Radical promoted cyclisations of trichloroacetamides with silyl enol ethers and enol acetates: The role of the hydride reagent [tris(trimethylsilyl)silane vs. tributylstannane]

Article abstract of DOI:10.1039/a900952c

Reactions between 1-(carbamoyl)dichloromethyl radicals and electron-rich alkenes acting as radical acceptors are reported for the first time. The intramolecular reaction of trichloroacetamides with silyl enol ethers gives ketones using (TMS)₃SiH as the mediator, and alcohols when using Bu₃SnH. The reaction with enol acetates gives acetates using either of the above hydride reagents. These radical processes have been applied to the synthesis of 2-azabicyclo[3.3.1]nonanes.

Full text of DOI:10.1039/a900952c

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Radical promoted cyclisations of trichloroacetamides with silyl
enol ethers and enol acetates: the role of the hydride reagent
[tris(trimethylsilyl)silane vs. tributylstannane]
Josefina Quirante, Carmen Escolano, Faïza Diaba and Josep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona,
08028-Barcelona, Spain
Received (in Cambridge) 3rd February 1999, Accepted 11th March 1999
Reactions between 1-(carbamoyl)dichloromethyl radicals and electron-rich alkenes acting as radical acceptors are
reported for the first time. The intramolecular reaction of trichloroacetamides with silyl enol ethers gives ketones using
(TMS)3SiH as the mediator, and alcohols when using Bu3SnH. The reaction with enol acetates gives acetates using
either of the above hydride reagents. These radical processes have been applied to the synthesis of 2-azabicyclo-
[3.3.1]nonanes.
the monoethylene acetal of cyclohexane-1,4-dione.12b We first
examined the behaviour of silyl enol ether 2, prepared in 87%
Introduction
In the last decade, carbocyclisation of 3-azacarbo radicals and
alkenes, with or without electron withdrawing groups, acting as
yield from cyclohexanone 1 by treatment with trimethylsilyl
iodide and hexamethyldisilazane18 (Scheme 1). When a solution
radical acceptors has emerged as a powerful tool in the building
of pyrrolidine or piperidine rings,1 the most usual way to con-
Bn
duct this reaction being the hydride method, working with
H
O
X
N
Bu3SnH (TBTH) or (Me3Si)3SiH (TTMSS) and a radical pre-
cursor.2 In contrast, the use of alkenes with electron releasing
groups in the construction of azacyclic derivatives has so far
received almost no attention.3 Moreover, although it is known
that electrophilic radicals react with silyl enol ethers,4–6 to our
knowledge7 there are only a few examples of radical cyclis-
ations promoted by hydride reagents and silyl enol ethers,8 or
related alkyl enol ethers9 or enol acetates.10
In this paper we report for the first time that trichloro-
acetamides as precursors of 1-(carbamoyl)dichloromethyl
radicals11–13 react with electron rich alkenes (Fig. 1) such as silyl
enol ethers and enol acetates, resulting in carbocyclisations that
lead to piperidine rings.14 We also study the different behaviour
of TTMSS and TBTH in these reactions.
Bn
N
Bn
N
ii
O
O
H
3, X = H, H
4, X = β-Cl, H
5, X = Cl, Cl
O
i
CCl3
CCl3
iii
Bn
N
O
OSiMe3
H
O
X
1
2
H
6, X = H, H
OH
7, X = β-Cl, H
8, X = Cl, Cl
From a synthetic standpoint, the radical cyclisation reported
here constitutes a new general approach to the synthesis of
2-azabicyclo[3.3.1]nonanes which allows the functionalization
at C-6, as occurs in many natural products that embody this
subunit, for example, the recently isolated marine alkaloids
sarains15 and mandangamines,16 or the novel immunosuppres-
sant FR-901483.17
Scheme 1 Reagents and conditions: i, TMSI, HMDS, Ϫ20 ЊC (87%);
ii, (TMS)3SiH, AlBN, benzene, reflux (69% for 3); iii, Bu3SnH, AlBN,
benzene, reflux (70% for 6).
of 2 in benzene was treated with TTMSS and AIBN at reflux
temperature, after work-up and chromatography, azabicyclic
dione 3 was isolated in 69% yield. The formation of 2-aza-
bicyclo[3.3.1]nonane-3,6-dione 3 directly from 2 is noteworthy,
since it constitutes an example of a new synthetic method for
the preparation of 1,4-dicarbonyl compounds (i.e. γ-keto-
amides). We suggest that the ketone carbonyl group comes from
the radical arising from the cyclization process, centered at C-6,
which may capture a chlorine atom (inter- or intramolecularly)
generating the α-chloro silyl ether followed by elimination of
trimethylchlorosilane (Scheme 2). If this is true, the reaction
should proceed with sub-stoichiometric amounts of TTMSS
since an atom transfer process occurs. Effectively, when the tri-
chloroacetamide was treated with only 0.25 equiv. of the hydride
reagent, cyclization still takes place (65% yield), the isolated
products being dichloro derivative 5 (43%) and monochloro
derivative 4 (22%). The results of other experiments involving
different quantities of TTMSS are depicted in Table 1.
Results and discussion
We have studied the radical cyclization of trichloroacetamides
with silyl enol ethers and enol acetates using trichloroacetamide
1 as the starting material, which is available in three steps from
N
O
N
O
N
O
Cl
Cl
• C
–
CH2
Ref. 11
This work
CH2
+
1-(Carbamoyl)dichloromethyl radicals
are ambiphilic
React with alkenes that have
withdrawing substituents
React with alkenes that have
donating substituents
The course of this radical cyclization can be explained by
the fact that the radical acceptor has a radical stabilizing
substituent (OSiMe3) that enables the radical I generated after
Fig. 1
J. Chem. Soc., Perkin Trans. 1, 1999, 1157–1162
1157

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Table 1 Radical cyclization of trichloroacetamide 2
Yield of individual compounds (%)
Overall
yield
Entry
Hydride
(Equiv.)
3
4
5
6
7
8
1
1
2
3
4
5
6
7
TTMSS
TTMSS
TTMSS
TTMSS
TBTH
TBTH
TBTH
3.5
0.5
0.25
0.15
4.5
3.5
1.2
69%
73%
65%
15%
70%
77%
77%
69
—
—
36
22
37
43
15
—
—
10
3
50
—
—
—
—
14
70
24
—
—
32
25
—
21
28
2
Bn
N
Bn
3
H
O
O
iv
N
ii or iii
i
Bn
N
Bn
Bn
N
1
CCl3
6
H
H
N
R
H
O
O
O
H
Cl
Cl
Cl
Cl
Cl
Cl
OAc
OAc
9
.
10 R = H
11 R = Cl
H
H
H
Cl
OSiMe3
OSiMe3
O
Scheme 3 Reagents and conditions: i, propen-2-yl acetate, TsOH,
reflux (85%); ii, (TMS)3SiH, AlBN, benzene, reflux (68% for 10);
iii, Bu3SnH, AlBN, benzene, reflux (56% for 10); iv, aqueous 2 M
NaOH, EtOH, reflux (92% from 10).
5
II
I
+ Me3SiCl
Scheme 2
the cyclization to survive and participate in an atom transfer
process. A plausible pathway for the formation of the ketone
carbonyl group in compounds 3–5 from the radical intermedi-
ate I is depicted in Scheme 2. This process implies that abstrac-
tion of a chlorine atom by the carbon radical occurs, either
from the starting material 2 or from (TMS)3SiCl, to give
α-chloro silyl ether II. Adduct II rapidly degrades to the ketone
carbonyl and trimethylchlorosilane, probably via a four-centre
type reaction,19 and as the affinity between silicon and chlorine
is strong, the reaction occurs very easily.20 An alternative path-
way for the formation of 5 without the intermediate II should
not be discarded.
When we used TBTH instead of TTMSS as the hydride
reagent to promote the radical cyclisation of 2 the end-products
differed. Thus, independent of the quantity of TBTH used
(from 4.5 to 0.25 equiv.) azabicyclic compounds containing a
hydroxy group were isolated in all cases, the synthetic condi-
tions using 4.5 equiv. being the best because they furnished
azabicyclo 6 as the sole compound in 70% overall yield after
cyclization and reduction. The equatorial disposition of the
hydroxy group at C-6 was easily deduced from the multiplicity
of H-6 (dt, J 11 and 5 Hz) in the 1H NMR spectrum of 6.
Use of TBTH in the above radical processes produced differ-
ent results probably because it is a better hydrogen atom donor
than TTMSS.21 The reaction course does not seem to proceed
through the azabicyclic ketone 5, because in separate experi-
ments 5 was not reduced to alcohol 8 when treated with
TBTH, either in radical or ionic conditions. In both cases, the
monochloro ketone 4 was isolated instead.22 The formation of
alcohols 6–8 when using TBTH can be explained, taking into
account their stereochemistry (only equatorial isomers were
isolated), by the reduction of the radical intermediate I which
generates a silyl ether23 that later undergoes an assisted
cleavage in the reaction medium.24
compound 10 (equatorial acetoxy group) was deduced from the
multiplicity (dt, J 11 and 4.5 Hz) of H-6ax. Additionally, the 13
C
NMR data are in agreement with this assignment. Further-
more, saponification of 10 produces the alcohol 6. The preferred
formation of this stereoisomer indicates that hydrogen atom
transfer from the hydride reagent to the α-acetoxy radical
intermediate occurs in an axial fashion, the kinetic mode for
such processes in cyclohexyl radicals.25
In order to explore the scope of this cyclization-type reaction
in the preparation of more complex compounds (e.g. indole
alkaloids), we examined the behaviour of the trichloro-
acetamides 13 and 15, which incorporate a tryptamine unit.
These radical precursors were obtained from 121a following the
procedures used to obtain 2 and 9, respectively, from 1 in
the N-benzyl series. Under the reaction conditions used for the
formation of enol acetate from indole ketone 12, acetylation
of NH-indole also took place, giving the acetylated indole
derivative 15 (Scheme 4). After radical cyclisation and the
CH2CH2Indolyl
O
N
i or ii
O
N
N
R
CCl3
O
CCl3
OR'
13, R = H, R' = SiMe3
15, R = R' = Ac
12
iii
H
H
13
O
O
N
N
N
H
14
H
H
We also studied the radical cyclization of enol acetate 9,
which was obtained by treatment of cyclohexanone 1 with
toluene-p-sulfonic acid and prop-2-enyl acetate. The treatment
of enol acetate 9 with TTMSS (3.5 equiv.) and AIBN under
reaction conditions identical to those used for 2, provided mor-
phan 10, as a single diastereoisomer in 68% yield (Scheme 3).
Thus, the reaction involves direct reduction of the acetoxy rad-
ical intermediate. When operating with TBTH the same result
was observed, although a small percentage of the monochloro
derivative 11 was isolated. The relative configuration at C-6 in
O
iii
15
N
Ac
16
OAc
Scheme 4 Reagents and conditions: i, trimethylsilyl iodide, HMDS,
Ϫ20 ЊC (85%); ii, propen-2-yl acetate, TsOH, reflux (56%); iii,
(TMS)3SiH, AlBN, benzene, reflux (58% for 14 and 60% for 16).
1158
J. Chem. Soc., Perkin Trans. 1, 1999, 1157–1162

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subsequent reductive process, using TTMSS under the same
reaction conditions as described above for the N-benzyl series,
azabicyclic systems 14 (60%) and 16 (58%) were isolated.
In conclusion, the results reported here not only expand the
usefulness of trichloroacetamides as starting materials for rad-
ical cyclisations but also enlarge the synthetic potential of silyl
enol ethers26 and enol acetates. The work outlined in this paper
allows 1-(carbamoyl)dichloromethyl radicals, derived from
the easily accessible trichloroacetamides, to be considered as
umpoled reagents,27 equivalent to α-carbonyl carbocations that
can react with electron-rich alkenes. This is therefore an excel-
lent method for conveniently synthesising 1,4-dicarbonyl
compounds (i.e. 3 and 14).
M, 243.1250); νmax/cmϪ1 1713, 1641; δH (COSY) 1.71 (1 H, tdd,
J 13.5, 5.5, 2.5, H-8ax), 1.99 (1 H, dm, J 13.5, H-9anti), 2.06 (1 H,
ddd, J 13, 6, 3, H-9syn), 2.13 (1 H, m, H-8eq), 2.28 (1 H, dd,
J 15.5, 5, H-7eq), 2.41 (1 H, ddd, J 16, 13, 7, H-7ax), 2.47 (1 H,
dd, J 17, 1.5, H-4eq), 2.74 (1 H, dd, J 17, 7.5, H-4ax), 2.76 (1 H,
m, H-5eq), 3.59 (1 H, m, W1/2 7,† H-1eq), 4.03 and 5.25 (each 1H,
2 d, J 15, CH2Ph), 7.20–7.30 (5 H, m, ArH); δC (HMQC)
29.9 (C-8), 32.3 (C-9), 34.0 (C-7), 35.0 (C-4), 44.2 (C-5),
48.4 (CH2Ph), 50.0 (C-1), 127.7, 127.9 and 128.8 (Ar), 137.1
(C-ipso), 168.3 (C-3), 210.7 (C-6).
Cyclisation of 2 with 0.5 equiv. of TTMSS
Operating as above, silyl enol ether 2 (250 mg, 0.57 mmol) in
benzene (5 cm3) was treated with AIBN (99 mg, 0.57 mmol)
and TTMSS (0.09 cm3, 0.28 mmol). The crude material was
chromatographed [hexane–AcOEt (1:1)]. The first eluate gave
2-benzyl-4,4-dichloro-2-azabicyclo[3.3.1]nonane-3,6-dione 5, (67
mg, 37%) as a white solid; mp 102–103 ЊC (from dichloro-
methane) (Found: Mϩ, 311.0468. C15H15Cl2NO2 requires M,
311.0479); νmax/cmϪ1 1720, 1660; δH 1.82 (1 H, m, H-8ax), 2.08
(1 H, ddd, J 14.5, 3.5, 2.5, H-9), 2.25 (1 H, dm, J 13, H-8eq),
2.44–2.56 (2 H, m, H-7), 2.76 (1 H, ddd, J 14.5, 6.5, 3.5, H-9),
3.57 (1 H, m, W1/2 7, H-5eq), 3.71 (1 H, m, W1/2 8, H-1eq), 4.10
and 5.37 (each 1 H, 2 d, J 15, CH2Ph), 7.20–7.40 (5 H, m, ArH);
δC 30.1 (C-8), 31.0 (C-9), 34.9 (C-7), 49.6 (CH2Ph), 51.1 (C-1),
62.9 (C-5), 81.2 (C-4), 127.8, 128.2 and 129.0 (Ar), 135.8
(C-ipso), 163.8 (C-3), 203.5 (C-6).
The second eluate gave (1RS,4SR,5RS)-2-benzyl-4-chloro-
2-azabicyclo[3.3.1]nonane-3,6-dione 4, (58 mg, 36%) as a white
solid; mp 129–130 ЊC (from dichloromethane) (Found: Mϩ,
277.0862. C15H16ClNO2 requires M, 277.0869); νmax/cmϪ1 1720,
1660; δH 1.79 (1 H, tdd, J 13.5, 5.5, 2.5, H-8ax), 2.10-2.21 (1 H,
m, H-9), 2.30 (1 H, ddd, J 13.5, 5.5, 2.5, H-8eq), 2.43 (1 H, dm,
J 15, H-7eq), 2.52 (1 H, ddd, J 15.5, 13.5, 6.5, H-7ax), 3.18 (1 H,
m, W1/2 13, H-5eq), 3.68 (1 H, m, W1/2 9, H-1eq), 4.18 and 5.26
(1 H each, 2 d, J 15, CH2Ph), 4.72 (1 H, d, J 7, H-4ax), 7.20–7.40
(5 H, m, ArH); δC 29.7 (C-8), 33.1 (C-9), 34.7 (C-7), 49.4
(CH2Ph), 50.8 (C-1), 52.1 (C-5), 55.1 (C-4), 128.0, 128.1 and
128.9 (Ar), 136.4 (C-ipso), 165.7 (C-3), 206.4 (C-6).
Experimental
1H and 13C NMR spectra were recorded at 300 and 50.3 MHz,
respectively, in chloroform-d1, unless otherwise stated. In add-
ition, 2D nuclear magnetic resonance COSY and HMQC
experiments were performed on a Varian XL-500 instrument.
Chemical shifts are reported as δ values (ppm) relative to
internal tetramethylsilane, and J values are given in Hz. Infra-
red spectra were recorded on a Nicolet 205 FT-IR spectrometer
as either an evaporated film or liquid film on sodium chloride
plates unless otherwise stated. Mass spectra were determined
on a Hewlett-Packard 5988 A mass spectrometer or on an
Autospec-VG (HRMS). TLC was performed on SiO2 (silica gel
60 F254, Merck). The spots were located by UV light and a 1%
KMnO4 solution or hexachloroplatinate reagent. Chrom-
atography refers to flash column chromatography and was
carried out on SiO2 (silica gel 60, SDS, 230–400 mesh). All
reactions were carried out under an argon or nitrogen atmos-
phere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Drying of organic extracts
during the work-up of reactions was performed over anhydrous
Na2SO4. Melting points were determined in a capillary tube
on a Büchi apparatus. Microanalyses were performed by the
“Centro de Investigación y Desarrollo” (CSIC), Barcelona.
N-Benzyl-2,2,2-trichloro-N-[4-(trimethylsilyloxy)cyclohex-3-
enyl]acetamide 2
Cyclisation of 2 with 0.25 equiv. of TTMSS
To a solution of ketone 1 (3.87 g, 10.7 mmol) in dichloro-
methane–pentane 1:1 (135 cm3) cooled at Ϫ20 ЊC, hexamethyl-
disilazane (6 cm3, 21.4 mmol) and iodotrimethylsilane (3.1 cm3,
21.4 mmol) were added dropwise. After stirring the reaction
mixture at Ϫ20 ЊC for 2 h, saturated aqueous sodium hydro-
gen carbonate (135 cm3) was added and the mixture stirred for
10 min. The dried organic phase was concentrated. The residue
was dissolved in dichloromethane and washed with saturated
aqueous sodium thiosulfate. The dried organic extracts were
concentrated to give 2 (4.66 g, 87%) as a yellow oil, which was
used without further purification in the next step (Found: C,
51.4; H, 5.7; N, 3.3; Cl, 25.7. C18H24Cl3NO2Si requires C, 51.4;
H, 5.75; N, 3.3; Cl, 25.3%); νmax/cmϪ1 1677; δH 0.2 (9 H, s, CH3),
1.85–2.40 (6 H, m), 4.56 and 4.69 (each 1 H, 2 d, J 15.5,
CH2Ph), 4.76 (2 H, m, H-1ax and H-3), 7.15–7.40 (5 H, m,
ArH); δC 0.2 (CH3), 27.2, 27.2 and 29.6 (C-2, C-5 and C-6), 47.8
(CH2Ph), 55.8 (C-1), 93.6 (CCl3), 101.0 (C-3), 126.0, 126.9 and
128.5 (Ar), 137.3 (C-ipso), 149.6 (C-4), 160.8 (CO).
Operating as above, silyl enol ether 2 (250 mg, 0.57 mmol) in
benzene (5 cm3) was treated with AIBN (93 mg, 0.57 mmol) and
TTMSS (0.05 cm3, 0.15 mmol), and the crude material was
chromatographed [dichloromethane–MeOH (99.5:0.5)]. The
first fraction gave ketone 1 (7 mg, 3%), the second gave 5 (77
mg, 43%) and the third gave 4 (35 mg, 22%).
(1RS,5SR,6SR)-2-Benzyl-6-hydroxy-2-azabicyclo[3.3.1] nonan-
3-one 6
A suspension of silyl enol ether 2 (500 mg, 1.19 mmol) and
AIBN (207 mg, 1.26 mmol) in benzene (10 cm3) was heated to
reflux. Then, TBTH (1.44 cm3, 5.35 mmol) was added dropwise
and the reaction mixture was stirred at this temperature for 3 h.
After evaporation of the solvent, the residue was chromato-
graphed [dichloromethane–MeOH (96:4)] to give 6 (200 mg,
70%) as a white solid (Found: Mϩ, 245.1415. C15H19NO2
requires M, 245.1420); νmax/cmϪ1 1616; δH 1.47–1.57 (5 H, m),
1.90 (1 H, dm, J 13, H-9), 2.27 (1 H, m, W1/2 13, H-5eq), 2.46
(1 H, dd, J 18.5, 7, H-4ax), 2.82 (1 H, d, J 18.5, H-4eq), 3.38 (1 H,
m, W1/2 8, H-1eq), 3.75 (1 H, dt, J 11, 5, H-6ax), 3.89 and 5.24
(each 1 H, 2 d, J 15, CH2Ph), 7.20–7.40 (5 H, m, ArH); δC 25.2
(C-7), 27.4 (C-8), 30.3 and 30.4 (C-9 and C-4), 33.5 (C-5), 47.8
(CH2Ph), 49.9 (C-1), 70.3 (C-6), 126.9, 127.3 and 128.2 (Ar),
137.1 (C-ipso), 171.2 (C-3).
2-Benzyl-2-azabicyclo[3.3.1]nonane-3,6-dione 3
A suspension of silyl enol ether 2 (300 mg, 0.71 mmol) and
AIBN (123 mg, 0.75 mmol) in benzene (6 cm3) was heated to
reflux. Then, TTMSS (0.76 cm3, 2.48 mmol) was added drop-
wise and the reaction mixture was stirred at this temperature for
3 h. Evaporation of the solvent and chromatography of the
residue [dichloromethane–MeOH (99:1)] gave 3 (120 mg, 69%)
as a colourless oil (Found: Mϩ, 243.1249. C15H17NO2 requires
† W1/2 is the width at half maximum height of the signal.
J. Chem. Soc., Perkin Trans. 1, 1999, 1157–1162
1159

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Cyclisation of 2 with 3.5 equiv. of TBTH
(1 H, dd, J 18.5, 7, H-4ax), 2.75 (1 H, dt, J 19, 1, H-4eq), 3.44
(1 H, br s, H-1eq), 4.85 (1 H, dt, J 11, 4.5, H-6ax), 3.93 and
5.26 (each 1 H, 2 d, J 15, CH2Ph), 7.24–7.34 (5 H, m, ArH);
δC (HMQC) 21.2 (CH3), 22.3 (C-7), 27.6 (C-8), 30.8 (C-9), 31.3
(C-5), 31.5 (C-4), 48.1 (CH2Ph), 49.9 (C-1), 73.3 (C-6), 127.3,
127.7 and 128,5 (Ar), 137.4 (C-ipso), 170.3 and 170.4 (C-3 and
CO).
Operating as above, silyl enol ether 2 (500 mg, 1.19 mmol) in
benzene (10 cm3) was treated with AIBN (207 mg, 1.26 mmol)
and TBTH (1.12 cm3, 4.16 mmol), and the crude material was
chromatographed [dichloromethane–MeOH (96:4)]. The first
fraction gave (1RS,5RS,6SR)-2-benzyl-4,4-dichloro-6-hydroxy-
2-azabicyclo[3.3.1]nonan-3-one 8 (80 mg, 21%) as a white solid,
mp 121–123 ЊC (from dichloromethane) (Found: C, 57.3; H,
5.6; N, 4.4. C15H17Cl2NO2 requires C, 57.3; H, 5.45; N, 4.45%);
νmax(KBr)/cmϪ1 3598, 1671; δH 1.45–1.65 (2 H, m), 1.72 (1 H,
dm, 1H), 1.85–2.05 (2 H, m), 2.64 (1 H, ddd, J 14, 6, 3, H-9),
3.17 (1 H, m, W1/2 8, H-5eq), 3.46 (1 H, br s, H-1eq), 3.86–3.93
(1 H, m, H-6ax), 3.90 and 5.33 (each 1 H, 2 d, J 15, CH2Ph),
7.20–7.40 (5 H, m, ArH); δC 26.4 (C-7), 28.0 (C-8), 31.0 (C-9),
49.2 (CH2Ph), 50.9 (C-1), 51.4 (C-5), 73.7 (C-6), 86.1 (C-4),
127.6, 127.8 and 128.8 (Ar), 136.0 (C-ipso), 164.6 (C-3).
The second fraction gave (1RS,4SR,5RS,6SR)-2-benzyl-
4-chloro-6-hydroxy-2-azabicyclo[3.3.1]nonan-3-one 7 (108 mg,
32%) as an oil (Found: C, 60.8; H, 6.55; N, 4.55. C15H18-
ClNO2ؒH2O requires: C, 60.5; H, 6.75; N, 4.7%); νmax/cmϪ1
3700, 1653; δH 1.48 (1 H, m, H-8ax), 1.60–2.12 (5 H, m), 2.89
(1 H, m, W1/2 11, H-5eq), 3.43 (1 H, m, W1/2 8, H-1eq), 3.83 (1 H,
dt, J 12, 3.5, H-6ax), 4.88 (1 H, d, J 6.5, H-4ax), 3.96 and 5.27
(each 1 H, 2 d, J 15, CH2Ph), 7.24–7.37 (5 H, m, ArH); δC 26.7
(C-7), 27.6 (C-8), 33.1 (C-9), 40.1 (C-5), 49.0 (CH2Ph), 50.6
(C-1), 58.9 (C-4), 74.5 (C-6), 127.6, 127.9 and 128.6 (Ar), 136.6
(C-ipso), 166.7 (C-3).
Conversion of 10 to 6
Aqueous sodium hydroxide (2 M, 25 cm3) was added to the
acetate 10 (500 mg, 1.74 mmol) in ethanol (25 cm3) and the
reaction mixture was heated at reflux temperature for 16 h. The
ethanol was evaporated and the resulting aqueous phase was
extracted with dichloromethane. Concentration of the dried
organic extracts gave the alcohol 6 (392 mg, 92%).
Cyclisation of 9 using TBTH
Following the procedure outlined for the cyclisation of 2, the
enol acetate 9 (230 mg, 0.64 mmol) was treated with TBTH
(0.59 cm3, 2.24 mmol) and AIBN. After work-up, the crude
material was chromatographed [hexane–AcOEt (1:9)]. The first
fraction gave (1RS,4SR,5RS,6SR)-6-acetoxy-2-benzyl-4-chloro-
2-azabicyclo[3.3.1]nonan-3-one 11 (27 mg, 13%) as an oil
(Found: Mϩ, 321.0865. C17H20ClNO3 requires M, 321.0871);
νmax/cmϪ1 1729, 1656; δH 1.53 (1 H, m, H-8ax), 1.8–2.2 (5 H, m),
2.07 (3 H, s, CH3), 3.03 (1 H, m, W1/2 10, H-5eq), 3.47 (1 H, br s,
H-1eq), 4.74 (1 H, d, J 5, H-4ax), 4.94 (1 H, m, H-6ax), 3.97 and
5.27 (each 1 H, 2 d, J 15, CH2Ph), 7.23–7.36 (5 H, m, ArH); δC
21.3 (CH3), 22.5 (C-7), 27.3 (C-8), 32.4 (C-9), 37.4 (C-5), 48.9
(CH2Ph), 50.6 (C-1), 57.1 (C-4), 74.0 (C-6), 127.6, 127.9 and
128.6 (Ar), 136.7 (C-ipso), 167.1 (C-3), 170.6 (CO).
The third fraction gave 6 (68 mg, 24%).
Cyclization of 2 with 1.2 equiv. of TBTH
Operating as above, silyl enol ether 2 (500 mg, 1.19 mmol) in
benzene (10 cm3) was treated with AIBN (207 mg, 1.26 mmol)
and TBTH (0.38 cm3, 1.43 mmol), and the crude material was
chromatographed [hexane–AcOEt (30:70)]. The initial elution
gave 5 (38 mg, 10%). Further elution gave 4 (45 mg, 14%), 8
(100 mg, 28%) and 7 (90 mg, 25%).
The second fraction gave the acetate 10 (104 mg, 56%).
2,2,2-Trichloro-N-[2-(indol-3-yl)ethyl]-N-[4-(trimethylsilyloxy)-
cyclohex-3-enyl]acetamide 13
Following the procedure outlined for the synthesis of the silyl
enol ether 2, ketone 12 (500 mg, 1.23 mmol) gave the title com-
pound 13 (500 mg, 85%) as a yellow solid which was used with-
out purification in the next step (Found: C, 52.8; H, 5.8; Cl,
23.3; N, 5.9. C21H27Cl3NO2Si requires: C, 53.2; H, 5.9; Cl, 23.45;
N, 5.9%); νmax/cmϪ1 1670; δH 0.24 (9 H, s, CH3), 1.85–2.45 (6 H,
m), 3.11 and 3.55 (each 2 H, 2 m, AAЈBBЈ system, InCH2-
CH2N), 4.64 (1 H, m, H-1Јax), 4.82 (1 H, m, W1/2 10, H-3Ј), 7.0
(1 H, s, H-2), 7.15 (1 H, t, J 7, H-5), 7.20 (1 H, t, J 7, H-6), 7.35
(1 H, d, J 8, H-7), 7.78 (1 H, d, J 7.5, H-4), 8.31 (1 H, br s, NH);
δC 0.2 (CH3), 23.8 (InCH2), 26.7 and 29.5 (C-2Ј, C-5Ј and C-6Ј),
46.1 (CH2N), 55.3 (C-1Ј), 93.7 (CCl3), 101.0 (C-3Ј), 111.1 (C-7),
112.3 (C-3), 118.8 (C-4), 119.2 (C-5), 121.8 (C-6), 122.1 (C-2),
127.1 (C-3a), 136.1 (C-7a), 149.5 (C-4Ј), 160.1 (CO).
N-(4-Acetoxycyclohex-3-enyl)-N-benzyl-2,2,2-trichloroacet-
amide 9
A solution of ketone 1 (3 g, 8.6 mmol) and toluene-p-sulfonic
acid (205 mg, 1.08 mmol) in prop-2-enyl acetate (30.7 cm3, 278
mmol) was heated at reflux for 24 h. The mixture was cooled
and sodium hydrogen carbonate was added. After filtration
of the solid, the solvent was evaporated and the residue was
chromatographed on alumina (dichloromethane) to give 9 (2.86
g, 85%) as a clear oil; νmax/cmϪ1 1756, 1676; δH 1.80–2.50 (6 H,
m), 2.10 (3 H, s, CH3), 4.55 and 4.73 (each 1 H, 2 d, J 16,
CH2Ar), 4.82 (1 H, m, H-1ax), 5.30 (1 H, br s H-3), 7.10–7.45
(5 H, m, ArH); δC 20.8 (CH3), 26.5 and 26.8 (C-2, C-5 and C-6),
47.6 (CH2Ph), 55.0 (C-1), 93.4 (CCl3), 111.5 (C-3), 125.9, 126.9
and 128.4 (Ar), 137.0 (C-ipso), 147.1 (C-4), 160.6 (NCO), 169.0
(CO).
2-[2-(Indol-3-yl)]ethyl]-2-azabicyclo[3.3.1]nonane-3,6-dione 14
A suspension of silyl enol ether 13 (200 mg, 0.42 mmol) and
AIBN (73 mg, 0.44 mmol) in benzene (3.5 cm3) was heated to
reflux. Then TTMSS (0.45 cm3, 1.47 mmol) was added drop-
wise and the reaction mixture was stirred at this temperature for
3 h. After evaporation of the solvent the residue was chromato-
graphed [dichloromethane–MeOH (99:1)] to give 14 (72 mg,
58%) as a white solid (Found: C, 69.7; H, 6.9; N, 9.0.
C18H20N2O2ؒ3/4 H2O requires C, 69.8; H, 7.0; N, 9.05%); νmax
(KBr)/cmϪ1 3404, 1712, 1620; δH (COSY) 1.72 (1 H, tdd, J 13.5,
5.5, 2, H-8ax), 1.86–1.87 (2 H, each apparent s, H-9), 2.16 (1 H,
dm, J 13, H-8eq), 2.31 (1 H, dd, J 16, 5, H-7eq), 2.41 (1 H, ddd,
J 16, 13, 7, H-7ax), 2.44 (1 H, d, J 17.5, H-4eq), 2.70 (1 H, dd,
J 18, 8, H-4ax), 2.73 (1 H, br s, H-5eq), 3.06–3.23 (m, 3 H, NCH
and InCH2), 3.39 (1 H, m, W1/2 8, H-1eq), 4.25 (1 H, m, NCH),
7.07 (1 H, d, J 2, H-2Ј), 7.13 (1 H, td, J 8, 1, H-5Ј), 7.20 (1 H, td,
J 8, 1, H-6Ј), 7.37 (1 H, d, J 8, H-7Ј), 7.66 (1 H, d, J 8, H-4Ј),
8.08 (1 H, br s, NH); δC (HMQC) 23.6 (InCH2), 30.4 (C-8), 31.9
(1RS,5SR,6SR)-6-Acetoxy-2-benzyl-2-azabicyclo[3.3.1] nonan-
3-one 10
A suspension of enol acetate 9 (2.23 g, 5.71 mmol) and AIBN
(975 mg, 5.93 mmol) in benzene (46 cm3) was heated to reflux.
Then, TTMSS (6.13 cm3, 19.8 mmol) was added dropwise and
the reaction mixture was stirred at this temperature for 3 h.
After evaporation of the solvent, the residue was chromato-
graphed [dichloromethane–MeOH (98:2)] to give 10 (1.11 g,
68%) as a white solid, mp 146–147 ЊC (from ether) (Found: C,
71.0; H, 7.4; N, 4.9. C17H21NO3 requires C, 71.05; H, 7.4; N,
4.9%); νmax (KBr)/cmϪ1 1731, 1639; δH (500 MHz, COSY) 1.46
(1 H, tdd, J 13, 3.5, 2, H-8ax), 1.53 (1 H, qd, J 13.5, 4.5, H-7ax),
1.74 (1 H, ddd, J 13.5, 5, 3, H-9anti), 1.83 (1 H, dm, J 12, H-7eq),
1.86 (1 H, dm, J 12, H-8eq), 1.95 (1 H, ddd, J 13.5, 7, 3.5,
H-9syn), 2.05 (3 H, s, CH3), 2.39 (1 H, m, W1/2 13, H-5eq), 2.54
1160
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2 For some starting materials leading to a radical centre at the
(C-9), 33.9 (C-7), 35.1 (C-4), 44.1 (C-5), 47.8 (CH2N), 52.0
(C-1), 111.2 (C-7Ј), 113.0 (C-3Ј), 118.7 (C-4Ј), 119.4 (C-5Ј),
121.9 (C-6Ј), 122.1 (C-2Ј), 127.4 (C-3a), 136.2 (C-7a), 168.1 (C-
3), 211.1 (C-6).
β-position to a nitrogen atom (3-azacarbon radicals) using the
hydride method, see inter alia: S. J. Danishefsky and J. S. Panek,
J. Am. Chem. Soc., 1987, 109, 917; Y. Watanabe, Y. Ueno, C.
Tanaka, M. Okawara and T. Endo, Tetrahedron Lett., 1987, 28, 3953;
G. Stork and R. Mah, Heterocycles, 1989, 28, 723; H. Ishibashi,
T. S. So, K. Okochi, T. Sato, N. Nakamura, H. Nakatani and
M. Ikeda, J. Org. Chem., 1991, 56, 95; P. F. Keusenkothen and
M. B. Smith, Tetrahedron, 1992, 48, 2977; M. Ishizaki, K. Kurihara,
E. Tanazawa and O. Hoshino, J. Chem. Soc., Perkin Trans. 1, 1993,
101; E. W. Della and A. M. Knill, J. Org. Chem., 1996, 61, 7529;
A. F. Parsons and R. M. Pettifer, Tetrahedron Lett., 1997, 38, 5907;
V. Gupta, M. Besev and L. Engman, Tetrahedron Lett., 1998, 39,
2429.
3 For examples of the use of (alkoxy)methoxyalkenes as radical
acceptors of 3-azaradicals, see: S. Knapp and F. S. Gibson, J. Org.
Chem., 1992, 57, 4802.
4 (a) For this intermolecular process mediated by a tin hydride, see:
B. Giese, H. Horler and M. Leising, Chem. Ber., 1986, 119, 444;
P. Renaud, Tetrahedron Lett., 1990, 31, 4601; (b) for addition of acyl
radicals to silyl enol ethers, see: D. L. Boger and R. J. Mathvink,
J. Org. Chem., 1992, 57, 1429.
5 For procedures to promote additions of electrophilic radicals to silyl
enol ethers other than the hydride method, see: (a) an oxidative
process, E. Baciocchi, A. Casu and R. Ruzziconi, Synlett, 1990,
679; Y. Kohno and K. Narasaka, Chem. Lett., 1993, 1689; (b) the
atom transfer method, K. Miura, Y. Takeyama, K. Oshima and
K. Utimoto, Bull. Chem. Soc. Jpn., 1991, 64, 1542; (c) thiol-
catalysed addition of aldehydes, H.-S. Dang and B. P. Roberts,
Chem. Commun., 1996, 2201; (d) photo-irradation, M. Mitani and
H. Sakata, Chem. Commun., 1998, 1877.
N-(4-Acetoxycyclohex-3-enyl)-N-[2-(1-acetylindol-3-yl)ethyl]-
2,2,2-trichloroacetamide 15
Following the procedure outlined above for the synthesis of the
enol acetate 9, the ketone 12 (3 g, 7.3 mmol) gave, after chroma-
tography on alumina (dichloromethane), the title compound 15
(3.5 g, 56%) as an oil, which solidified on standing: mp 178.5–
179 ЊC (in ether) (Found: Mϩ, 484.0723. C22H23Cl3N2O4
requires M, 484.0730) (Found: C, 53.05; H, 4.6; N, 5.5.
C22H23Cl3N2O4ؒ1/2H2O requires C, 53.4; H, 4.9; N, 5.65%);
νmax/cmϪ1 1754, 1704, 1681; δH (COSY): 2.00 (1 H, m, H-6Јeq),
2.03 (1 H, qd, J 12.5, 6, H-6Јax), 2.14 (3 H, s, CH3), 2.26 (1 H,
dm, J 13.5, H-5Јeq), 2.32–2.51 (3 H, m, H-2Ј and H-5Јax), 2.63
(3 H, s, CH3CON), 3.06 and 3.56 (each 2 H, 2 m, AAЈBBЈ
system, InCH2CH2N), 4.70 (1 H, m, H-1Јax), 5.34 (1 H, m,
W1/210.5, H-3Ј), 7.27 (1 H, br s, H-2), 7.33 (1 H, td, J 7.5, 0.5,
H-5), 7.38 (1 H, t, J 7.5, H-6), 7.73 (1 H, d, J 8, H-4), 8.43 (1 H,
br d, J 8, H-7); δC (HMQC) 21.0 (CH3), 23.6 (InCH2), 24.0
(CH3CON), 26.4 and 26.5 (C-2Ј, C-5Ј and C-6Ј), 45.3 (CH2N),
54.7 (C-1Ј), 93.5 (CCl3), 111.7 (C-3Ј), 116.6 (C-7), 119.1 (C-4
and C-3), 122.7 (C-2), 123.7 (C-5), 125.4 (C-6), 130.1 (C-3a),
135.8 (C-7a), 147.3 (C-4Ј), 160.3 (NCO), 168.3 and 169.3 (CO).
6 It has been noted that nucleophilic alkyl radicals do not react with
silyl enol ethers: H. Urabe and I. Kuwajima, Tetrahedron Lett., 1986,
27, 1355.
7 For a review on radical cyclisation reactions, see: B. Giese,
B. Kopping, T. Göbel, J. Dickhaut, G. Thoma, K. J. Kulicke and
F. Trach, Org. React., 1996, 48, 301.
(1RS,5SR,6SR)-6-Acetoxy-2-[2-(1-acetylindol-3-yl)ethyl]-2-
azabicyclo[3.3.1]nonan-3-one 16
A suspension of enol acetate 15 (1.5 g, 3.08 mmol) and AIBN
(537 mg, 3.57 mmol) in benzene (27 cm3) was heated to reflux.
Then, TTMSS (3.6 cm3, 10.8 mmol) was added dropwise and
the reaction mixture was stirred at this temperature for 3 h.
After evaporation of the solvent the residue was chromato-
graphed [dichloromethane–MeOH (98:2)] to give 16 (690 mg,
60%) as a white solid: mp 113–113.5 ЊC (from ether) (Found,
Mϩ, 382.1892. C22H26N2O4 requires M, 382.1882) (Found: C,
67.6; H, 7.1; N, 7.1. C22H26N2O4ؒ1/2H2O requires C, 67.5; H,
6.95; N, 7.15%); νmax/cmϪ1 1731, 1704, 1633; δH (COSY) 1.46
(1 H, qd, J 13.5, 3.5, H-7ax), 1.48 (1 H, tm, J 13.5, H-8ax), 1.66
8 For references on (a) carbocyclic series, see ref. 6; (b) 1-oxa-2-
silacyclohexanes, see R. D. Walkup, R. R. Kane and N. U.
Obeyesekere, Tetrahedron Lett., 1990, 31, 1531; for related
heterocyclic compounds: J. H. Hutchinson, T. S. Daynard and
J. W. Gillard, Tetrahedron Lett., 1991, 32, 573; A. G. Myers, D. Y.
Gin and D. H. Rogers, J. Am. Chem. Soc., 1993, 115, 2036.
9 (a) For cyclisations of alkyl radicals with enol ethers, see: A. L. J.
Beckwith and D. H. Roberts, J. Am. Chem. Soc., 1986, 108, 5893;
T. V. RajanBabu, T. Fukunaga and G. S. Reddy, J. Am. Chem. Soc.,
1989, 111, 1759; J.-C. Lopez and B. Fraser-Reid, J. Am. Chem.
Soc., 1989, 111, 3450; J. Marco-Contelles and B. Sánchez, J. Org.
Chem., 1993, 58, 4293; C. Imboden, T. Bourquard, O. Corminboeuf,
P. Renaud, K. Schenk and M. Zahouily, Tetrahedron Lett., 1999, 40,
495; (b) for cyclisations with aryl radicals, see: S. Atarashi, J.-K.
Choi, D.-C. Ha, D. J. Hart, D. Kuzmich, C.-S. Lee, S. Ramesh and
S. C. Wu, J. Am. Chem. Soc., 1997, 119, 6226; (c) for cyclisations
with acyl radicals, see ref. 4b.
10 (a) For cyclisations of stabilized radicals with enol acetates, see:
F. Barth and C. O-Yang, Tetrahedron Lett., 1991, 32, 5873; (b) for
cyclisations from aryl radicals, see: S. A. Ahmad-Junan and D. A.
Whiting, J. Chem. Soc., Chem. Commun., 1988, 1160.
11 For hydride reagent promoted radical cyclisations of
trichloroacetamides with alkenes with an electron-withdrawing
substituent, see: (a) Y. Hirai, A. Hagiwara, T. Terada and
T. Yamazaki, Chem. Lett., 1987, 2417; (b) A. F. Parsons and R. J. K.
Taylor, J. Chem. Soc., Perkin Trans. 1, 1994, 1945; (c) K. Goodall
and A. F. Parsons, Tetrahedron, 1996, 52, 6739; (d) J. Quirante,
C. Escolano, M. Massot and J. Bonjoch, Tetrahedron, 1997, 53,
1391.
12 For hydride reagent promoted radical cyclisations of trichloro-
acetamides with non-activated alkenes, see: (a) H. Nagashima,
N. Ozaki, M. Ishii, K. Seki, M. Washiyama and K. Itoh, J. Org.
Chem., 1993, 58, 464; (b) J. Quirante, C. Escolano, F. Diaba and
J. Bonjoch, Heterocycles, 1999, 50, in the press.
13 For hydride reagent promoted radical cyclisations of N-vinylic
trichloroacetamides, see: H. Ishibashi, M. Higuchi, M. Ohba and
M. Ikeda, Tetrahedron Lett., 1998, 39, 75; M. Ikeda, S. Ohtani,
T. Yamamoto, T. Sato and H. Ishibashi, J. Chem. Soc., Perkin Trans
1, 1998, 1763.
14 For a preliminary report of part of this work, see: J. Quirante,
C. Escolano, L. Costejà and J. Bonjoch, Tetrahedron Lett., 1997, 38,
6901.
15 (a) Y.-W. Guo, A. Madaio, G. Scognamiglio and E. Trivellone,
Tetrahedron, 1996, 52, 8341; (b) R. Downham, F. W. Ng and L. E.
Overman, J. Org. Chem., 1998, 63, 8096.
(1 H, ddd, J 13.5, 3.5, 2.5, H-9anti), 1.76–1.89 (3 H, m, H-9syn
,
H-7eq and H-8eq), 1.93 (3 H, s, CH3), 2.27 (1 H, m, W1/2 13.5,
H-5eq), 2.37 (1 H, dd, J 18.5, 7, H-4ax), 2.50 (3 H, s, NCOCH3),
2.61 (1 H, dd, J 19, 1.5, H-4eq), 2.88–3.05 (3 H, m, NCH and
InCH2), 3.27 (1 H, br s, H-1eq), 4.09–4.17 (1 H, m, NCH), 4.80
(1 H, dt, J 11.5, 5, H-6ax), 7.29 (1 H, td, J 7.5, 1, H-5Ј), 7.32
(1 H, s, H-2Ј), 7.34 (1 H, td, J 7.5, 1, H-6Ј), 7.59 (1 H, d, J 7.5,
H-4Ј), 8.40 (1 H, d, J 6.5, H-7Ј); δC (HMQC) 21.2 (CH3), 22.1
(C-7), 23.4 (InCH2), 24.0 (CH3CON), 28.2 (C-8), 30.6 (C-9),
31.1 (C-5), 31.6 (C-4), 46.5 (CH2N), 51.9 (C-1), 73.2 (C-6),
116.6 (C-7Ј), 118.8 (C-4Ј), 119.7 (C-3Ј), 122.5 (C-2Ј), 123.5
(C-5Ј), 125.3 (C-6Ј), 130.3 (C-3a), 135.7 (C-7a), 168.3 (NCO),
170.3 and 170.4 (C-3 and CO).
Acknowledgements
Support for this research was provided by DGES, Spain (pro-
ject PB97-0877). Thanks are also due to “Comissionat per a
Universitats i Recerca” (Catalonia) for Grant 1997SGR-00166
and for a fellowship to C. E.
Notes and references
1 For recent examples in natural product synthesis, see: (a) J.
Quirante, C. Escolano, A. Merino and J. Bonjoch, J. Org. Chem.,
1998, 63, 968; (b) L. Boiteau, J. Boivin, A. Liard, B. Quiclet-Sire and
S. Z. Zard, Angew. Chem., Int. Ed., 1998, 37, 1128; (c) M. Ikeda,
M. Hamada, T. Yamashita, F. Ikegami, T. Sato and H. Ishibashi,
Synlett, 1998, 1246; (d) M. Ikeda, T. Sato and H. Ishibashi, Rev.
Heteroatom Chem., 1998, 18, 169.
J. Chem. Soc., Perkin Trans. 1, 1999, 1157–1162
1161

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16 (a) F. Kong, R. J. Andersen and T. M. Allen, J. Am. Chem. Soc.,
1994, 116, 6007; (b) N. Matzanke, R. J. Gregg and S. M. Weinreb,
J. Org. Chem., 1997, 62, 1920.
percentatge of ketones 4 and 5 are isolated, suggesting that a
competitive mechanism, similar to that depicted in Scheme 2, is also
operating.
17 K. Sakamoto, E. Tsujii, F. Abe, T. Nakanishi, M. Yamashita, N.
Shigematsu, S. Izumi and M. Okuhara, J. Antibiot., 1996, 49, 37.
18 R. D. Miller and D. R. McKean, Synthesis, 1979, 730.
19 For a related process catalysed by a ruthenium() phosphine
complex, see: N. Kamigata, K. Udodaira and T. Shimizu, J. Chem.
Soc., Perkin Trans. 1, 1997, 783.
24 (a) The direct formation of alcohols in reactions promoted by
TBTH and silyl enol ethers has not previously been noted, see refs. 4
and 8; (b) for a simple reduction of α-silyloxyl radicals by TBTH,
see: S.-Y. Chang, W.-T. Jiaang, C.-D. Cherng, K.-H. Tang, C.-H.
Huang and Y.-M. Tsai, J. Org. Chem., 1997, 62, 9089.
25 D. P. Curran, N. A. Porte and B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996; W. Damm, B. Giese, J. Hartung,
T. Hasskerl, K. N. Houk, O. Hüter and H. Zipse, J. Am. Chem. Soc.,
1992, 114, 4067.
20 The great strength of the Si–Cl bond in Me3SiCl (112 kcal molϪ1
can drive the process.
)
21 C. Chatgilialoglu, J. Dickhaut and B. Giese, J. Org. Chem., 1991, 56,
6399.
26 J. Burfeindt, M. Patz, M. Müller and H. Mayr, J. Am. Chem. Soc.,
1998, 120, 3629 and refs. therein.
27 D. P. Curran, Synlett, 1991, 63.
22 Attempts to reduce ketone 3 were also unsuccessful when working
with TBTH–AIBN, alone, with tributylchlorostannane or with
trimethylchlorosilane in the reaction medium.
Paper 9/00952C
23 When the ratio of TBTH is low (see Table 1) a significant
1162
J. Chem. Soc., Perkin Trans. 1, 1999, 1157–1162