Highly diastereoselective samarium diiodide induced cyclizations of new 3-substituted indole derivatives

Article abstract of DOI:10.1039/b913015b

Herein, we describe the synthesis of new functionalized tricyclic and tetracyclic indole derivatives via samarium diiodide induced ketyl cyclizations. The intermediate samarium organyls were either protonated using different proton sources or alkylated wi

Full text of DOI:10.1039/b913015b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly diastereoselective samarium diiodide induced cyclizations of new
-substituted indole derivatives†
3
Christine Beemelmanns and Hans-Ulrich Reissig*
Received 1st July 2009, Accepted 20th July 2009
First published as an Advance Article on the web 21st August 2009
DOI: 10.1039/b913015b
Herein, we describe the synthesis of new functionalized tricyclic and tetracyclic indole derivatives
via samarium diiodide induced ketyl cyclizations. The intermediate samarium organyls were either
protonated using different proton sources or alkylated with various electrophiles in a highly
diastereoselective manner. The obtained products were subjected to further transformations leading
to synthetically interesting building blocks.
Introduction
Results and discussion
Samarium diiodide is a one-electron reducing agent that promotes
a variety of important synthetic transformations. Cyclization
SmI induced 6-exo-trig cyclizations
2
1
First, we used compound 1 as model substrate for the cyclizations
reactions are perhaps the most useful processes induced by this
reagent and they have been used for the construction of various
(
Table 1). A mixture of 1 (1.0 eq.) and a proton source (10.0 eq.)
2,3
1b
was subjected to a solution of SmI
an excess of HMPA (10.0 eq.). The expected tricyclic product
2
(2.4 eq.) in THF along with
ring sizes, especially in natural product synthesis. We have
previously studied the stereoselective formation of tricyclic and
7
2
could be obtained in moderate to very good yields and with
tetracyclic 3-methoxycarbonyl substituted indole derivatives via
4
diastereoselectivities depending on the added proton source. As
Table 1 shows, addition of tBuOH furnished compound 2 in
SmI
2
induced ketyl cyclizations (Scheme 1). Subsequent alky-
lation of the generated intermediate samarium enolate was also
possible giving highly functionalized tricyclic indole derivatives in
high yields as single diastereomers.
88% yield and in almost diastereomerically pure form. Similar
◦
results were obtained with phenol at 0 C (entry 3). At ambient
temperature, HMPA was even not necessary to achieve high
conversion but, unfortunately, the protonation was unselective
providing a 60:40 mixture of 2 and 3 (entry 4). All further attempts
to exclude or substitute HMPA by addition of LiBr or DMI (N,N -
8
dimethylimidazolidone) gave lower yields and stereoselectivities.
Thus, under optimized reaction conditions three stereogenic
centres can be controlled in this transformation. The relative
9
configuration of 2 was determined by NOE experiments and
finally by a single crystal structure analysis. In all experiments,
Scheme 1 SmI
2
induced cyclization and subsequent alkylation.
10
deacylated 3-cyano indole was isolated as single byproduct
The general importance of the indole moiety derives from
the presence in numerous classes of natural products and phar-
maceutically relevant compounds. One of the most intriguing
Table 1 SmI induced conversion of 1 into 2 and 3 using different proton
2
5
sources
classes of indole alkaloids is the family of strychnos alkaloids with
strychnine as prime example. Members of the vinca and tacaman
families with a similar core structure also occupy an important
role in natural product chemistry because of their interesting
6
pharmacological potential as cerebral vasodilator agents.
Herein, we present our recent results demonstrating that novel
suitable 3-cyanoindole and 3-indolyl acetonitrile derivatives are
a
Yield
b
excellent substrates for SmI
2
induced ketyl cyclizations providing
Entry
Conditions
2+3 (%)
dr (2:3)
interesting building blocks for the construction of indole alkaloid
derivatives.
1
2
3
4
5
6
7
r.t., 10.0 eq. HMPA, 10.0 eq. tBuOH
88
50
95:5
90:10
95:5
60:40
80:20
90:10
—
c
r.t., 10.0 eq. HMPA, 10.0 eq. Phenol
◦
0 C, 10.0 eq. HMPA, 10.0 eq. Phenol
89
80
80
35
—
r.t., 10.0 eq. Phenol
r.t., 10.0 eq. HMPA
Hans-Ulrich Reissig, Institut f u¨ r Chemie und Biochemie, Takustr. 3, 14195,
Berlin, Germany. E-mail: hans.reissig@chemie.fu-berlin.de; Fax: +49-30-
c
r.t., 2.4 eq. LiBr, 24.0 eq. DMI
◦
d
0 C, 6.0 eq. LiBr, tBuOH
8
38-55367; Tel: +49-30-838-55366
a
b
1
†
Electronic supplementary information (ESI) available: Additional exper-
Yield after column chromatography. Determined by H-NMR spec-
1
13
c
d
imental procedures, analytical data, H and C NMR spectra. See DOI:
0.1039/b913015b
troscopy. Deacylation reaction ~50%. Only starting material.
Org. Biomol. Chem., 2009, 7, 4475–4480 | 4475
1
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Table 2 SmI
2
induced cyclizations of 1 and alkylation with electrophiles
Table 3 SmI induced cyclizations using 3-indolyl acetonitrile 5
2
a
Yield
a
Entry Electrophiles
R
Yield 4 (%) 2 (%)
b
b
1
2
3
4
5
6
7
8.0 eq. ICH
8.0 eq. ICH
2
2
CH=CH
2
CH
CH
CH
CH
2
2
2
2
CH=CH
2
48
43
32
41
32
49
51
50
20
16
19
CN
CN
a
t
t
Yield
6+7 (%) dr (6:7)
8.0 eq. BrCH
8.0 eq. BrCH
2
CO
CO
2
2
Bu
CO
CO
Et
2
Bu
b
b
b
Entry Conditions
2
Et
2
Et
8.0 eq. ClCO
8.0 eq. ClCO
8.0 eq. NCCO
2
Et
Bn
CO
Bn
2
67c
35
61
1
2
3
4
5
6
r.t., 10.0 eq. HMPA, 10.0 eq. tBuOH
76
90
51
5
95:5
95:5
60:40
n.d.
90:10
90:10
2
◦
Bn
CO
2
Bn
0 C, 10.0 eq. HMPA, 10.0 eq. tBuOH
2
r.t., 10.0 eq. HMPA, 10.0 eq. Phenol
r.t., 10.0 eq. HMPA
r.t., 6.0 eq. LiBr, 10.0 eq. DMI, 10.0 eq. tBuOH 27
r.t., 8.0 eq. allyl iodide, 10.0 eq. HMPA
a
c
b
c
d
e
Yield after column chromatography. Based on recovered compound 1.
Product with R = CO
2
Bn in 15% yield.
30
a
b
1
Yield after column chromatography. Determined by H-NMR spec-
(
in particular see entries 2 and 6, Table 1). The observed amide
c
d
e
troscopy. 8 in 60% yield. Deacylation ~50%. 8 in 40% yield.
bond cleavage is known to occur via Lewis acid [Sm(III)] assisted
11
hydrolysis in the presence of alcohols.
To our delight, it was also possible to irreversibly trap the
intermediate samarium species with various electrophiles after
cyclization leading to the highly substituted indole derivatives
generating a samarium ketyl (radical anion), addition of this
ketyl to the aromatic system, a second electron transfer and
subsequent protonation or alkylation (Scheme 2). The high degree
4
4
. Contrary to the protonation of the intermediate samarium
of diastereoselectivity for the cyclization may be explained by
assumption of a highly ordered cyclic transition state during ketyl
radical addition to the (het)aryl ring. For steric and electronic
reasons, the samarium alcoholate favours an equatorial position
organyl, the alkylation proceeds from the convex face of the
molecule giving only one diastereomer as depicted in Table 2.
Depending on the reactivity of the reagents, the alkylated products
were obtained in moderate to good yields. In all cases, protonated
product 2 was isolated in relatively high amounts (Table 2).
Interestingly, when chloro benzylformate was used as electrophile,
in situ decarboxylation occurred probably generating a reactive
benzyl halide which was trapped by the present samarium
organyl (Table 2, entry 6). Changing to the less reactive cyano
benzylformate, the desired product was obtained in good yield.
The relative configurations of the alkylated products were proven
by NOE experiments and were consistent with those of previously
12
during the cyclization process. The diastereoselectivity of the
protonation seems to be governed by thermodynamic control,
which positions the cyano group at the convex face of the
9
molecule. Contrary to the assumed reversible protonation of the
intermediate samarium organyl, the alkylation proceeds under
kinetic control giving only one diastereomer, as depicted in
Scheme 2.
4a
reported products.
After these promising results we turned to 3-indolyl acetonitrile
as a less activated cyclization precursor. Table 3 shows the
5
expected tricyclic product 6 which was obtained in high yield and
with excellent diastereoselectivity using the optimized conditions
(
entries 1 and 2, Table 3). The relative configuration of 6 was
10
unequivocally proven by X-ray analysis. When no proton source
was added (entry 4, Table 3), cyanide elimination took place
and tricyclic compound 8 with an exo-methylene moiety was
isolated in up to 60% yield. Substitution of HMPA by addition
of LiBr and DMI afforded compound 6 in only 27% yield,
beside significant amounts of deacylation product (3-indolyl
acetonitrile). Unfortunately, all attempts to trap the intermediate
samarium species with alkyl halides failed. Addition of allyl iodide
Scheme 2 Mechanism of the SmI induced cyclization and subsequent
alkylation. The bulky HMPA ligands at Sm /Sm are omitted for
simplicity but certainly play a crucial role in the cyclization process.
2
2+
3+
(
entry 6, Table 3) after complete cyclization furnished up to 40%
the elimination product 8 beside 30% of 6.
SmI induced 7-exo-trig cyclizations
2
Mechanism
Next, we envisaged the synthesis of seven-membered tricyclic
indole derivatives, as shown in Table 4. Cyclization under standard
conditions using phenol or tBuOH as proton source gave the
The mechanism of this type of reaction is usually described
as a sequence of an electron transfer to the carbonyl group
4
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Table 4 SmI
2
induced formation of seven-membered rings using 3-
cyanoindole derivative 9
Table 5 SmI
2
induced formation of seven-membered rings using 3-
cyanoindole derivative 13
a
a
a
Additive
Yield 10 (%)
Yield 11 (%)
Yield 12 (%)
a
a
Additive
Yield 14 (%)
Yield 15 (%)
tBuOH
42
18
< 5
39
—
7
Phenol
tBuOH
41
5
—
40
Phenol
a
Yield after column chromatography.
a
Yield after column chromatography.
desired tri- and tetracyclic compounds in moderate yields. In both
cases, significant amounts of deacylation was observed. The amide
bond cleavage seems to be faster than the less favoured formation
of seven-membered rings. Analogously to previous results, tBuOH
as proton source delivered the best yields and diastereoselectivities
for this transformation. Surprisingly, in the presence of phenol
the expected product 10 (18%) was accompanied by lactone 11
13
(
39%) and rearomatized carboxylic acid 12 (7%). The formation
of lactone 11 is easily explained by intramolecular attack of the
samarium alcoholate to the cyano group, whereas acid 12 may be
the result of a Lewis acid [Sm(III)] assisted hydrolysis followed
by rearomatization during work-up. The relative configuration
of compound 10 is partially determined by NOE experiments
(
10a,11-trans) and is assumed to be analogous to reported
4b,9
compounds at the remaining stereogenic centres.
Similar results were obtained using compound 13 and tBuOH as
proton source (Table 5). Beside ca. 40% deacylation product, 41%
of tetracyclic compound 14 was obtained in diastereomerically
pure form. In the presence of phenol, pentacyclic lactone 15
was isolated in moderate yield as a single diastereomer. The
corresponding rearomatized acid was observed only in traces.
1
Although the H-NMR spectra of the crude product mixture
Scheme 3 Further transformations of cyclization products 2, 18, and 6.
indicated the presence of another cyclization product (~45%),
which is assumed to be nitrile derivative 16, this compound could
not be isolated after purification by column chromatography.
Instead, the corresponding lactone 15 was obtained. This result
suggests that during work-up and column chromatography on
silica gel, the cyano group of 16 is intramolecularly attacked by
the hydroxy group and transformed into lactone 15.
in high yield. Under the applied basic conditions, it is assumed
that the tertiary alcoholate deprotonates the fairly acidic lactam
a-proton which is subsequently alkylated by the second equivalent
of allyl iodide. Subsequently, TBS-protected compound 18 was
deprotonated with LDA and stereoselectively alkylated with allyl
iodide to furnish monoalkylated compound 19 in excellent yield.
In the case of using an excess of LDA for the alkylation reaction,
traces of dialkylated product (C-7, C-10) were isolated. For LDA
experiments without HMPA, mainly alkylation at the less hindered
C-7 was observed. In addition, the cyano group of compounds 2
and 6 was easily reduced with hydrogen in the presence of Raney-
Ni and Boc-anhydride affording Boc-protected amines 20 and 21
in high yields.
Further functionalization of cyclization products
In preliminary studies we could demonstrate that products such
as 2 and 6 can be converted into synthetically interesting inter-
mediates. In a first experiment, compound 2 was deprotonated
with 2.2 eq. of LDA in the presence of HMPA. The generated
dianion was trapped with allyl iodide surprisingly affording the
diallylated compound 17 as a single diastereomer (Scheme 3)
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Conclusions
8-H), 2.58 (1H, ddd J = 7.9, 11.5, 18.8 Hz, 7-H), 2.74 (1H, ddd,
J = 2.0, 7.9, 18.8 Hz, 7-H), 4.39 (1H, d, J = 10.6 Hz, 10-H), 4.51
In conclusion, we demonstrated that indole derivatives with
(
1H, d, J = 10.6 Hz, 9a-H), 4.72 (1H, s, OH), 7.17 (1H, dt, J = 1.0,
3
-cyano or 3-cyanomethyl groups are suitable substrates for SmI
2
7
1
Me
.6 Hz, 2-H), 7.34 (1H, t, J ª 7.8 Hz, 3-H), 7.44 (1H, d, J = 7.6 Hz,
induced cyclizations. Tricyclic and tetracyclic products were ob-
tained in good to very good yields and with high diastereoselectivi-
ties. Subsequent transformations such as alkylation and reduction
show the synthetic potential of the compounds obtained. Allyl
derivative 17 and amines 20 and 21 are ideal precursors for
subsequent reactions towards other interesting heterocycles and
are currently under further investigation.
13
-H), 8.18 (1H, d, J = 8.1 Hz, 4-H). C NMR (100 MHz, CDCl
3
,
4
Si): d
C
= 19.5 (q, 9-CH
3
), 30.9 (t, C-7), 33.1 (d, C-10), 35.6 (t,
C-8), 68.9 (s, C-9), 71.1 (d, C-9a), 117.1 (d, C-4), 118.9 (s, CN),
1
24.0 (s, Ar), 124.2, 124.7, 129.7 (3d, C-1, C-3, C-2), 141.7, 167.2
-1
(
(
2 s, Ar, C-6). IR: nmax/cm = 3270 (OH), 3070 (ArH), 2990–2985
CH), 2250 (CN), 1630 (CO), 1480 (C=C). Calcd for C14
H
14
N
2
2
O :
C 69.41, H 5.82, N 11.56%; found C 69.04, H 5.12, N 11.48%.
+
ESI-Tof (m/z): calcd for C14
[M+Na] ; found 243.1137 [M+H] , 265.0958 [M+Na] .
H
14
N
2
O : 243.1134 [M+H] , 265.0948
2
+
+
+
Experimental
Representative experimental procedures
General procedure for SmI
alkylation (compound 4)
2
induced cyclization and subsequent
Preparation of 1-(4-oxopentanoyl)-1H-indole-3-carbonitrile (1).
SOCl
0.90 g, 7.76 mmol). The resulting solution was stirred for 2 h
under exclusion of water. The excess of SOCl was evaporated
under reduced pressure. The obtained acid chloride was dissolved
in CH Cl (10 mL) and added to a mixture of indole (0.71 g,
.00 mmol), DMAP (40 mg, 0.33 mmol) and TEA (1.0 mL,
.10 mmol) in CH Cl (25 mL). The resulting mixture was stirred
Cl solution (20 mL)
and washed twice with water and brine (each 20 mL). The
organic phase was dried (MgSO ), filtrated and the organic solvent
2
(1.19 g, 10.0 mmol) was added dropwise to levulinic acid
To a solution of SmI (1.20 mmol) in THF (12 mL) was added
2
(
under an argon atmosphere HMPA (0.9 mL, 5.00 mmol). In a
second flask, indole derivative 1 (120 mg, 0.50 mmol) was dissolved
in THF (8 mL) and argon was bubbled through the solution for 10–
2
2
2
2
0 min. The solution was added to the deep purple solution of SmI
2
5
7
in THF/HMPA in one portion. After the solution colour changed
yellow-grew (in most cases after less than 1 minute) the alkylation
reagent (4.00–5.00 mmol) was added in one portion. The mixture
was stirred at room temperature for at least one hour. The reaction
2
2
over night, then quenched with sat. aq. NH
4
4
was quenched with sat. aq. NaHCO
with Et O (25 mL) and extracted three times with Et
combined organic phases were washed with water and brine, dried
with MgSO and evaporated. The crude mixture was purified by
column chromatography on silica gel (hexane/EtOAc 3:1, 1:1,
:3) affording compounds 2 and 4. In single cases additional
3
solution (30 mL), diluted
evaporated under reduced pressure. The obtained residue was
purified by column chromatography (3:1, 2:1 hexane/EtOAc) on
2
2
O. The
◦
silica gel affording 1 as yellow solid (1.09 g, 91%), mp 135–137 C.
4
1
H NMR (400 MHz, CDCl
2H, t, J = 5.9 Hz, 2-H), 3.21 (2H, t, J = 5.9 Hz, 3-H), 7.43 (2H,
, ArH), 7.70 (1H, d, J = 7.8 Hz, ArH), 8.11 (1H, s, ArH), 8.38
1H, d, J = 7.8 Hz, ArH). C NMR (100 MHz, CDCl , Me Si):
= 29.6 (t, C-2), 29.9 (q, C-5), 37.1 (t, C-3), 94.2 (s, CN), 113.9 (s,
Ar), 116.9, 119.7, 125.2, 127.1 (4d, Ar), 127.8 (s, Ar), 131.9 (d, Ar),
3
, Me
4
Si): d
H
= 2.28 (3H, s, 5-H), 2.99
(
m
(
d
1
c
purification by HPLC was necessary.
1
3
3
4
rac-(9S*,9aR*,10S*)-10-Allyl-9-hydroxy-9-methyl-6-oxo-7,8,9,
C
9
a,10-hexahydropyrido[1,2-a]indole-10-carbonitrile (compound 4,
-
1
entry 1). Colourless solid (61 mg, 48% based on recovered
1
(
34.7, 170.0, 206.1 (3 s, Ar, C-1, C-4). IR: nmax/cm = 3120–3070
ArH), 2930 (CH), 2230 (CN), 1720, 1700 (CO), 1550 (CH). Calcd
: C, 69.99; H, 5.03; N, 11.66%; found: C, 70.25; H,
.17; N, 12.03%. ESI-Tof (m/z): calcd for C14 : 263.0791
◦
1
starting material), mp. 120–123 C. H NMR (500 MHz, CDCl
Me Si): d ), 1.94 (1H, m , 8-H), 2.04 (1H, m
8
3
,
,
4
H
= 1.50 (3H, s, 9-CH
3
c
c
for C14
5
H
12
N
2
O
2
-H), 2.59 (1H, td, J = 8.2, 18.0 Hz, 7-H), 2.76 (1H, ddd, J = 4.6,
.1, 18.0 Hz, 7-H), 2.82 (2H, m , 10-CH ), 4.14 (1H, s, 9a-H), 5.25
, CH=CH ) 5.73 (1H, dddd, J = 6.6, 7.8, 10.2, 16.8 Hz,
H
12
N
2
O
2
+
+
9
c
2
[M+Na] ; found 263.0800 [M+Na] .
(
2H, m
c
2
Preparation of rac-(9S*,9aR*,10R*)-9-hydroxy-9-methyl-6-
CH=CH
2
), 7.15 (1H, dt, J = 1.1, 7.6 Hz, 2-H), 7.33 (1H, ddd, J
oxo-7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-carbonitrile (2).
To a solution of SmI (2.4 mmol) in THF (24 mL) was added under
=
1.3, 7.6, 8.2 Hz, 3-H), 7.39 (1H, ddd, J = 0.5, 1.2, 7.6 Hz, 1-H),
2
13
8
.20 (1H, dd, J = 0.4, 8.2 Hz, 4-H). C NMR (100 MHz, CDCl
3
,
an argon atmosphere HMPA (1.8 mL, 10.0 mmol). In a second
flask indole derivative 1 (240 mg, 1.00 mmol) and tBuOH (800 mg,
Me
CH
4
Si): d
), 46.4 (s, C-10), 71.0 (d, C-9a), 71.3 (s, C-9), 116.7 (d, C-4),
), 123.8, 124.8, 128.0 (3d, C-1,
C
= 20.7 (q, 9-CH
3
), 31.0, 37.6, 44.4 (3t, C-7, C-8, 10-
2
1
0.8 mmol) were dissolved in THF (16 mL) and argon was bubbled
through the solution for 10–20 min. This solution was added in one
portion to the deep purple solution of SmI in THF/HMPA. The
1
20.3 (s, CN), 121.9 (t, CH=CH
2
C-2, CH=CH
2
), 130.1 (s, Ar), 130.3 (d, C-3), 141.5, 168.2 (2 s, Ar,
2
-1
C-6). IR: nmax/cm = 3460 (OH), 3115–3020 (ArH), 2975–2880
mixture was stirred for 1 h, even though the colour of the mixture
turned grey after a few minutes. The reaction was quenched with
(
CH), 2235 (CN), 1655 (CO), 1595 (C=C). ESI-Tof (m/z): calcd
+ +
18 2 2
for C17
H
N
O
: 305.1266 [M+Na] ; found: 305.1256 [M+Na] .
: C 72.32, H 6.43, N 9.92%; found: C 71.85,
sat. aq. NaHCO
and extracted three times with Et
were washed with water and brine, dried with MgSO
3
solution (30 mL), diluted with Et
O. The combined organic phases
and evapo-
2
O (50 mL)
Calcd for C17
H
18
N
2
O
2
2
H 6.19, N 9.80%.
4
rated. The crude mixture was purified by column chromatography
Further functionalization
on silica gel (hexane/EtOAc 3:1, 1:1, 1:3) affording compound 2
◦
1
as colourless solid (213 mg, 88%, dr 95:5), mp. 195–200 C. H
NMR (500 MHz, CDCl + 5% DMSO-d , Me Si): d
= 1.31 (3H,
s, 9-CH
), 2.01 (1H, ddd, J = 2.0, 7.9, 13.2 Hz, 8-H), 2.11 (1H, m
Preparation of rac-(7R*,9S*,9aR*,10S*)-7,10-diallyl-9-hydroxy-
9-methyl-6-oxo-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-car-
bonitrile (17). 3.7 mL of a freshly prepared LDA (0.5 M)
3
6
4
H
3
c
,
4
478 | Org. Biomol. Chem., 2009, 7, 4475–4480
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solution was added to compound 2 (200 mg, 0.83 mmol) in THF
0.21 mmol) and Boc
2
O (50 mg, 0.23 mmol) in MeOH (3 mL) was
◦
(
5 mL) at -78 C. After addition of HMPA (0.52 mL, 3.0 mmol),
added and the mixture was stirred at room temperature under an
atmosphere of hydrogen. Completion of the reaction was followed
by TLC analysis. The solid residue was filtered off through a pad
◦
the solution was stirred at -78 C for 20 min, then shortly warmed
up to 0 C to redissolve the lithiated compound and cooled to
◦
◦
-
78 C again. Allyl iodide (0.2 mL, 2.2 mmol) was added and
of silica gel which was thoroughly washed with CH
2
Cl /MeOH.
2
the mixture was warmed up to room temperature over night.
The reaction was quenched with sat. aq. NH Cl and extracted
three times with Et O. The combined organic phases were washed
with water and brine, dried with MgSO and evaporated. The
crude mixture was purified by column chromatography on silica
gel (hexane/EtOAc 9:1, 3:1) affording compound 17 as colourless
The organic solvent was removed under reduced pressure and
the crude product was purified by column chromatography on
silica gel (hexane/EtOAc 1:1 to EtOAc/MeOH 3:1) affording
4
2
◦
4
compound 20 as colourless solid (70 mg, 91%), mp. 204–206 C.
1
H NMR (400 MHz, CDCl
3
, Me
4
Si): d
H
= 1.30 (3H, s, 9-CH
3
),
1.44 (9H, s, C(CH
3
)
3
), 1.97 (1H, m
c
, 8-H), 2.03 (1H, ddd, J = 2.6,
1
oil (222 mg, 83%). H NMR (400 MHz, CDCl
3
, Me
4
Si): d
H
=
7.9, 12.9 Hz, 8-H), 2.58 (1H, ddd, J = 7.9, 10.9, 18.6 Hz, 7-H),
1
.57 (3H, s, 9-CH
.03 (1H, dd, J = 8.2, 13.0 Hz, 8-H), 2.26 (1H, s, OH), 2.51 (1H,
), 2.66 (1H, m , 7-CH ),
.74 (1H, dtd, J = 4.0, 8.3, 10.5 Hz, 7-H), 2.85 (1H, dd, J = 8.3,
4.0 Hz, 10-CH ),
), 2.92 (1H, tdd, J = 1.4, 6.2, 14.0 Hz, 10-CH
.12 (1H, tdd, J = 1.0, 2.0, 10.1 Hz, CH=CH ), 5.18 (1H, m
), 5.26 (1H, ddd, J = 1.6, 2.7, 17.0 Hz, CH=CH ),
), 5.77 (2H, m
), 7.17 (1H, dt, J = 1.1, 7.6 Hz, 2-H), 7.35 (1H, ddd, J
3
), 1.78 (1H, ddd, J = 1.0, 10.5, 13.0 Hz, 8-H),
2.71 (1H, ddd, J = 2.6, 7.6, 18.6 Hz, 7-H), 3.45 (1H, dd, J = 8.8,
2
19.4 Hz, 10-CH
2
), 3.57 (1H, m
c
, 10-H), 3.90 (1H, m
c
, 10-CH ),
2
dddd, J = 1.0, 2.1, 7.3, 13.8 Hz, 7-CH
2
c
2
3.96 (1H, d, J = 9.8 Hz, 9a-H), 4.11 (1H, s, OH), 5.34 (1H, s,
NH), 7.10 (1H, dt, J = 0.9, 7.4 Hz, 2-H), 7.22 (1H, d, J = 7.4 Hz,
1-H), 7.26 (1H, t, J ª 7.7 Hz, 3-H), 8.21 (1H, d, J = 8.1 Hz, 4-
2
1
5
2
2
1
3
2
c
,
H). C NMR (100 MHz, CDCl
3
, Me
4
Si): d
C
= 20.0 (q, 9-CH
3
),
CH=CH
2
2
28.3 (q, C(CH
CH NHBoc), 70.1 (s, C-9), 80.1 (s, C(CH
128.4 (4d, C-4, C-1, C-2, C-3), 130.6, 142.6, 157.1, 167.8 (4 s, 2Ar,
3
)
3
), 31.3, 37.3 (2t, C-7, C-8), 43.2 (d, C-10), 69.8 (t,
5
.29 (1H, ddd, J = 1.0, 2.2, 10.1 Hz, CH=CH
2
c
,
2
3 3
)
), 116.9, 123.1, 124.3,
CH=CH
2
-
1
=
1.3, 7.6, 8.2 Hz, 3-H), 7.40 (1H, ddd, J = 0.6, 1.3, 7.6 Hz, 1-H),
CO
(CH), 1705 (CO), 1625 (CO), 1590 (C=C). ESI-Tof (m/z): calcd
: 369.1785 [M+Na] ; found: 369.1790 [M+Na] .
2
tBu, C-6). IR: nmax/cm = 3310 (OH), 3045 (ArH), 2990–2855
1
3
8
.28 (1H, ddd, J = 0.6, 1.1, 8.2 Hz, 4-H). C NMR (100 MHz,
CDCl , Me Si): d ), 37.2 (t, C-8), 40.9 (d, C-7),
3.9 (t, 7-CH ), 44.3 (s, C-10), 46.6 (t, 10-CH
1.2 (d, C-9a), 117.1 (d, C-4), 118.5 (t, CH=CH
21.9 (t, CH=CH
+
+
3
4
C
= 20.1 (q, 9-CH
3
for C19
H
26
N
2
O
4
4
7
1
1
2
2
2
), 71.0 (s, C-9),
), 120.5 (s, CN),
2
), 123.8, 125.0 (2d, C-1, C-3), 127.9 (s, Ar),
Acknowledgements
30.4 (d, C-2), 130.5, 134.4 (2d, CH=CH
2
), 141.9, 169.7 (2 s, Ar,
C-6). IR: nmax/cm-1 = 3075–3060 (ArH), 2990–2870 (CH), 1770
Support of this work by the Studienstiftung des deutschen Volkes,
the Fonds der Chemischen Industrie (fellowships to C. B.),
the Deutsche Forschungsgemeinschaft and the Bayer Schering
Pharma AG is most gratefully acknowledged. We also thank Dr
R. Zimmer for his help during the preparation of this manuscript.
(
3
3
CO), 1620, 1595 (C=C). ESI-Tof (m/z): calcd for C20
H
22
N
2
O :
2
+
+
+
23.1754 [M+H] , 345.1573 [M+Na] ; found: 323.1757 [M+H] ,
+
45.1579 [M+Na] .
rac-(9S*,9aR*,10S*)-10-Allyl-9-(tert-butyl-dimethyl-silyloxy)-
9
-methyl-6-oxo-7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-car-
◦
bonitrile (19). Colourless solid (40 mg, 93%), mp. 143–146 C.
References
1
H NMR (500 MHz, CDCl
.26 (3H, s, SiCH
.01 (2H, m
3
, Me
), 0.96 (9H, s, SiC(CH
, 8-H), 2.57 (1H, m
.7, 18.2 Hz, 7-H), 2.79 (1H, dd, J = 8.8, 13.9 Hz, 10-CH
), 4.11 (1H, s, 9a-H), 5.20 (1H,
), 5.24 (1H, d, J = 10.1 Hz, CH=CH ),
), 7.14 (1H, t, J =
4
Si): d
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3
),
),
1
(a) Selected recent reviews on samarium diiodide promoted reactions,
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7
1
Me
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For the formation of medium-sized carbocycles and heterocycles by
intramolecular samarium ketyl addition to alkene and alkyne units,
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1
3
3
,
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C
3
)
3 3
(
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2
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3
3
4
(
s, CN), 121.7 (t, =CH
2
(a) For the intramolecular additions of samarium ketyls to aryl groups,
see: C. U. Dinesh and H.-U. Reissig, Angew. Chem., 1999, 111, 874–876;
C. U. Dinesh and H.-U. Reissig, Angew. Chem., Int. Ed., 1999, 38, 789–
Ar), 130.1, 130.6 (2d, C-3, CH=CH
2
), 141.6, 167.7 (2 s, Ar, C-6).
IR: nmax/cm- = 3080–3010 (ArH), 2950–2860 (CH), 2235 (CN),
1
7
91; (b) F. Aulenta, M. Berndt, I. Br u¨ dgam, H. Hartl, S. S o¨ rgel and
1
3
4
660 (CO), 1595 (C=C). ESI-Tof (m/z): calcd for C23
H
32
N
2
O Si:
2
H.-U. Reissig, Chem.–Eur. J., 2007, 13, 6047–6062; (c) R. S. Kumaran,
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+
+
+
70.2197 [M-CN] , 419.2125 [M+Na] ; found: 370.2213 [M-CN] ,
+
19.2148 [M+Na] .
3
635–3646; (e) F. Aulenta, U. K. Wefelscheid, I. Br u¨ dgam and H.-U.
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9
-methyl-6-oxo-7,8,9,9a,10-hexahydropyrido[1,2-a]indol-10-yl)-
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sion of activated Raney-Ni (50 mg, 0.26 mmol, 30 wt% in H O) in
MeOH (10 mL) for 1 h. Then a solution of compound 2 (50 mg,
2
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 4475–4480 | 4479

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5
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7
(a) The use of HMPA as additive strongly raises the reducing ability of
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480 | Org. Biomol. Chem., 2009, 7, 4475–4480
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