Synthesis of benzolactams by 11-endo selective aryl radical cyclisation of 2-iodobenzamides

Article abstract of DOI:10.1039/b002416n

Regioselective 11-endo aryl radical cyclisation of methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α-D- glucopyranoside 4 and N-(3-allyloxypropyl)-2-iodobenzamide 9 with tri-n-butyltin hydride provided the benzolactams 5 and 10, respectively. The unequivocal structures of 5 and 10 were supported by ¹H and ¹³C NMR spectroscopy and by PENDANT or DEPT, COSY and HMQC experiments. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b002416n

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Synthesis of benzolactams by 11-endo selective aryl radical
cyclisation of 2-iodobenzamides
Maria A. F. Prado,*a Ricardo J. Alves,a José D. Souza Filho,b Rosemeire B. Alves,b
Maria T. C. Pedrosa,a Renata F. Pradoa and André A. G. Faracob
1
a Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de
Minas Gerais, Avenida Olegário Maciel 2360, Belo Horizonte — 30.180-112, Brazil
b Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas
Gerais, Avenida Antônio Carlos 6627, Belo Horizonte — 31.270-200, Brazil
Received (in Cambridge, UK) 27th March 2000, Accepted 20th April 2000
Published on the Web 31st May 2000
Regioselective 11-endo aryl radical cyclisation of methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoyl-
amino)-α--glucopyranoside 4 and N-(3-allyloxypropyl)-2-iodobenzamide 9 with tri-n-butyltin hydride provided
the benzolactams 5 and 10, respectively. The unequivocal structures of 5 and 10 were supported by 1H and 13
C
NMR spectroscopy and by PENDANT or DEPT, COSY and HMQC experiments.
methyl
4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoyl-
Introduction
amino)-α--glucopyranoside 4. We were somewhat encouraged
by the possibility of the carbohydrate unit of the aryl radical
precursor adopting a conformation in which the cyclisation
reaction would occur prior to 1,5-hydrogen-atom transfer. This
hypothesis was also supported by the observation of ring
closure of radicals derived from precursors with an oxygen
atom in the chain, such as in 4. These radicals cyclise much
more rapidly than do their carbon analogues.11–13 The effect of
an oxygen atom in the chain on the rate of cyclisation has been
attributed to a decrease in the strain energy of the cyclisation
transition structures resulting from the replacement of a carbon
atom by oxygen, a hypothesis supported by molecular mech-
anics calculations.14
Bu3SnH-mediated aryl radical cyclisations are now widely used
in organic synthesis for the construction of fused aromatic
compounds.1 There are several examples of fused aromatic
compounds obtained by Bu3SnH-mediated aryl radical cyclis-
ation from ortho-halogen compounds bearing a carbon–carbon
double bond in the side chain. Most of them have a five- or six-
membered ring fused to a benzene ring.1–9 Some of these com-
pounds are γ- or δ-lactams fused to the aromatic ring.1–6 To the
best of our knowledge, there are only two reports to date of
Bu3SnH-mediated aryl radical cyclisation to give fused aro-
matic compounds in which the carbocyclic rings have more
than six members,8,9 and there are no benzolactams with lactam
rings larger than six members obtained by the same method.
One possible explanation for this involves an assumption that,
in the ortho-halogenobenzamides bearing a hydrogen on the
saturated carbon at the 5-position relative to the aryl radical
centre, generation of the aryl radical is followed by intra-
molecular hydrogen-atom transfer to the aryl group with
formation of an amidoyl radical which undergoes a variety of
new radical addition and cyclisation reactions.10
Results and discussion
We began our investigations by examining the cyclisation of
the o-iodobenzamide 4, which was obtained from methyl
α--glucopyranoside in eight conventional synthetic steps
(Scheme 1). The C-4 and C-6 hydroxy groups of the starting
material were protected as a benzylidene acetal15 and the C-2
and C-3 hydroxy groups were O-benzylated.16 After removal of
the benzylidene group under mild acidic conditions17 the
hydroxy group at C-6 of methyl 2,3-di-O-benzyl-α--gluco-
pyranoside was selectively replaced by an iodine atom18 to give
methyl 2,3-di-O-benzyl-6-deoxy-6-iodo-α--glucopyranoside.
Treatment of the 6-iodo derivative with sodium azide in DMF
Despite our knowledge of 1,5-hydrogen-atom transfer, we
decided to explore the possibility of using Bu3SnH-mediated
radical cyclisation to create benzomacrolactams such as A
and B by 11-endo and/or 10-exo cyclisation, respectively, from
* e-mail: doraprad@dedalus.lcc.ufmg.br
DOI: 10.1039/b002416n
J. Chem. Soc., Perkin Trans. 1, 2000, 1853–1857
This journal is © The Royal Society of Chemistry 2000
1853

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Scheme 1 Reagents, conditions and yields: i, 3 equiv. NaH, 2.4 equiv. allyl bromide, DMF, rt, 93%; ii, 1.5 equiv. triphenylphosphine, toluene, water,
reflux, 85%; iii, 1 equiv. 2-iodobenzoyl chloride, 10% aq. NaOH, CH2Cl2, rt, 51%; iv, 1.5 equiv. Bu3SnH, benzoyl peroxide (cat.), benzene, reflux, 5
40%, 6 42%.
gave the 6-azido derivative 1,19 which was treated with allyl
bromide in the presence of sodium hydride in DMF to give
methyl 4-O-allyl-6-azido-2,3-di-O-benzyl-6-deoxy-α--gluco-
pyranoside 2. Selective reduction of the azido group using
the Staudinger reaction20 gave methyl 4-O-allyl-6-amino-2,3-
di-O-benzyl-6-deoxy-α--glucopyranoside 3. Compound 4 was
obtained by reaction of 3 with 2-iodobenzoyl chloride.
Consideration of the competing reactions available to the
radicals involved in this cyclisation suggested that the form-
ation of cyclised products should be improved by conducting
the experiment with very low concentrations of both the 4-O-
allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α--
glucopyranoside 4 and Bu3SnH and slow addition of Bu3SnH/
benzoyl peroxide in benzene solution, thus respectively decreas-
ing the intermolecular reactions and the rate of hydrogen-atom
transfer to uncyclised radicals.6,14,21 Thus, a mixture of Bu3SnH
(1.5 mol equiv.) and benzoyl peroxide (catalytic amount) in
nitrogen-saturated anhydrous benzene was added over a period
of one hour to a solution of the o-allyloxyiodobenzamide 4 in
nitrogen-saturated anhydrous benzene maintained at 80 ЊC to
give a reaction mixture 0.012 mol dmϪ3 in Bu3SnH. The reac-
tion mixture was heated under reflux for a further one hour.
Subsequent solvent removal and column chromatography on
silica gel gave two main crystalline products identified as the
benzomacrolactam 5, resulting from 11-endo aryl radical
cyclisation in 40% yield and the hydrogenolysis product 6 in
42% yield (Scheme 1).
Encouraged by the success of the Bu3SnH-mediated radical
cyclisation reaction of 4, we then applied this methodology to
the synthesis of benzomacrolactams such as C and D from
N-(3-allyloxypropyl)-2-iodobenzamide 9 to examine whether or
not this methodology would be applicable to other systems
where the conformational restraints imposed by the carbo-
hydrate unit are lacking.
The 2-iodobenzamide 9 was readily prepared by conden-
sation of 3-aminopropan-1-ol 7 with 2-iodobenzoyl chloride,
followed by O-alkylation of the resulting N-(3-hydroxypropyl)-
2-iodobenzamide 8 with allyl bromide. Similar treatment of
compound 9 as described above for 4, but using AIBN as
radical initiator, gave an oil identified as the hydrogenolysis
product 11 (85% yield) and a crystalline substance identified as
the macrolactam 10 (14% yield), resulting from 11-endo aryl
radical cyclisation (Scheme 2).
The structures of lactams 5 and 10, hydrogenolysis products
6 and 11, and precursors 4 and 9 were supported by 1H and 13
C
NMR spectroscopy. The unequivocal structures of 5 and 10
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Table 1 Selected 13C NMR (CDCl3) data for compounds 4, 5, 6, 9, 10 and 11
Compound
Carbon
δ (ppm)
MHz
100
4
1-C
2-C
142.24
92.26
8-C
7-C
134.62
117.30
5
6
1-C, 2-C
8-C
7-C
1-C
2-C
One of 4 signals between 139.04 and 137.38
31.79
28.00
134.93
100
100
One of 9 signals between 129.06 and 127.27
8-C
7-C
135.08
117.80
9
10
11
1-C
2-C
11-C
12-C
1-C
142.27
92.40
134.37
116.88
140.2
137.4
28.3 or 31.3
29.6
134.52
50
100
50
2-C
11-C
12-C
1-C
2-C
11-C
12-C
128.34 or 126.81
134.34
117.27
Scheme 2 Reagents, conditions and yields: i, 2 equiv. 2-iodobenzoyl chloride, 1 equiv. triethylamine CH2Cl2, rt, 67%; ii, 0.2 equiv. Bu4NBr, 5% aq.
NaOH, 3 equiv. allyl bromide, rt, 29%, iii, 1.5 equiv. Bu3SnH, AIBN (cat.), benzene, reflux, 10 14%, 11 85%.
were also confirmed by PENDANT or DEPT, COSY and
HMQC experiments. Selected 13C NMR data for these six
compounds are listed in Table 1.
benzamide 4 (1:1) with the ratio lactam:hydrogenolysis product
isolated from the reaction of the benzamide 9 (1.5:8.5) suggests
that our previous hypothesis might be correct: conformational
restraints imposed by the sugar unit in the carbohydrate aryl
radical precursor favoured the cyclisation. On the other hand,
in the reaction of the benzamide 9, where the conformational
restraints are lacking, direct hydrogen-atom transfer to the
initially formed aryl radical, or 1,5-hydrogen-atom transfer to
give the amidoyl radical and, subsequently, the uncyclised
product, occurred prior to the cyclisation.
In conclusion, the present investigation shows the potential
of aryl radical macrocyclisation from o-iodobenzamides bear-
ing a hydrogen atom on the saturated carbon in position 5
relative to the halogen atom in the synthesis of condensed
lactams incorporating large rings. We have also found that the
11-endo cyclisation mode is preferred over a 10-exo ring closure
in those systems having an allyloxy group at the 7 position
relative to the aryl radical centre.
The unsatisfactory elemental analysis of 5, 10 and 11 could
be due of the presence of tri-n-butyltin compounds as impur-
ities, since it is well known that a major drawback in employing
the tri-n-tributyltin reagent can be the poor separation of the
products from tin residues.22 Attempts to obtain compounds 5,
10 and 11 with correct analytical data were not successful. The
NMR spectra of 5 and 10 do not indicate the presence of sig-
nificant quantities of tri-n-butyltin residues and the elemental
analyses for these compounds are almost good. On the other
hand, the analytical data for the uncyclised product 11 are
incorrect and the signals relative to the butyl group in its NMR
spectra indicate the presence of tri-n-butyltin compounds.
These results can be attributed to the difficulty of purifying 11,
which is an oil.
Thus we found that the Bu3SnH-induced aryl radical cyclis-
ation of the o-iodobenzamides 4 and 9 provided exclusively the
lactams 5 and 10, respectively, resulting from 11-endo aryl
radical cyclisation. Our results are in agreement with the
guideline for radical macrocyclisation that ‘endo cyclisation
modes are favored’23 and with other literature data of macro-
cyclisations.8,9 Comparison of the ratio lactam:hydrogenolysis
product isolated from the Bu3SnH-mediated reaction of the
Experimental
General procedures
Mps were determined on a Kofler Sybron apparatus and are
uncorrected. Optical rotations were determined at 25 ЊC with a
J. Chem. Soc., Perkin Trans. 1, 2000, 1853–1857
1855

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Bellingham & Stanley P20 Polarimeter; [α]D-values are given
in units of 10Ϫ1 deg cm2 gϪ1 NMR spectra were measured in
deuteriochloroform with TMS as the internal standard with a
Bruker Avance DRX-400 or a Bruker Avance-200 instrument;
chemical shifts are given on the δ-scale, and J-values are given
in Hz. Column chromatography was performed with silica gel
60, 70–230 mesh (Merck). The term ‘standard work-up’ means
that the organic layer was washed with water, dried over
anhydrous sodium sulfate, filtered and the solvent was removed
under reduced pressure.
J1Ј,2Ј 3.5, 1Ј-H), 4.36 (1 H, dd, Jgem 12.0, J9,8 5.6, one of 9-H),
4.25 (1 H, dd, Jgem 12.0, J9,8 5.9, one of 9-H), 3.95 (1 H, t,
J3Ј,2Ј = J3Ј,4Ј = 9.63, 3Ј-H), 3.87 (1 H, qd, Jgem 13.60, J6Ј,5Ј 6.94,
J6Ј,NH 5.31, one of 6Ј-H), 3.80–3.76 (1 H, m, 5Ј-H), 3.64 (1 H, dt,
J6Ј,5Ј = J6Ј,NH = 4.03, one of 6Ј-H), 3.44 (1 H, dd, 2Ј-H), 3.38
(3 H, s, MeO), 3.31 (1 H, t, 4Ј-H); δC(100 MHz, CDCl3) 169.11
(C᎐O), 142.24 (1-C), 139.83 (3-C), 138.50, 138.00 (a- and b-C),
᎐
134.62 (HC᎐CH ), 131.02 (4-C), 128.43, 128.41, 128.38, 128.31,
᎐
2
128.27, 128.25, 128.23, 128.17, 128.07, 127.97, 127.94, 127.89,
127.86, 127.58 (6-C, 5-C, Ar), 117.30 (HC᎐CH ), 98.07 (1Ј-C),
᎐
2
92.26 (CI), 81.61 (3Ј-C), 79.61 (2Ј-C), 78.94 (4Ј-C), 75.69, 74.09,
73.31 (2 × PhCH2 and 9-C), 68.93 (5Ј-C), 55.43 (MeO), 40.18
(6Ј-C) (Found: C, 57.9; H, 5.4; N, 2.6. Calc. for C31H34INO6: C,
57.9; H, 5.3; N, 2.2%).
Methyl 4-O-allyl-6-azido-2,3-di-O-benzyl-6-deoxy-ꢀ-D-gluco-
pyranoside 2
A solution of allyl bromide (1.7 cm3, 2.3 g, 19 mmol) in DMF
(10 cm3) was added to a mixture of sodium hydride (0.6 g, 24
mmol) and methyl 6-azido-2,3-di-O-benzyl-6-deoxy-α--gluco-
pyranoside 119 (3.8 g, 7.9 mmol) in DMF (10 cm3). The mixture
was stirred for 18 h at room temperature (rt). Distillation under
reduced pressure gave a residue. Addition of water, extraction
with CH2Cl2 and standard work-up gave the product 2 (3.3 g,
93%) as an oil; [α]D ϩ73.2 (c 2.0 in CHCl3); δH(200 MHz,
Radical cyclisation of compound 421
To a stirred, boiling solution of compound 4 (0.1 g, 0.155
mmol) in nitrogen-saturated benzene (15 cm3) was added a
solution of Bu3SnH (0.06 cm3, 0.07 g, 0.25 mmol) and benzoyl
peroxide (0.002 g) in nitrogen-saturated benzene (5 cm3) via an
addition funnel during 1 h. The reaction mixture was heated
under reflux and a nitrogen atmosphere for a further 1 h. Sub-
sequent solvent removal and column chromatography (hexane–
ethyl acetate 6:4) gave, successively, the uncyclised product 6
(0.034 g, 42%) and the lactam 5 (0.032 g, 40%).
The lactam 5 was obtained as a solid; mp 218–220 ЊC; [α]D
ϩ20.4 (c 1.7 in CHCl3); δH(400 MHz, CDCl3) 7.39–7.27 (12 H,
m, ArH), 7.20–7.16 (2 H, m, ArH), 6.30 (1 H, br s, NH), 4.96
(1 H, d, Jgem 10.9, one of PhCH2), 4,76 (1 H, d, Jgem 12.3, one of
PhCH2), 4.73 (1 H, d, Jgem 10.9, one of PhCH2), 4.54 (1 H, d,
Jgem 12.3, one of PhCH2), 4.55 (1 H, d, J1Ј,2Ј 3.3, 1Ј-H), 4.09
(1 H, m, 5Ј-H), 3.97 (1 H, dd, J3Ј,2Ј 9.9, J3Ј,4Ј 8.3, 3Ј-H), 3.92–3.86
(2 H, m, one of 6Ј-H and one of 9-H), 3.44 (1 H, dd, 2Ј-H), 3.42
(3 H, s, MeO), 3.28–3.14 (4 H, m, 4Ј-H, one of 6Ј-H, one of 9-H,
one of 7-H), 2.59 (1 H, dt, Jgem 13.88, J7,8 4.52, one of 7-H),
1.99–1.92 (1 H, m, one of 8-H), 1.58–1.52 (1 H, m, one of 8-H);
CDCl ) 7.35–7.28 (10 H, m, Ph), 5.93–5.79 (1 H, m, CH ᎐CH),
᎐
3
2
5.23 (1 H, dd, one of CH ᎐CH, J
17.2, Jgem 1.4), 5.16 (1 H,
᎐
2
trans
dd, one of CH ᎐CH, Jcis 11.4, Jgem 1.4), 4.95 (1 H, d, Jgem 10.7,
᎐
2
one of PhCH2), 4.79 (1 H, d, Jgem 12.4, one of PhCH2), 4.77
(1 H, d, Jgem 10.7, one of PhCH2), 4.64 (1 H, d, Jgem 12.4, one
of PhCH2), 4.60 (1 H, d, J1,2 3.8, 1-H), 4.34 (1 H, dd, Jgem 12.3,
J 5.6, one of OCH2), 4.10 (1 H, dd, J 12.3, J 5.8, one of OCH2),
3.91 (1 H, t, J3,2 = J3,4 = 9.2, 3-H), 3.77–3.71 (1 H, m, 5-H),
3.54–3.36 (3 H, m, 6-H2, 2-H), 3.39 (3 H, s, MeO), 3.29 (1 H, t,
4-H); δC(50 MHz, CDCl3) 138.47 (one of Ph ipso), 137.91
(other Ph ipso), 134.36 (HC᎐CH ), 128.37, 128.30, 127.96,
᎐
2
127.88, 127.56 (Ph), 117.17 (HC᎐CH ), 97.92 (1-C), 81.57
᎐
2
(3-C), 79.65 (2-C), 78.09 (4-C), 75.63, 73.82, 73.31 (2 ×
PhCH2O and OCH2), 69.84 (5-C), 55.25 (MeO), 51.26 (6-C)
(Found: C, 65.4; H, 6.7; N, 9.4. Calc. for C24H29N3O5: C, 65.6;
H, 6.6; N, 9.6%).
δ (100 MHz, CDCl ) 170.65 (C᎐O), 139.04, 138.62, 138.07,
᎐
C
3
137.38 (1-, 2-, a- and b-C), 130.74, 129.85, 128.45, 128.38,
128.22, 128.03, 127.97, 127.89, 127.61, 126 65, 126.00 (Ar),
98.07 (1Ј-C), 82.14 (3Ј-C), 81.65 (4Ј-C), 79.39 (2Ј-C), 75.68,
73.16 (2 × PhCH2), 68.54 (9-C), 65.80 (5Ј-C), 55.54 (MeO),
43.51 (6Ј-C), 31.79 (8-C), 28.00 (7-C) (Found: C, 70.8; H, 6.8;
N, 2.7. Calc. for C31H35NO6: C, 71.9; H, 6.8; N, 2.7%).
The uncyclised product 6 was obtained as a white solid; mp
148–151 ЊC; [α]D ϩ19 (c 2.7 in CHCl3); δH(400 MHz, CDCl3)
7.74–7.72 (2 H, m, 2- and 6-H), 7.51–7.47 (1 H, m, Ph), 7.44–
7.39 (2 H, m, Ph), 7.34–7.27 (10 H, m, Ph), 6.40 (1 H, br s, NH),
5.98–5.89 (1 H, m, 8-H), 5.27 (1 H, dd, J7,8 17.2, Jgem 1.3, one of
7-H), 5.15 (1 H, dd, J7,8 10.1, Jgem 1.3, one of 7-H), 4.93 (1 H, d,
Jgem 10.7, one of PhCH2), 4.80 (1 H, d, Jgem 12.1, one of
PhCH2), 4.79 (1 H, d, Jgem 10.7, one of PhCH2), 4.65 (1 H, d,
Jgem 12.1, one of PhCH2), 4.57 (1 H, d, J1Ј,2Ј 3.5, 1Ј-H), 4.33
(1 H, dd, Jgem 12.1, J9,8 5.58, one of 9-H), 4.19 (1 H, dd, Jgem
12.1, J9,8 5.96, one of 9-H), 3.94 (1 H, t, J3Ј,2Ј = J3Ј,4Ј = 9.26, 3Ј-
H), 3.85 (1 H, qd, Jgem 13.49, J6Ј,5Ј 6.72, J6Ј,NH 5.59, one of 6Ј-H),
3.79–3.74 (1 H, m, 5Ј-H), 3.64 (1 H, dt, J6Ј,5Ј = J6Ј,NH = 4.07, one
of 6Ј-H), 3.46 (1 H, dd, 2Ј-H), 3.37 (3 H, s, MeO), 3.23 (1 H, t,
Methyl 4-O-allyl-6-amino-2,3-di-O-benzyl-6-deoxy-ꢀ-D-gluco-
pyranoside 320
To a solution of methyl 4-O-allyl-6-azido-2,3-di-O-benzyl-6-
deoxy-α--glucopyranoside 2 (3.5 g, 7.9 mmol) in toluene (100
cm3) was added triphenylphosphine (3.2 g, 12 mmol). The solu-
tion was stirred for 18 h at reflux. Water (2 cm3) was added and
the solution was stirred under reflux for 2 h. Distillation of the
toluene gave a residue, which was submitted to column chrom-
atography. Elution with CHCl3–CH3OH 9.8:0.2 gave methyl
4-O-allyl-6-amino-2,3-di-O-benzyl-6-deoxy-α--glucopyrano-
side 3 (2.8 g, 85%).
Methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoyl-
amino)-ꢀ-D-glucopyranoside 4
To a solution of 2-iodobenzoyl chloride (1.0 g, 3.9 mmol) in
dichloromethane (10 cm3) were added 10% aq. NaOH (5 cm3)
and a solution of methyl 4-O-allyl-6-amino-2,3-di-O-benzyl-6-
deoxy-α--glucopyranoside 3 (1.6 g, 3.9 mmol) in CH2Cl2. The
mixture was stirred for 12 h at rt. The organic layer was separ-
ated and the aqueous phase was extracted with CH2Cl2. Stand-
ard work-up gave a residue, which was submitted to column
chromatography. The iodobenzamide 4 (1.3 g, 51%), eluted
with hexane–ethyl acetate 7:3, was obtained as a white solid;
mp 150–153 ЊC; [α]D ϩ22.3 (c 0.9 in CHCl3); δH(400 MHz,
CDCl3) 7.85 (1 H, d, J6,5 7.9, 6-H), 7.37–7.26 (12 H, m, ArH),
7.09 (1 H, m, ArH), 6.03 (1 H, br s, NH), 5.94 (1 H, m, 8-H),
5.27 (1 H, dd, J7,8 17.2, Jgem 1.4, one of 7-H), 5.15 (1 H, d, J7,8
10.3, one of 7-H), 4.95 (1 H, d, Jgem 10.8, one of PhCH2), 4.81
(1 H, d, Jgem 10.8, one of PhCH2), 4.79 (1 H, d, Jgem 12.1, one of
PhCH2), 4.64 (1 H, d, Jgem 12.1, one of PhCH2), 4.59 (1 H, d,
4Ј-H); δ (100 MHz, CDCl ) 167.66 (C᎐O), 138.96, 138.52 (a-C
᎐
C
3
and b-C), 135.08 (HC᎐CH ), 134.93 (1-C), 131.86 (4-C), 129.06,
᎐
2
128.95, 128.86, 128.78, 128.46, 128.41, 128.32, 128.06, 127.27
(Ph), 117.80 (HC᎐CH ), 98.49 (1Ј-C), 82.12, 80.28, 79.36 (2Ј-,
᎐
2
3Ј- and 4Ј-C), 76.19, 74.40, 73.80 (2 × PhCH2 and 9-C), 69.50
(5Ј-C), 55.69 (MeO), 40.75 (6Ј-C) (Found: C, 71.8; H, 6.8; N,
2.5. Calc. for C31H35NO6: C, 71.9; H, 6.8; N, 2.7%).
N-(3-Hydroxypropyl)-2-iodobenzamide 8
To a solution of 3-aminopropan-1-ol 7 (2 cm3, 2.02 g, 26.7
mmol) and triethylamine (3.7 cm3, 2.75 g, 27.2 mmol) in
anhydrous CH2Cl2 (115 cm3) was added a solution of 2-iodo-
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benzoyl chloride (14.11 g, 53 mmol) in CH2Cl2 (40 cm3). The
mixture was stirred for 20 h at room temperature. Water was
added, the organic layer was separated and the aqueous layer
was extracted with CH2Cl2. Standard work-up gave a residue,
which was submitted to column chromatography. The iodo-
benzamide 8 (5.42 g, 67%), eluted with ethyl acetate, was
obtained as a syrup; δH(200 MHz, CDCl3) 7.80 (1 H, d, J6,5 7.9,
6-H), 7.39–7.25 (2 H, m, ArH), 7.05 (1 H, m, ArH), 6.86 (1 H,
br s, NH), 3.68 (2 H, t, J9,8 5.6, 9-H2), 3.80 (1 H, br s, OH), 3.48
t, J10,11 5.3, 10-H2), 3.00 (2 H, t, J12,11 6.4, 12-H2), 1.85 (4 H, m,
8- and 11-H ); δ (100 MHz, CDCl ) 171.0 (C᎐O), 140.2 (1-C),
137.4 (2-C), 130.8, 129.7, 127.2, 126.0 (Ar), 70.9 (9-C), 69.1
(10-C), 39.5 (7-C), 31.3, 28.3 (8- and 11-C), 29.6 (12-C) (Found:
C, 70.8; H, 8.6; N, 5.9. Calc. for C13H17NO2: C, 71.2; H, 7.8; N,
6.4%).
The uncyclised product 11 was obtained as an oil; δH(200
MHz, CDCl3) 7.76 (2 H, d, J2,3 7.2, o-H), 7.54–7.35 (3 H, m,
Ph), 7.18 (1 H, br s, NH), 6.02–5.82 (1 H, m, 11-H), 5.32–5.17
(2 H, m, 12-H2), 4.00 (2 H, d, J10,11 5.6, 10-H2), 3.65–3.53
(4 H, m, 9- and 7-H2), 1.90 (2 H, quintet, J8,7 = J8,9 = 5.8, 8-H2);
᎐
2
C
3
(2 H, q, J7,NH = J7,8 = 6.1, 7-H2), 1.72 (2 H, quintet, J8,7 = J8,9
=
5.9, 8-H ); δ (50 MHz, CDCl ) 170.43 (C᎐O), 141.78 (1-C),
᎐
2
C
3
139.70 (3-C), 131.01, 128.02 (Ar), 92.45 (CI), 59.41 (9-C), 36.88
(7-C), 31.62 (8-C) (Found: C, 38.9; H, 4.1; N, 4.3. Calc. for
C10H12INO2: C, 39.4; H, 3.9; N, 4.6%).
δ (50 MHz, CDCl ) 167.25 (C᎐O), 134.52 (1-C), 134.34
᎐
C 3
(HC᎐CH ), 131.16 (4-C), 128.34, 126.81 (2- and 3-C), 117.27
᎐
2
(HC᎐CH ), 72.05, 69.93 (9- and 10-C), 39.14 (7-C), 28.73 (8-C)
᎐
2
(Found: C, 65.4; H, 7.0; N, 5.2. Calc. for C13H17NO2: C, 71.2; H,
7.8; N, 6.4%).
N-(3-Allyloxypropyl)-2-iodobenzamide 9
To a solution of the iodobenzamide 8 (2.04 g, 6.69 mmol) in
CH2Cl2 (40 cm3) were added, under magnetic stirring, 5% aq.
NaOH (15 cm3) and Bu4NBr (0.43 g, 1.33 mmol), as phase-
transfer catalyst. The mixture was stirred for 30 min. Allyl
bromide (1.7 cm3, 2.4 g, 20 mmol) was added and the mixture
was stirred for 68 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. Standard work-up
gave a residue, which was submitted to column chromato-
graphy. The allyloxyiodobenzamide 9 (0.67 g, 29%), eluted with
hexane–ethyl acetate 1:1, was obtained as a syrup; δH(200
MHz, CDCl3) 7.82 (1 H, d, 6-H), 7.39–7.32 (2 H, m, ArH), 7.07
(1 H, m, ArH), 6.55 (1 H, br s, NH), 5.87 (1 H, m, 11-H), 5.27–
5.08 (2 H, m, 12-H2), 3.96 (2 H, dt, J10,11 5.2, J10,12 1.33, 10-H2),
References
1 H. Ishibashi, H. Kawanami and M. Ikeda, J. Chem. Soc., Perkin
Trans. 1, 1997, 817.
2 K. Jones and J. Wilkinson, J. Chem. Soc., Chem. Commun., 1992,
1767.
3 A. G. Schultz, M. A. Holoboski and M. S. Smith, J. Am. Chem.
Soc., 1993, 115, 7904.
4 K. Jones, J. Wilkinson and R. Ewin, Tetrahedron Lett., 1994, 35,
7673.
5 W. R. Bowman, H. Heaney and B. M. Jordan, Tetrahedron Lett.,
1988, 29, 6657.
6 K. Jones, M. Thompson and C. Wright, J. Chem. Soc., Chem.
Commun., 1986, 115.
7 A. L. J. Beckwith and W. Gara, J. Chem. Soc, Perkin Trans. 2, 1975,
593.
8 S. E. Gibson, N. Guilo and M. J. Tozer, Chem. Commun., 1997, 637.
9 P. Chattopadhayay, M. Mukherjee and S. Ghosh, Chem. Commun.,
1997, 2139.
3.62–3.49 (4 H, m, 7- and 9-H2), 1.90 (2 H, quintet, J8,7
=
J8,9 = 6.1, 8-H ); δ (50 MHz, CDCl ) 169.28 (C᎐O), 142.27 (1-
᎐
2
C
3
C), 139.66 (3-C), 134.37 (HC᎐CH ), 130.83, 127.97 (Ar), 116.88
᎐
2
(HC᎐CH ), 92.40 (CI), 71.84, 69.11 (9- and 10-C), 38.55 (7-C),
᎐
2
28.77 (8-C) (Found: C, 44.1; H, 4.6; N, 3.9. Calc. for C13H16-
INO2: C, 45.2; H, 4.7; N, 4.1%).
10 V. Snieckus, J. C. Cuevas and C. P. Sloan, J. Am. Chem. Soc., 1990,
112, 896.
11 A. N. Abeywickrema and A. L. Beckwith, J. Chem. Soc., Chem.
Commun., 1986, 464.
12 A. L. J. Beckwith and S. A. Glover, Aust. J. Chem., 1987, 40, 157.
13 A. L. J. Beckwith, V. W. Bowry and G. Moad, J. Org. Chem., 1988,
53, 1632.
14 A. L. J. Beckwith, K. Drok, B. Maillard, M. Degueil-Castaing and
A. Philippon, Chem. Commun., 1997, 499.
15 D. M. Hall, Carbohydr. Res., 1980, 86, 158.
16 R. C. Bernotas, Tetrahedron Lett., 1990, 31, 469.
17 D. J. Bell and J. Lorber, J. Chem. Soc., 1940, 453.
18 A. Kohn and R. R. Schmidt, Liebigs Ann. Chem., 1987, 1045.
19 S. Wmezawa, Y. Nishimura, Y. Hata and T. Tsuchiya, J. Antibiot.,
1974, 27, 722.
Radical cyclisation of compound 921
To a stirred, boiling solution of compound 9 (0.345 g, 1 mmol)
in nitrogen-saturated benzene (70 cm3) was added a solution of
Bu3SnH (0.42 cm3, 0.44 g, 1.5 mmol) and AIBN (0.01 g) in
nitrogen-saturated benzene (12 cm3) via an addition funnel
during 1 h. The reaction mixture was heated under reflux and
a nitrogen atmosphere for a further 1 h. Subsequent solvent
removal and column chromatography (hexane–ethyl acetate)
gave, successively, the uncyclised product 11 (hexane–ethyl
acetate 8:2; 0.19 g, 85%) and the lactam 10 (hexane–ethyl
acetate 3:7; 0.030 g, 14%).
The macrolactam 10 was obtained as a solid; mp 143–147 ЊC;
δH(400 MHz, CDCl3) 7.40 (1 H, d, J6,5 7.5, 6-H), 7.30 (1 H, m,
ArH), 7.21–7.17 (2 H, m, ArH), 6.17 (1 H, br s, NH), 3.66 (2 H,
t, J9,8 4.9, 9-H2), 3.61 (2 H, q, J7,NH = J7,8 = 5.8, 7-H2), 3.40 (2 H,
20 M. Vautier, N. Knouzi and R. Carrie, Tetrahedron Lett., 1983, 24,
763.
21 N. N. Marinovic and H. Ramanathan, Tetrahedron Lett., 1983, 24,
1871.
22 J. M. Berge and S. M. Roberts, Synthesis, 1979, 471.
23 N. A. Porter, J. Am. Chem. Soc., 1987, 109, 4976.
J. Chem. Soc., Perkin Trans. 1, 2000, 1853–1857
1857