Synthesis of functionalized benzannulated compounds

Article abstract of DOI:10.1016/j.tet.2008.07.098

Functionalized indane and naphthalene derivatives have been prepared according to two routes involving a nickel-catalyzed electrochemical arylation of activated olefins as the key step. The first method is a cascade process including the intramolecular nucleophilic addition of the first formed enolate intermediate. In the second method the cascade reaction is prevented by in situ protonation of the enolate, and the cyclization is further conducted chemically. This is an overall more efficient method than the first one, based on the electrochemical process.

Full text of DOI:10.1016/j.tet.2008.07.098

Tetrahedron 64 (2008) 9388–9395
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized benzannulated compounds
,
a
a
a
b
Sylvie Condon a , Amane El Ouarradi , Estelle Metay , Eric Leonel , Maryse Bourdonneau ,
*
´
´
a
´ ´
Jean-Yves Nedelec
a
´
´
´
´
`
Universite Paris-Est, site de Creteil, Institut de Chimie et des Materiaux, Paris-Est-UMR 7182-CNRS, equipe Electrochimie Synthese Organique,
2 rue Henri-Dunant, 94320 Thiais, France
b Laboratoire d’applications RMN, Bruker Biospin SA, 34 rue de l’industrie, 67166 Wissembourg cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2008
Received in revised form 21 July 2008
Accepted 23 July 2008
Available online 29 July 2008
Functionalized indane and naphthalene derivatives have been prepared according to two routes in-
volving a nickel-catalyzed electrochemical arylation of activated olefins as the key step. The first method
is a cascade process including the intramolecular nucleophilic addition of the first formed enolate in-
termediate. In the second method the cascade reaction is prevented by in situ protonation of the enolate,
and the cyclization is further conducted chemically. This is an overall more efficient method than the first
one, based on the electrochemical process.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
zinc powder followed by cyclocondensation12 have been reported
for the preparation of 1H-indenes11,12 and dihydronaphthalenes.11
Benzannulated structures are the core of several biological active
substances. Particularly, dihydronaphthalene scaffolds such as 1-
cyano-2-tetralone and 2-amino-1-cyano-3,4-dihydronaphthalene
are involved in the synthesis of analgesic 6,7-benzomorphane,1 py-
rimethamine analogues2 and are precursors of functionalized
naphthalene derivatives possessing pharmaceutical activity.3 1,2-Di
and 1,2,3-trisubstituted indanes4 also constitute relevant pharma-
ceutical scaffolds. Indane 1-acetic acids possess antiinflammatory,
analgesic and antipyretic activities,5 and the moiety has been
We have recently investigated a route to medium ring benzan-
nulated lactones through the formation of hydroxyacids, according
to Scheme 1.13 The methodology involves the sequential attach-
ment, ortho to each other on a benzene ring, of a tethered carbonyl
(ketone) and a tethered ester group, which are later converted into
hydroxy and carboxy groups, respectively. One key step is an effi-
cient nickel-catalyzed electrochemical Michael addition, which
interestingly does not require functional groups’ protection like for
the chemical route. Also, the sequence in introducing the first group
(i.e., the ketone or the ester) is mostly designed according to the
availability (ease of preparation). There is, however, one drawback,
which can divert this reaction towards the formation of an un-
wanted bicyclic product. This is because the organometallic enolate
intermediate resulting from the Michael addition can add in-
tramolecularly when there is an electrophile ideally placed on the
other chain to allow the formation of C5 and C6 ring. This is notably
observed from a carbonyl group (Scheme 2, model I, EWG1¼ester;
n¼0, 1) or a conjugated double bond (Scheme 2, model II, EWG1,
EWG2¼ester, ketone; n¼0, 1). In the previous study13 it was chal-
lenging to avoid such a side reaction. We now want to examine the
synthetic potential of this cascade reaction, with the aim of either
favouring it or alternatively design the best way to avoid it.
identified as head group of potent PPAR a/g/d
pan agonists.6 ortho-
Substituted aryl halides are very convenient starting materials from
which new fused rings of controlled size can be constructed usually
in a one-pot process. These approaches require the activation of the
aryl halide by a transition metal catalyst and the organometallic
intermediate is then involved in a cyclization process to give the
bicyclic compound. Alternatively, nickel7 or cobalt8 complexes in the
presence of zinc powder as well as palladium complexes9 have
been reported for the carboannulation of disubstituted alkynes with
2-halophenyl-ketones, -aldehydes or (2-halophenyl)malonates to
prepare indenes, indenols and indenones. Recently a facile approach
to the construction of indenone by intramolecular Heck reaction10
followed by aerial oxidation of the allylic alcohol has been described.
Domino processes involving Heck reaction restricted to allylic or
homoallylic alcohols followed by aldol condensation11 and conju-
gate addition reaction mediated by cobalt catalysis in the presence of
2. Results and discussion
2.1. Syntheses of functionalized five-membered ring
annulation
We first investigated the five-membered ring annulation with
(E)-ethyl 3-(2-bromophenyl)prop-2-enoate 1 and acrylonitrile 2.
* Corresponding author. Tel.: þ33 1 49781126; fax: þ33 1 49781148.
E-mail address: condon@icmpe.cnrs.fr (S. Condon).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.098

S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
9389
Reduction of
carbonyl and/or
Saponification
then lactonisation
Br
NiBr2.xH2O/ 2e-
O
double bond
OH
O
O
CO2Et
n'
CO2Et
n'
CO2Et
n'
n: 0,1; n': 0,1,2
O
n
n
n'
n
n
Scheme 1. Concise synthesis of ring benzannulated lactones.
EWG1
EWG2
The NOESY experiment of the trans-4 stereoisomer is shown in
Fig. 2.
EWG1
O
n
In all runs, and whatever the reaction conditions, the same di-
astereoisomer ratio of 4 (28/72) has been found from GC analysis,
the cis isomer 4b being the major product. This diastereoselectivity
can be explained by a chelation of the two functional groups with
the metallic cations (Ni2þ, Fe2þ), which would occur after the
conjugate addition step and drive the cyclization in favour of the cis
stereoisomer.
n
MODEL I
MODEL II
Scheme 2. Two adapted models for the access to bicyclic compounds.
The reaction was conducted in the reaction conditions previously
described.14 In an undivided cell fitted with a stainless steel cathode
and a metal rod as the anode, a short pre-electrolysis of (1/1) DMF/
acetonitrile (AN) solution containing 1,2-dibromoethane and mix-
ture of Bu4NBr/Bu4NI as supporting electrolyte was run at constant
current intensity for 15 min at 20 ꢀC. Then, NiBr2$3H2O (0.1 equiv),
2 (2.5–4 equiv), and 1 were added, and the reaction mixture was
heated up to 80 ꢀC before running the electrolysis at constant
current intensity (0.5 A dmꢁ2). Two key parameters have been ex-
amined: the amount of 2 versus 1, and the nature of the anode. The
results are reported in Table 1. The reaction of 1 with 2 afforded
a mixture of four compounds: ethyl cinnamate, which is the re-
duction product of the aryl bromide derivative, the conjugate ad-
dition product 3 and the two diastereoisomeric bicyclic products 4a
and 4b. Considering that 3 and 4 are formed from the same in-
termediate, this amounts to an overall yield of up to 85%. In all
experiments 3 is formed, even predominantly in several cases. Cis
and trans stereoisomers 4 have been separated and their structures
have been established on the basis of 1H and 13C NMR spectra, and
mass spectra. Five-membered ring assignment was carried out by
heteronuclear multiple bond correlation (HMBC). The stereo-
chemistry of 4a and 4b (Fig. 1) has been assigned on the basis of
NOESY experiments with the elimination of zero-quantum in-
terference.15 A sample of 4a subjected to NOESY experiment dis-
We previously reported that the conjugate addition reaction
mediated by nickel catalysis is best performed in the presence of an
excess of olefin (2.5 equiv), which plays both as reagent and as li-
gand to the catalyst. We first tried (Table 1, run 1) to use less than
2.5 equiv of the activated olefin in this reaction because of the
presence of the ethenyl group on the side chain of the aryl moiety,
which could also ligate to the catalyst. However, decreasing the
amount of activated olefin resulted in the decrease of the chemical
yield (Table 1, run 1 vs 2) along with a longer reaction time,
whereas an amount larger than 2.5 equiv allowed the enhancement
of the overall yield of the reaction (Table 1, run 3 vs 2). Compared to
nickel and stainless steel, iron as the anode (Table 1, run 3) gives the
highest overall yield in 3 plus 4. With a stainless steel rod (Table 1,
run 5) compound 4 is the major product, while use of a nickel anode
(Table 1, run 4) is not appropriate, ethyl cinnamate being the main
product. These results indicate that a significative amount of
iron(II) salts are necessary to promote efficiently the trans-
metallation reaction and allow the intramolecular reaction. For this
reason, iron rod is preferred to stainless steel rod (run 5 vs 3).
With nickel rod, the conjugate addition reaction is disrupted (Table
1, run 4). Probably the electroreduction of free nickel(II) salts gen-
erated at the anode occurs and affords low valent nickel, which
precipitates.
plays a correlation between Hc (
d
: 3.20 ppm) and distinguishable
: 2.73 ppm and 2.89 ppm). This result indicates that Ha/
Ha0 and Hc are close to each other, thus ascertaining the trans ge-
ometry. The cis geometry of 4b has been also assigned on the basis
of the NOESY experiment not showing any correlation between Ha
Ha/Ha0 (
d
Then we turned our attention onto the selectivity of the re-
action. The formation of 3 can be partly explained by in situ pro-
tonation of the enolate species by residual water in the solvent and
structural water of nickel catalyst precursor.14 We could show, by
(d: 2.94 ppm) and Hc (d: 3.71 ppm).
Table 1
Ni-catalyzed electrochemical Michael addition of 1 onto acrylonitrilea
CN
Br
CN
CN
+
10% NiBr2. H2O, e-
DMF/CH3CN: 1/1
+
CO2Et
CO2Et
CO2Et
70 °C
4 cis/trans
1
2
3
Run
Anode
Acrylonitrile (equiv)
Reaction time
Additive (equiv)
Ratiob of 4a/4b
Ratio of 3/4
Yieldc in 3
Yieldc in 4
1
2
3
4
5
6
7
8
Fe
Fe
Fe
Ni
1.2
2.5
4
4
4
4
4
4
5 h 30 min
3 h 30 min
3 h 30 min
7 h
4 h 20 min
5 h 30 min
2 h 40 min
2 h 40 min
None
None
None
None
28/72
28/72
28/72
27/73
29/71
29/71
31/69
56/44
52/48
47/53
15/85
27/73
24/76
67/33
26
37
42
n.a.
22
14
18
32
43
n.a.
45
49
24
Traces
Stainless steel
None
Fe
Fe
Fe
NaHd (0.2)
EtOH (2.5)
EtOH (5)
55
60
a
Reaction conditions. Compound 1: 7.5 mmol; solvent: DMF/AN (15/15, mL/mL); supporting electrolytes: Bu4NBr, Bu4NI; cathode: stainless steel; current intensity: 0.15 A;
theoretical reaction time: 2 h 40 min.
b
Isomer ratio, as determined by GC.
Isolated yield.
Added before electrolysis.
c
d

9390
S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
Br
COCH3
CO2Et
CN
Hc
Hc
CN
1. 10% NiBr2, 2 e-
DMF/CH3CN: 1/1
3.5H, 70 °C
2. H+/H2O
CO2Et
H
Hb
b
coupling
no coupling
a
a,a'
CO2Et
1
8
(56%)
+
CO2Et
+
4a (trans)
4b (cis)
COCH3
COCH3
Figure 1. Stereochemistry of 4a and 4b.
6 (2.5 equiv.)
CO2Et
10 (14%)
addition of NaH (0.20 equiv) prior to the electrolysis (Table 1, run 6),
that removal of all proton sources favours the formation of 4 over 3.
This methodology has been applied to other models as shown be-
low. Compound 1 was thus added to methylvinylketone 6 (Scheme
3), while 5 was added to ethyl acrylate 7 (Scheme 4).
Scheme 3.
CO2Et
CN
Br
1. 10% NiBr2, 2 e-
DMF/CH3CN: 1/1
3.5H, 70 °C
2. H+/H2O
In these reactions, the uncyclized conjugate addition product is
obtained as the main product and the yields in carbocycles are
lower than those obtained from 1 and acrylonitrile (Table 1).
To summarize, the cascade cyclocondensation is not easily
controlled under the above electrochemical conditions and not
fully achieved one pot. We thus attempted to find reaction condi-
tions allowing now to form selectively 3 without 4, with the aim of
performing the cyclization chemically. Some years ago, we have
reported16 that the electrochemical conjugate addition reaction
mediated by nickel–dipyridylamine complexes could be conducted
in ethanol. We found that the addition of 5 equiv of ethanol as
proton source (Table 1, run 8) enables to obtain 3 in 60% isolated
yield. Compound 3 was then cyclized in the presence of sodium
hydride (2 equiv) at low temperature to give 4 in 56% isolated yield
based on 1 (Scheme 5).
CN
5
9 (41%)
+
+
CO2Et
CO2Et
CN
(2.5 equiv.)
7
11 (12%)
Scheme 4.
Br
CN
1. 10% NiBr2, 2 e-
DMF/CH3CN: 1/1
5 equiv. EtOH
70 °C
CO2Et
CO2Et
3
(7,5 mmol)
+
60%
1
1. NaH (2 equiv.)
DMF, -20 °C
CN
2.2. Syntheses of functionalized six-membered ring
annulation
2
2. NH4Cl, -20 °C
CN
2.5 equiv.
Next, we examined the reactivity of 2-bromophenylacetonitrile
12, 2-bromophenylacetone 13 and ethyl 2-(2-bromophenyl)acetate
14 with activated olefins in order to perform six-membered ring
annulation under electrosynthesis conditions. It is worth noting
that 12–14 are characterized by the presence of acidic hydrogen at
the benzylic position and which may interfere with the main pro-
cess. The reactions are conducted in the same conditions as above.
Compounds 12 and 13 have been reacted with methylvinylketone
6, ethyl acrylate 7 and acrylonitrile 2 under nickel catalysis to get
functionalized dihydro and tetrahydronaphthalenes. The results are
reported in Table 2. Each reaction led to the formation of the
CO2Et
94%
cis/trans ratio: 66/34
4
Scheme 5. A two step-reaction for the preparation of 4.
bicyclic product either as dihydro- or tetrahydronaphthalene, in-
dicating that intramolecular trapping of the enolate species oc-
curred, though in low yields. The formation of compounds 17, 21
and 22 is explained by a direct trapping of the enolate intermediate
by the electrophilic group (CN, CO) located on the opposite chain of
the aryl halide. The formation of 15 and 19 is explained by the in-
volvement of the enolate species in a transprotonation reaction
with the benzylic methylene to give the most stable carbanion
before the cyclization, as depicted in Scheme 6 for 19.
There is a third outcome for the enolate species, which accounts
for the low yields obtained in the conjugate addition and the bi-
cyclic compounds. Indeed the enolate species also promotes the
alkylation at the benzylic position to give by-products. Thus, in the
reaction of 2-bromophenylacetonitrile 12 with acrylonitrile 2, side
products 23 and 2417 have been identified (Scheme 7).
Thus, in order to avoid the formation of undesired alkylated
compounds we decided to add some ethanol to the medium as
proton source. This afforded several changes. Firstly, alkylated side
products were avoided. Also, in the reaction of 2-bromoacetophe-
none 13 with acrylonitrile, 21 was obtained in 67% isolated yield
(Scheme 8).
With 12 and 14 as substrates, the enolate intermediates were
protonated by ethanol (1–4 equiv) and the conjugate addition
products were obtained in good yield as shown in Table 3.
Figure 2. NOESY experiment of the trans-4 stereoisomer.

S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
9391
Table 2
Preparation of dihydro and tetrahydronaphthalenes by conjugate addition–cyclizationa
Run
Ar–Br
Reaction time
Bicyclic product No.
Yieldc in bicyclic product
Conjugate addition
product No.
Yieldc in conjugate
addition product
EWG
Br
1
COCH3
4 h 30 min
13
16
18
20
34
8
CN
CN
15
12
CO2Et
2
12
12
CO2Et
4 h 30 min
4 h 10 min
20
9
NH2
17
NH2
CN
19
3
CN
10
CN
Br
4b
CN
6 h 30 min
23
30
None
None
COCH3
OH
21
13
CO2Et
5
13
CO2Et
7 h
OH
22
a
Reaction conditions. Aryl bromide: 7.5 mmol; activated olefin: 2.5 equiv; solvent: DMF/AN (15/15, mL/mL); supporting electrolyte: Bu4NBr, Bu4NI; cathode: stainless steel;
anode: iron (runs 1–3) or stainless steel (runs 4–5) rod; current intensity: 0.20 A; theoretical reaction time: 2 h.
b
Addition of acrylonitrile (4 equiv).
Isolated yield %.
c
The conjugate addition products are obtained in 48–62% iso-
NiBr2.3H2O/ 2e-/ Fe
CN
OH
Br
+
lated yield. The by-product is the reduction product of the aryl
bromide derivative. The release of iron(II) ions as Lewis acid by the
oxidation of the anode accounts for the enhancement of the acidity
of ethanol. The conjugate addition products undergo cyclization in
the presence of sodium ethylate (1.04 equiv) in ethanol to give
dihydro and tetrahydronaphthalenes (Fig. 3). The overall yields in
CN
DMF/CH3CN:1/1, 70 °C
4 equiv. EtOH
COCH3
13
21
(I: 0.2 A)
67 %
4 equiv.
(7.5 mmol)
Scheme 8.
carbocycle from ortho-substituted aryl halides 12–14 are in 33–43%
range. The two-step procedure appears to be the most convenient
way to obtain the naphthalene derivatives. Compounds 19, 20
and 27 are intermediates for the preparation of bridged
Br
CN
Ni2+/2 e-
FeX+
CN
CN
C
N
12
Table 3
CN
N
FeX+
Nickel-catalyzed electrochemical conjugate addition in the presence of ethanol
C
Runa ArylBr No.
EtOH (equiv)
Product Formula
and No.
Yield (%)
NH2
EWG
CN
19
No.
Scheme 6. Formation of compound 19.
COCH3
CN
16
1
2
12
12
6
2
50
48
Br
CO2Et
CN
18
CN
NiII/2 e-
Br
FeX+
CN
7
2
1–4
C
N
+
CN
CN
+
CN
CN
CN
CN
CN
3
4
12
14
1
3
62
48
Br
20
CN
CN
COCH3
CO2Et
25
24
CN
CN
6
a
CN
CN
Scheme 7. Alkylation at benzylic position.
Reactions conditions. Aryl bromide: 7.5 mmol; activated olefin: 2.5 equiv; NiBr2:
23
10%; solvent: DMF/AN (15/15, mL/mL); EtOH: 1–4 equiv; supporting electrolytes:
Bu4NBr, Bu4NI; temperature: 70 ꢀC; cathode and anode: stainless steel; current
intensity: 0.20 A.

9392
S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
and MeCN (15 mL). 1,2-Dibromoethane (80 mL, 0.93 mmol,) was
OH
CO2Et
introduced. A short pre-electrolysis was run at 0.15 A for 20 min, at
room temperature, to generate small amount of iron ions. Then the
current was turned off. NiBr2$3H2O (164 mg, 0.75 mmol) and ac-
tivated olefin (2.5–4 equiv) were added. The mixture was stirred for
5 min at room temperature before the addition of ortho-substituted
aryl bromide (7.5 mmol). Then the mixture was heated at 70 ꢀC and
the electrolysis was run at constant current intensity (0.5 A dmꢁ2).
The reaction mixture was monitored by GC to establish the com-
pletion. The reaction mixture was cooled, hydrolyzed with HCl (1 N,
20 mL) and diluted with diethyl ether (40 mL). The aqueous layer
was extracted twice with diethyl ether (40 mL). The organic layer
was washed with H2O and saturated NaCl solution, dried over
MgSO4 and the solvent was evaporated.
OH
NH2
15
27
19
26
CN
CN
CN
85% from 16
42.5% from 12
70% from 18
33.5% from 12
70% from 20
43.5% from 12
76% from 25
36.5% from 14
Figure 3.
pyrimethamine.2 The preparation of dinitrile 20 required four steps
in the chemical route2 (22% overall yield) whereas it can be pre-
pared in a one step procedure by the electrochemical reaction (62%
isolated yield). Compound 27, which is obtained in six steps (16.5%
overall yield) is prepared by our method in two steps from 12
(33.5% overall yield). It is worth noting that in the reaction of 2-
bromophenylacetonitrile 12 with ethyl acrylate 7, the bicyclic
compound obtained by the two methods (chemical cyclization and
electrochemical cyclization) are interestingly different (Table 2,
product 17 and Fig. 3, compound 27). Compound 17 is obtained in
the one step method by the direct trapping of the enolate species. In
the second method, the synthesis of 27 involves the formation of
the more stabilized enolates from 18.
4.2.1. Ethyl 2-(2-cyanoethyl)cinnamate 3 and ethyl 2-(2-cyano-
2,3-dihydro-1H-inden-1-yl)acetate 4
The products were isolated by chromatography on silica gel
(eluent: diethyl ether content increasing from 3 to 50% in pentane)
to give 0.72 g (42%) of 3 and 0.74 g (43%) of 4.
4.2.1.1. Ethyl 2-(2-cyanoethyl)cinnamate 3. Oil; 1H NMR (300 MHz,
CDCl3)
d
: 7.93 (d, 1H, J¼15.73 Hz), 7.63–7.30 (m, 4H), 6.43 (d, 1H,
3. Conclusion
J¼15.73 Hz), 4.32 (q, 2H, J¼7.13 Hz), 3.15 (t, 2H, J¼7.40 Hz), 2.63 (t,
2H, J¼7.40 Hz), 1.38 (t, 3H, J¼7.13 Hz). 13C NMR (75 MHz, CDCl3)
d:
We have shown that the electrochemical conjugate addition
reaction mediated by nickel catalysis is an efficient tool to get
functionalized carbocycles or carbocycle precursors. Indeed, this
study has revealed that the cascade process could occur. Its syn-
thetic scope is, however, somewhat limited since under these
conditions the trapping of the enolate species is not fully achieved
and a mixture of the carbocycle and of its precursor is obtained. We
can alternatively prevent the cascade reaction by in situ pro-
tonating the enolate intermediate. The obtained product can later
be converted more advantageously into the bicyclic derivative by
a chemical route.
166.6, 140.6, 137.2, 133.2, 130.4, 130.0, 128.0, 127.2, 121.2, 118.6, 60.7,
28.8, 18.9, 14.3. MS: m/z (%) 229, 200, 183, 175 (100%), 156, 147, 143,
129, 115, 103, 89, 77, 63. IR (neat), cmꢁ1: 2960, 2926, 2254, 1713,
1480, 1460, 908, 732. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59.
Found: C, 73.07; H, 6.85.
4.2.1.2. Ethyl 2-(2-cyano-2,3-dihydro-1H-inden-1-yl)acetate 4. Char-
acterization of cis-4 was achieved as a pure fraction of the isolated
compound: 1H NMR (300 MHz, CDCl3)
d: 7.26 (m, 4H), 4.26 (q, 2H,
J¼7.11 Hz), 3.91 (q, 1H, J¼7.47 Hz), 3.71 (dt, 1H, J¼7.46 and 6.60 Hz),
3.33 (d, 2H, J¼6.60 Hz), 2.94 (d, 2H, J¼7.47 Hz), 1.33 (t, 3H,
J¼7.11 Hz). 13C NMR (75 MHz, CDCl3)
d: 171.6, 142.0, 139.5,
4. Experimental section
4.1. General
128.0, 127.5, 124.8, 123.8, 120.4, 61.0, 42.7, 36.3, 36.1, 34.3, 14.2. MS:
m/z (%) 229, 203, 184, 174, 156, 154, 142, 130, 128 (100%), 115, 102, 89,
77, 63. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59. Found: C, 73.07;
H, 6.85.
Unless indicated, all solvents and reagents were purchased from
commercial sources and used as-received. DMF was stored under
argon. The electrochemical cell has been previously described.18
(E)-Ethyl 3-(2-bromophenyl)prop-2-enoate 1 and (E)-3-(2-bromo-
phenyl)prop-2-en-1-nitrile 5 were prepared according to the
known procedures.19 1H and 13C spectra were recorded on a Bruker
Avance 300 (300 and 75 MHz, respectively). Chemical shifts are
quoted in parts per million (ppm). The NOESY experiments15 were
run on a Bruker Avance 600 MHz with a mixing time of 800 ms.
Mass spectra were obtained with a GCQ Thermoquest Spectrometer
coupled to a chromatograph fitted with a 25-m CPSIL5 CB capillary
column. The infrared spectra were recorded on a Perkin Elmer FT-IR
Spectrometer 1720X. Melting points were measured on Electro-
thermal IA 9100 digital point apparatus in an open capillary tubes
and were uncorrected. Elemental analyses and high resolution
mass spectral analyses were made by the Service Central d’Analyse
(CNRS, Lyon).
Characterization of trans-4 was achieved as a pure fraction of
the isolated compound: 1H NMR (300 MHz, CDCl3)
d: 7.28 (m, 4H),
4.26 (q, 2H, J¼7.14 Hz), 3.96 (m, 1H), 3.44 (dd, 1H, J¼15.40 and
8.48 Hz), 3.33 (m, 1H), 3.20 (m, 1H), 2.89 (dd, 1H, J¼15.66 and
5.86 Hz), 2.73 (dd, 1H, J¼15.66 and 7.53 Hz), 1.33 (t, 3H, J¼7.14 Hz).
13C NMR (75 MHz, CDCl3)
d: 171.0, 141.8, 139.4, 128.0, 127.6, 124.6,
123.5, 121.5, 61.0, 46.4, 38.1, 36.2, 33.8, 14.1. MS: m/z (%) 229, 203,
184, 174, 156, 154, 142, 130, 128, 115, 102, 89, 77, 63. IR (neat), cmꢁ1
:
2254,1713, 908, 732. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N,
6.11. Found: C, 73.38; H, 6.70; N, 5.71.
4.2.2. (E)-Ethyl 3-[2-(3-oxobutyl)phenyl]prop-2-enoate 8 and ethyl
2-(2-acetyl-2,3-dihydro-1H-inden-1-yl)acetate 10
The products were isolated by chromatography on silica gel
(eluent: diethyl ether, content increasing from 3 to 25% in pentane)
to give 1.05 g (56%) of 8, 0.102 g (5.5%) and 0.153 g (8%) of the two
diastereoisomers of 10.
4.2. General procedure for the preparation of indane by the
electrochemical way
4.2.2.1. (E)-Ethyl 3-[2-(3-oxobutyl)phenyl]prop-2-enoate 8. Oil; 1H
NMR (300 MHz, CDCl3)
d
: 8.00 (d, 1H, J¼15.8 Hz), 7.71–7.24 (m, 4H),
6.45 (d, 1H, J¼15.8 Hz), 4.23 (q, 2H, J¼7.0 Hz), 3.03–2.98 (m, 2H),
In an undivided cell equipped with stainless steel grid as the
cathode (area 30 cmꢁ2) and an iron rod as the anode, under argon,
Bu4NBr (0.15 g, 0.46 mmol) and Bu4NI (0.11 g, 0.29 mmol) were
dissolved as supporting electrolytes in a mixture of DMF (15 mL)
2.80–2.74 (m, 2H), 2.12 (s, 3H), 1.30 (t, 3H, J¼7.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 206.8, 66.1, 141.4, 141.0, 132.9, 130.1, 129.8, 126.7,
126.6,119.8, 59.9, 44.1, 28.9, 26.6,13.7. MS: m/z (%) 246 (3), 201 (17),
200 (18), 172 (30), 158 (16), 157 (100), 131 (11), 130 (17), 129 (60),

S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
9393
128 (15), 115 (17). IR, cmꢁ1: 3068, 2985, 2940, 2905, 2876, 1704,
1634, 1601, 1368. HRMS m/z calcd for C15H18O3: (MþH) 247.1334;
found: 247.1335.
ions. Then the current was turned off. NiBr2 (164 mg, 0.75 mmol)
and activated olefin (2.5–4 equiv) were added. The mixture was
stirred for 5 min at room temperature before the addition of ortho-
substituted arylbromide (7.5 mmol). Then the mixture was heated
at 70 ꢀC and the electrolysis was run at constant current intensity
(0.5 A dmꢁ2). The reaction mixture was monitored by GC to es-
tablish the completion. For compounds 15, 21 and 22, the reaction
mixture was cooled, hydrolyzed with HCl (1 N, 50 mL) and diluted
with diethyl ether (50 mL). The aqueous layer was extracted
twice with diethyl ether (50 mL). The organic layer was washed
twice with 1 N HCl (50 mL) and saturated NaCl solution, dried over
MgSO4, filtered and the solvent was evaporated. For compounds 17
and 19, the work up has been carried out as follows. After removal
of the solvent by vacuo, the residue was solubilized in CH2Cl2
(100 mL) and washed with H2O (50 mL). The aqueous layer was
extracted with CH2Cl2 (50 mL). The organic layers are collected,
dried over Na2SO4 and evaporated.
4.2.2.2. Ethyl 2-(2-acetyl-2,3-dihydro-1H-inden-1-yl)acetate 10. First
diastereoisomer: oil; 1H NMR (300 MHz, CDCl3)
d: 7.27–7.16 (m, 4H),
4.16 (q, 1H, J¼7.17 Hz), 4.16 (q, 1H, J¼7.11 Hz), 3.99 (m, 1H), 3.67 (m,
1H), 3.32 (dd, 1H, J¼15.91 and 9.26 Hz), 2.95 (dd, 1H, J¼15.91 and
7.77 Hz), 2.59 (dd, 1H, J¼16.28 and 7.11 Hz), 2.43 (dd, 1H, J¼16.28
and 7.80 Hz), 2.28 (s, 3H), 1.27 (t, 3H, J¼7.12 Hz). 13C NMR (75 MHz,
CDCl3) d: 209.2, 172.3, 144.3, 141.2, 127.4, 126.8, 124.8, 124.0, 60.6,
55.4, 43.0, 35.8, 33.0, 30.5, 14.2. MS: m/z (%) 246 (M), 233, 228, 217,
201, 185, 172, 159, 143, 129 (100%), 115, 102, 91, 77. IR (neat), cmꢁ1
:
3070, 2980, 2930, 2853, 1728, 1709, 1477, 1366, 1162, 1028, 750.
HRMS (MþNa) m/z calcd for C15H18O3Na: 269.1154; found: 269.1155.
Second diastereoisomer: 1H NMR (300 MHz, CDCl3)
d: 7.24–7.19
(m, 4H), 4.17 (q, 2H, J¼7.14 Hz), 4.00 (m, 1H), 3.36–3.27 (m, 2H), 3.10
(dd, 1H, J¼18.67 and 11.12 Hz), 2.84 (dd, 1H, J¼15.38 and 5.23 Hz),
2.57 (dd, 1H, J¼15.38 and 8.82 Hz), 2.32 (s, 3H), 1.30 (t, 3H,
4.3.1. 2-Methyl-3,4-dihydronaphthalene-1-carbonitrile 15
The product was purified by column chromatography on silica
gel (eluent: pentane/diethyl ether 8/2) to give 165 mg (13%) of
viscous the desired compound 15.
J¼7.14 Hz). 13C NMR (75 MHz, CDCl3)
d: 208.9, 172.2, 143.8, 140.7,
127.4, 127.3, 124.5, 123.7, 60.7, 57.9, 43.2, 39.6, 34.9, 28.7, 14.2. MS:
m/z (%) 246 (M), 233, 228, 217, 201, 185, 172, 159, 143, 129 (100%),
115, 102, 91, 77. IR (neat), cmꢁ1: 3070, 2980, 2930, 2853, 1728, 1710,
1479, 1367, 1158, 1025, 748.
Solid, mp: <40 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 7.47 (d, 1H,
J¼7.15 Hz), 7.27 (m, 2H), 7.16 (d, 1H, J¼6.96 Hz), 2.85 (t, 2H,
J¼7.76 Hz), 2.46 (t, 2H, J¼7.76 Hz), 2.30 (s, 3H). 13C NMR (75 MHz,
4.2.3. (E)-Ethyl 3-[2-(2-cyanovinyl)phenyl]propanoate 9 and ethyl
1-(cyanomethyl)-2,3-dihydro-1H-indene-2-carboxylate 11
The products were isolated by chromatography on silica gel
(eluent: diethyl ether content increasing from 5 to 25% in pentane)
to give 198 mg (11.5%) of only one diastereoisomer of 11 and
704 mg (41%) of 9.
CDCl3) d: 155.3, 133.1, 129.7, 128.1, 127.6, 127.1, 124.3, 116.6, 109.2,
30.1, 26.5, 23.4. MS: m/z (%) 169, 154 (100%), 141, 127, 115, 84, 75, 63.
IR (neat), cmꢁ1: 3065, 3023, 2937, 2836, 2220, 1622, 1492, 1454,
1435. Anal. Calcd for C12H11N: C, 85.17; H, 6.55; N, 8.28. Found: C,
85.08; H, 6.69; N, 8.26.
4.3.2. Ethyl 3-amino-1,4-dihydronaphthalene-2-carboxylate 17
The product was purified by column chromatography on neutral
aluminium oxide (eluent: pentane/ethyl acetate 7/3) to afford
325 mg (20%) of compound 17 as yellow solid.
4.2.3.1. (E)-Ethyl 3-[2-(2-cyanovinyl)phenyl]propanoate 9. White
crystals, mp: 65 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 7.77 (d, 1H,
J¼16.46 Hz), 7.51–7.26 (m, 4H), 5.86 (d, 1H, J¼16.46 Hz), 4.16 (q, 2H,
J¼7.12 Hz), 3.06 (t, 2H, J¼7.76 Hz,), 2.59 (t, 2H, J¼7.76 Hz), 1.27 (t,
Yellow solid, mp: 86–86.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 7.32–
3H, J¼7.12 Hz). 13C NMR (75 MHz, CDCl3)
d
: 172.2,147.9,139.7,132.3,
7.15 (m, 4H), 4.29 (q, 2H, J¼7.11 Hz), 3.70 (t, 2H, J¼2.90 Hz), 3.54 (t,
131.2, 130.1, 127.3, 126.0, 118.2, 98.1, 60.7, 35.6, 28.0, 14.2. MS: m/z
(%) 229, 215, 201, 183, 156 (100%), 140, 129, 115, 89, 77, 63. IR (in
solution in CDCl3), cmꢁ1: 3060, 3025, 2984, 2941, 2907, 2254, 2220,
1728, 1616, 1600, 1484, 1465, 1453, 1375, 964, 911, 733. Anal. Calcd
for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 72.94; H, 6.58; N,
5.84.
2H, J¼2.90 Hz), 1.41 (t, 3H, J¼7.10 Hz). 13C NMR (75 MHz, CDCl3)
d:
169.6, 155.5, 136.1, 132.2, 127.9, 127.2, 126.4, 125.9, 90.3, 59.3, 35.8,
29.1, 14.8. MS: m/z (%) 217 (M), 188, 170, 144 (100%), 127, 115. IR (in
solution in CDCl3), cmꢁ1: 3499, 3338, 3029, 2982, 2904, 2826, 2252,
1664, 1619, 1542, 1458, 1277, 1223, 908, 732. Anal. Calcd for
C13H15NO2: C, 71.87; H, 6.96; N, 6.45; O 14.73. Found: C, 71.71; H,
6.96; N, 6.45.
4.2.3.2. Ethyl 1-(cyanomethyl)-2,3-dihydro-1H-indene-2-carboxyl-
ate 11. 1H NMR (300 MHz, CDCl3)
d: 7.40–7.28 (m, 4H), 4.28 (q, 2H,
4.3.3. 2-Amino-3,4-dihydronaphthalene-1-carbonitrile 19
The black viscous residue was purified by column chromatog-
raphy on aluminium oxide (eluent: diethyl ether/pentane 8/2) to
afford 115 mg (9%) of compound 19, which darkens rapidly in the
light.
J¼7.13 Hz), 3.84 (m,1H), 3.36 (dd,1H, J¼15.86 and 9.36 Hz), 3.27 (m,
1H), 3.18 (m, 1H), 2.98 (dd, 1H, J¼17.02 and 5.43 Hz), 2.91 (dd, 1H,
J¼17.02 and 6.01 Hz), 1.30 (t, 3H, J¼7.13 Hz). 13C NMR (75 MHz,
CDCl3) d: 173.6, 141.1 (2C), 128.2, 127.3, 124.8, 123.2, 118.0, 61.3, 49.5,
44.1, 34.9, 21.9, 14.4. MS: m/z (%) 229, 209, 200, 183, 174, 156 (100%),
140, 129, 115, 102, 89, 77, 63. IR (neat), cmꢁ1: 2980, 2858, 2927,
2855, 2246, 1726, 1449, 1372, 1244, 1215, 1174, 1037, 1015, 752.
HRMS m/z calcd for C14H15NO2Na: 252.1000; found: 252.1014.
White powder, mp: 83 ꢀC (lit.2 83–84 ꢀC); 1H NMR (300 MHz,
CDCl3) d: 7.30–7.22 (m, 2H), 7.14–7.04 (m, 2H), 5.20 (s br d, 2H), 2.88
(t, 2H, J¼7.75 Hz), 2.53 (t, 2H, J¼7.75 Hz). 13C NMR (75 MHz, CDCl3)
d: 159.5, 131.5, 129.7, 127.3, 127.2, 124.5, 122.2, 118.4, 28.7, 26.9. MS:
m/z (%) 170 (100%), 155, 142, 127, 115, 102, 89. IR (in solution in
CDCl3), cmꢁ1: 3512, 3403, 3069, 2947, 2900, 2252, 2195, 1628, 1592,
1566, 1493, 909, 735.
4.3. General procedure for the preparation of dihydro
and tetrahydronaphthalene
In an undivided cell equipped with stainless steel grid as the
cathode (area 30 cmꢁ2) and an iron rod (entries 1–3, Table 2) or
stainless steel rod (entries 4 and 5, Table 2) as the anode, under
argon, Bu4NBr (0.15 g, 0.46 mmol) and Bu4NI (0.11 g, 0.29 mmol)
were dissolved as supporting electrolyte in a mixture of DMF
(15 mL) and MeCN (15 mL). 1,2-Dibromoethane (80 mL, 0.93 mmol)
was introduced. A short pre-electrolysis was run at 0.15 A for
20 min, at room temperature, to generate small amount of iron
4.3.4. Ethyl 3-hydroxy-3-methyl-1,2,3,4-tetrahydro-naphthalene-
2-carboxylate 22
The two diastereoisomers were purified by column chroma-
tography on silica gel (eluent: pentane/diethyl ether 8/2) to give
378 mg (21.5%) of the first diastereoisomer as a white solid and
149 mg (8.5%) of the second one as a liquid.
First diastereoisomer: white powder; 1H NMR (300 MHz, CDCl3)
d: 7.21–7.11 (m, 4H), 4.30 (m, 2H), 3.50 (br s, 1H, OH), 3.34 (dd, 1H,

9394
S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
J¼16.36 and 11.67 Hz), 3.04–2.97 (m, 2H), 2.86 (d, 1H, J¼17.03 Hz),
2.81 (dd, 1H, J¼11.66 and 5.43 Hz), 1.45 (s, 3H), 1.38 (t, 3H,
White crystals, mp: 57 ꢀC (lit.2 57 ꢀC); 1H NMR (300 MHz, CDCl3)
d
: 7.46–7.31 (m, 4H), 3.80 (s, 2H), 3.05 (t, 2H, J¼7.33 Hz), 2.72 (t, 2H,
J¼7.14 Hz). 13C NMR (75 MHz, CDCl3)
d: 175.9, 133.9, 133.6, 129.3,
J¼7.35 Hz). 13C NMR (75 MHz, CDCl3)
d: 136.1, 129.8, 129.7, 129.2,
128.3, 126.3, 126.0, 68.9, 61.0, 48.6, 42.2, 30.0, 28.3,14.3. MS: m/z (%)
235, 216, 202, 191, 173, 155, 143 (100%), 128, 117, 104, 91, 78. IR
(neat), cmꢁ1: 3530, 3062, 3020, 2978, 2935, 1715, 1585, 1498, 1456,
1379. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.69; H,
7.99.
128.4, 128.3, 118.9, 117.7, 28.1, 21.6, 18.3. MS: m/z (%) 170 (M), 143,
130 (100%), 116, 103, 89, 77. IR (neat), cmꢁ1: 3030, 2920, 2220, 1410,
1350, 715. Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.45.
Found: C, 77.60; H, 6.10; N, 16.25.
Second diastereoisomer: oil; 1H NMR (300 MHz, CDCl3)
d
: 7.20–
4.4.4. 3-Hydroxy-3-methyl-1,2,3,4-tetrahydronaphthalene-2-
carbonitrile 21
7.10 (m, 4H), 4.30 (q, 2H, J¼7.14 Hz), 3.28 (dd, 1H, J¼16.66 and
5.58 Hz), 3.10–2.90 (m, 4H), 1.38 (t, 3H, J¼7.14 Hz), 1.34 (s, 3H), 1.30
Characterization of the separated pure diastereoisomer: white
(s, OH). 13C NMR (75 MHz, CDCl3)
d
: 173.9, 134.5, 133.4, 129.3, 128.5,
solid, mp: 178.5 ꢀC; 1H NMR (300 MHz, CDCl3)
d: 7.15–7.06 (4H, m),
126.2, 126.2, 70.4, 61.0, 49.4, 44.6, 30.6, 22.6, 14.3. MS: m/z (%) 235,
225, 216 (100%), 170, 155, 142 (100%), 133, 117, 104, 91, 77. HRMS
(MþNa) m/z calcd for C15H18O3Na: 269.1154; found: 269.1163.
3.36 (1H, dd, J¼16.90 and 10.27 Hz), 3.15 (dd, J¼16.90 and 5.75 Hz,
0
H3 ), 3.05 (d, J¼17.06 Hz, 1H, H10), 2.93 (1H, dd, J¼10.27 and
5.75 Hz), 2.93 (d, 1H, J¼17.06 Hz), 2.61 (s br d, OH), 1.57 (s, 3H). 13
C
NMR (75 MHz, CDCl3) d: 207.4, 132.9, 131.5, 129.5, 128.4, 126.8,
4.4. General procedure for nickel-catalyzed conjugate
addition reaction in the presence of ethanol
126.5, 120.5, 67.8, 42.0, 37.8, 30.0, 27.8. MS: m/z (%) 187, 169 (100%),
154, 145, 129, 115, 104, 91, 78. IR (in solution in CDCl3), cmꢁ1: 3448,
2945, 2972, 2929, 2898, 2248,1649,1463,1428,1382,1114, 907, 732.
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.64;
H, 6.80; N, 7.39.
In an undivided cell equipped with stainless steel grid as the
cathode (area 30 cmꢁ2) and stainless steel rod as the anode, under
argon, Bu4NBr (0.11, 0.34 mmol), Bu4NI (77 mg, 0.21 mmol) and 1,2-
dibromoethane (80
m
L, 0.93 mmol) were added in a mixture of DMF
4.4.5. Ethyl [2-(3-oxo-butyl)phenyl]ethanoate 25
The reaction mixture was purified on silica gel column chro-
matography using pentane/diethyl ether (7/3) as eluent to afford
0.84 g (48%) of 25.
(15 mL) and MeCN (15 mL). A short pre-electrolysis was conducted
at controlled intensity (0.15 A) for 20 min, at room temperature.
Then the current was turned off. NiBr2$3H2O (164 mg, 0.75 mmol),
the activated olefin (2.5 equiv), aryl bromide (7.50 mmol) and
ethanol (1–4 equiv) were successively added. The mixture was
warmed at 70 ꢀC and the electrolysis was run at constant intensity
(0.2 A). The reaction mixture was monitored by GC to establish the
completion. The reaction mixture was cooled, hydrolyzed with HCl
(1 N, 50 mL) and diluted with diethylether (50 mL). The aqueous
layer was extracted twice with ether (50 mL); the organic layers
were collected, washed with 2ꢂ50 mL portion of 1 N HCl and then
brine, dried over MgSO4 and filtered. After evaporation of the sol-
vent, the product was subjected to chromatography on silica gel
column.
Oil; 1H NMR (300 MHz, CDCl3)
d: 7.34–7.15 (m, 4H), 4.16 (q, 2H,
J¼7.14 Hz), 3.69 (s, 2H), 2.93 (t, 2H, J¼7.5 Hz), 2.77 (t, 2H, J¼7.5 Hz),
2.16 (s, 3H), 1.27 (t, 3H, J¼7.14 Hz,). 13C NMR (75 MHz, CDCl3)
d:
207.6, 171.6, 139.7, 132.5, 130.6, 129.2, 127.5, 126.4, 60.8, 44.3, 38.6,
29.9, 26.5, 14.2. MS: m/z (%) 234 (M), 219, 216, 188, 170, 145 (100),
129, 117, 103, 91. IR (neat), cmꢁ1: 3064, 2982, 1718, 1734, 1492, 1457.
HRMS m/z calcd for C14H18O3: (MþH) 235.1334; found: 235.1329.
4.5. Intramolecular cyclization by chemical way
4.5.1. Ethyl 2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalene-1-
carboxylate 26
4.4.1. 2-[(3-Oxo-butyl)phenyl]acetonitrile 16
After consumption of sodium (63 mg, 2.74 mmol) in ethanol
(4 mL), ethyl [2-(3-oxo-butyl)phenyl]ethanoate 25 (0.50 g,
2.13 mmol) in ethanol (1 mL) was slowly added. The temperature is
allowed to rise to 38 ꢀC. After 40 min at room temperature, the
reaction mixture was diluted with CH2Cl2 (15 mL) and hydrolyzed
with H2O (10 mL). The aqueous layer was extracted with CH2Cl2
(25 mL). The organic layers are collected, rinsed with H2O (20 mL)
and dried over MgSO4. After removal of the solvent, the mixture of
the diastereoisomers found in proportion 50/50 was purified by
column chromatography (eluent: pentane/ethyl acetate 7/3) to give
382 mg (76%) of diastereoisomers 26.
The reaction mixture was purified by column chromatography
using pentane/diethyl ether (7/3) as eluent to afford 0.70 g (50%) of
the desired compound.
1H NMR (300 MHz, CDCl3)
d
7.38–7.19 (4H, m), 3.80 (2H, s), 2.85
(4H, m), 2.16 (3H, s). 13C NMR (75 MHz, CDCl3)
207.3, 139.1, 129.4,
129.2,128.6,128.4,127.1,118.2, 43.8, 30.1, 25.9, 21.5. MS: m/z (%) 187,
169, 154, 144 (100%), 129, 117, 115, 103, 91, 77, 63. IR (neat), cmꢁ1
d
:
3020, 2240, 1720, 1600, 1490, 1400, 1360, 1160, 750. HRMS (MþNa)
m/z calcd for C12H13NONa: 210.0895; found: 210.0905.
4.4.2. Ethyl 3-(2-cyanomethylphenyl)propionate 18
The reaction mixture was purified by column chromatography
using 5–40% ethyl acetate gradient in pentane as eluent to afford
0.78 g (48%) of the desired compound.
The partial characterization of the first diastereoisomer has
been achieved on a 95/5 ratio of enrichissed fraction.
Oil; 1H NMR (300 MHz, CDCl3)
d: 7.26–7.14 (m, 4H), 4.33 (q, 2H,
J¼7.13 Hz), 3.82 (s, 1H), 3.41 (s, OH), 3.18 (dt, 1H, J¼17.50 and
6.90 Hz), 2.83 (dt, 1H, J¼17.50 and 6.48 Hz), 2.32 (dt, 1H, J¼13.24
and 6.48 Hz), 1.78 (dt, 1H, J¼13.24 and 6.90 Hz), 1.39 (t, 3H,
1H NMR (300 MHz, CDCl3)
d: 7.41–7.22 (m, 4H), 4.13 (q, 2H,
J¼7.14 Hz), 3.80 (s, 2H), 2.96 (t, 2H, J¼7.60 Hz), 2.65 (t, 2H,
J¼7.61 Hz),1.23 (t, 3H, J¼7.15 Hz). 13C NMR (75 MHz, CDCl3)
d
: 172.5,
J¼7.13 Hz), 1.37 (s, 3H). 13C NMR (75 MHz, CDCl3)
d: 174.3, 135.7,
138.5, 129.3, 129.1, 128.6, 128.4, 127.2, 117.9, 60.4, 34.6, 27.2, 21.4,
14.2. MS: m/z (%) 217 (M), 189, 171, 144 (100%), 129, 116, 103, 91, 77.
IR (neat), cmꢁ1: 3060, 2983, 2938, 2248, 1729, 1600, 1494, 1455,
1420, 1375, 1189, 1040, 757. Anal. Calcd for C13H15O2N: C, 71.86; H,
6.96; N, 6.45. Found: C, 71.97; H, 7.10; N, 6.24.
132.4, 129.2, 128.7, 127.2, 126.0, 69.6, 61.2, 55.3, 33.8, 27.9, 26.7, 14.3.
MS: m/z (%) 235, 216, 201, 188, 170, 143 (100%),128, 117, 91. IR (neat),
cmꢁ1: 3463, 3062, 3020, 2977, 2932, 1719, 1582, 1497, 1450, 1371.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.43; H, 7.97.
4.5.2. 2-Hydroxy-3,4-dihydronaphthalen-1-carbonitrile 27
4.4.3. 3-(2-Cyanomethylphenyl)propionitrile 20
After consumption of sodium (66 mg, 2.87 mmol) in ethanol
(4 mL), ethyl 3-(2-cyanomethylphenyl)propionate 18 (0.50 g,
2.30 mmol) in ethanol (1 mL) was slowly added. After 15 min at
80 ꢀC, the reaction mixture was cooled, diluted with diethyl ether
The reaction mixture was purified by column chromatography
using 25–75% diethyl ether gradient in pentane as eluent to yield
0.79 g (62%) of the desired compound.

S. Condon et al. / Tetrahedron 64 (2008) 9388–9395
9395
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310–316.
(10 mL) and hydrolyzed with H2O (10 mL). The aqueous layer was
extracted with diethyl ether (25 mL). The organic layers are col-
lected, washed with brine and dried over MgSO4. After removal of
the solvent, the mixture was purified by column chromatography
(pentane/ethyl acetate: 9/1) to yield 275 mg (70%) of 27.
6. Rudolph, J.; Chen, L.; Majumdar, D.; Bullock, W. H.; Burns, M.; Claus, T.; Dela
Cruz, F. E.; Daly, M.; Ehrgott, F. J.; Johnson, J. S.; Livingston, J. N.; Schoenleber, R.
W.; Shapiro, J.; Yang, L.; Tsutsumi, M.; Ma, X. J. Med. Chem. 2007, 50, 984–1000.
7. Rayabarapu, D. K.; Yan, C.-H.; Cheng, C.-H. J. Org. Chem. 2003, 68, 6726–6731.
8. Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. Org. Lett. 2003, 5, 3963–3966.
9. (a) Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58, 4579–4583; (b) Gevorgyan, V.;
Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089–4092; (c) Zhang, D.;
Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251–262.
10. Chen, B.; Xie, X.; Lu, J.; Wang, Q.; Zhang, J.; Tang, S.; She, X.; Pan, X. Synlett 2006,
259–262.
1H NMR (300 MHz, CDCl3)
d: 7.70 (s br d, OH), 7.34–7.16 (m, 4H),
2.98 (t, 2H, J¼7.98 Hz), 2.67 (t, 2H, J¼7.98 Hz). 13C NMR (75 MHz,
CDCl3)
d 171.8, 130.5, 129.8, 127.5, 127.3, 126.2, 123.2, 116.4, 85.1,
28.3, 27.1. MS: m/z (%) 171 (100%), 154, 143, 129, 115. IR (in solution
in CDCl3), cmꢁ1: 3220, 2254, 2219, 1640, 1611, 1572, 1494, 1390, 908,
734. 1H NMR spectrum is in good agreement with the literature
data.2
11. Dyker, G.; Grundt, P. Tetrahedron Lett. 1996, 37, 619–622.
12. Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 2004, 69, 4781–4787.
´
´
´ ´
13. (a) Metay, E.; Leonel, E.; Sulpice-Gaillet, C.; Nedelec, J. Y. Synthesis 2005, 1682–
1688; (b) Me´tay, E.; Le´onel, E.; Condon, S.; Ne´de´lec, J. Y. Tetrahedron 2006, 62,
8515–8524.
´
´
14. Condon, S.; Nedelec, J.-Y. Synthesis 2004, 18, 3070–3078.
15. Thrippleton, M. J.; Keeler, J. Angew. Chem., Int. Ed. 2003, 42, 3938–3941.
16. Courtois, V.; Barhdadi, R.; Condon, S.; Troupel, M. Tetrahedron Lett. 1999, 40,
5993–5996.
Acknowledgements
´
The authors thank the technical staffs (D. Dupre, C. Gaillet) for
their supports.
17. 2-(2-Bromophenyl)pentan-1,5-dinitrile (24). 1H NMR (300 MHz, CDCl3)
d: 7.65
(dd, 1H, J¼7.97 and 1.16 Hz), 7.59 (dd, 1H, J¼7.63 and 1.66 Hz), 7.44 (m, 1H), 7.29
(m, 1H), 4.49 (dd, 1H, J¼9.10 and 5.43 Hz), 2.71–2.54 (m, 2H), 2.40–2.17 (m, 2H).
13C NMR (75 MHz, CDCl3)
d: 133.8, 133.2, 130.6, 129.0, 128.7, 123.0, 118.7, 117.8,
36.3, 29.9, 15.2. IR (neat), cmꢁ1: 2254, 1670, 1473, 1442, 909, 732. MS: m/z (%)
250, 248, 210, 208, 196, 194, 183, 181, 169 (100%), 142, 128, 115, 102, 88, 75, 63.
Anal. Calcd for C11H9N2Br: C, 53.04; H, 3.64; N, 11.25; Br, 32.08. Found: C, 53.50;
H, 3.73; N, 11.12; Br, 31.90. (23): MS: m/z (%) 223, 209, 195, 183, 169, 155, 142,
129, 115, 102, 89, 78, 63.
References and notes
1. (a) Parfitt, R. T. J. Chem. Soc. C 1967, 140–142; (b) Eddy, N. B.; May, E. L. Synthetic
Analgesics, Part IIB; Pergamon: Oxford, 1966; p 115.
2. Burrows, E. P.; Rosowsky, A.; Modest, E. J. J. Org. Chem. 1967, 32, 4090–4092.
3. Sukuda, T.; Kawasaki, K.-I.; Komiyama, S.; Isshiki, Y.; Shiratori, Y.; Hasegawa, K.;
Fukami, T.; Miura, T.; Ono, N.; Yamazaki, T.; Na, Y.-J.; Yoon, D.-O.; Kim, S.-J. PCT
Int. Appl. WO2007138994, 2007.
18. Chaussard, J.; Folest, J. C.; Ne´de´lec, J. Y.; Pe´richon, J.; Sibille, S.; Troupel, M.
Synthesis 1990, 369–380.
19. Gibson, S. E.; Guillo, N.; Middelton, R.; Thuilliez, A.; Tozer, M. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 447–455.
4. Navarro, C.; Csa´ky¨, A. G. Org. Lett 2008, 10, 217–219 and references therein.