Synthesis of polycyclic lactams and sultams by a cascade ring-closure metathesis/isomerization and subsequent radical cyclization

Article abstract of DOI:10.1055/s-2005-862386

Starting from readily available substrates, a new one-pot procedure has been devised to prepare polycyclic lactams and sultams. 2-Pyrrolines obtained from N,N-bisallylamides by ring-closure metathesis and subsequent isomerization promoted by ruthenium hyd

Full text of DOI:10.1055/s-2005-862386

LETTER
577
Synthesis of Polycyclic Lactams and Sultams by a Cascade Ring-Closure
Metathesis/Isomerization and Subsequent Radical Cyclization
S
ynthesis of Poly
y
cyclic Lacta
r
m
s
and
S
i
ultamsl Bressy, Christine Menant, Olivier Piva*
Université Claude Bernard LYON I, UMR 5181 CNRS, Laboratoire de Chimie Organique-Photochimie et Synthèse, Bat Raulin,
43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72448136; E-mail: piva@univ-lyon1.fr
Received 24 November 2004
polycyclic structures from dienes easily available from
RCM of enynes.4,5
Abstract: Starting from readily available substrates, a new one-pot
procedure has been devised to prepare polycyclic lactams and sul-
tams. 2-Pyrrolines obtained from N,N-bisallylamides by ring-clo-
sure metathesis and subsequent isomerization promoted by
ruthenium hydride complexes can undergo radical cyclization to
furnish polycyclic lactams in good yields. The process was success-
fully conducted on bisallylsulfonamides to give the corresponding
sultams.
In connection with our interest in metathesis reactions,11
we have explored a new approach to polycyclic aza com-
pounds by using a RCM process combined with a subse-
quent radical cyclization an overall process which has
been to date scarcely investigated.12 The overall strategy
is depicted in Scheme 1.
Key words: polycyclic lactams, 2-pyrrolines, ring-closure meta-
thesis
EWG
EWG
( )
n
N
( )
N
n
The discovery of powerful ruthenium and molybdenum
catalysts has considerably improved the scope of metathe-
sis. Ring-closure reactions (RCM) considered nowadays
as a cornerstone to prepare cyclic alkenes have been deep-
ly studied and fruitfully applied to the synthesis of numer-
ous natural products.1–5 The success of these strategies is
also connected to the tolerance of the catalysts to a wide
number of functionalities present on the substrates. Even
Br
n
( )
EWG
EWG
( )
n
N
N
Br
Br
sulfur derivatives which commonly interfere in a number Scheme 1 Retrosynthetic analysis for the preparation of aza poly-
cyclic compounds from bromoarylamides and sulfonamides
of organometallic processes have been converted into
cyclized products under RCM conditions.6
As already pointed out, the presence of an electron-with-
drawing group (EWG) like a sulfonamide or an amide
group is essential for the success of the first process. After
migration of the new carbon-carbon double bond, the
homolytic cleavage of the C-Br bond was expected to
generate a free radical, which could interact with the
enamino subunit. By this way, fused polycyclic aza com-
pounds 4 could be prepared from easily available starting
materials 1. There are some precedents for migration of
double bonds under metathesis conditions.13 For example,
Snapper et al. have performed a related reaction under a
hydrogen atmosphere,14 while Schmidt was able to isolate
rearranged compounds after the addition in the medium of
hydride species like NaH or NaBH4, in a short and
efficient dihydropyran synthesis.15 Under these conditions
new catalysts which are responsible for the isomerization
step have been identified as ruthenium hydride com-
plexes.
Of great synthetic interest, unsaturated amines and nitriles
are less reactive under neutral conditions but this lack of
reactivity can be overtaken by performing the reaction in
acidic media or in the presence of a Lewis acid like cop-
per(I) chloride7 which prevent the deactivation of the cat-
alyst. Another possibility with aza compounds is offered
by decreasing the nucleophilicity of the nitrogen atom.
This can be conveniently achieved by using amides or sul-
fonamides instead of amines. By this way, the formation
of medium-sized unsaturated lactams and sultams has
been developed and applied to the synthesis of natural or
biologically active compounds.8,9 In some cases, the first
cyclization procedure has been also combined with subse-
quent reactions in order to gain in complexity. Grigg et al.
and later Evans have combined a RCM process with a
further intramolecular Heck reaction to have an access to
aza-bridged compounds.10
Other reactions have been associated with metathesis in
order to gain in complexity. For example, Diels–Alder re-
actions have been carried out in one pot to prepare new
Amides 2a–c were conveniently prepared by condensa-
tion of commercially 2-bromobenzoic acids with bisallyl-
amine as depicted in Scheme 2.16 Acid 1d prepared from
piperonyl alcohol17–19 was condensed with the same
amine to give compound 2d (Scheme 3).
SYNLETT 2005, No. 4, pp 0577–0582
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862386; Art ID: D35104ST
© Georg Thieme Verlag Stuttgart · New York

578
C. Bressy et al.
LETTER
O
O
O
O
O
DCC, bisallylamine
R1
CO2H
Br
R1
S
( )m
m( )
S
DMAP, 0°C
N
Cl
Et3N, CH2Cl2
N
+ H
N
R
CH2Cl2
R
Br
Br
Br
1a (R1 = H)
1b (R1 = OMe)
2a (R1 = H)
2b (R1 = OMe)
2c (R1 = NO2)
5a (R = H, m = 1) 89%
4
95%
99%
88%
5b (R = Allyl, m = 1) 90%
1c (R
1 = NO2)
O
O
O
O
Scheme 2
S
N
S
Br
K2CO3, MeCN, ∆
N
H
O
Br
Br
1) NBS, CH2Cl2
2) PCC, CH2Cl2
O
O
OH
O
OH
5c 86%
5a
3) CrO3, H2SO4, acetone
O
Br
42%
Scheme 4
3
1d
o-Bromobenzamide 2a was first engaged in a RCM pro-
cess in the presence of bis(tricyclohexylphosphine) ben-
zylidene ruthenium(IV) dichloride known as Grubbs’
type I catalyst and delivered as expected the pyrrolinyl
amide 6a in 96% (Scheme 5, Table 1).
O
O
DCC, bisallylamine
O
O
O
OH
N
DMAP, 0 °C
Br
O
CH2Cl2
Br
2d
In a next experiment, after total conversion of 2a, sodium
hydride was added in small portion in the media and the
resulting suspension was heated to reflux. The new orga-
nometallic species generated by this way were expected to
promote the isomerization of the new double bond
formed. Fortunately, we were pleased to observe the mi-
gration of the double bond as reported in the oxygenated
series.15 By careful adjustment of the amounts of hydride
and the ruthenium catalyst added, we obtained after
complete conversion, amide 7a with yield up to 72%. Best
1d
63%
Scheme 3
Similarly, sulfonamides 5a,b were obtained by condensa-
tion of 2-bromobenzenesulfonyl chloride 4 with allyl-
amine and bisallylamine, respectively (Scheme 4). N-
substitution of secondary sulfonamide 5a was achieved
with 4-bromobutene under mild conditions20 and deliv-
ered 5c in high yield.
O
O
O
Grubbs I catalyst
NaH
N
N
N
+
Br
Br
Br
PhMe, ∆
2a
6a
7a
Scheme 5
Table 1 Tandem RCM/Isomerization of Bisallylamide 2a
Entry
Catalyst (mol%)
2.5
NaH (mol%)
–
Concentratin (mol/L) Time (h)
Yield of 6a (%)
Yield of 7a (%)
1
2
3
4
5
6
7
10–2
24
21
24
36
48
48
48
96
51
20
22
–
–
5
30
10–2
48
55
60
68
72
43
2 × 2.5
3 × 2.5
4 × 2.5
4 × 2.5
4 × 2.5
2 × 30
3 × 30
4 × 30
4 × 30
4 × 30a
4·10–2
4·10–2
4·10–2
10–2
–
10–2
48
a NaBH4 used instead of NaH.
Synlett 2005, No. 4, 577–582 © Thieme Stuttgart · New York

LETTER
Synthesis of Polycyclic Lactams and Sultams
579
results required 10% of Grubbs’ I catalyst and 120 mol% sulfonamides 5b,c. As in the tetrahydropyranne series, the
of NaH as shown in Table 1 (entry 5).21
isomerization of 5c was totally regioselective and deliv-
ered only enamide 9c. Compared to results obtained with
amides 2, the yields for the RCM/isomerization and also
for the radical cyclization were better in the sulfonamide
series. No trace of compounds resulting from the reduc-
tion of the C-Br bond was noticed. The dimeric approach
has been also investigated. In some cases, the formation of
dimeric species has been suggested before the ring-
closure.28
Other amides were submitted to these selected conditions
(Scheme 6) and the results are collected in Table 2. The
reaction was effective in almost all cases except with
amide 2c. The presence of the nitro group seems compat-
ible with the metathesis but problematic for the isomeriza-
tion step promoted by the in situ generated ruthenium
hydride complex.
Table 2 Tandem RCM/Isomerization of Amides 2a–d
Table 3 RCM/Isomerization of Amides 7a–d
Amide
R1
R2
Yield of 6 Yield of 7
Substrate R1
R2
Conditions Yield of 10 Yield of 11
(%)
(%)
(%)
(%)
2a
2b
2c
2d
H
H
H
H
–
7a (68)
7b (86)
7c (43)
7d (71)
7a
7a
7b
7c
7d
H
H
H
H
H
Aa
Bb
Bb
Bb
Bb
a (45)
a (77)
b (52)
cc (–)
d (50)
a (0)
a (20)
b (0)
c (0)
d (0)
OMe
NO2
–
H
31
–
OMe
NO2
-O-CH2-O-
-O-CH2-O-
While an alternative and apparently more direct approach
from enamides could be also considered,22 our strategy
described therein seems more attractive if considering the
availability and stability of the required substrates.
a Conditions A: Bu3SnCl + NaBH4, AIBN, PhMe, 130 °C.
b Conditions B: TTMSS (2 equiv) + AIBN, PhMe, 130 °C.
c Compound 10c was obtained only in traces.
We next considered the free radical cyclization23,24 to
reach tricyclic lactam structures and chose 7a as a model
(Scheme 7). The combination of Bu3SnCl and sodium
borohydride in toluene under high dilution, known as
Stork’s conditions,25 afforded lactam 10a in moderate
Bissulfonamide 5d was easily prepared from 5a
(Scheme 8). Under the same tandem cyclization/isomer-
ization conditions and after a similar time of reaction, an
unseparable 1:3 mixture of 8b:9b was isolated in 90%
yield and without significant formation of the reduced yield. This result shows that the formation of dimeric
amide 11a. To enhance the efficiency of the radical cy- compounds as intermediate cannot be totally excluded
clization, tris(trimethylsilyl)silane (TTMSS)26 was also during the first metathesis step.
used. A slow addition of this reagent to a highly diluted
Finally, we have investigated a one-pot procedure to
solution of 7a gave in far better yield 10a, which was eas-
prepare polycyclic lactams and sultams from amides 2 or
ily isolated by chromatography with the reduced com-
sulfonamides 5. According to the classification of tandem
pound 11a. Amides 7b and 7d resulting from the RCM/
isomerization process were engaged under these condi-
and sequential reactions,29 this procedure could be de-
scribed as a tandem RCM/isomerization followed by a se-
tions and converted into polycyclic derivatives in good
quential radical cyclization (Scheme 9). The reaction
yields (Table 3).27 This overall sequence was applied to
applied to compounds 2a,d and 5c gives the tricyclic
Br
O
Grubbs I catalyst
NaH
N
Ar
N
Ar
N
+
R2
PhMe, ∆
O
O
R1
6
2
7
Scheme 6
O
O
O
R1
R1
R2
R1
R2
conditions
N
N
N
+
R2
PhMe
(10–2 M), ∆
Br
7
10
11
Scheme 7
Synlett 2005, No. 4, 577–582 © Thieme Stuttgart · New York

580
C. Bressy et al.
LETTER
O
O
O
O
( )n
( )n
Grubbs I catalyst
(5 x 2.5%)
S
S
N
N
Br
Br
NaH (5 x 0.3 equiv)
PhMe, ∆
5b (n = 1)
5c (n = 2)
9b (88%)
9c (97%)
O
S
O
O
O
( )n
S
TTMSS (2 equiv)
+ AIBN
N
( )n
N
Br
PhMe, ∆
9b (n = 1)
9c (n = 2)
12b (52%)
12c (62%)
O
O
O
O
N
S
H
Br
N
S
N
Br
S
O
O
Br
Br
K2CO3, MeCN, ∆
Br
5d (84%)
5a
O
O
S
O
O
Grubbs I catalyst
(5 x 2.5%)
N
S
N
S
N
O
O
Br
Br
NaH, PhMe
Br
∆
8b,9b (90%)
5d
Scheme 8
lactams and sultam in moderate to good overall yields.30 amides a short access to tri- or tetracyclic lactams and sul-
By this way, isolation of sensitive pyrroline intermediates tams. Work is under way to apply this cascade reaction to
is avoided.
the synthesis of biologically active compounds.
In conclusion, we have combined a ring-closing metathe-
sis, an isomerization step and a radical cyclization which
could be carried out in a one-pot procedure and afford
from readily available unsaturated amides and sulfon-
Acknowledgment
C.B. and C.M. thank the ‘Ministère de l’Education Nationale, de la
Recherche et de la Technologie’ for doctoral fellowships.
O
O
(i), (ii)
R1
R1
N
(iii)
N
R2
R2
Br
10a (36%)
10d (35%)
2a
2d
O
O
O
O
O
O
(i), (ii)
(iii)
S
S
S
N
N
N
+
Br
12c (62%)
13c (16%)
5c
Scheme 9 Reagents and conditions: (i) Grubbs’ I catalyst (2.5% mol), PhMe, 1 h; (ii) 5 × [Grubbs I catalyst (2.5% mol) + NaH (0.15 equiv)],
PhMe, 130 °C, 60 h; (iii) TTMSS (2 equiv) + AIBN (10%), PhMe, 130 °C, 6 h.
Synlett 2005, No. 4, 577–582 © Thieme Stuttgart · New York

LETTER
Synthesis of Polycyclic Lactams and Sultams
581
6.98 (s, 1 H). 13C NMR (CDCl3): d = 46.7, 50.5, 102.4,
References
107.8, 110.4, 113.1, 118.4, 131.3, 132.6, 133.0, 147.7,
149.1, 168.9. HRMS: m/z calcd [MH+]: 324.02353; found:
324.02315.
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(2) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
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42, 4592.
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Zahmani, H.; Hacini, S.; Charonnet, E.; Rodriguez, J. Synlett
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Weinreb, S. M. J. Org. Chem. 1999, 64, 587.
To a solution of N-allyl-2-bromobenzene sulphonamide (5a,
276 mg, 1 mmol) in MeCN (4 mL) was added 4-bromo-
butene (148 mg, 1.1 mmol) and K2CO3 (553 mg, 4 mmol).
The resulting suspension was heated for 16 h. After filtration
and concentration, the product was purified by flash
chromatography (eluent: EtOAc–hexanes 10:90).
Compound 5c (86%): 1H NMR (CDCl3): d = 2.27 (t, J = 7.4
Hz, 2 H), 3.36 (t, J = 7.4 Hz, 2 H), 3.99 (d, J = 6.4 Hz, 2 H),
4.95–5.15 (m, 2 H), 5.15–5.35 (m, 2 H), 5.59–5.85 (m, 2 H),
7.37 (dt, J = 1.8, 7.5 Hz, 1 H), 7.45 (dt, J = 1.8, 7.5 Hz, 1 H),
7.75 (dd, J = 7.5, 1.3 Hz, 1 H), 8.18 (dd, J = 8.7, 2.1 Hz, 1
H). 13C NMR (CDCl3): d = 32.7, 46.6, 50.3, 117.5, 119.3,
120.7, 127.9, 132.5, 133.4, 133.9, 134.8, 136.0, 139.8. IR
(film): 3070, 2985, 1640, 1575, 1445, 1340, 1155, 915, 755
cm–1.
(17) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc.
1998, 120, 3664.
(9) (a) Jun, J. H.; Dougherty, J. M.; del Sol Jimenez, M.;
Hanson, P. R. Tetrahedron 2003, 59, 8901. (b) Karsch, S.;
Freitag, D.; Schwab, P.; Metz, P. Synthesis 2004, 1696.
(10) (a) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett.
1998, 39, 4139. (b) Grigg, R.; York, M. Tetrahedron Lett.
2000, 41, 7255. (c) Evans, P.; McCabe, T.; Morgan, B. S.;
Reau, S. Org. Lett. 2005, 7, 43.
(18) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446.
(19) Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38,
2569.
(20) Selvamurugan, V.; Aidhen, I. S. Synthesis 2001, 2239.
(21) Metathesis and Isomerization of Amides 2, Typical
Procedure.
(11) (a) Bressy, C.; Piva, O. Synlett 2003, 87. (b) Virolleaud, M.
A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44, 8081.
(c) Virolleaud, M. A.; Piva, O. Synlett 2004, 2087.
(12) (a) Clive, D. L. J.; Cheng, H. Chem. Commun. 2001, 605.
(b) Quayle, P.; Fengas, D.; Richards, S. Synlett 2003, 1797.
(13) Alcaide, B.; Almendros, P. Chem.–Eur. J. 2003, 9, 1258;
and references therein.
(14) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390.
(15) (a) Schmidt, B. Eur. J. Org. Chem. 2003, 816. (b) Schmidt,
B. Chem. Commun. 2004, 742. (c) Schmidt, B. Eur. J. Org.
Chem. 2004, 1865. (d) Schmidt, B. J. Org. Chem. 2004, 69,
7672.
To a solution of amide 2a (140 mg, 0.5 mmol) in toluene was
added first generation Grubbs’ catalyst (11 mg, 2.5% mol).
After stirring at r.t. for 1 h and complete disappearance of the
starting material, NaH (7 mg, 1.5 mmol) was added at once
and the mixture was heated to reflux. A new addition of both
Grubbs’ catalyst (11 mg, 2.5% mol) and NaH (7 mg, 1.5
mmol) was performed after 12 h of heating and this sequence
was repeated three times more. After cooling to r.t., the
solvent was removed by concentration and the resulting
crude mixture was purified by flash chromatography on
silica (eluent: hexanes–EtOAc 7:3).
Compound 7a (72%): 1H NMR (CDCl3) 2 rotamers (ratio
4.2:1): d (major rotamer) = 2.76 (dt, J = 8.6, 2.4 Hz, 2 H),
4.07 (t, J = 9.0 Hz, 2 H), 5.23 (dt, J = 4.3, 2.4 Hz, 1 H), 6.02
(dt, J = 6.4, 1.2 Hz, 1 H), 7.35 (m, 3 H), 7.60 (d, J = 7.5 Hz,
1 H); d (minor rotamer) = 2.76 (dt, J = 8.6, 2.4 Hz, 2 H), 3.58
(t, J = 9.0 Hz, 2 H), 5.42 (dt, J = 4.3, 2.4 Hz, 1 H), 7.11 (dt,
J = 6.4, 2.1 Hz, 1 H), 7.35 (m, 3 H), 7.60 (d, J = 7.5 Hz, 1 H).
13C NMR (CDCl3): d (major rotamer) = 27.6, 43.8, 111.8,
118.4, 126.7, 127.4, 128.6, 129.7, 131.9, 136.9, 173.4;
d (minor rotamer) = 28.8, 45.7, 111.8, 117.7, 126.7, 127.4,
128.6, 129.7, 131.9, 137.6, 173.4. IR (film): 3065, 2955,
1645, 1420, 1045, 1025, 830 cm–1. HRMS: m/z calcd [MH+]:
252.00240; found: 252.00229.
(16) Preparation of the N,N-Bisallylamides 2.
To a solution of acid (2 mmol) in CH2Cl2 (4 mL) were
successively added DMAP (0.073 g, 0.6 mmol) and
bisallylamine (0.195 g, 2 mmol). The reaction was next
cooled to 0 °C and a solution of dicyclohexylcarbodiimide
(0.412 g, 2 mmol) in the same solvent (1 mL) was added
dropwise. After stirring 10 min at 0 °C, the ice-water bath
was removed and the mixture stirred overnight at r.t. Urea
was filtered off and the solvent removed by concentration
under vacuo. Amide 2 was obtained pure by flash
chromatography (eluent: EtOAc–hexanes 10:90).
Compound 2a (95%): 1H NMR (CDCl3): d = 3.65 (d, J = 4.5
Hz, 2 H), 3.75 (dd, J = 15.2, 6.8 Hz, 1 H), 4.48 (dd, J = 15.2,
3.7 Hz, 1 H), 5.03 (dd, J = 1.3, 16.9 Hz, 1 H), 5.10 (dd,
J = 11.5, 1.3 Hz, 1 H), 5.18 (dd, J = 10.1, 1.3 Hz, 1 H), 5.23
(dd, J = 17.9, 1.3 Hz, 1 H), 5.59 (ddt, J = 16.9, 10.1, 5.8 Hz,
1 H), 5.83 (ddt, J = 16.9, 10.1, 5.4 Hz, 1 H), 7.13–7.31 (m, 3
H), 7.50 (d, J = 7.9 Hz, 1 H). 13C NMR (CDCl3): d = 46.70,
50.60, 118.50, 118.51, 119.50, 127.90, 128.00, 130.60,
132.80, 133.00, 133.20, 138.50, 169.40. IR (film): 3080,
2923, 1637, 1415, 1285, 1115, 995, 925, 770 cm–1.
Compound 2d (63%): 1H NMR (CDCl3): d = 3.74 (d, J = 5.6
Hz, 2 H), 3.80 (m, 1 H), 4.35–4.55 (m, 1 H), 5.11 (ddt,
J = 17.0, 1.5, 1.5 Hz, 1 H), 5.18 (ddt, J = 10.2, 1.5, 1.5 Hz, 1
H), 5.23 (ddt, J = 10.4, 1.5, 1.5 Hz, 1 H), 5.27 (ddt, J = 15.6,
1.5, 1.5 Hz, 1 H), 5.67 (ddt, J = 17.0, 10.4, 5.6 Hz, 1 H), 5.87
(ddt, J = 16.4, 10.2, 6.0 Hz, 1 H), 6.00 (s, 2 H), 6.71 (s, 1 H),
Compound 7d (71%): yellow oil. 1H NMR (CDCl3):
d = 2.73 (dt, J = 6.0, 0.8 Hz, 2 H), 4.01 (t, J = 8.3 Hz, 2 H),
5.22 (dt, J = 5.3, 2.6 Hz, 1 H), 6.02 (s, 2 H), 6.06 (dt, J = 4.3,
2.1 Hz, 1 H), 6.80 (s, 1 H), 7.01 (s, 1 H). 13C NMR (CDCl3):
d = 28.9, 45.1, 102.4, 108.2, 108.5, 110.9, 113.0, 113.1,
130.0, 147.7, 149.4, 164.5. HRMS: m/z calcd [MH+]:
294.98441; found: 294.98497.
(22) (a) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3,
2045. (b) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60,
9559.
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Vol. 1; Wiley VCH: Weinheim, 2001. (b) Renaud, P.; Sibi,
M. P. Radicals in Organic Synthesis, Vol. 2; Wiley VCH:
Weinheim, 2001.
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LETTER
(24) (a) Kamimura, A.; Taguchi, Y.; Omata, Y.; Hagihara, M. J.
Org. Chem. 2003, 68, 4996. (b) Zhang, W.; Pugh, G.
Tetrahedron 2003, 59, 3009. (c) Kato, I.; Higashimoto, M.;
Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983.
(25) (a) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303.
(b) Majumdar, K. C.; Mukhopadhyay, P. P. Synthesis 2003,
97.
(26) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(b) Bennasar, M.-L.; Zulaica, E.; Juan, C.; Alonso, Y.;
Bosch, J. J. Org. Chem. 2002, 67, 7465.
(dd, J = 3.2, 11.3 Hz, 1 H), 7.37 (dd, J = 1.1, 7.5 Hz, 1 H),
7.50 (t, J = 7.5 Hz, 1 H), 7.58 (dt, J = 1.1, 7.5 Hz, 1 H), 7.79
(d, J = 7.5 Hz, 1 H). 13C NMR (CDCl3): d = 23.9, 24.3, 30.5,
40.4, 58.8, 121.4, 123.2, 129.3, 132.8, 135.4, 138.8. IR:
3080, 2955, 2850, 1645, 1450, 1285, 1170, 1130 cm–1.
HRMS: m/z calcd [MH+]: 224.07452; found: 224.07453.
(28) (a) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan,
D. A.; Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc.
1997, 119, 10302. (b) Fürstner, A.; Thiel, O. R.;
Ackermann, L. Org. Lett. 2001, 3, 449. (c) Fürstner, A.;
Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.;
Mynott, R.; Stelzer, F.; Thiel, O. R. Chem.–Eur. J. 2001, 7,
3236.
(27) Radical Cyclization of Amides 7, Typical Procedure
Described from Amide 7a.
A solution of amide 7a (100 mg, 0.4 mmol) in toluene (40
mL) containing small amounts of AIBN (7 mg, 0.04 mmol)
was bubbled by a dried stream of nitrogen for 10 min and
heated to reflux. A solution of tristrimethylsilylsilane (140
mL, 0.44 mmol) in toluene (10 mL) was carefully added drop
by drop in 15 min. The reaction was heated for additional 6
h. The solvent was removed by concentration and the crude
mixture was purified by flash chromatography on silica
(eluent: EtOAc–hexanes 50:50) and gave lactam 10a.
Compound 10a (77%): viscous oil. 1H NMR (CDCl3):
d = 1.25 (m, 2 H), 2.34 (m, 2 H), 3.43 (m, 1 H), 3.72 (dt,
J = 11.3, 8.3 Hz, 1 H), 4.68 (dd, J = 10.3, 5.3 Hz, 1 H), 7.45
(m, 3 H), 7.80 (d, J = 7.2 Hz, 1 H). 13C NMR (CDCl3):
d = 28.2, 28.7, 40.9, 63.7, 114.9, 121.7, 122.9, 127.3, 130.6,
145.4, 170.6. IR: 3075, 2960, 1685, 1385, 1220, 1145, 740
cm–1. HRMS: m/z calcd [MH+]: 174.09189; found:
174.09163.
(29) (a) Denmark, S. E.; Thoraransen, A. Chem. Rev. 1996, 96,
137. (b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551.
(30) Tandem Process from Amides 2a,d, Typical Procedure.
To a solution of amide 2a (140 mg, 0.5 mmol) in toluene was
added first generation Grubbs’ catalyst (11 mg, 2.5% mol).
After stirring at r.t. for 1 h and complete disappearance of the
starting material, NaH (7 mg, 1.5 mmol) was added at once
and the mixture was heated to reflux. A new addition of both
Grubbs’ catalyst (11 mg, 2.5% mol) and NaH (7 mg, 1.5
mmol) was performed after 12 h of heating and this sequence
was repeated three times more. After cooling to r.t., AIBN (8
mg, 0.05 mmol) was added. The mixture was bubbled with a
dried nitrogen stream and next heated. A solution of TTMSS
(320 mL, 1 mmol) in toluene (10 mL) containing AIBN (8
mg, 0.05 mmol) was slowly added to the reaction mixture in
10 min. After heating at 130 °C for 6 h, the mixture was
cooled to r.t., and the solvent removed by concentration
under vacuum. The products were purified after flash
chromatography on silica.
Compound 12c (62%): white solid; mp 103–109 °C. 1H
NMR (CDCl3): d = 1.40–1.85 (m, 4 H), 2.03 (dt, J = 11.3,
3.0 Hz, 1 H), 2.28 (dd, J = 3.0, 11.3 Hz, 1 H), 3.02 (dt,
J = 3.2, 11.3 Hz, 1 H), 3.86 (dt, J = 10.2, 2.7 Hz, 1 H), 4.20
Synlett 2005, No. 4, 577–582 © Thieme Stuttgart · New York