Reductive cleavage of benzannelated cyclic ethers and amines: Synthetic applications

Article abstract of DOI:10.1016/S0040-4020(00)00783-3

Reduction of symmetrical intramolecular diarylmethyl ethers (3a and 8a) and amines (3b and 8b) with alkali metals in THF allows the generation of unsymmetrical oxy- or amino-functionalised arylmethyl organometallics. Such intermediates were successfully trapped with various electrophiles, allowing a new access to unsymmetrically 2,2'-disubstituted-1,1'-biaryls (5aa-5bf) and 1,8-disubstituted naphthalenes (10aa-10be). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00783-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8375±8382
Reductive Cleavage of Benzannelated Cyclic Ethers and Amines:
Synthetic Applications
*
Ugo Azzena, Salvatore Demartis, Luciano Pilo and Elisabetta Piras
Á Á
Dipartimento di Chimica e Facolta di Farmacia, Universita degli Studi di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 28 June 2000; revised 8 August 2000; accepted 23 August 2000
AbstractÐReduction of symmetrical intramolecular diarylmethyl ethers (3a and 8a) and amines (3b and 8b) with alkali metals in THF
allows the generation of unsymmetrical oxy- or amino-functionalised arylmethyl organometallics. Such intermediates were successfully
trapped with various electrophiles, allowing a new access to unsymmetrically 2,20-disubstituted-1,10-biaryls (5aa±5bf) and 1,8-disubstituted
naphthalenes (10aa±10be). q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Reductive cleavage of the arylalkyl carbon±heteroatom
bond of 2-aryl-substituted oxygen or nitrogen heterocycles
by electron transfer from alkali metals in ethereal solvents is
a useful approach to the generation of 1-arylalkyl organo-
metallics which are functionalised with an oxyanionic or an
aminoanionic group, suitable for further elaboration
(Scheme 1). Interesting results on this topic include: the
reductive cleavage of styrene oxide,1 1,3-dihydroisobenzo-
furans (phthalans),2,3 N-phenylisoindoline,4 4-phenyl-1,3-
dioxanes,5 2-aryl-1,3-oxazolidines.6 Due to these satisfac-
tory results and to the current interest in electron-transfer
reactions mediated by alkali metals,7±11 we further investi-
gated the synthetic exploitation of this approach.
Synthesis of unsymmetrically 2,20-disubstituted-1,10-
biaryls
Unsymmetrically disubstituted biaryls are an important
class of organic compounds which ®nd useful application
in the synthesis of pharmaceuticals, ligands, polymers, and
liquid crystals. Most approaches to their synthesis rely on
the cross-coupling of aromatic halides or tri¯ates with
suitable partners.12,13
We investigated an alternative approach to 2,20-disubsti-
tuted-1,10-biaryls having 6,7-dihydro-5H-dibenz[c,e]oxe-
pine (diphenane), 3a, or 6,7-dihydro-6-methyl-5H-
dibenz[c,e]azepine (N-methyldibenzazepine), 3b, as key
intermediates (Scheme 2). Commercially available
anhydride 1 was reduced with LiAlH4 in THF, affording
2,20-hydroxymethyl-1,10-diphenyl, 2, in 80% yield; diol 2
was cyclised with 85% H3PO4 to give ether 3a in 82%
isolated yield.
As already observed with phthalan2,3 and N-phenylisoindo-
line,4 reductive metalation of symmetrical oxygen and
nitrogen heterocycles allows the generation of unsymmetri-
cal organometallics. Accordingly, we wish to present here
applications of this procedure to suitable six- and seven-
membered dibenzo-oxygen and -nitrogen heterocycles
leading to the synthesis of unsymmetrically disubstituted
biaryls and naphthalenes.
Alternatively, reaction of diol 2 with 48% HBr, followed by
aminolysis of the crude dibromide with 40% aqueous
CH3NH2, afforded amine 3b in 85% overall yield.
Reductive cleavage of ether 3a by electron transfer from
alkali metals in ethereal solvents should generate the
corresponding unsymmetrical dianion 4a. Further reaction
of such an intermediate with electrophilic reagents
should lead to the synthesis of 2-hydroxymethyl-20-
substituted-1,10-biaryls 5a. Application of
a similar
Scheme 1. XˆO, NCH3; Mˆalkali metal
reaction sequence to amine 3b should allow the synthesis
of 2-N-methylaminomethyl-20-substituted-1,10-biaryls 5b
via the intermediate formation of the corresponding
dianion 4b.
Keywords: amines; ethers; carbanions; lithium and compounds; reduction.
* Corresponding author. Tel.: 139-079229549; fax: 139-079229559;
e-mail: ugo@ssmain.uniss.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00783-3

8376
U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
Scheme 2. XˆO, NCH3
Reductive lithiation of ether 3a
substitution reactions of 3a were performed at 2158C.
The dilithium derivative 4a was ef®ciently trapped with
primary and secondary alkyl halides, chlorotrimethylsilane
and acetone, affording the corresponding 2-hydroxymethyl-
20-substituted-1,10-biphenyl derivatives 5ac±5af, respec-
tively, in satisfactory yields (Table 1, entries 4±7).
Reductive cleavage reactions were carried out under Ar in
THF with an excess of Li dispersion. Selected results are
reported in Table 1. The results of D2O quenching experi-
ments, carried out to check the formation of intermediate
organometallic derivatives are also reported.
Reductive lithiation of amine 3b
Effective reductive cleavage of 3a was accomplished with
Li metal (5 equiv.) in the presence of a catalytic amount of
naphthalene (10 mol%) in THF at rt during 2 h. Under these
conditions we observed exclusive formation of 2-hydroxy-
methyl-20-methyl-1,10-biphenyl, 5aa; quenching the
reaction mixture with D2O resulted in 70% deuteration at
the arylmethyl position, as evidenced by H NMR spectro-
scopic analysis of the crude reaction mixture (Table 1,
entries 1 and 2).
Reductive lithiation of amine 3b was ef®ciently obtained at
08C in the presence of 5 equiv. of Li metal and a catalytic
amount of naphthalene (10 mol%) after 6 h. Under
these conditions 2-methyl-20-N-methylaminomethyl-1,10-
biphenyl, 5ba, was obtained in quantitative yield via
quantitative intermediate formation of the corresponding
dilithium derivative 4b (Table 1, entries 8 and 9).
1
Under these conditions, quenching the intermediate 4b with
(CH3)2CHBr and chlorotrimethylsilane afforded compounds
5bc and 5bd, respectively, in satisfactory yields (Table 1,
entries 10 and 11). At variance with these results, quenching
the intermediate 4b with n-BuBr at 08C afforded an intract-
able reaction mixture (not reported in Table 1). However,
addition of the electrophile to a suspension of the organo-
lithium reagent at 2408C afforded compound 5be in 75%
A similar result was obtained when the reaction was
performed at 08C (not reported in Table 1), whilst perform-
ing the reaction at 2158C and quenching it with D2O
showed quantitative intermediate formation of the corre-
sponding arylmethyllithium derivative (Table 1, entry 3).
Due to the above reported results, reductive eletrophilic
Table 1. Reductive cleavage and electrophilic substitution of compounds 3a and 3b
Entry
Compound, Xˆ
T (8C)
t (h)
EX
Product, Eˆ
5aa, H
5ab, D
5ab, D
5ac, Bu
5ad, (CH3)2CH
5ae, (CH3)3Si
5af, (CH3)2COH
5ba, H
Yield (%)a,b
1
2
3
4
5
6
7
8
3a, O
3a, O
3a, O
3a, O
3a, O
3a, O
3a, O
3b, NCH3
3b, NCH3
3b, NCH3
3b, NCH3
3b, NCH3
3b, NCH3
20
20
2
2
3
3
3
3
3
6
6
6
6
6
6
H2O
D2O
D2O
.95
70c
.95c
85
56
72
215
215
215
215
215
0
0
0
0
0
BuBr
(CH3)2CHBr
(CH3)3SiCl
Acetone
H2O
57
.95
.95c
47
68
75
9
D2O
5bb, D
10
11
12
13
(CH3)2CHBr
(CH3)3SiCl
BuBrd
5bc, (CH3)2CH
5bd, (CH3)3Si
5be, Bu
0
Acetonee
5bf, (CH3)2COH
75
a All reactions run in the presence of 5 equiv. of Li and 10 mol% of naphthalene; reaction time with the electrophile (1.1 equiv.)ˆ15 min.
b Isolated yield, unless otherwise indicated.
c As determined by 1H NMR spectroscopy, unless otherwise indicated.
d Added at 2408C.
e Added at 2808C.

U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
8377
Scheme 3. XˆO, NCH3; MˆLi, K
isolated yield (Table 1, entry 12). A related procedure
allowed us to obtain aminoalcohol 5bf in good isolated
yield (Table 1, entry 13).
Reductive metallation of ether 8a
Reductive cleavage reactions were carried out under Ar in
dry THF using Li dispersion or K sand as reducing agents;
selected results are reported in Table 2.
Synthesis of unsymmetrically 1,8-disubstituted naphth-
alenes
Depending upon the reaction conditions, reductive cleavage
of 8a afforded, besides the expected 1-hydroxymethyl-8-
methylnaphthalene, 10aa, variable amounts of 1,8-
dimethylnaphthalene, 11a, i.e. the product of a double
reductive cleavage reaction (Eq. (1)).
Regioselective synthesis and functionalization of the
naphthalene core skeleton is an attractive topic in organic
synthesis: indeed, this skeleton is present in several
biologically active compounds.14,15
Unsymmetrically 1,8-disubstituted naphthalenes can be
synthesised by perilithiation of suitable 1-substituted
naphthalenes16±20 or via elaboration of symmetrically 1,8-
disubstituted naphthalenes.17
ꢀ1†
However, perilithiation suffers competing ortholithiation
and is restricted to N,N-dimethylaminonaphthalene or
N,N-dimethylaminomethylnaphthalene; furthermore, as
recently pointed out,17 several dif®culties can be
encountered in the unsymmetrical elaboration of com-
mercially available 1,8-disubstituted naphthalenes, like
acenaphthenequinone or 1,8-naphthalic anhydride. As an
alternative to these procedures, we investigated the
synthetic route depicted in Scheme 3.
Indeed, reaction of 8a with 5 equiv. of Li and 10 mol% of
naphthalene at 08C led to the formation of alcohol 10aa as
the main reaction product (Table 2, entry 1). Decreasing the
reaction temperature led to low conversion of the substrate
and did not result in complete suppression of the second
cleavage reaction (Table 2, entries 2 and 3). We ran several
other experiments (not reported in Table 2) with different
amounts of Li and different reaction times and temperatures,
but were unable to avoid the second cleavage reaction under
practical reaction conditions. Furthermore, D2O quenching
experiments (not reported in Table 2) suggested that forma-
tion of 11 occurred via an intermediate dicarbanion. These
observations strongly suggest formation of the hydrocarbon
via two successive reductive cleavage reactions, as already
observed in the reductive cleavage of 1,3-dihydro-
naphtho[2,3-c]furan (2,3-naphthalan);2 lithium oxide
probably acts as a leaving group in the second cleavage step.
Reduction of 1,8-naphthalic anhydride 6 with LiAlH4 in
THF afforded the corresponding diol 7 in 54% isolated
yield. Diol 7 was cyclised with 50% H3PO4 to give
1H,3H-benzo[de]isochromene (1,8-naphthalan), 8a, in
85% isolated yield.
Alternatively, reaction of diol 7 with PBr3, followed by
aminolysis of the crude dibromide with 40% aqueous
CH3NH2, afforded 2-methyl-2,3-dihydro-1H-benzo[de]iso-
quinoline, 8b, in 79% overall yield.
Looking for a practical and selective access to alcohol 10aa,
we investigated the reductive cleavage of ether 8a with
5 equiv. of K metal and 10 mol% of naphthalene at
2308C; under these reaction conditions, aqueous work up
of the reaction mixture afforded alcohol 10aa as the only
reaction product (Table 2, entry 4); quenching the reaction
Application of the reductive eletrophilic substitution
procedure to compounds 8 should result in a new synthesis
of 1,8-unsymmetrically disubstituted naphthalenes 10 via
intermediate organometallics 9.

8378
U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
Table 2. Reductive cleavage and electrophilic substitution of compounds 8a and 8b
Entry
Compound, Xˆ
M (equiv.)
T (8C)
t (h)
EX
Product, Eˆ
10aa, H
10aa, H
10aa, H
10aa, H
Yield (%)a,b
1
2
3
4
5
6
7
8
8a, O
8a, O
8a, O
8a, O
8a, O
8a, O
8a, O
8a, O
Li (5)
Li (5)
Li (5)
K (5)
K (5)
K (5)
K (5)
K (5)
K (5)
K (5)
Li (5)
Li (10)
Li (10)
Li (10)
Li (10)
Li (10)
Li (10)
Li (10)
0
2
7
7
5
5
5
5
5
5
5
4
4
4
4
4
4
4
4
H2O
H2O
H2O
H2O
D2O
D2O
BuBr
42c,d
55c,e
28c,f
.95
45c
83c
63
215
265
230
230
245
245
245
245
245
215
215
215
215
215
215
215
215
10ab, D
10ab, D
10ac, Bu
10ad, (CH3)2CH
10ae, CO2
(CH3)2CHBr
CO2
Acetone
H2O
H2O
61
35
35
g
9
8a, O
8a, O
10
11
12
13
14
15
16
17
18
10af, (CH3)2COH
10ba, H
10ba, H
10bb, D
10bc, Bu
10bc, Bu
10bd, (CH3)2CH
10bd, (CH3)2CH
10be, (CH3)2COH
8b, NCH3
8b, NCH3
8b, NCH3
8b, NCH3
8b, NCH3
8b, NCH3
8b, NCH3
8b, NCH3
70c
.95
83c
24
D2O
BuBr
BuBrh
53
(CH3)2CHBrh
(CH3)2CHBrh,i
Acetoneh,i
38c
66
38
a All reactions run in the presence of 10 mol% of naphthalene; reaction mixtures were quenched with 1.1 equiv. of the electrophile, unless otherwise
indicated; reaction time with the electrophileˆ15 min.
b Isolated yield, unless otherwise indicated.
c As determined by 1H NMR spectroscopy.
d 47% of 8a and 11% of 11 were also detected.
e 11% of 8a and 34% of 11 were also detected.
f 70% of 8a and 2% of 11 were also detected.
g Lactonization occured during acidic workup.
h Added at 2808C.
i In the presence of 3 equiv. of the electrophile.
mixture with D2O resulted in low deuteriation at the aryl-
methyl position (Table 2, entry 5). A better result was
obtained performing the reaction at 2458C: under these
conditions the corresponding organometallic was obtained
in 83% yield, as evidenced by D2O quenching (Table 2,
entry 6).
23% yield (Table 2, entry 14). A better result was obtained
adding the electrophile to the organometallic intermediate
9b at 2808C: under these conditions, amine 10bc was
obtained in 53% isolated yield (Table 2, entry 15). Reaction
of organometallic 9b at 2808C with an excess of
(CH3)2CHBr or acetone afforded compounds 10bd±
10be, respectively, in satisfactory yields (Table 2,
entries 16±18).
Due to the above results, reductive electrophilic substitution
reactions of ether 8a were performed using K metal as the
reducing agent at 2458 C. The intermediate dipotassium
derivative 9a was trapped with primary and secondary
alkyl halides, CO2 and acetone, affording the corresponding
1,8-disubstituted naphthalenes 10ac±10af in satisfactory
yields (Table 2, entries 7±10; Scheme 3, MˆK).
Concluding Remarks
The results obtained in the present work provide further
evidence of the synthetic usefulness of the reductive metal-
lation of arylalkyl ethers and amines. This procedure allows
the transformation of symmetrically substituted starting
materials into unsymetrically substituted reaction inter-
mediates, affording new synthetic routes to unsymmetri-
cally 2,20-disubstituted-1,10-biphenyls and 1,8-disubstitued
naphthalenes.
Reductive lithiation of amine 8b
Reductive and selective cleavage of amine 8b was accom-
plished with Li metal. Reduction at 2158C in the presence
of 5 equiv. of Li metal and a catalytic amount of naphtha-
lene was somewhat sluggish, resulting in non-complete
conversion of the starting amine after 4 h (Table 2, entry
11). Quantitative cleavage was obtained increasing the
relative amount of the reducing agent to 10 equiv.; under
these conditions, the corresponding intermediate dilithium
derivative 9b was obtained in 84% yield (Table 2, entries 12
and 13). At variance with the reductive lithiation of ether 8a,
we did not observe a second cleavage reaction.
Reductive cleavage of naphthalene derivatives deserves
some comment. In particular, the different reactivities
evidenced in the lithium- and potassium-mediated reductive
cleavages of ether 8a can be attributed to several factors: (i)
different redox potentials of the metals; (ii) different
solubilities (and reactivities) of the intermediates 9a with
MˆLi or K; (iii) different leaving group abilities of lithium
and potassium oxides. The results obtained with the amino
intermediate 9b (MˆLi) suggest that the nature of the
leaving group is important in determining whether the
(un)stability of intermediates 9 leads to a second reductive
cleavage step.
Reductive electrophilic substitution reactions of the amine
8b were performed with 10 equiv. of Li metal at 2158C.
Under these conditions, quenching the reaction mixture with
n-BuBr afforded a complex reaction mixture; careful ¯ash
chromatography allowed the recovery of amine 10bc in

U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
8379
Experimental
1,8-Dihydroxymethylnaphthalene (7). 1,8-Naphthalic
anhydride (10.0 g, 0.050 mol) was added in 1 g portions to
a mechanically stirred suspension of LiAlH4 (3.8 g,
0.10 mol) in 250 mL of dry THF over 2 h. The mixture
was stirred at rt for 16 h. Excess hydride was decomposed
by slow dropwise addition of H2O (80 mL, Caution),
followed by 1 M H2SO4 (100 mL) and 1:1 H2SO4 (ca.
50 mL) until complete dissolution of a white precipitate.
The organic phase was separated, washed with 2 M NaOH
(2£50 mL), H2O (50 mL), and dried (Na2SO4). Evaporation
of the solvent afforded a white solid, which was recrystal-
lised from EtOH to give 5.2 g (0.028 mol, 55%) of
compound 7. White solid; mp 155±1568C (EtOH, lit.21 mp
154±154.58C).
General
Boiling and melting points are uncorrected; the air bath
temperature on bulb-to-bulb distillations are given as boil-
ing points. Starting materials were of the highest commer-
cial quality and were used without further puri®cation. D2O
was 99.8% isotopic purity. THF was distilled from Na/K
1
alloy under N2 immediately prior to use. H NMR spectra
were recorded on a Varian VXR 300 at 300 MHz and 13C
NMR spectra were recorded at 75 MHz in CDCl3 with
SiMe4 as internal standard. Deuterium incorporation was
1
calculated by monitoring the H NMR spectra of the crude
mixtures and comparing the integration of the signal corre-
sponding to the protons in the arylmethyl position with that
of known signals. IR spectra were recorded on thin ®lms,
unless otherwise indicated. Elemental analyses were
performed by the Microanalytical Laboratory of the
1H,3H-Benzo[de]isochromene (8a). Diol
7 (10.0 g,
0.053 mol) was suspended in 75 mL of 50% H3PO4 and
heated at re¯ux temperature for 1 h. The mixture was cooled
to rt and extracted with Et2O (3£20 mL), washed with H2O
(20 mL), NaHCO3 (20 mL), and dried (Na2SO4). Evapora-
tion of the solvent afforded a white solid, which was recrys-
tallised from hexane to give 7.7 g (0.045 mol, 85%) of
compound 3a. White solid; mp 83±848C (hexane, lit.21 mp
83.0±83.58C).
Á
Dipartimento di Chimica, Universita di Sassari.
Preparation of starting materials
2,20-Dihydroxymethyl-1,10-biphenyl (2). Diphenic anhy-
dride (10.0 g, 0.045 mol) was added in 1 g portion to a
mechanically stirred suspension of LiAlH4 (3.4 g,
0.09 mol) in 250 mL of dry THF over 2 h. The mixture
was heated at re¯ux temperature for 16 h. Excess hydride
was decomposed by slow dropwise addition of H2O (80 mL,
Caution), followed by 1 M H2SO4 (100 mL) and 1:1 H2SO4
(ca. 50 mL) until complete dissolution of a white precipi-
tate. The organic phase was separated, washed with 2 M
NaOH (2£50 mL), H2O (50 mL), and dried (Na2SO4).
Evaporation of the solvent afforded a light yellow solid,
which was recrystallised from benzene to give 8.0 g
(0.037 mol, 83%) of compound 2. White solid; mp 109±
1118C (benzene, lit.21 mp 110.5±111.58C).
2-Methyl-2,3-dihydro-1H-benzo[de]isoquinoline
(8b).
Following the procedure of Carpino,24 reaction of diol 7
(4.1 g, 0.022 mol) in CH2Cl2 (60 mL) with PBr3 (11.7 g,
0.043 mol) at rt over 5 h afforded the corresponding crude
dibromide (5.9 g, 0.019 mol, 88%). Without further puri®-
cation, the dibromide was dissolved in benzene (120 mL)
and mechanically stirred at rt, whilst a 40% aqueous solu-
tion of CH3NH2 (8.3 mL, 0.095 mol) was slowly added
dropwise. After 4 h at rt, the mixture was heated at 408C
for 12 h, then cooled to rt, the organic phase separated,
washed with 2 M NaOH (2£50 mL) and H2O (50 mL),
and dried (K2CO3). Evaporation of the solvent afforded a
light yellow solid, which was recrystallised from hexane to
give 3.2 g of compound 8b (0.017 mol, 79%). White solid;
mp 58±608C (hexane, lit.25 mp 60±618C).
6,7-Dihydro-5H-dibenz[c,e]oxepine (3a). Diol 2 (8.0 g,
0.037 mol) was suspended in 50 mL of 85% H3PO4 and
heated at re¯ux temperature for 1 h. The mixture was cooled
to rt and extracted with Et2O (3£20 mL), washed with H2O
(20 mL), NaHCO3 (20 mL), and dried (Na2SO4). Evapora-
tion of the solvent afforded a white solid, which was recrys-
tallised from hexane to give 5.9 g (0.030 mol, 82%) of
compound 3a. White solid; mp 70±728C (hexane, lit.21 mp
71.5±728C).
Reductive cleavage of compounds 3 and 8 and reaction
with electrophilesÐgeneral procedure
Li metal (5±10 equiv. of a 30% wt. dispersion in mineral
oil) was placed under Ar in a two-necked ¯ask equipped
with a re¯ux condenser and magnetic stirrer, washed with
THF (3£10 mL), and suspended in THF (30 mL). Alterna-
tively, K dispersion was prepared in a similar apparatus by
vigorously stirring the freshly cut metal (5 equiv.) in THF
(30 mL) at re¯ux temperature for 10 min; the metal suspen-
sion was then allowed to cool to rt without stirring. A
catalytic amount of naphthalene (10 mol%) was added to
the suspension of the metal, and the mixture was stirred
until a dark green colour appeared. The mixture was chilled
to the reported temperature (Tables 1 and 2) and a solution
of the substrate (5 mmol) in THF (2 mL) was added drop-
wise. After stirring for the reported time (Tables 1 and 2), a
solution of the appropriate electrophile (1.1±3 equiv.) in
THF (5 mL) was slowly added. After stirring for 15 min,
the mixture was quenched by slow dropwise addition of
H2O (10 mL, Caution), the cold bath removed, and the
resulting mixture extracted with Et2O (3£20 mL). The
6,7-Dihydro-6-methyl-5H-dibenz[c,e]azepine (3b). Accord-
ing to Cohen et al.,22 reaction of diol 2 (5.2 g, 0.024 mol)
with boiling 48% aqueous HBr (100 mL) over 0.5 h
afforded the corresponding crude dibromide (8.1 g,
0.024 mol, quantitative). Without further puri®cation, the
dibromide was dissolved in benzene (80 mL) and added
dropwise at rt to a vigorously stirred suspension of 40%
aqueous solution of CH3NH2 (10.3 mL, 0.120 mol) in ben-
zene (15 mL). After 4 h at rt, the mixture was heated at 408C
for 12 h, then cooled to rt, the organic phase separated,
washed with 2 M NaOH (2£50 mL) and H2O (50 mL),
dried (K2CO3) and the solvent evaporated. Vacuum distilla-
tion afforded azepine 3b (4.3 g, 0.020 mol, 83%). Light
yellow viscous oil; bp 155±1588C/8 mmHg (lit.23 bp 175±
1788C/10 mmHg).

8380
U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
organic phase was washed with brine (10 mL), dried
(Na2SO4 or K2CO3) and the solvent evaporated.
ArCH), 2.00 (1H, d, Jˆ13.5 Hz, ArCH), 4.40 (2H, s,
CH2O), 7.03±7.15 (4H, m, ArH), 7.18±7.25 (1H, m,
ArH), 7.27±7.40 (2H, m, ArH), 7.48±7.54 (1H, m, ArH);
dC 21.1, 23.5, 63.2, 124.1, 127.2, 127.3, 127.5, 127.5,
129.1, 129.9, 130.5, 138.5, 138.5, 138.5, 140.5.
D2O quenching was performed by slow dropwise addition
of 1 mL of the electrophile, followed by aqueous work-up as
described above.
2-Hydroxymethyl-20-(2-methyl-2-hydroxy)propyl-1,10-
biphenyl (5af). Puri®ed by ¯ash chromatography (petro-
leum ether/AcOEtˆ1:1), colourless oil; (Found: C, 79.80;
H, 8.01; C17H20O2 requires C, 79.64; H, 7.88); Rf (petroleum
ether/AcOEtˆ1:1) 0.26; bp 2108C/1 mmHg; nmax 3420,
3080, 1600, 1480, 1380, 1150 cm21; dH 1.01 (3H, s, CH3),
1.07 (3H, s, CH3), 2.15 (2H, b s, 2£OH), 2.53 (1H, d,
Jˆ13.5 Hz, ArCH), 2.89 (1H, d, Jˆ13.5 Hz, ArCH), 4.32
(1H, d, Jˆ12.6 Hz, CHO), 4.50 (1H, d, Jˆ12.6 Hz, CHO),
7.11±7.19 (2H, m, ArH), 7.23±7.41 (5H, m, ArH), 7.49±
7.56 (1H, m, ArH); dC 28.5, 30.7, 45.6, 62.8, 71.9, 126.2,
127.1, 127.2, 127.6, 128.7, 130.2, 130.4, 131.6, 135.8,
138.9, 140.6, 141.0.
CO2 quenching was performed by bubbling gaseous CO2
into the reaction vessel for 10 min; the mixture was
quenched by slow dropwise addition of H2O (10 mL,
Caution), the cold bath removed, and the resulting mixture
acidi®ed to pH 1 with conc. HCl, stirred at rt for 1 h, and
worked up as described above.
Crude products were puri®ed by ¯ash chromatography
(petroleum ether/AcOEt or petroleum ether/AcOEt/Et3N);
compounds 5aa26 and 10aa27 are already known.
Deuterated compounds 5ab, 5bb, 10ab and 10bb were
1
characterised by H- and 13C NMR spectroscopy: the reso-
nances of the arylmethyl CHD protons appear as unresolved
broad triplets shifted 0.02±0.04 ppm (d) up®eld relatively
to the corresponding arylmethyl CH2 protons; the reso-
nances of the arylmethyl CHD carbons appear as triplets
(Jˆ19±21 Hz) shifted 0.3±0.4 ppm (d) up®eld relatively
to the corresponding arylmethyl CH2 carbons.
2-N-Methylaminomethyl-20-methyl-1,10-biphenyl (5ba).
Puri®ed by ¯ash chromatography (petroleum ether/AcOEt/
Et3Nˆ3:7:1), colourless oil; (Found: C, 85.10; H, 8.24;
C15H17N requires C, 85.25; H, 8.12); Rf (petroleum ether/
AcOEt/Et3Nˆ3:7:1) 0.60; bp 145±1508C/1 mmHg; nmax
3320, 2930, 1595, 1470, 1440, 760 cm21; dH 1.35 (1H, b
s, NH), 2.06 (3H, s, CH3Ar), 2.27 (3H, s, CH3N), 3.45 (1H,
d, Jˆ14.0 Hz, CHAr), 3.51 (1H, d, Jˆ14.0 Hz, CHAr),
7.08±7.15 (2H, m, ArH), 7.18±7.38 (5H, m, ArH), 7.47
(1H, dd, Jˆ7.4, 1.5 Hz, ArH); dC 20.0, 35.9, 53.2, 125.5,
126.7, 127.3, 127.4, 128.5, 129.3, 129.6, 129.9, 135.8,
137.7, 140.6, 141.1.
Other products were characterised as follows.
2-Hydroxymethyl-20-pentyl-1,10-biphenyl (5ac). Puri®ed
by ¯ash chromatography (petroleum ether/AcOEtˆ7:3),
colourless oil; (Found: C, 84.86; H, 8.90; C18H22O requires
C, 84.98; H, 8.73); Rf (petroleum ether/AcOEtˆ7:3) 0.48;
bp 1958C/1 mmHg; nmax 3615, 3451, 3059, 2927, 1621,
1473, 1006 cm21; dH 0.78 (3H, t, Jˆ6.6 Hz, CH3), 1.07±
1.22 (4H, m, 2£CH2), 1.34±1.46 (2H, m, CH2), 1.59 (1H, b
s, OH), 2.22±2.45 (2H, m, CH2Ar), 4.39 (2H, s, CH2O),
7.08±7.24 (3H, m, ArH), 7.27±7.42 (4H, m, ArH), 7.51±
7.56 (1H, m, ArH); dC 13.9, 22.3, 30.5, 31.5, 33.0, 53.1,
125.5, 127.1, 127.4, 127.6, 127.7, 129.0, 129.5, 129.9,
138.5, 139.6, 140.1, 140.6.
2-N-Methylaminomethyl-20-pentyl-1,10-biphenyl (5bc).
Puri®ed by ¯ash chromatography (petroleum ether/AcOEt/
Et3Nˆ8:2:1), colourless oil; (Found: C, 85.44; H, 9.51;
C19H25N requires C, 85.32; H, 9.44); Rf (petroleum ether/
AcOEt/Et3Nˆ8:2:1) 0.37; bp 1658C/1 mmHg; nmax 3350,
3060, 2980, 2940, 1590, 1480, 1440, 760 cm21; dH 0.78
(3H, t, Jˆ7.0 Hz, CH3), 1.04±1.24 (5H, m, 2£CH2, NH),
1.32±1.50 (2H, m, CH2), 2.20±2.44 (2H, m, CH2Ar), 2.28
(3H, s, CH3N), 3.47 (2H, s, CH2N), 7.07±7.15 (2H, m,
ArH), 7.17±7.40 (5H, m, ArH), 7.47 (1H, dd, Jˆ7.4,
1.5 Hz, ArH); dC 13.9, 22.3, 30.5, 31.6, 33.0, 36.0, 53.3,
125.3, 126.4, 127.3, 127.4, 128.2, 128.9, 129.5, 129.9,
137.9, 140.2, 140.6, 140.8.
2-Hydroxymethyl-20-(2-methyl)propyl-1,10-biphenyl (5ad).
Puri®ed by ¯ash chromatography (petroleum ether/
AcOEtˆ7:3), colourless oil; (Found: C, 85.08; H, 8.32;
C17H20O requires C, 84.94; H, 8.40); Rf (petroleum ether/
AcOEtˆ7:3) 0.40; bp 1358C/1 mmHg; nmax 3321, 3017,
2949, 1595, 1462, 1006 cm21; dH 0.68 (3H, d, Jˆ7.0 Hz,
CH3), 0.76 (3H, d, Jˆ7.0 Hz, CH3), 1.59 (1H, b s, OH), 1.67
(1H, n, Jˆ7.0 Hz, CH), 2.16 (1H, dd, Jˆ13.5, 7.0 Hz,
ArCH), 2.34 (1H, dd, Jˆ13.5, 7.0 Hz, ArCH), 4.38 (2H, s,
CH2O), 7.09±7.16 (2H, m, ArH), 7.20±7.42 (5H, m, ArH),
7.51±7.57 (1H, m, ArH); dC 19.2, 19.5, 26.2, 39.1, 60.1,
122.5, 124.0, 124.3, 124.3, 124.5, 126.5, 126.7, 127.0,
135.4, 136.3, 136.9, 137.1.
2-N-Methylaminomethyl-20-(2-methyl)propyl-1,10-bi-
phenyl (5bd). Puri®ed by ¯ash chromatography (petroleum
ether/AcOEt/Et3Nˆ8:2:1), colourless oil; (Found: C, 85.19;
H, 9.10; C18H23N requires C, 85.31; H, 9.17); Rf (petroleum
ether/AcOEt/Et3Nˆ8:2:1) 0.25; bp 165±1708C/1 mmHg;
nmax 3300, 3080, 2980, 1590, 1455, 755 cm21; dH 0.68
(3H, d, Jˆ7.0 Hz, CH3), 0.77 (3H, d, Jˆ7.0 Hz, CH3),
1.43 (1H, bs, NH), 1.68 (1H, n, Jˆ7.0 Hz, CH), 2.17 (1H,
dd, Jˆ13.5, 7.0 Hz, CHAr), 2.27 (3H, s, CH3), 2.33 (1H, dd,
Jˆ13.5, 7.0 Hz, CH2), 3.45 (2H, s, CH2), 7.08±7.15 (2H, m,
ArH), 7.18±7.38 (5H, m, ArH), 7.46 (1H, dd, Jˆ7.4, 1.2 Hz,
ArH); dC 22.3, 22.5, 29.2, 36.0, 42.2, 53.3, 125.4, 126.3, 127.2,
127.3, 128.1, 129.5, 129.6, 130.1, 137.8, 139.4, 140.6, 140.9.
2-Hydroxymethyl-20-trimethylsilyl-1,10-biphenyl (5ae).
Puri®ed by ¯ash chromatography (petroleum ether/
AcOEtˆ7:3), colourless oil; (Found: C, 75.53; H, 8.10;
C17H22OSi requires C, 75.48; H, 8.22); Rf (petroleum
ether/AcOEtˆ7:3) 0.37; bp 1408C/1 mmHg; nmax 3335,
3055, 2949, 1625, 1470, 1244, 1036 cm21; dH 20,17 (9H,
s, 3£CH3Si), 1.52 (1H, b s, OH), 1.78 (1H, d, Jˆ13.5 Hz,
2-N-Methylaminomethyl-20-trimethylsilyl-1,10-biphenyl
(5be). Puri®ed by ¯ash chromatography (petroleum ether/

U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
8381
AcOEt/Et3Nˆ7:3:1), colourless oil; (Found: C, 76.37; H,
9.01; C18H25NSi requires C, 76.25; H, 8.91); Rf (petroleum
ether/AcOEt/Et3Nˆ7:3:1) 0.45; bp 165±1708C/1 mmHg;
nmax 3350, 3080, 2980, 1590, 1480, 1450, 1250,
860 cm21; dH 20.14 (9H, s, 3£CH3Si), 1.26 (1H, b s,
NH), 1.81 (1H, d, Jˆ14.0 Hz, CHSi), 2.00 (1H, d,
Jˆ14.0 Hz, CHSi), 2.27 (3H, s, CH3N), 3.49 (2H, s,
CH2N), 7.04±7.14 (3H, m, ArH), 7.18±7.40 (3H, m,
ArH), 7.45 (1H, dd, Jˆ7.8, 1.2 Hz, ArH); dC 21.1, 23.5,
36.0, 53.4, 124.0, 126.5, 127.1, 127.3, 128.3, 128.9, 129.8,
130.5, 137.9, 138.5, 139.2, 141.2.
71.7, 125.4, 126.3, 127.3, 127.7, 128.5, 128.7, 130.4,
130.5, 131.1, 134.7, 171.9.
1-Hydroxymethyl-8-(20-hydroxy-20-methyl)propylnaph-
thalene (10af). Puri®ed by ¯ash chromatography (Petro-
leum ether/AcOEtˆ3:7), white solid; (Found: C, 78.07; H
7.73; C15H1802 requires C, 78.21; H, 7.89); Rf (Petroleum
ether/AcOEtˆ3:7) 0.26; mp 109±1118C (petroleum ether);
nmax (nujol) 3380, 1580, 1420, 1350, 1190, 900 cm21; dH
1.25 (6H, s, 2£CH3), 1.53 (1H, b s, OH), 3.57 (2H, s, CH2),
3.95 (1H, b s, OH), 5.17 (2H, s, CH2O), 7.34 (1H, dd, Jˆ7.2,
1.5 Hz, ArH), 7.40 (1H, t, Jˆ7.2 Hz, ArH), 7.42 (1H, t,
Jˆ7.2 Hz, ArH), 7.53 (1H, dd, Jˆ7.2, 1.5 Hz, ArH), 7.79
(1H, dd, Jˆ7.2, 1.5 Hz, ArH), 7.81 (1H, dd, Jˆ7.2, 1.5 Hz,
ArH); dC 29.4, 47.7, 66.4, 72.7, 124.6, 125.0, 129.2, 130.5,
131.5, 132.4, 132.6, 133.6, 135.7, 136.9.
2-N-Methylaminomethyl-20-(2-methyl-2-hydroxy)propyl-
1,10-biphenyl (5bf). Puri®ed by ¯ash chromatography
(petroleum ether/AcOEt/Et3Nˆ5:5:1), white solid;
(Found: C, 80.07; H, 8.78; C18H23N requires C, 80.23; H,
8.62); Rf (petroleum ether/AcOEt/Et3Nˆ5:5:1) 0.25; mp
85±878C (petroleum ether); nmax (nujol) 3280, 3150,
1560, 1350, 1220, 1150, 750 cm21; dH 1.03 (3H, s, CH3),
1.08 (3H, s, CH3), 1.12 (2H, b s, OH, NH), 2.22 (3H, s,
CH3N), 2.55 (1H, d, Jˆ14.0 Hz, CHAr), 2.91 (1H, d,
Jˆ14.0 Hz, CHAr), 3.43 (1H, d, Jˆ13.0 Hz, CHN), 3.65
(1H, d, Jˆ13.0 Hz, CHN), 7.12±7.20 (2H, m, ArH),
7.23±7.44 (6H, m, ArH); dC 29.1, 30.8, 36.0, 45.8, 53.4,
70.9, 126.1, 126.7, 127.0, 127.4, 129.0, 130.1, 130.6, 131.6,
136.4, 137.7, 141.4, 145.1.
1-N-Methylaminomethyl-8-methylnaphthalene (10ba).
Puri®ed by ¯ash chromatography (petroleum ether/AcOEt/
Et3Nˆ5:5:1), colourless oil; (Found: C, 84.36; H 8.26;
C13H15N requires C, 84.26; H, 8.18); Rf (petroleum ether/
AcOEt/Et3Nˆ5:5:1) 0.54; bp 115±1208C/1 mmHg; nmax
3300, 3020, 2920, 1580, 1450 cm21; dH 1.42 (1H, b s,
NH), 2.54 (3H, s, CH3), 3.01 (3H, s, CH3N), 4.23 (2H, s,
CH2N), 7.32 (1H, d, Jˆ6 Hz, ArH), 7.37 (1H, d, Jˆ8.1 Hz,
ArH), 7.43 (1H, dd, Jˆ6.9, 1.4 Hz, ArH), 7.66±7.74 (2H, m,
ArH), 7.77 (1H, dd, Jˆ9.0, 1.8 Hz, ArH); dC 24.3, 36.1,
57.1, 124.7, 125.1, 127.9, 129.4, 129.6, 130.1, 132.0,
134.7, 135.7, 136.6.
1-Hydroxymethyl-8-pentylnaphthalene (10ac). Puri®ed
by ¯ash chromatography (Petroleum ether/AcOEtˆ8:2),
colourless oil; (Found: C, 84.23; H 8.57; C16H20O
requires C, 84.15; H, 8.85); Rf (Petroleum ether/
AcOEtˆ8:2) 0.52; bp 185±1908C/1 mmHg; nmax 3337,
2951, 2921, 1600, 1462, 1001 cm21; dH 0.90 (3H, t,
Jˆ7.2 Hz, CH3), 1.30±1.49 (4H, m, 2£CH2), 1.57±1.68
(2H, m, CH2), 1.76 (1H, b s, OH), 3.25 (2H, t, Jˆ8.0 Hz,
CH2Ar), 5.11 (2H, s, CH2O), 7.35±7.43 (3H, m, ArH), 7.52
(1H, dd, Jˆ6.9, 0.9 Hz, ArH), 7.69±7.76 (1H, m, ArH), 7.82
(1H, dd, Jˆ8.1, 1.5 Hz, ArH); dC 14.1, 22.6, 31.9, 33.1,
36.2, 66.5, 124.7, 125.4, 128.0, 129.0, 129.6, 130.5, 130.7,
135.9, 136.7, 139.7.
1-N-Methylaminomethyl-8-pentylnaphthalene (10bc).
Puri®ed by ¯ash chromatography (petroleum ether/AcOEt/
Et3Nˆ7:3:1), colourless oil; (Found: C, 84.42; H, 9.75;
C16H21N requires C, 84.57; H, 9.62); Rf (petroleum ether/
AcOEt/Et3Nˆ7:3:1) 0.50; bp 145±1508C/1 mmHg; nmax
3320, 3040, 2900, 1560, 1450; dH 0.92 (3H, t, Jˆ7.2 Hz,
CH3), 1.26 (1H, b s, NH), 1.32±1.51 (4H, m, 2£CH2, 1.59±
1.72 (2H, m, CH2), 2.52 (3H, s, CH3N), 3.23 (2H, t,
Jˆ7.8 Hz, CH2), 4.14 (2H, s, CH2N), 7.33±7.40 (3H, m,
ArH), 7.44 (1H, dd, Jˆ7.2, 1.5 Hz, ArH), 7.68±7.74 (1H,
m, ArH), 7.78 (1H, dd, Jˆ8.4, 1.5 Hz, ArH); dC 14.1, 22.6,
32.0, 33.3, 36.3, 36.6, 57.5, 124.5, 125.1, 128.1, 129.6,
129.8, 129.9, 130.9, 136.1, 136.1, 139.7.
1-Hydroxymethyl-8-(20-methyl)propylnaphthalene (10ad).
Puri®ed by ¯ash chromatography (Petroleum ether/
AcOEtˆ1:1), colourless oil; (Found: C, 84.31; H 8.62;
C16H20O requires C, 84.05; H, 8.48); Rf (Petroleum ether/
AcOEtˆ1:1) 0.59; bp 175±1808C/1 mmHg; nmax 3350,
3060, 2980, 1600, 1460, 1390 cm21; dH 0.92 (6H, d,
Jˆ6.6 Hz, 2£CH3), 1.60 (1H, bs, OH), 1.77 (1H, n,
Jˆ6.6 Hz, CH), 3.12 (2H, d, Jˆ6.6 Hz, CH2), 5.12 (2H, s,
CH2O), 7.31 (1H, dd, Jˆ5.1, 1.5 Hz, ArH), 7.37±7.43 (2H,
m, ArH), 7.54 (1H, dd, Jˆ6.1, 1.5 Hz, ArH), 7.75 (1H, dd,
Jˆ8.1, 1.5 Hz, ArH), 7.84 (1H, dd, Jˆ8.1, 1.5 Hz, ArH); dC
22.4, 30.7, 45.5, 66.6, 124.7, 125.0, 128.3, 129.1, 130.5,
130.8, 131.0, 136.0, 136.8, 137.9.
1-N-Methylaminomethyl-8-(20-methyl)propylnaphtha-
lene (10bd). Puri®ed by ¯ash chromatography (petroleum
ether/AcOEt/Et3Nˆ7:3:1), colourless oil; (Found: C, 84.74;
H, 9.20; C16H21N requires C, 84.51; H, 9.33); Rf (petroleum
ether/AcOEt/Et3Nˆ7:3:1) 0.54; bp 115±1208C/1 mmHg;
nmax 3320, 3060, 2960, 1590, 1470; dH 0.91 (6H, d,
Jˆ6.6 Hz, 2£CH3), 1.47 (1H, b s, NH), 1.80 (1H, n,
Jˆ6.6 Hz, CH), 2.51 (3H, s, CH3N), 3.07 (2H, d,
Jˆ6.6 Hz, CH2), 4.14 (2H, s, CH2N), 7.27 (1H, dd, Jˆ6.9,
1.5 Hz, ArH), 7.35 (2H, t, Jˆ7.7 Hz, ArH), 7.43 (1H, dd,
Jˆ7.7, 1.5 Hz, ArH), 7.72 (1H, dd, Jˆ7.7, 1.5 Hz, ArH),
7.78 (1H, dd, Jˆ7.7, 1.5 Hz, ArH); dC 22.4, 30.6, 36.2, 45.8,
57.6, 124.5, 124.7, 128.4, 129.9, 129.9, 130.9, 131.0, 136.2,
136.2, 137.9
1H,4H-Naphth(1,8-cd)oxepin-3-one (10ae). Puri®ed by
¯ash chromatography (Petroleum ether/AcOEtˆ6:4),
white solid; (Found: C, 78.53; H 5.31; C13H10O requires
C, 78.76; H, 5.10); Rf (Petroleum ether/AcOEtˆ6:4) 0.35;
mp 160±1618C (isopropanol); nmax (nujol) 3025, 1944,
1738, 1596, 1583, 1378 cm21; dH 4.45 (2H, b s, CH2),
5.60 (2H, b s, CH2), 7.35±7.48 (4H, m, ArH), 7.81 (1H, d,
Jˆ8.1 Hz, ArH), 7.87 (1H, d, Jˆ8.1 Hz, ArH); dC 42.3,
1-N-Methylaminomethyl-8-(20-hydroxy)propylnaphtha-
lene (10be). Puri®ed by ¯ash chromatography (petroleum
ether/AcOEt/Et3Nˆ5:5:1), white solid which decomposes
when exposed to air (we were unable to obtain a satisfactory

8382
U. Azzena et al. / Tetrahedron 56 (2000) 8375±8382
9. Azzena, U. Trend. Org. Chem. 1997, 6, 55±65.
elemental analysis); bp 145±1508C/1 mmHg; Rf (petroleum
ether/AcOEt/Et3Nˆ5:5:1) 0.29; nmax (nujol) 3400, 3260,
1640, 1370;; dH 1.21 (6H, s, 2£CH3), 1.93 (2H, b s, OH,
NH), 2.60 (3H, s, CH3N), 3.44 (2H, s, CH2), 4.22 (2H, s,
CH2N), 7.28±7.34 (3H, m, ArH), 7.39 (1H, t, Jˆ7.5 Hz,
ArH), 7.72±7.82 (m, 2H, ArH); dC 30.1, 35.9, 48.3, 57.3,
70.4, 124.2, 124.2, 129.0, 130.6, 131.7, 132.6, 133.1, 134.5,
134.8, 135.9.
Â
Â
Â
Â
10. Saa, J. M.; Ballester, P.; Deya, P. M.; Capo, M.; Garcõas, X.
J. Org. Chem. 1996, 61, 1035±1046 (and references therein).
11. Yus, M. Chem. Soc. Rev. 1996, 155±161.
12. Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.;
Petersen, J. L. J. Org. Chem. 1999, 64, 6797±6803 (and references
therein).
13. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457±2483
(and references therein).
14. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem.
Soc., Perkin Trans. 1 2000, 787±797.
Acknowledgements
15. Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967±8976.
16. Clayden, J.; Westlund, N.; Frampton, C. S. J. Chem. Soc.,
Perkin Trans. 1 2000, 1379±1385.
Financial support from MURST (40 and 60% funds) and
Regione Autonoma della Sardegna (R. A. S.) are gratefully
acknowledged. L. P. thanks R. A. S. for a fellowship.
17. Clayden, J.; Frampton, C. S.; McCarthy, C.; Westlund, N.
Tetrahedron 1999, 55, 14161±14184.
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