Regiochemistry in radical cyclisations (4-exo-trig versus 5-endo-trig) of 2-halo-N-(3,4-dihydro-2-naphthyl)acetamides

Article abstract of DOI:10.1039/a801714j

The regioselectivity in Bu₃SnH-mediated radical cyclisations (4-exo-trig versus 5-endo-trig) of a range of 2-halo-N-(3,4-dihydro-2-naphthyl)acetamides has been examined from the standpoint of the effects of substituents on the radical centre and on the nitrogen atom as well as the reaction temperature. When the substituent on the radical centre is a hydrogen or chlorine atom, 4-exo-trig cyclisation (β-lactam formation) is favoured in boiling toluene, while radical stabilising substituents such as methyl, phenyl, phenylthio, dimethyl and dichloro groups bring about 5-endo-trig cyclisation (γ-lactam formation) predominantly or exclusively. In boiling benzene, however, the predominant formation of β-lactam is observed for the methyl-substituent. On the other hand, no remarkable difference in the product distributions between the methyl and benzyl substituents on the nitrogen atom is observed. These results are discussed in terms of kinetic or thermodynamic considerations.

Full text of DOI:10.1039/a801714j

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Regiochemistry in radical cyclisations (4-exo-trig versus 5-endo-trig)
of 2-halo-N-(3,4-dihydro-2-naphthyl)acetamides
Masazumi Ikeda,*,a Shinji Ohtani,a Taeka Yamamoto,a Tatsunori Satoa and
Hiroyuki Ishibashi*,b
a Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
b Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi,
Kanazawa 920-0934, Japan
The regioselectivity in Bu3SnH-mediated radical cyclisations (4-exo-trig versus 5-endo-trig) of a range of
2-halo-N-(3,4-dihydro-2-naphthyl)acetamides has been examined from the standpoint of the effects of
substituents on the radical centre and on the nitrogen atom as well as the reaction temperature. When
the substituent on the radical centre is a hydrogen or chlorine atom, 4-exo-trig cyclisation (â-lactam
formation) is favoured in boiling toluene, while radical stabilising substituents such as methyl, phenyl,
phenylthio, dimethyl and dichloro groups bring about 5-endo-trig cyclisation (ã-lactam formation)
predominantly or exclusively. In boiling benzene, however, the predominant formation of â-lactam is
observed for the methyl-substituent. On the other hand, no remarkable difference in the product
distributions between the methyl and benzyl substituents on the nitrogen atom is observed. These
results are discussed in terms of kinetic or thermodynamic considerations.
Introduction
5-endo
R2 = H
•
The control of the regiochemistry of radical cyclisations is a
O
N
O
N
subject of intense investigation.1 We and others have demon-
strated that the N-vinylic carbamoylmethyl radicals 1, gener-
ated from the corresponding α-halo amides, cyclise generally in
a 5-endo-trig manner yielding γ-lactams 3 through the inter-
mediates 2,2,3 while introduction of radical stabilising group(s)
such as phenylthio or phenyl at the terminus of the N-vinyl
group leads to the formation of β-lactams 5 (Scheme 1).4,5 These
results suggest that the high stability of the radical intermedi-
ates 4 plays a crucial role in the switch of regioselectivity from
the 5-endo-trig mode to the 4-exo-trig mode in the ring closure
of 1. On the other hand, Bu3SnH-mediated radical cyclisation
of 2-chloro-N-(3,4-dihydro-2-naphthyl)-N-methylacetamides
6a–c in boiling toluene gave β-lactams 8 and/or γ-lactams 9,
depending upon the nature of the substituents on the radical
centre of the initially formed carbamoylmethyl radicals 7.2b
The 2-chloroacetamide 6a afforded exclusively the β-lactam
8a, while the 2-chloro-2-phenylacetamide 6c gave solely the
γ-lactam 9c. The 2-chloropropanamide 6b showed an inter-
mediate behaviour to give a mixture of the β-lactam 8b (29%)
and the γ-lactam 9b (40%). These observations indicate that
the substituents on the radical centre of the carbamoylmethyl
radicals 7 also affect the regiochemistry of cyclisation. In order
to obtain more information on the factors determining the
regiochemistry of the radical cyclisation of 6, we now examined
in detail the effects of the substituents on the radical centre and
on the nitrogen atom of 7 as well as the reaction temperature.
R1
R1
R2
N
R2
2
3
•
R2
•
R2
O
R1
R2
R2
1
4-exo
N
N
R2 = SPh
or Ph
O
R1
O
R1
4
5
R
R
O
O
•
Cl
N
N
Me
Me
i
6a; R = H
6b; R = Me
6c; R = Ph
7a–c
O
R
H
R
O
N
H
Me
N
and/or
Me
8a,b
9b,c
Scheme 1 Reagents and conditions: i, Bu3SnH, AIBN, toluene, reflux
Results and discussion
The N-methyl substituted radical precursors 6d–f were readily
prepared by acylation of the imines derived from β-tetralone
and methylamine. The 2,2-bis(phenylthio)acetamide 6g was
prepared by a nucleophilic substitution reaction of the 2,2-
dichloroacetamide 6d with benzenethiolate ion.
When the dichloroacetamide 6d was treated with Bu3SnH
(3.6 equiv.) and a small amount of azoisobutyronitrile (AIBN)
in boiling toluene, the β-lactam 8a was obtained in 52% yield
through reduction of the corresponding chloro lactam 8d
(Scheme 2). Interestingly, the trichloroacetamide 6e, upon
treatment with Bu3SnH (1.2 equiv.) and AIBN, gave the aroma-
tised product 10 in 40% yield. Since only 1.2 equiv. of Bu3SnH
was used, it was assumed that the aromatisation took place by a
non-radical process which involved dehydrochlorination from
the initially formed dichloro γ-lactam 9e.
Treatment of 2-bromo-2-methylpropanamide 6f with Bu3SnH
(1.2 equiv.) and AIBN in boiling toluene gave the γ-lactam
9f as the sole product in 68% yield. The cis-stereochemistry of
J. Chem. Soc., Perkin Trans. 1, 1998
1763

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Cl
ally more stable 1β(exo)-PhS isomer. Thermal elimination of
benzenesulfenic acid from the corresponding sulfoxide gave
the aromatised product 10 in 38% yield. The formation of 10
may be rationalised by assuming that migration of the
double bond from the initially formed C-1᎐C-9b position to the
C-3a᎐C-9b position is followed by subsequent dehydrogenation.
Apparently, aromatisation is the driving force of this reaction.
Next, in order to see the steric effects of the substituent on
the nitrogen atom, we prepared the N-benzyl congeners 6h–j
O
R
O
Cl
N
i
Me
N
Me
6d
8d; R = Cl
8a; R = H
i
Cl
Cl
Cl
Cl
Cl
H
O
O
R
Cl
Cl
Cl
N
O
O
N
Me
i
Cl
Me
H
N
N
Bn
Bn
6e
9e
6h; R = H
6i; R = Me
6j
O
O
Me
H
N
R
O
Me
N
H
Bn
N
Bn
10
Me
Me
8h; R = H
9i-β;1β−Me
9i-α;1α−Me
Me
O
O
8i; R = Me
Me
H
Br
R2
N
N
Me
i
9b
O
Me
3a
O
H
N
N
Bn
R1
6f
9f
SPh
O
PhS
H
O
1
13; R1 = Bn, R2 = H
14; R1 = Bn, R2 = Me
15; R1 = R2 = Me
PhS
16
i
N
H
Me
N
9b
3a
Me
and subjected them to the radical cyclisation conditions. Treat-
ment of the 2-chloroacetamide 6h with Bu3SnH and AIBN in
boiling toluene gave the β-lactam 8h (44%), along with the
reduction product 13 (23%). The propanamide 6i gave a mixture
of the β-lactam 8i and the γ-lactams 9i-β (1β-Me) and 9i-α (1α-
Me) in 21, 45 and 6% yields, respectively, in addition to the
reduction product 14 (12%). The 1H NMR spectrum of 8i
showed it to be a mixture of two diastereoisomers in a ratio of
ca. 1.8:1. Stereochemistries of 9i-β and 9i-α were confirmed by a
comparison of the chemical shifts of their C-1-methyl protons
with those of the N-methyl congeners 9b. Thus, the signal due
to the 1β-methyl protons of 9b appeared at δ 1.41, whereas the
signal due to the 1α-methyl protons shifted upfield to δ 0.90. In
the cases of 9i-β and 9i-α, the corresponding signals appeared
at δ 1.46 and 0.97, respectively, indicating the C-1-methyl
groups of 9i-β and 9i-α to have the β- and α-configurations,
respectively. The trichloroacetamide 6j gave the aromatised
compound 16 in 53% yield. Thus, no remarkable difference was
observed in the behaviour of cyclisations between the N-methyl
and N-benzyl derivatives.
6g
9g
+
SPh
O
N
Me
O
11
H
N
H
Me
i
ii
9g
iii,iv
9f
12
10
Scheme 2 Reagents and conditions: i, Bu3SnH, AIBN, toluene, reflux;
ii, LDA, MeI, THF, Ϫ78 ЊC; iii, NaIO4, H2O–acetone, room temp.;
iv, toluene, reflux
the ring-junction was assigned on the basis of the coupling
constant (J 8.6 Hz) between 3a-H and 9b-H, which closely
resembled that (J 7.8 Hz) for 9b obtained as the major product
of the cyclisation of 6b.
Treatment of the bis(phenylthio)acetamide 6g with Bu3SnH
(1.2 equiv.) and AIBN in boiling toluene gave the γ-lactam 9g
in 52% yield as a single stereoisomer along with the reduction
product 11 (13%). The cis ring-junction of 9g was determined
by transformation to compound 9f through desulfurisation
followed by dimethylation of the resulting lactam 12. The anti-
relationship between 1-H and 9b-H of 9g was confirmed by an
epimerisation experiment: treatment of 9g with potassium tert-
butoxide in boiling 2-methylpropan-2-ol resulted in recovery of
the starting material, indicating that 9g is the thermodynamic-
The above results revealed that the substituent(s) on the
initially formed carbamoylmethyl radical 17 play(s) a crucial
role in determining the regiochemistry. When R2 = H or Cl in
17, then β-lactam formation is favoured, while radical stabilis-
ing substituents such as methyl, phenyl, phenylthio, dimethyl
or dichloro groups lead to γ-lactams predominantly or
exclusively. One possible explanation for these results is based
on a consideration of the reversibility of the 4-exo-trig cyclis-
ation and ring-opening between 17 and 18.6 The 4-exo-trig
cyclisation might be a kinetically favoured process compared to
the 5-endo-trig one, so that the carbamoylmethyl radicals 17
would give initially the benzylic radicals 18 (see Scheme 3). In
the former case (R2 = H or Cl), the subsequent reduction step is
faster than the ring-opening step, and hence β-lactam form-
1764
J. Chem. Soc., Perkin Trans. 1, 1998

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R2
Me
O
Me
O
R
O
Me
O
R
•
R
•
O
Br
H
N
R
N
N
+
R1
i
N
N
8
H
R1
17
18
6k; R = Me
6l; R = Bn
8b; R = Me
8i; R = Bn
9b; R = Me
9i; R = Bn
Scheme 4 Reagents and conditions: i, Bu3SnH, AIBN, benzene or
toluene, reflux
O
R2
Table 1 Effects of the reaction temperature on the regioselectivity in
radical cyclisations of 6k and 6la
H
R1
N
9
•
Productsb
19
8b:9b
or 8i:9i
Entry
Compound
Solvent
Yield (%)c
Scheme 3
1
2
3
4
6k
6k
6l
benzene
toluene
benzene
toluene
8b ϩ 9b
8b ϩ 9b
8i ϩ 9i
8i ϩ 9i
56
60
49
63
73:27
38:62
69:31
30:70
ation takes place. On the other hand, in the latter case having
the radical-stabilising substituent(s), the ring-opening of 18
occurs rapidly to give the relatively stable initial radicals 17, and
the reduction step takes place after the thermodynamically
more stable radicals 19 have been formed by the 5-endo-trig
cyclisation of 17 to lead to the formation of the γ-lactams 9.
Support for the proposed mechanistic scheme was derived
from an examination of the effects of the reaction temperature7
using the 2-bromopropanamides 6k and 6l as radical precursors
instead of the corresponding chloro amides 6b and 6i. Thus, a
solution of the N-methyl derivative 6k in boiling benzene (at
80 ЊC) was treated slowly with a mixture of Bu3SnH and AIBN
during 3 h to give the β-lactam 8b as the major product (see
entry 1 in Table 1), whereas in boiling toluene (at 110 ЊC) the
γ-lactam 9b was obtained as the major product (see entry 2).
This was also the case for the N-benzyl congener 6l (see entries
3 and 4). These results clearly indicate that the 4-exo cyclisation
is a kinetically favoured process, whereas at higher temperature
(in boiling toluene), the ring-opening of the radicals 18 formed
by 4-exo cyclisation rapidly occurs, and the resulting radicals 17
cyclise in a 5-endo-trig manner to give the thermodynamically
stable radicals 19. If Bu3SnH was added rapidly to a solution of
these radical precursors, the kinetically favoured radicals 18
might be immediately trapped by Bu3SnH to result in an
increase in the amount of the β-lactams. This was realised by
adding a mixture of Bu3SnH and AIBN to a boiling toluene
solution of 6k within 30 min; these conditions gave an
approximately equal amount (54:46) of the β-lactam 8b and
the γ-lactam 9b (compare with entry 2).
6l
a For the reaction conditions, see the text. b Simple reduction product 15
(19 and 13% yields for entries 1 and 2, respectively) or 14 (16 and 13%
yields for entries 3 and 4, respectively) was also obtained. c Combined
yield of 8b and 9b, or 8i and 9i.
and a solution of an appropriate acyl chloride (bromide for 6f)
(25 mmol) in diethyl ether (10 cm3). The mixture was stirred at
room temperature for 30 min and water (10 cm3) was added to
the reaction mixture. The organic layer was separated and the
aqueous layer was extracted with diethyl ether. The combined
organic layer and extracts were dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel [hexane–
AcOEt (4:1)] to give an enamide. The following compounds
were thus obtained.
2,2-Dichloro-N-(3,4-dihydro-2-naphthyl)-N-methylacetamide
6d. Yield 73%, crystals, mp 104–104.5 ЊC (from hexane–AcOEt)
(Found: C, 57.6; H, 4.8; N, 5.2. C13H13Cl2NO requires C, 57.8;
H, 4.85; N, 5.2%); νmax(CCl4)/cmϪ1 1695; δH(300 MHz, CDCl3)
2.53 (2 H, t like, J ca. 8), 3.04 (2 H, t like, J ca. 8), 3.18 (3 H, s,
NMe), 6.52 (2 H, s, 1-H, COCH) and 7.07–7.27 (4 H, m, ArH).
2,2,2-Trichloro-N-(3,4-dihydro-2-naphthyl)-N-methyl-
acetamide 6e. Yield 43%, an oil (Found: C, 51.2; H, 4.0; N,
4.3. C13H12Cl3NO requires C, 51.3; H, 4.0; N, 4.6%), νmax(CCl4)/
cmϪ1 1695; δH(60 MHz, CDCl3) 2.35–3.2 (4 H, m), 3.33 (3 H, s,
NMe), 6.54 (1 H, br s, 1-H) and 7.05–7.3 (4 H, m, ArH).
2-Bromo-N-(3,4-dihydro-2-naphthyl)-2,N-dimethylpropan-
amide 6f. Yield 80%, an oil (Found: C, 58.5; H, 5.9; N, 4.4.
C15H18BrNO requires C, 58.45; H, 5.9; N, 4.5%); νmax(CCl4)/
cmϪ1 1630; δH(60 MHz, CDCl3) 2.04 (6 H, s, 2 × Me), 2.4–3.1
(4 H, m), 3.24 (3 H, s, NMe), 6.50 (1 H, br s, 1-H) and 6.85–7.4
(4 H, m, ArH).
Experimental
Mps were measured on a Yanaco MP-J3 micro melting point
apparatus and are uncorrected. IR spectra were recorded on a
1
JASCO-IR-A-100 spectrophotometer. H NMR (60 and 300
MHz) and 13C NMR (75.4 MHz) spectra were measured on a
JEOL-JNM-PMX 60 or a Varian XL-300 spectrometer for
solutions in CDCl3. δ Values quoted are relative to tetramethyl-
silane, and J values are given in Hz. Exact mass determinations
(FAB and EI mass spectra) were obtained on a JEOL-SX 102A
instrument. Column chromatography was performed on Silica
gel 60 PF254 (Nacalai Tesque) under pressure.
N-(3,4-Dihydro-2-naphthyl)-N-methyl-2,2-bis(phenylthio)-
acetamide 6g
Benzenethiol (897 mg, 8.14 mmol) was added to a solution of
sodium ethoxide (558 mg, 8.14 mmol) in ethanol (10 cm3) at
0 ЊC, and the mixture was stirred at room temperature for 10
min. To this was added a solution of 6d (1.0 g, 3.7 mmol) in
ethanol (3 cm3) and the mixture was stirred at room temper-
ature overnight. The solvent was evaporated off, dichloro-
methane (15 cm3) was added to the residue, and the whole was
washed with water, dried (MgSO4), and concentrated. The resi-
due was chromatographed on silica gel [hexane–AcOEt (7:1)]
to give 6g (1.39 g, 90%), mp 106–106.5 ЊC (from hexane–
AcOEt) (Found: C, 72.1; H, 6.0; N, 3.1. C25H23NOS2 requires C,
71.9; H, 5.5; N, 3.35%); νmax(CCl4)/cmϪ1 1640; δH(60 MHz,
CDCl3) 1.75–2.85 (4 H, m), 3.04 (3 H, s, NMe), 5.38 (1 H, s,
COCH), 6.01 (1 H, br s, 1-H) and 6.6–7.7 (14 H, m, ArH).
General procedure for the preparation of 2-halo-N-(3,4-dihydro-
2-naphthyl)-N-methylacetamides 6d–f
β-Tetralone (3.0 g, 21 mmol) was added to anhydrous methyl-
amine (10 cm3) at Ϫ78 ЊC and the mixture was heated in a
sealed tube at 100 ЊC for 2 h. The reaction vessel was cooled to
Ϫ78 ЊC, the stopper was removed, and the reaction mixture was
allowed to warm to room temperature to remove any excess of
methylamine. To the residue cooled to 0 ЊC were successively
added diethyl ether (30 cm3), triethylamine (2.5 g, 25 mmol),
J. Chem. Soc., Perkin Trans. 1, 1998
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Radical cyclisation of 6d
Base treatment of 9g
General procedure. A solution of Bu3SnH (1.36 g, 4.66 mmol)
and AIBN (129 mg, 0.79 mmol) in toluene (100 cm3) was added
to a boiling solution of compound 6d (350 mg, 1.30 mmol) in
toluene (100 cm3) by using a syringe pump over a period of 1 h
and the mixture was heated under reflux overnight. After
removal of the solvent, diethyl ether (20 cm3) and 8% aq. KF
(20 cm3) were added to the residue, and the mixture was stirred
vigorously at room temperature for 30 min. The organic layer
was separated, dried (MgSO4), and concentrated. The residue
was chromatographed on silica gel [hexane–AcOEt (5:1)]
to give 1-methylspiro[azetidine-4,2Ј-1Ј,2Ј,3Ј,4Ј-tetrahydronaph-
thalen]-2-one 8a (137 mg, 52%), mp 96.5–97.5 ЊC (from hexane)
(lit.,2b 93.5–94.5 ЊC); νmax(CCl4)/cmϪ1 1755; δH(300 MHz,
CDCl3) 1.85–1.94 (1 H, m), 2.12 (1 H, ddd, J 12.4, 10.3, 6.8),
2.69 (1 H, d, J 14.5), 2.76 (3 H, s), 2.76 (1 H, d, J 14.5), 2.82
(1 H, d, J 16.3), 2.88–3.08 (2 H, m), 3.20 (1 H, d, J 16.3) and
7.06–7.18 (4 H, m).
A mixture of 9g (69 mg, 0.2 mmol) and potassium tert-butoxide
(46 mg, 0.41 mmol) in 2-methylpropan-2-ol (5 cm3) was heated
under reflux for 1 h. Water (10 cm3) was added to the reaction
mixture and the whole was extracted with diethyl ether. The
organic phase was washed with brine and dried (MgSO4). The
solvent was evaporated off and the residue was chromato-
graphed on silica gel [hexane–AcOEt (2:1)] to give crystals
1
whose H NMR spectrum was identical to that of the starting
material 9g.
(3aR*,9aS*)-2,3,3a,4,5,9b-Hexahydro-1H-3-methylbenz[e]-
indol-2-one 12
A solution of Bu3SnH (259 mg, 0.89 mmol) and AIBN (23 mg,
0.14 mmol) in toluene (2 cm3) was added all at once to a boiling
solution of compound 9g (232 mg, 0.69 mmol) in toluene (5
cm3) and the mixture was heated under reflux for 2 h. After
removal of the solvent, diethyl ether (10 cm3) and 8% aq. KF (10
cm3) were added to the residue, and the mixture was stirred
vigorously at room temperature for 30 min. The organic layer
was separated, dried (MgSO4), and concentrated. The residue
was chromatographed on silica gel [hexane–AcOEt (1:1)] to
give 12 (119 mg, 84%), mp 88–89 ЊC (from hexane–AcOEt)
(Found: C, 77.3; H, 7.7; N, 7.2. C13H15NO requires C, 77.6; H,
7.5; N, 7.0%); νmax(CCl4)/cmϪ1 1695; δH(300 MHz, CDCl3) 1.69–
1.82 (1 H, m), 2.02–2.12 (1 H, m), 2.40 (1 H, dd, J 16.7, 8.1, one
of 1-H2), 2.61–2.80 (2 H, m), 2.90 (1 H, dd, J 16.7, 9.8, one of
1-H2), 2.91 (3 H, s, NMe), 3.65 (1 H, q, J 8.7, 9b-H), 3.84 (1 H,
td, J 8.1, 4.0, 3a-H) and 7.09–7.23 (4 H, m, ArH).
Radical cyclisation of 6e
Following the general procedure, compound 6e (500 mg, 1.64
mmol) was treated with Bu3SnH (573 mg, 1.97 mmol) and
AIBN (80 mg, 0.33 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane–AcOEt (10:1)] to
give 3-methyl-2,3-dihydro-1H-benz[e]indol-2-one 10 (129 mg,
40%), mp 143–144 ЊC (from hexane–AcOEt) (Found: C,
78.9; H, 5.65; N, 7.1. C13H11NO requires C, 79.7; H, 5.6; N,
7.1%); νmax(CCl4)/cmϪ1 1705; δH(300 MHz, CDCl3) 3.31 (3 H, s,
NMe), 3.78 (2 H, s, 1-H2), 7.16 (1 H, d, J 8.5), 7.34–7.39 (1 H,
m), 7.48–7.53 (1 H, m), 7.65 (1 H, d, J 8.5) and 7.84 (2 H, dd,
J 8.2, 3.1); δC(75 MHz, CDCl3) 26.5 (CH2), 34.9 (CH3), 109.6,
117.8, 122.6, 123.9, 127.3, 128.9, 129.1, 129.6, 130.0, 142.6 and
Preparation of 9f from 12
A solution of 12 (119 mg, 0.59 mmol) in THF (2 cm3) was
added to a solution of LDA in THF [prepared from diisopro-
pylamine (573 mg, 5.67 mmol) in THF (2 cm3) and butyllithium
(1.6  in hexane solution, 1.47 cm3, 2.36 mmol) at Ϫ78 ЊC] and
the whole was stirred for 1 h at the same temperature. To this
was added a solution of methyl iodide (1.79 g, 12.6 mmol) and
hexamethylphosphoramide (2 cm3) in THF (2 cm3) at Ϫ78 ЊC
and the mixture was stirred for 1.5 h at the same temperature.
After quenching with sat. aq. ammonium chloride (10 cm3), the
mixture was extracted with diethyl ether and the extract was
washed with 5% HCl and brine, dried (MgSO4), and concen-
trated. The residue was chromatographed on silica gel [hexane–
AcOEt (1:1)] to give a mixture of the monomethylated and
dimethylated derivatives. This mixture was again treated with
LDA and methyl iodide to give 9f (129 mg, 96%), whose mp
(84–85.5 ЊC) and spectroscopic data were identical to those of
the compound obtained by cyclisation of 6f.
175.7 (C᎐O).
᎐
Radical cyclisation of 6f
Following the general procedure, compound 6f (650 mg, 2.11
mmol) was treated with Bu3SnH (737 mg, 2.53 mmol) and
AIBN (69 mg, 0.42 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane–AcOEt (4:1)] to
give (3aR*,9aR*)-2,3,3a,4,5,9b-hexahydro-1H-1,1,3-trimethyl-
benz[e]indol-2-one 9f (326 mg, 68%), mp 85–86 ЊC (from
hexane–AcOEt) (Found: C, 78.75; H, 8.4; N, 6.15. C15H19NO
requires C, 78.6; H, 8.35; N, 6.1%); νmax(CCl4)/cmϪ1 1680;
δH(300 MHz, CDCl3) 0.79, 1.47 (3 H each, both s, 1-Me2), 1.65–
1.77 (1 H, m), 2.05–2.15 (1 H, m), 2.61–2.81 (2 H, m), 2.95 (3 H,
s, NMe), 3.40 (1 H, d, J 8.6, 9b-H), 3.79 (1 H, td, J 8.6, 4.4,
3a-H) and 7.10–7.23 (4 H, m, ArH); δC(75 MHz, CDCl3) 23.2
(CH3), 25.8 (CH2), 26.8 (CH2), 28.0 (CH3), 28.6 (CH3), 44.6
(quaternary C), 45.8 (CH), 57.4 (CH), 126.1, 126.3, 128.6,
Preparation of 10 from 9g
A solution of sodium metaperiodate (192 mg, 0.9 mmol) in
water (3 cm3) was added dropwise to a solution of compound
9g (252 mg, 0.81 mmol) in acetone (3 cm3) at 0 ЊC, and the
mixture was stirred at room temperature overnight. The pre-
cipitated salts were removed by filtration and the filtrate was
concentrated under reduced pressure. Water was added and the
whole was extracted with ethyl acetate. The extract was dried
(MgSO4) and concentrated, and the residue was purified by
column chromatography on silica gel [hexane–AcOEt (2:1)] to
give the corresponding sulfoxide (105 mg, 40%). This sulfoxide
(105 mg, 0.32 mmol) was dissolved in toluene (5 cm3) and the
mixture was heated under reflux in the presence of NaHCO3 (30
mg, 0.36 mmol) overnight. The insoluble material was removed
by filtration and the filtrate was concentrated. The residue was
chromatographed on silica gel [hexane–AcOEt (4:1)] to give 10
(24 mg, 38%), whose spectroscopic data were identical to those
of the compound obtained by cyclisation of 6e.
129.1, 134.7, 137.2 and 178.9 (C᎐O).
᎐
Radical cyclisation of 6g
Following the general procedure, compound 6g (700 mg, 1.56
mmol) was treated with Bu3SnH (544 mg, 1.87 mmol) and
AIBN (51 mg, 0.31 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane–AcOEt (9:2)].
The first fraction gave N-(3,4-dihydro-2-naphthyl)-N-methyl-2-
(phenylthio)acetamide 11 (64 mg, 13%) as an oil (Found: C,
73.6; H, 6.4; N, 4.4. C19H19NOS requires C, 73.75; H, 6.2; N,
4.5%); νmax(CHCl3)/cmϪ1 1635; δH(60 MHz, CDCl3) 2.2–3.2
(4 H, m), 3.09 (3 H, s, NMe), 3.80 (2 H, s, COCH2), 6.28 (1 H,
br s, 1-H) and 6.9–7.6 (9 H, m, ArH).
The second fraction gave (1R*,3aS*,9bR*)-2,3,3a,4,5,9b-
hexahydro-1H-1-phenylthio-3-methylbenz[e]indol-2-one 9g (252
mg, 52%), mp 91.5–92.5 ЊC (from hexane–AcOEt) (Found: C,
73.5; H, 6.5; N, 4.8%); νmax(CCl4)/cmϪ1 1680; δH(300 MHz,
CDCl3) 1.82–1.93 (2 H, m), 2.54–2.71 (2 H, m), 2.87 (3 H, s,
NMe), 3.50–3.55 (1 H, m), 3.59–3.67 (2 H, m), 7.05–7.46 (7 H,
m, ArH) and 7.63–7.70 (2 H, m, ArH).
General procedure for the preparation of N-benzyl-2-halo-N-
(3,4-dihydro-2-naphthyl)acetamides 6h–j
A solution of β-tetralone (1.02 g, 7.0 mmol) and benzylamine
1766
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
(897 mg, 8.4 mmol) in benzene (30 cm3) was heated under reflux
with azeotropic removal of water for 3 h. The solvent was evap-
orated to give the crude imine which was dissolved in dichloro-
methane (30 cm3). To this was added an appropriate acyl
chloride (9.1 mmol) at 0 ЊC and the mixture was stirred at room
temperature overnight. After saturated aq. NaHCO3 (30 cm3)
had been added at 0 ЊC, the whole was stirred for 10 min. The
organic layer was separated, dried (MgSO4), and concentrated.
The residue was chromatographed on silica gel [hexane–AcOEt
(3:1)] to give an enamide. The following compounds were thus
obtained.
N-Benzyl-2-chloro-N-(3,4-dihydro-2-naphthyl)acetamide 6h.
Yield 99%, an oil (Found: C, 73.6; H, 6.1; N, 4.2. C19H18ClNO
requires C, 73.2; H, 5.8; N, 4.5%); νmax(CCl4)/cmϪ1 1665; δH(60
MHz, CDCl3) 2.1–2.6 (2 H, m), 2.7–3.1 (2 H, m), 4.19 (2 H, s,
COCH2), 4.76 (2 H, CH2Ph), 6.20 (1 H, br s, 1-H) and 6.8–7.5
(9 H, m, ArH).
N-Benzyl-2-chloro-N-(3,4-dihydro-2-naphthyl)propanamide
6i. Yield 82%, an oil (Found: C, 73.5; H, 6.2; N, 4.0. C20H20-
ClNO requires C, 73.7; H, 6.2; N, 4.3%); νmax(CCl4)/cmϪ1 1670;
δH(60 MHz, CDCl3) 1.65 (3 H, d, J 7, Me), 2.15–2.6 (2 H, m),
2.7–3.2 (2 H, m), 4.73 (2 H, br s, CH2Ph), 4.82 (1 H, q, J 7,
COCH), 6.21 (1 H, br s, 1-H) and 6.8–7.5 (9 H, m, ArH).
N-Benzyl-2,2,2-trichloro-N-(3,4-dihydro-2-naphthyl)acet-
amide 6j. Yield 25%, a glass [Found: (M ϩ H)ϩ, 380.0362.
C19H1735Cl3NO requires MHϩ, 380.0376]; νmax(CCl4)/cmϪ1 1675;
δH(60 MHz, CDCl3) 2.3–3.2 (4 H, m), 4.83 (2 H, br s, CH2Ph),
6.27 (1 H, br s, 1-H) and 6.7–7.6 (9 H, m, ArH).
one of 5-H2), 2.73 (1 H, ddd, J 16.0, 6.6, 4.6, one of 5-H2), 3.07
(1 H, br t, J 8.6, 9b-H), 3.70 (1 H, td, J 8.0, 4.6, 3a-H), 4.11
(1 H, d, J 15.0, one of CH2Ph), 5.05 (1 H, d, J 15.0, one of
CH2Ph), 7.09–7.24 (4 H, m, ArH) and 7.25–7.39 (5 H, m, ArH).
The third fraction gave a mixture of 1-benzyl-3-methyl-
spiro[azetidine-4,2Ј-1Ј,2Ј,3Ј,4Ј-tetrahydronaphthalen]-2-one
8i
and (1S*,3aR*,9bR*)-2,3,3a,4,5,9b-hexahydro-1H-1-methyl-3-
benzylbenz[e]indol-2-one 9i-α (total 146 mg, total 27%) as an oil.
1
The H NMR spectrum of the mixture showed the compound
8i to be a mixture of two diastereoisomers in a ratio of ca. 1.8:1
and the ratio of 8i:9i-α to be 3.4:1, thereby indicating the
yields of 8i and 9i-α to be 21 and 6%, respectively. A careful
separation of the mixture by chromatography on silica gel
afforded a small quantity of an analytical sample of 8i (Found:
C, 82.5; H, 7.8; N, 5.0%); νmax(CCl4)/cmϪ1 1745; δH(300 MHz,
CDCl3) for the major isomer 1.27 (3 H, d, J 7.5), 1.88 (2 H, br t,
J 7.2), 2.70–3.02 (5 H, m), 4.19 (1 H, d, J 15.6), 4.37 (1 H, d,
J 15.6) and 6.93–7.36 (9 H, m); δH(300 MHz, CDCl3) for the
minor isomer (diagnostic data only) 1.06 (3 H, d, J 7.5), 4.26 (1
H, d, J 15.4) and 4.41 (1 H, d, J 15.4); for 9i-á: νmax(CCl4)/cmϪ1
1690; δH(300 MHz, CDCl3) 0.97 (3 H, d, J 7.7), 1.57–1.79 (2 H,
m), 2.61–2.80 (3 H, m), 3.68–3.79 (2 H, m), 4.15 (1 H, d, J 15.1),
5.04 (1 H, d, J 15.1) and 7.1–7.4 (9 H, m).
Radical cyclisation of 6j
Following the general procedure, compound 6j (497 mg, 1.30
mmol) was treated with Bu3SnH (468 mg, 1.61 mmol) and
AIBN (42 mg, 0.26 mmol). After work-up, the crude material
was chromatographed on silica gel [hexane–AcOEt (7:1)] to
give 3-benzyl-2,3-dihydro-1H-benz[e]indol-2-one 168 (188 mg,
53%), mp 160–160.5 ЊC (from hexane–AcOEt) (Found: C, 83.5;
H, 5.5; N, 5.0. C19H15NO requires C, 83.5; H, 5.5; N, 5.1%);
νmax(CCl4)/cmϪ1 1715; δH(300 MHz, CDCl3) 3.86 (2 H, s,
1-H2), 5.00 (2 H, s, CH2Ph), 7.01 (1 H, d, J 8.6, ArH), 7.21–7.37
(6 H, m, ArH), 7.48 (1 H, td, J 8.3, 1.2, ArH), 7.63 (1 H, d,
J 8.3, ArH), 7.69 (1 H, d, J 8.5, ArH) and 7.76 (1 H, d, J 8.3,
ArH).
Radical cyclisation of 6h
Following the general procedure, compound 6h (1.29 g, 4.15
mmol) was treated with Bu3SnH (1.45 g, 4.98 mmol) and AIBN
(145 mg, 0.88 mmol). After work-up, the crude material was
chromatographed on silica gel [hexane–AcOEt (5:1)]. The first
fraction gave N-benzyl-N-(3,4-dihydro-2-naphthyl)acetamide 13
(260 mg, 23%) as an oil (Found: C, 82.2; H, 6.9; N, 4.8.
C19H19NO requires C, 82.3; H, 6.9; N, 5.05%); νmax(CCl4)/cmϪ1
1640; δH(300 MHz, CDCl3) 2.16 (3 H, s, COMe), 2.32 (2 H, br t,
J 8.0), 2.86 (2 H, br t, J 8.2), 4.76 (2 H, s, CH2Ph), 6.15 (1 H, s,
1-H), 6.92–6.98 (1 H, m, ArH), 7.08–7.19 (3 H, m, ArH) and
7.20–7.32 (5 H, m, ArH).
The second fraction gave 1-benzylspiro[azetidine-4,2Ј-1Ј,2Ј,
3Ј,4Ј-tetrahydronaphthalen]-2-one 8h (502 mg, 44%) as an oil
(Found: C, 81.8; H, 7.1; N, 5.0%); νmax(CCl4)/cmϪ1 1735; δH(300
MHz, CDCl3) 1.71–1.81 (1 H, m), 1.89 (1 H, dt, J 12.5, 8.5),
2.68–2.88 (5 H, m), 3.06 (1 H, d, J 16.4), 4.30, 4.44 (1 H, each,
ABq, J 15.4, CH2Ph), 6.96–7.15 (4 H, m) and 7.24–7.35 (5 H,
m).
2-Bromo-N-(3,4-dihydro-2-naphthyl)-N-methylpropanamide 6k
Following the general procedure, the imine prepared from β-
tetralone (1.55 g, 10.6 mmol) and a large excess of methylamine
was treated with 2-bromopropanoyl bromide (2.74 g, 12.7
mmol) in the presence of triethylamine (1.3 g, 12.7 mmol), and
the crude material was chromatographed on silica gel [hexane–
AcOEt (4:1)] to give 6k (2.39 g, 76%) as an oil (Found: Mϩ,
293.0402. C14H1679BrNO requires Mϩ, 293.0415); νmax(CCl4)/
cmϪ1 1670; δH(60 MHz, CDCl3) 1.80 (3 H, d, J 7), 2.3–2.7 (2 H,
m), 2.8–3.2 (2 H, m), 3.10 (3 H, s), 4.83 (1 H, q, J 7), 6.40 (1 H,
br s) and 7.10 (4 H, br s).
Radical cyclisation of 6i
A solution of Bu3SnH (683 mg, 2.35 mmol) and AIBN (59 mg,
0.36 mmol) in toluene (70 cm3) was added to a solution of
compound 6i (590 mg, 1.81 mmol) in boiling toluene (150 cm3)
over a period of 4 h and the mixture was heated under reflux
overnight. After work-up as described in the general procedure,
the crude material was chromatographed on silica gel [hexane–
AcOEt (9:1)]. The first fraction gave N-benzyl-N-(3,4-dihydro-
2-naphthyl)propanamide 14 (63 mg, 12%) as an oil (Found: C,
82.4; H, 7.2; N, 4.75. C20H21NO requires C, 82.4; H, 7.3; N,
4.8%); νmax(CCl4)/cmϪ1 1660; δH(300 MHz, CDCl3) 1.17 (3 H, t,
J 7.5, CH2CH3), 2.32 (2 H, br t, J 8.1), 2.43 (2 H, q, J 7.5,
CH2CH3), 2.87 (2 H, br t, J 8.3), 4.75 (2 H, s, CH2Ph), 6.14
(1 H, s, 1-H), 6.92–6.97 (1 H, m, ArH), 7.07–7.19 (3 H, m, ArH)
and 7.20–7.34 (5 H, m, ArH).
The second fraction gave (1R*,3aR*,9bR*)-2,3,3a,4,5,9b-
hexahydro-1H-1-methyl-3-benzylbenz[e]indol-2-one 9i-β (235
mg, 45%) as a glass, mp 100–100.5 ЊC (from hexane–AcOEt)
(Found: C, 82.6; H, 7.3; N, 5.1%); νmax(CCl4)/cmϪ1 1690; δH(300
MHz, CDCl3) 1.46 (3 H, d, J 7.1, 1-Me), 1.71–1.95 (2 H, m,
4-H2), 2.41–2.52 (1 H, m, 1-H), 2.61 (1 H, ddd, J 16.0, 9.0, 4.6,
N-Benzyl-2-bromo-N-(3,4-dihydro-2-naphthyl)propanamide 6l
Following the general procedure, the imine prepared from β-
tetralone (1.17 g, 8.0 mmol) and benzylamine (943 mg, 8.8
mmol) was treated with 2-bromopropanoyl bromide (2.25 g,
10.4 mmol), and the crude material was chromatographed on
silica gel [hexane–AcOEt (5:1)] to give 6l (2.83 g, 95%) as an oil
(Found: Mϩ, 369.0725. C20H2079BrNO requires Mϩ, 369.0728);
νmax(CCl4)/cmϪ1 1665; δH(60 MHz, CDCl3) 1.80 (3 H, d, J 7),
2.15–2.6 (2 H, m), 2.7–3.1 (2 H, m), 4.70 (2 H, s), 4.82 (1 H, q,
J 7), 6.17 (1 H, br s) and 6.8–7.4 (9 H, m, ArH).
Studies on the effect of temperature on the regioselectivity in
radical cyclisations of 6k and 6l
A mixture of Bu3SnH (348 mg, 1.2 mmol) and AIBN (33 mg,
0.2 mmol) in benzene or toluene (50 cm3) was added to a boiling
solution of 6k (293 mg, 1 mmol) or 6l (369 mg, 1 mmol) in the
same solvent (100 cm3) as that described above by using a
syringe pump over a period of 3 h. For the reactions in benzene,
heating was continued for a further hour. After usual work-up,
the crude material was chromatographed on silica gel [hexane–
J. Chem. Soc., Perkin Trans. 1, 1998
1767

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Perkin Trans. 1, 1992, 2399; (c) T. Sato, N. Chono, H. Ishibashi and
AcOEt (9:1)]. The first fraction gave the simple reduction
product 15 (from 6k) or 14 (from 6l).
M. Ikeda, J. Chem. Soc., Perkin Trans. 1, 1995, 1115; (d) H. Ishibashi,
Y. Fuke, T. Yamashita and M. Ikeda, Tetrahedron: Asymmetry, 1996,
7, 2531.
3 (a) K. Goodall and A. F. Parsons, J. Chem. Soc., Perkin Trans. 1,
1994, 3257; (b) K. Goodall and A. F. Parsons, Tetrahedron, 1996, 52,
6739; (c) K. Goodall and A. F. Parsons, Tetrahedron Lett., 1997, 37,
491.
4 (a) H. Ishibashi, C. Kameoka, R. Ueda, K. Kodama, T. Sato and M.
Ikeda, Synlett, 1993, 649; (b) H. Ishibashi, C. Kameoka, H. Iriyama,
K. Kodama, T. Sato and M. Ikeda, J. Org. Chem., 1995, 60, 1276; (c)
H. Ishibashi, C. Kameoka, K. Kodama and M. Ikeda, Tetrahedron,
1996, 52, 489; (d) H. Ishibashi, K. Kodama, C. Kameoka,
H. Kawanami and M. Ikeda, Tetrahedron, 1996, 52, 13 867; (e)
H. Ishibashi, C. Kameoka, K. Kodama, H. Kwanami, M. Hamada
and M. Ikeda, Tetrahedron, 1997, 53, 9611.
The second fraction gave a mixture of the radical cyclisation
products 8b and 9b (from 6k) or 8i and 9i (from 6l), whose
ratios were estimated by the integrated intensities of the peak
height of the C-methyl protons at δ 1.02 and 1.20 (for the two
diastereoisomers of 8b), δ 0.90 and 1.41 (for the two diastereo-
isomers of 9b), δ 1.06 and 1.27 (for the two diastereoisomers of
8i) and δ 0.97 and 1.46 (for the two diastereoisomers of 9i).
These results are summarised in Table 1.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture of Japan and Ciba-Geigy Foundation (Japan) for the
Promotion of Science (H. I.).
5 J. L. Belletire, C. E. Hagedorn, D. M. Ho and J. Krause, Tetrahedron
Lett., 1993, 34, 797.
6 For the reversibility of cyclisation of pent-4-enyl radicals and related
species, see ref. 4(b) and references cited therein.
7 H. Ishibashi, M. Higuchi, M. Ohba and M. Ikeda, Tetrahedron Lett.,
1998, 39, 75.
8 J. Axon, L. Boiteau, J. Boivin, J. E. Forbes and S. Z. Zard,
Tetrahedron Lett., 1994, 35, 1719.
References
1 For reviews, see (a) B. Giese, Radicals in Organic Synthesis: Formation
of Carbon-Carbon Bonds, Pergamon, New York, 1986; (b) D. P.
Curran, Synthesis, 1988, 417 and 489; (c) C. P. Jasperse, D. P. Curran
and T. L. Fevig, Chem. Rev., 1991, 91, 1237.
2 (a) H. Ishibashi, N. Nakamura, T. Sato, M. Takeuchi and M. Ikeda,
Tetrahedron Lett., 1991, 32, 1725; (b) T. Sato, N. Nakamura,
K. Ikeda, M. Okada, H. Ishibashi and M. Ikeda, J. Chem. Soc.,
Paper 8/01714J
Received 2nd March 1998
Accepted 18th March 1998
1768
J. Chem. Soc., Perkin Trans. 1, 1998