-1(2H)-one (3.13)
Yellow liquid; yield: 90 mg (60%).
IR (CHCl3): 3409, 2926, 2856, 2290, 1695, 1641, 1444, 1165, 1067,
616, 521 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.15 (d, J = 7.0 Hz, 3 H), 1.42–
1.67 (m, 6 H), 1.73–1.83 (m, 4 H), 2.26–2.58 (m, 2 H), 2.67–2.70
(m, 1 H).
1H NMR (200 MHz, CDCl3): δ = 1.19 (s, 3 H), 1.32 (s, 3 H), 1.47
(d, J = 7.4 Hz, 3 H), 3.30 (q, J = 7.5 Hz, 1 H), 7.58–7.69 (m, 3 H),
7.84 (d, J = 8.3 Hz, 1 H), 7.93–8.01 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 15.6, 21.2, 25.6, 43.4, 54.5, 120.1,
123.8, 126.2, 127.8, 128.1, 128.4, 129.4, 131.6, 133.4, 136.0, 140.0,
178.1, 205.8.
13C NMR (50 MHz, CDCl3): δ = 18.9, 23.1, 26.3, 26.5, 31.1, 31.4,
37.0, 43.1, 141.7, 181.0, 208.1.
Anal. Calcd for C18H16O: C, 87.06; H, 6.49. Found: C, 87.30; H,
6.71.
Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.61; H,
9.59.
8,8-Dimethyl-9-methylene-8,9-dihydro-7H-cyclopenta[a]ace-
naphthylen-7-ol (3.16c)
Yellow solid; yield: 27 mg (18%).
1H NMR (200 MHz, CDCl3): δ = 1.30 (s, 3 H), 1.34 (s, 3 H), 1.71
(br s, 1 H, –OH), 4.86 (s, 1 H), 5.02 (s, 1 H), 5.50 (s, 1 H), 7.46–7.54
(m, 3 H), 7.64–7.85 (m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 22.9, 28.6, 52.5, 79.2, 103.5, 123.2,
123.8, 127.33, 127.6, 127.9, 128.8, 133.0, 133.7, 134.3, 146.4,
149.6, 154.4.
3-Methyl-2,3,4,5,6,7,8,9-octahydro-1H-cyclopenta[8]annulen-
1-one (3.14)
Faint-yellow liquid; yield: 94 mg (63%).
IR (CHCl3): 3385, 1685, 1656, 1447, 1254, 1042, 814, 627 cm –1
1H NMR (200 MHz, CDCl3): δ = 1.19 (d, J = 7.0 Hz, 3 H), 1.49–
1.72 (m, 8 H), 2.29–2.32 (m, 4 H), 2.48–2.69 (m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 19.1, 21.1, 25.8, 26.0, 27.9, 28.2,
36.3, 43.3, 140.2, 178.7, 208.3.
.
Anal. Calcd for C18H16O: C, 87.06; H, 6.49. Found: C, 87.33; H,
6.67.
Anal. Calcd for C12H18O; C, 80.85; H, 10.18. Found: C, 81.13; H,
9.91.
3-Methyl-1H-inden-1-ol (3.17a)
3-Methyl-2,3,4,5-tetrahydro-1H-cyclopenta[a]naphthalen-1-
one (3.15)
Faint-yellow oil; yield: 93 mg (62%).
White solid; yield: 118 mg (59%); mp 90 °C.
1H NMR (200 MHz, CDCl3): δ = 2.09 (d, J = 1.2 Hz, 3 H), 5.14 (br
s, 1 H), 6.08 (br s, 1 H), 7.19–7.32 (m, 3 H), 7.49 (d, J = 6.7 Hz, 1
H).
13C NMR (50 MHz, CDCl3): δ = 10.9, 71.4, 117.2, 121.2, 124.1,
126.4, 130.4, 139.5, 141.9, 144.2.
IR (CHCl3): 3063, 2930, 2244, 1692, 1670, 1627, 1506, 1429, 1391,
1252, 1068, 817 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.24 (d, J = 7.1 Hz, 3 H), 2.21–
2.83 (m, 4 H), 2.87–2.97 (m, 3 H), 7.17–7.68 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 18.5, 24.7, 27.6, 35.3, 44.7, 124.1,
126.4, 126.9, 127.5, 127.8, 128.3, 134.0, 178.8, 205.5.
Anal. Calcd for C10H10O: C, 81.77; H, 6.89. Found: C, 81.94, H,
6.65.
Anal. Calcd for C14H14O: C, 84.81, H, 7.12. Found: C, 84.97; H,
7.08.
3-Methyleneindan-1-ol (3.17b)
Pale-yellow solid; yield: 60 mg (30%); mp 92 °C.
1H NMR (400 MHz, CDCl3): δ = 2.61 (d, J = 12.8 Hz, 1 H), 3.13 (d,
J = 16.8 Hz, 1 H), 5.08 (s, 1 H), 5.18 (br s, 1 H), 5.52 (s, 1 H), 7.30–
7.33 (m, 2 H), 7.43 (d, J = 4.8 Hz, 1 H), 7.51 (d, 1 H, J = 6.4 Hz).
13C NMR (50 MHz, CDCl3): δ = 42.3, 73.1, 104.1, 120.5, 125.1,
128.6, 128.8, 140.1, 146.4, 146.9.
HRMS (ESI, 70 eV): m/z [M – OH]+ calcd for C10H9: 129.0533;
found: 129.1829.
9-Methyl-8,9-dihydro-7H-cyclopenta[a]acenaphthylen-7-one
(3.16)
Yellow solid; yield: 107 mg (71%); mp 148 °C.
IR (CHCl3): 1679, 1628 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.56 (d, J = 7 Hz, 3 H), 2.56–2.65
(dd, Jcis = 2.0 Hz and Jgem = 18.0 Hz, 1 H), 3.23–3.32 (dd, Jtrans = 6.2
Hz and Jgem = 18.0 Hz, 1 H), 3.60–3.68 (m, 1 H), 7.55–7.69 (m, 2
H), 7.82–8.02 (m, 4 H).
Anal. Calcd for C10H10O: C, 81.77; H, 6.89. Found: C, 81.75; H,
6.90.
Synthesis 2013, 45, 1261–1269
© Georg Thieme Verlag Stuttgart · New York

PAPER
Palladium-Catalyzed Intramolecular Oxidative Heck Cyclization
1269
Other compounds 1.21–3.37 have been reported previously.7a,9,14
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Computational Details
Density functional theory (DFT) calculations were performed by
using the BP8615 and B3LYP16 functionals with empirical disper-
sion correction (DFT-D)17 in conjunction with the def2-SVP18 basis
set and effective core potentials on Ni. The resolution of the identity
(RI) approximation was used to speed up the BP86 calculations.
TURBOMOLE V6.219 software was used in all the calculations.
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Karlsruhe, 2011, http://www.turbomole.com.
Acknowledgment
Financial support from CSIR DST is gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1261–1269