Samarium diiodide induced cyclizations of γ-,δ-and ε-indolyl ketones: Reductive coupling, intermolecular trapping, and subsequent transformations of indolines

Article abstract of DOI:10.1002/chem.201100981

This comprehensive study describes our results of samarium diiodide induced 5-exo-trig to 8-exo-trig cyclization/alkylation sequences of 3′-acceptor-substituted indolyl ketones. All cyclization precursors were easily prepared by simple N-alkylation or N-a

Full text of DOI:10.1002/chem.201100981

DOI: 10.1002/chem.201100981
Samarium Diiodide Induced Cyclizations of g-, d- and e-Indolyl Ketones:
Reductive Coupling, Intermolecular Trapping, and Subsequent
Transformations of Indolines
Christine Beemelmanns, Dieter Lentz, and Hans-Ulrich Reissig*[a]
Abstract: This comprehensive study
describes our results of samarium di-
ACHTUNGTRENNUNGiodide induced 5-exo-trig to 8-exo-trig
G
center, a common structural motif in
various indole alkaloids. The relative
configurations of the products were es-
tablished by NOE experiments and by
single-crystal analysis and follow the
rules already established. Furthermore,
the obtained products were subjected
to a series of chemical transformations,
such as oxidation, reduction, and meta-
thesis reactions resulting in a range of
interesting synthetic building blocks
valuable for further applications.
cyclization/alkylation sequences of 3’-
acceptor-substituted indolyl ketones.
All cyclization precursors were easily
prepared by simple N-alkylation or N-
acylation of indole derivatives with the
corresponding iodo alkanones, acid
chlorides, or lactones. After treatment
of indolyl ketones with two equivalents
of SmI2, the generated stabilized carb-
Introduction
tionalized C6 skeletons.[10,11] In further consequence, we sys-
tematically investigated appropriately substituted ketones
with aryl and naphthyl groups as acceptors for the electron-
rich ketyl radicals.[12] An obvious extension of the described
SmI2-induced cyclization–dearomatization reaction involved
the employment of N-heteroaromatic ring systems, such as
quinoline,[13] pyrrole, and indole derivatives.[14]
It is well established that radical chemistry offers a wide
array of useful transformations for the construction of com-
plex molecular architectures.[1] Among those, the cycliza-
tions of carbon-centered radicals onto unsaturated function-
al groups have been considered as one of the most useful re-
À
actions for C C bond formation and have been used as key
The general importance of N-heterocycles, of indole de-
rivatives in particular,[15] originates from their ubiquitous
presence in natural products and pharmaceutically relevant
compounds. Among these, strychnos alkaloids belong to the
transformations in many natural-product syntheses.[2] Since
the introduction of samarium diiodide in organic synthesis[3]
it has played a central role in radical chemistry as a unique
electron-transfer reagent.[4] Along this line, Molander and
co-workers,[5] our group,[6] and others[7] have widely investi-
gated the intramolecular ketyl–olefin coupling, which led to
interestingly functionalized (poly)cyclic compounds and has
also successfully been exploited for the synthesis of natural
products and pharmaceutically relevant compounds.[8]
During our investigations of ketyl–alkynyl couplings for
the synthesis of cyclooctanol derivatives we serendipitously
gained access to hexahydronaphthalenes by a novel ketyl–
aryl coupling.[6b,9] These transformations occur under dearo-
matization of the arene ring and hence are of high synthetic
value with the aryl group serving as a precursor for func-
most fascinating indole derivatives.[16] The interesting biolog-
ical activities have motivated organic chemists to provide
not only efficient routes towards the synthesis of natural
products, but also to generate analogous and novel struc-
tures that could potentially lead to useful drugs. Therefore,
development of new concepts and synthetic methods to-
wards the synthesis of indole alkaloids is an ongoing topic in
organic chemistry.
[a] Dr. C. Beemelmanns, Prof. Dr. D. Lentz,+ Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustr. 3, 14195 Berlin (Germany)
Fax : (+49)30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
[+] Responsible for X-ray analyses
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100981.
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FULL PAPER
Intrigued by the “privileged” indole moiety we started a
systematic investigation of SmI2-induced ketyl couplings of
indolyl ketones. As depicted in Scheme 1 we could convert
lective chemical transformations provided interesting build-
ing blocks illustrating the potential of the obtained products
to serve as intermediates for the construction of complex
indole structures.
Results and Discussion
Formation of tri- and tetracyclic compounds: To investigate
the applicability of the SmI2-induced cyclization/alkylation
procedure, we prepared a series of simple indolyl ketones
differing in chain length (g- to e-substituted ketones) and in
the C-3ꢃ substituent of the indole moiety. The indolyl ke-
tones were generally obtained by simple acylation of the
corresponding indole derivatives with different acid chlor-
ides or lactones (Weinreb protocol[18]), a procedure already
described and optimized by our group.[14]
Scheme 1. Samarium diiodide induced cyclizations of substituted g-indol-
yl ketones with tBuOH as the proton source. X=O or H,H.
differently substituted indolyl ketones in the presence of
SmI2 and a proton source into highly functionalized dihy-
droindole derivatives with good to excellent diastereoselec-
tivities in up to 92% yield. In particular, electron-deficient
systems proved to be excellent acceptors for the electron-
rich ketyl radicals. Here the reductive cyclizations could be
performed even in the absence of hexamethylphosphor-
For a first systematic investigation we chose 3’-methoxy-
carbonyl-substituted indole derivative 1, which was subject-
ed to the standard cyclization/alkylation procedure (2.2–
2.5 equiv of SmI2 and 10.0 equiv of HMPA in THF, 3.0–
10.0 equiv of trapping reagent).[18] In analogy to previous re-
sults of the cyclization of 3’-cyano-substituted indolyl ketone
3,[14d] it was possible to irreversibly trap the intermediate sa-
marium enolate D (see Scheme 4) in the presence of HMPA
with a series of electrophiles including allyl and alkyl halides
or a-bromo esters (Table 1). Depending on the reactivity of
the electrophile the expected substituted tricyclic dihydroin-
dole products 2 were obtained in moderate to very good
yields and with almost perfect diastereoselectivities. In all
cases, the protonated cyclization product 5 was isolated in
minor amounts leading to an overall yield of 70–90% of cyc-
lization products. Changing from methyl iodide as the trap-
ping reagent (Table 1, entry 1) to ethyl or propyl iodide (en-
tries 2 and 3) the yield decreased from 80 to 47 and 40%,
respectively. By using the more reactive benzyl bromide
(entry 4) and prenyl bromide (entry 5) the process afforded
the desired compounds 2 f and 2g in 70 and 57% yield. Al-
kylation with electrophiles of similar reactivity, such as a-
bromo ethyl acetate (entry 6), TMS-protected propargyl
bromide (entry 7) or bromo acetonitrile (entry 8) furnished
the expected cyclization/alkylation products in 71–86%
yield. In comparison, previously reported 3-cyano-substitut-
ed derivative 3 afforded the alkylated cyclization products
in only 35–50% yield.[14d]
ACHTUNGTRENNUNG
intermediate samarium organyls[17] of 3’-methoxycarbonyl-
and 3’-cyano-substituted indolyl ketones. In preliminary
studies, cyclization intermediates of 3’-methoxycarbonyl-sub-
stituted indolyl ketone 1 could stereoselectively be trapped
with allyl iodide affording compound 2a in 53% yield.[14a]
The presence of HMPA strongly increased the alkylation
rate, probably due to the ability of this additive to break ag-
gregates, providing 2a in excellent yields (Scheme 2).[14e]
Similar results were obtained with 3’-cyano-substituted in-
dolyl ketone 3 furnishing 4a in moderate yield, in which
competing protonation of the carbanionic intermediate
lowers the conversion.[14d]
When chloro benzylformate was used as an electrophile,
in situ decarboxylation occurred probably generating a reac-
tive benzyl halide that was trapped by the samarium enolate
affording compound 2 f in 45% yield (Scheme 3). As al-
ready described for 3-cyano-substituted derivative 3,[14d]
changing to the less reactive cyano benzylformate (Manderꢃs
reagent), the desired product 2k was obtained in good yield.
Scheme 2. Samarium diiodide induced cyclizations of g-indolyl ketones
with allyl iodide as the trapping reagent.
Based on these promising results, we decided to investi-
gate the substrate scope of the cyclization/alkylation se-
quence in greater detail. Herein, we summarize our compre-
hensive results demonstrating that 3’-alkoxycarbonyl-substi-
tuted indolyl ketones are excellent substrates for the SmI2-
induced cyclization/alkylation and cyclization/acylation se-
quences by using various trapping reagents. Subsequent se-
Mechanism: The earlier proposed mechanism of the SmI2-
induced ketyl–hetaryl cyclization of 3’-substituted indolyl
ketones is assumed to follow predominately the “carbonyl-
first” mechanism as depicted in Scheme 4.[12] However, it
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H.-U. Reissig et al.
Table 1. SmI2-induced cyclization of 3’-methoxycarbonyl-substituted in-
dolyl ketone 1 and subsequent trapping experiments with different alkyl
and allyl halides.[a]
Yield [%][b]
À
Entry R X
Product
Scheme 3. SmI2-induced cyclization of precursor 1 and subsequent acyl-
AHCTUNGTREGaNNNU tion experiments.
2b
2c
80
1
CH3I
(2b/2c d.r. ꢀ7:1)
47
2
3
2d
2e
(d.r. >99:1)
40
(d.r. >99:1)
70
Scheme 4. Proposed mechanism and transition state for ketyl–indolyl cyc-
lizations (HMPA ligands at the samarium are omitted for simplicity, but
certainly play an important role in the reaction outcome).[21]
4
5
2 f
2g
(d.r. >99:1)
cannot be excluded that the reductive radical cyclization
mechanism proceeds through an “arene-first”[4g] mechanism
as suggested by Kise et al.[19] It is believed that in a first step
samarium ketyl B is formed in equilibrium from SmI2 and
indolyl ketone A. The ketyl radical B subsequently adds to
the activated aromatic system through a six-membered tran-
sition state C. For steric and electronic reasons, the bulky sa-
marium alkoxide, presumably bearing three or four ligands,
is assumed to favor an equatorial position leaving the
methyl group in an axial position.[20]
57
(d.r. >99:1)
71
6
2h
(d.r. >99:1)
The attack of the trapping reagent to intermediate samari-
um enolate D occurs (almost) exclusively from the less-hin-
dered side due to steric shielding of the concave face of the
intermediate by the adjacent ring. This kinetic control leads
to the expected product as the major or single diastereomer.
As described in our previously published work, the SmI2-in-
duced 6-exo-trig cyclizations of 3’-methoxycarbonyl-substi-
tuted indolyl ketones proceed even in the absence of
HMPA.[14,21] However, subsequent successful trapping of the
enolate D requires the presence of HMPA to achieve high
yields.
86
7
8
2i
2j
(d.r. >99:1)
79
(d.r. >99:1)
[a] All reactions were carried out with 2.2–2.5 equiv of SmI2, 10.0 equiv
of HMPA; after cyclization (1–2 min) 3.0–10.0 equiv of the alkylating re-
agent were added. For further details, see the Supporting Information.
[b] All yields refer to analytically pure samples.
Thus, under optimized reaction conditions, three stereo-
genic centers can be controlled in this transformation in-
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Samarium Diiodide Induced Cyclizations of Indolyl Ketones
FULL PAPER
cluding a quaternary carbon atom at the benzylic position of
the dihydroindole moiety. This structural motif can be found
in many indole alkaloids. The relative configurations of the
obtained compounds were determined by NOE experiments.
In addition, after O-TBS-protection of compound 2j a solid-
state structure of the resulting compound 2l could be ob-
tained by X-ray crystallography (Figure 1).
Scheme 6. SmI2-induced 7- and 8-exo-trig cyclizations of indolyl ketones
8 and 11 and subsequent trapping experiments.
pete with the reductive cyclization, thus diminishing the
amount of starting material available for the cyclization
step. In addition, dihydroindole formation and reduction to
the secondary alcohol were observed when the increasing
distance of the carbonyl group and the indolyl acceptor
moiety disfavor the cyclization for entropic and enthalpic
reasons.[14e]
Figure 1. Molecule structure (ORTEP)[22] of TBS-protected derivative 2l.
Thermal ellipsoids at 50% probability.
To further extend the scope of the SmI2-induced cycliza-
tion/functionalization sequence, we investigated alternative
3’-alkoxycarbonyl-substituted indole derivatives. For exam-
ple, the benzyl and allyl esters 14 and 16 were converted
into the expected cyclization products 15 and 17 in excellent
yields (Scheme 7).
Substrate scope: Encouraged by the described successful
cyclization sequence, SmI2-induced ketyl coupling of precur-
sor 6 containing a cycloalkanone moiety was also examined.
As expected, the 6-exo-trig cyclization/allylation sequence
proceeded smoothly in a highly diastereoselective fashion,
yielding the tetracyclic product 7 in good yield as a single
diastereomer (Scheme 5).
Scheme 5. SmI2-induced 6-exo-trig cyclization/allylation sequence of cy-
clohexanone derivative 6.
We also envisaged the synthesis of highly substituted
seven- and eight-membered tri- or tetracyclic indole deriva-
tives, as depicted in Scheme 6. The 7-exo-trig cyclization of
indolyl ketone 8 under standard conditions and subsequent
addition of allyl iodide furnished lactone 9 in 51% yield.
The analogous 8-exo-trig cyclization of precursor 11 afford-
ed the alkylated derivatives 12a and 12b, respectively, only
in moderate yield. The cyclized, but unalkylated lactones 10
and 13 were isolated in small or considerable quantities. As
already observed for the simple cyclization reactions,[14e] the
(reductive) deacylations of starting materials 8 and 11 com-
Scheme 7. SmI2-induced cyclization/alkylation sequence of benzyl and
allyl esters 14 and 16.
We were very pleased to learn that (3’-bromopropoxy)car-
bonyl-substituted derivative 18[18] furnished under standard
cyclization/allylation conditions indole derivatives 19–21 in
an overall yield of 70%. Besides the expected bromo-substi-
tuted product 19 and lactone 20, a subsequent in situ Finkel-
stein reaction (by the unavoidable samarium(II) and (III)
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H.-U. Reissig et al.
Table 2. SmI2-induced cyclization/alkylation sequence of chain-elongated
iodide species present in the mixture) afforded iodo-substi-
tuted compound 21 in 28% yield (Scheme 8). Reductive re-
moval of the bromine atom of 19 was observed only in
minor amounts (<5%).
indolyl ketones 22.[a]
Entry
R1 X
R2–Y Product
Yield
[%][b]
CO2Me
H,H
1
22a
22b
22c
23a 91
Scheme 8. Cyclization/allylation sequence of (3’-bromopropoxy)carbonyl-
substituted indole derivative 18.
CO2Me
O
2
3
23b 91
23c 86
In preliminary experiments, we had already demonstrated
that the SmI2-induced cyclization/allylation sequence of
chain-elongated derivatives 22a and 22b proceeds smoothly
giving products of type 23.[14e] Hence, we investigated the
scope of the process with a few typical examples as present-
ed in Table 2. They involve N-alkylated derivative 22a, 3’-
methoxy- and 3’-benzyloxycarbonyl-substituted derivatives
22b and 22c, and the cyano compound 22d. Gratifyingly,
esters 22a–c (Table 2, entries 1–3) provided good to excel-
lent yields of the cyclization products 23a–c, whereas cyano-
substituted indolyl ketone 22d (entry 4) yielded only 42%
of the alkylated product 23d in addition to 33% (d.r. 4:1) of
the protonated product 23e.[19]
CO2Bn
O
23d 42
CN
O
4
22d
33
23e
ACHTUNGTRENNUNG(d.r. 4:1)
Subsequent transformations: In subsequent studies we also
demonstrated by standard transformations that the cycliza-
tion products are versatile precursors of synthetically inter-
esting indole building blocks. The allylic double bond of
compound 2a was smoothly epoxidized with meta-chloroper-
benzoic acid (m-CPBA) under standard conditions, provid-
ing compound 24 in 73% yield (Scheme 9). Probably due to
the steering effect of the hydroxyl group, this reaction oc-
curred in a stereoselective fashion generating 24 as a single
diastereomer (with yet unknown relative configuration).
Synthesis of aldehyde 26 was also achieved in good overall
yield by protection of the hydroxyl group, subsequent dihy-
droxylation of the allylic double bond with potassium
osmate,[23] and final diol cleavage with sodium periodate.
The direct ozonolysis of unprotected alcohol 2a was also at-
tempted, but it yielded only an inseparable mixture of oxi-
dized products.
[a] All reactions were carried out with 2.2–2.5 equiv of SmI2, 10.0 equiv
of HMPA; after cyclization (1–2 min) 3.0–10.0 equiv of trapping reagent
were added. [b] All yields refer to analytically pure samples.
Protected compound 25 was also subjected to a cross-
metathesis reaction with Grubbs second-generation catalyst
(GII) and tert-butyl acrylate (Scheme 10) affording the ex-
pected trans-substituted alkene 27 in excellent yield
(89%).[24]
Scheme 9. Epoxidation and oxidative cleavage of the allylic double bond
of indole derivative 2a leading to 24 and 26. NMO=N-methylmorpho-
line-N-oxide; TBSOTf=tert-butyldimethylsilyl triflate; TEA=triethyl-
Based on previous results,[14d] the acetonitrile moiety of
indole derivative 2j was smoothly reduced in the presence
of Raney-nickel and tert-butoxycarbonyl (Boc)-anhydride
AHCTUNGTRENGNaUN mine.
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Samarium Diiodide Induced Cyclizations of Indolyl Ketones
FULL PAPER
Scheme 10. Cross-metathesis reaction of compound 25 with Grubbs 2nd-
generation catalyst and tert-butyl acrylate providing compound 27.
under an atmosphere of hydrogen affording Boc-protected
amine 28 in high yield (Scheme 11). Reduction in the ab-
sence of Boc-anhydride furnished the interesting spirolac-
Scheme 12. Raney-nickel reduction of cyclization product 23b and subse-
quent Boc-protection of spirolactam 31 leading to tetracyclic spirolactam
32.
Scheme 11. Raney-nickel reductions of precursors 2j and 4b providing
isomeric indole spirolactam derivatives 29 and 30.
Scheme 13. CuI-catalyzed [3+2]-cycloaddition of alkyne 33 and d-glu-
cose-derived azide 34 affording triazoles 35a and 35b. TBAF=tetra-n-
butylammonium fluoride.
tam 29 in excellent yield (92%). A very similar result was
obtained by starting from indole derivative 4b,[14d] which
gave the constitutional isomer 30 in 92% yield. Our ap-
proach by samarium diiodide induced cyclizations of indole
derivatives followed by reductive processes hence opens an
efficient and selective route to indole spirolactam deriva-
tives, which are important substructures in biologically
active compounds.[25,26]
Similar results were obtained by subjecting indole deriva-
tive 23b to the standard reduction protocol with Raney-
nickel affording the chain-elongated functionalized spirolac-
tam 31 (Scheme 12). For better characterization of the prod-
uct, the free NH group of spirolactam 31 was treated with
Boc-anhydride affording protected lactam 32 in 92% yield.
Finally, alkynyl-substituted indole derivative 2i was
one hour and afforded a 1:1 mixture of the two diastereo-
mers 35a and 35b, which could be easily separated by
column chromatography.
These exemplary transformations demonstrate that the
side chains introduced as electrophilic components in the
cyclization/alkylation protocol offer a great versatility for
the synthesis of many dihydroindole containing products. It
also allows the preparation of hybrid natural products (e.g.
indole/carbohydrate conjugates).[29]
Conclusion
desilylACHTUNGTRENNUNGated to monosubstituted alkyne 33, which was subject-
ed to a CuI-catalyzed [3+2]-cycloaddition[27] with enantio-
pure d-glucose derived azide 34 and TBTA (tris[(1-benzyl-
In extension to our previous results we could show that dif-
ferent 3’-alkoxycarbonyl-substituted and 3’-cyano-substitut-
ed indolyl ketones with varying side chain length could be
cyclized in a highly diastereoselective manner. The inter-
1H-1,2,3-triazol-4-yl)methyl]amine)[28]
as
the
ligand
(Scheme 13). The reaction proceeded smoothly in less than
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H.-U. Reissig et al.
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
mediate samarium organyls were stereoselectively trapped
with a variety of electrophiles affording a broad range of
cyclization products. Although HMPA was not necessary for
the SmI2-induced reductive 6-exo-trig cyclizations, the addi-
tive significantly facilitated the alkylation reactions of the
intermediate samarium enolates, presumably by formation
of more reactive ion pairs. Hence, the SmI2-induced cycliza-
tion constitutes a modular method for the diastereoselective
construction of highly substituted synthetically valuable tri-
and tetracyclic building blocks. Furthermore, the newly in-
troduced substitution pattern allowed a series of smooth
chemical transformations, such as oxidation of the allylic
double bond, reductions of cyano groups, metathesis reac-
tion, or CuI-catalyzed [3+2]-cycloaddition. The selected ex-
amples feature the broad applicability of the obtained prod-
ucts in functional-group transformations leading to structur-
ally highly diversified compounds.
Syntheses of cyclization precursors
General procedure for acylation reactions (GP1): SOCl2 (1.5 equiv) was
added dropwise to the corresponding carboxylic acid (1.3 equiv). The re-
sulting solution was stirred for 2 h under exclusion of water. The excess
of SOCl2 was evaporated under reduced pressure. The obtained carboxyl-
ic acid chloride was dissolved in CH2Cl2 (1 mL per mmol acid chloride)
under argon and added to a mixture of the corresponding indole deriva-
tive (0.8–1.0 equiv), 4-dimethylaminopyridine (DMAP) (0.05–0.10 equiv),
and Et3N (1.1–1.3 equiv) in CH2Cl2 (5 mL per mmol indole). The result-
ing mixture was stirred overnight under an atmosphere of argon at the
indicated temperature, quenched with sat. aq. NH4Cl solution, and
washed several times with water and brine. The organic phase was dried
with MgSO4, filtrated, and the solvent evaporated under reduced pres-
sure. The obtained residue was purified by column chromatography on
silica gel (hexane/EtOAc).
Benzyl 1-(4-oxopentanoyl)-1H-indole-3-carboxylate (14): According to
GP1, levulinic acid chloride (1.39 g, 10.3 mmol) was added to a solution
of 3’-benzyloxycarbonyl indole (1.42 g, 6.31 mmol), DMAP (60 mg,
0.49 mmol), and Et3N (1.44 g, 14.3 mmol) in CH2Cl2 (40 mL) at 08C. The
mixture was stirred at RT for 1 d and worked up as stated above. Purifi-
cation by column chromatography on silica gel (Hex/EtOAc 5:1 to 1:1)
afforded compound 14 (1.95 g, 88%) as a slightly red solid. M.p. 65–
688C; 1H NMR (400 MHz, CDCl3): d=2.29 (s, 3H; 5-H), 2.97 (t, J=
6.4 Hz, 2H; 3-H), 3.25 (t, J=6.4 Hz, 2H; 2-H), 5.41 (s, 2H; OCH2Ph),
7.31–7.45 (m, 6H; Ar), 7.45–7.50 (m, 2H; Ar), 8.16 (dd, J=1.4, 7.2 Hz,
1H; Ar), 8.26 (s, 1H; Ar), 8.40 ppm (dd, J=1.5, 7.9 Hz, 1H; Ar);
13C NMR (125 MHz, CDCl3): d=29.6 (t; C-2), 30.0 (q; C-5), 37.2, 66.4
(2t; C-3, OCH2), 114.0 (s; Ar), 116.5, 121.7, 124.9, 126.1 (4d; Ar), 127.4
(s; Ar), 128.4, 128.4, 128.7, 130.7 (4d; Ar), 136.1, 136.2, 163.8, 170.6,
Experimental Section
General information: Reactions were performed under argon in flame-
dried flasks and solvents and reagents were added by syringes. THF was
transferred from a MB SPS-800-dry solvent system directly into a flame-
dried flask. HMPA was distilled from calcium hydride (1308C, 12 mbar)
and stored over molecular sieves (4 ꢄ) under argon. Argon was purged
through the solutions in THF to eliminate residual oxygen prior to use.
206.3 ppm (5s; 2Ar, C-1, CO2Bn, C-4); IR (KBr): n˜ =3135–3010
À1
À
À
G
Warning: HMPA has been identified as a carcinogenic reagent. Use of
gloves is required during handling. Reactions, handling, and chromatogra-
phy should be performed in well-ventilated hoods.
MS (ESI-TOF): m/z: calcd for C21H19NO4: 372.1206 [M+Na]+, 388.0951
[M+K]+; found: 372.1215 [M+Na]+, 388.0953 [M+K]+; elemental analy-
sis calcd (%) for C21H19NO4 (349.4): C 72.19, H 5.48, N 4.01; found: C
71.87, H 5.47, N 4.05.
Triethylamine and diisopropylamine were distilled from potassium hy-
droxide and stored over KOH under argon. Dichloromethane was dis-
tilled over calcium hydride and stored over molecular sieves (4 ꢄ) under
argon. Dry DMF and dry DMSO were purchased from Aldrich and
stored under an atmosphere of argon before used. Products were purified
by flash chromatography on silica gel (230–400 mesh, Merck) or neutral
alumina (activity III, Fluka). Preparative HPLC was carried out on a nu-
cleosil 50–5 column (diameter 16 mm, length 244 mm); a Knauer variable
UV detector (l=254 nm), and Knauer refractometer were used. Unless
otherwise stated, yields refer to analytically pure samples. NMR spectra
were recorded on Bruker (AC 250, WH 270, AC 500, AVIII) and JOEL
(ECX 400, Eclipse 500) instruments. Chemical shifts are reported relative
to TMS (1H: d=0.00 ppm) and CDCl3 (13C: d=77.0 ppm). Integrals are
in accordance with assignments, coupling constants are given in Hz. All
13C NMR spectra are proton-decoupled. For detailed peak assignments
2D spectra were measured (COSY, HMQC, HMBC, NOESY, and NOE
if necessary). IR spectra were measured with a Nicolet 5 SXC FTIR
spectrometer or with a Nexus FTIR spectrometer equipped with a Nico-
let Smart DuraSample IR ATR. MS and HRMS analyses were per-
formed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT CH7A (EI,
80 eV, 3 kV) and Varian Ionspec QFT-7 (ESI-FT ICRMS) instruments.
Elemental analyses were carried out with CHN-Analyzer 2400 (Perkin–
Elmer), Vario EL, or Vario EL III. Melting points were measured with a
Reichert apparatus Thermovar and are uncorrected.
General procedure for the preparation of a SmI2 stock solution (0.1 m in
THF; GP2): Iodine (3.81 g, 15.0 mmol, 1.0 equiv) and samarium (2.71 g,
18.0 mmol, 1.2 equiv) were suspended in THF (150 mL, 10 mL per mmol
I2) under an argon atmosphere and stirred at room temperature until the
color of the solution turned into dark blue (1–5 h). The flask was then
wrapped in aluminum foil to exclude light and stored at room tempera-
ture under argon.
General procedure for samarium diiodide induced cyclization and subse-
quent alkylation (GP3): HMPA (10.0 equiv) was added to a solution of
SmI2 and the blue-purple solution was stirred for 15 min under an atmos-
phere of argon. The indole derivative (1.0 equiv) was dissolved in THF
(16 mL per mmol indole) and argon was bubbled through the solution
for 10–20 min. The resulting solution was added in one portion to the
deep-blue solution of SmI2/HMPA. After the solution color turned
brownish/yellow the alkylation/acylation reagent (3.0–10.0 equiv) was
added in one portion. After 30–60 min, the reaction was quenched with a
sat. aq. solution of NaHCO3, the organic phase was separated, and the
aq. phase was extracted three times with diethyl ether. The combined
ether extracts were washed with brine, dried with MgSO4, filtrated, and
evaporated. The resulting crude product was purified by flash chromatog-
raphy on silica gel by using hexane/ethyl acetate mixtures; in singular
cases additional purification by HLPC yielded the pure compounds.
Methyl
hexahydropyrido
(9S*,9aR*,10S*)-9-hydroxy-9,10-dimethyl-6-oxo-6,7,8,9,9a,10-
[1,2-a]indole-10-carboxylate (2b): According to GP3,
X-ray crystallography: Single crystals for the X-ray diffraction experi-
ment were selected by using a microscope and mounted on the top of a
glass fiber. Data were collected by using a Bruker-AXS SMART CCD
diffractometer with MoKa radiation (l=0.71073 ꢄ, graphite monochro-
mator) at 133 K. The structures were solved by direct methods and re-
fined anisotropically (C, N, O) by least-squares methods including the hy-
drogen atoms on calculated positions (riding model) by using the pro-
gram SHELX-97.[30] CCDC-818109 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
AHCTUNGTRENNUNG
SmI2 solution (12.0 mL, 1.20 mmol), HMPA (800 mg, 8.70 mmol), indole
derivative 1 (140 mg, 0.51 mmol), and methyl iodide (600 mg, 4.23 mmol)
afforded after purification by column chromatography on silica gel (Hex/
EtOAc 4:1, 1:1, EtOAc) and HPLC purification diastereomer 2b
(114 mg, 70%) as colorless solid and diastereomer 2c (15 mg, 10%) as
1
colorless oil. M.p. 171–1738C; H NMR (500 MHz, CDCl3): d=1.25, 1.80
(2s, each 3H; 10-CH3, 9-CH3), 1.88 (ddd, J=2.0, 7.5, 12.5 Hz, 1H; 8-H),
9726
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 9720 – 9730

Samarium Diiodide Induced Cyclizations of Indolyl Ketones
FULL PAPER
1.99 (dt, Jꢀ7.5, 12.5 Hz, 1H; 8-H), 2.58 (ddd, J=7.5, 11.8, 18.6 Hz, 1H;
7-H), 2.70 (ddd, J=2.0, 7.5, 18.6 Hz, 1H; 7-H), 3.63 (s, 3H; OCH3), 4.16
(s, 1H; 10-H), 7.09 (t, Jꢀ7.4 Hz, 1H; 3-H), 7.13 (d, J=7.4 Hz, 1H; 1-H),
7.27 (dt, Jꢀ1.5, 8.1 Hz, 1H; 2-H), 8.27 ppm (d, J=8.1 Hz, 1H; 4-H);
13C NMR (125 MHz, CDCl3): d=19.9, 27.2 (2q; 10-CH3, 9-CH3), 30.8,
37.9 (2t; C-7, C-8), 52.8 (q; OCH3), 52.9 (s; C-10), 70.5 (s; C-9), 77.3 (d;
C-9a), 116.9, 123.4, 124.3, 128.8 (4d; C-4, C-1, C-2, C-3), 132.7, 142.1,
emental analysis calcd (%) for C21H27NO4Si (385.5): C 64.66, H 6.78, N
3.77; found: C 64.82, H 7.01, N 3.51.
Methyl
(9S*,9aR*,10S*)-10-(cyanomethyl)-9-hydroxy-9-methyl-6-oxo-
[1,2-a]indole-10-carboxylate (2j): Accord-
6,7,8,9,9a,10-hexahydropyrido
AHCTUNGTRENNUNG
ing to GP3, SmI2 solution (48.0 mL, 4.80 mmol), HMPA (4.00 g,
22.3 mmol), indole derivative 1 (546 mg, 2.00 mmol), and bromo acetoni-
trile (800 mg, 6.67 mmol) afforded after purification by column chroma-
tography on silica gel (Hex/EtOAc 4:1, 1:1, EtOAc) and HPLC com-
pound 2j (500 mg, 79%) as a colorless solid. M.p. 73–748C; 1H NMR
(500 MHz, CDCl3): d=1.30 (s, 3H; 9-CH3), 1.89 (ddd, J=1.7, 7.0,
13.0 Hz, 1H; 8-H), 2.07 (dt, Jꢀ7.0, 13.0 Hz, 1H; 8-H), 2.55–2.67 (m, 1H;
7-H), 2.73 (ddd, J=1.7, 7.0, 18.6 Hz, 1H; 7-H), 2.79 (s, 1H; OH), 3.31 (d,
J=17.1 Hz, 1H; 10-CH2), 3.40 (d, J=17.1 Hz, 1H; 10-CH2), 3.64 (s, 3H;
OCH3), 4.34 (s, 1H; 9a-H), 7.16 (dt, Jꢀ1.0, 7.6 Hz, 1H; 2-H), 7.31 (dd,
J=1.2, 7.6 Hz, 1H; 1-H), 7.38 (dt, Jꢀ1.2, 7.6 Hz, 1H; 3-H), 8.30 ppm (d,
J=8.2 Hz, 1H; 4-H); 13C NMR (125 MHz, CDCl3): d=20.0 (q; 9-CH3),
25.9, 31.0, 38.5 (3t; 10-CH2, C-7, C-8), 53.2 (s; C-10), 54.0 (q; OCH3),
70.5 (s; C-9), 74.1 (d; C-9a), 116.9 (s; CN), 117.4, 122.6, 124.9 (3d; C-4,
C-1, C-2), 129.0 (s; Ar), 130.0 (d; C-3), 142.7, 167.0, 171.5 ppm (3s; Ar,
À
167.4, 175.3 ppm (4s; 2Ar, C-7, CO2Me); IR (KBr): n˜ =3285 (O H),
À1
À
À
3065–3040 (=C H), 3000–2845 (C H), 1715, 1620 (C=O), 1600 cm
ACHTUNGTRENNUNG
(C=C); MS (ESI-TOF): m/z: calcd for C16H19NO4: 290.1387 [M+H]+,
312.1206 [M+Na]+, 328.0946 [M+K]+; found: 290.1399 [M+H]+,
312.1217 [M+Na]+, 328.0958 [M+K]+.
Data for methyl (9S*,9aR*,10R*)-9-hydroxy-9,10-dimethyl-6-oxo-
6,7,8,9,9a,10-hexahydropyridoACHTUNGTRNEUNG
[1,2-a]indole-10-carboxylate (2c): 1H NMR
(500 MHz, CDCl3): d=1.25, 1.62 (2 s, each 3H; 10-CH3, 9-CH3), 1.94
(ddd, J=2.4, 7.4, 12.8 Hz, 1H; 8-H), 2.03 (dt, Jꢀ7.0, 12.8 Hz, 1H; 8-H),
2.62 (ddd, J=7.4, 11.8, 18.6 Hz, 1H; 7-H), 2.76 (ddd, J=2.4, 7.0, 18.6 Hz,
1H; 7-H), 3.86 (s, 3H; OCH3), 4.79 (s, 1H; 9a-H), 7.10 (dt, Jꢀ1.1,
7.3 Hz, 1H; 2-H), 7.29 (t, Jꢀ7.3 Hz, 1H; 3-H), 7.34 (dd, J=1.6, 8.2 Hz,
1H; 1-H), 8.27 ppm (d, J=8.2 Hz, 1H; 4-H); 13C NMR (100 MHz,
CDCl3): d=21.8, 23.2 (2q; 10-CH3, 9-CH3), 31.3, 39.9 (2t; C-7, C-8), 53.2
(q; OCH3), 55.1 (s; C-10), 70.86 (d; C-9a), 70.89 (s; C-9), 117.0, 123.3,
124.6, 128.9 (4d; C-4, C-1, C-2, C-3), 133.4, 140.6, 168.1, 175.5 ppm (4s;
À
À
C-6, CO2Me); IR (KBr): n˜ =3400 (O H), 3040 (=C H), 3000–2850
À
(C H), 2250 (CꢁN), 1730, 1660–1635 (C=O), 1595 (C=C) cmÀ1; elemen-
tal analysis calcd (%) for C17H18N2O4 (314.3): C 64.96, H 5.77, N 8.91;
found: C 64.61, H 5.61, N 8.65.
À
2Ar, C-7, CO2Me); IR (KBr): n˜ =3290 (OH), 3065–3035 (=C H), 3000–
Benzyl
(9S*,9aR*,10S*)-10-(cyanomethyl)-9-hydroxy-9-methyl-6-oxo-
[1,2-a]indole-10-carboxylate (15): Accord-
À1
À
2835 (C H), 1720, 1625 (C=O), 1590 cm (C=C); MS (ESI-TOF): m/z:
6,7,8,9,9a,10-hexahydropyrido
AHCTUNGTRENNUNG
calcd for C16H19NO4: 312.1206 [M+Na]+; found: 312.1208 [M+Na]+.
ing to GP3, SmI2 (50.0 mL, 5.00 mmol), HMPA (3.60 g, 20.1 mmol),
indole derivative 14 (700 mg, 2.00 mmol), and bromo acetonitrile (1.00 g,
8.34 mmol) furnished after workup and purification by column chroma-
tography on silica gel (Hex/EtOAc 3:1, 1:1, EtOAc) compound 15
(670 mg, 85%) as a colorless solid. M.p. 72–758C; 1H NMR (500 MHz,
CDCl3): d=1.24 (s, 3H; 9-CH3), 1.85 (ddd, J=1.7, 7.0, 12.7 Hz, 1H; 7-
H), 2.04 (dt, Jꢀ7.0, 12.7 Hz, 1H; 7-H), 2.53 (ddd, J=7.0, 12.7, 18.5 Hz,
1H; 8-H), 2.69 (ddd, J=1.7, 7.0, 18.5 Hz, 1H; 8-H), 2.79 (brs, 1H; OH),
3.34 (d, J=17.2 Hz, 1H; 10-CH2), 3.38 (d, J=17.2 Hz, 1H; 10-CH2), 4.36
(s, 1H; 9a-H), 4.95 (d, J=12.7 Hz, 1H; OCH2Ph), 5.22 (d, J=12.7 Hz,
1H; OCH2Ph), 6.95–6.99 (m, 2H; Ar), 7.14 (dt, Jꢀ0.9, 7.4 Hz, 1H; 2-H),
7.24–7.27 (m, 4H; Ar, 1-H), 7.38 (dt, Jꢀ1.2, 7.4 Hz, 1H; 3-H), 8.31 ppm
(dd, J=0.4, 8.2 Hz, 1H, 4-H); 13C NMR (100 MHz, CDCl3): d=20.2 (q;
9a-CH3), 25.6, 30.9, 38.4 (3t; 10-CH2, C-7, C-8), 54.3 (s; C-10), 67.7 (t;
OCH2), 70.6 (s; C-9), 74.1 (d; C-9a), 116.8 (s; CN), 117.5, 122.6, 124.8
(3d; C-4, C-1, C-2), 127.3*, 128.3, 128.5* (3d; Ar), 129.1 (s; Ar), 130.1
(d; C-3), 134.0, 142.8, 167.0, 170.7 ppm (4s; 2Ar, C-6, CO2Bn) (*double
Methyl
(9S*,9aR*,10S*)-10-benzyl-9-hydroxy-9-methyl-6-oxo-
[1,2-a]indole-10-carboxylate (2 f): Accord-
6,7,8,9,9a,10-hexahydropyrido
AHCTUNGTRENNUNG
ing to GP3, SmI2 solution (24.0 mL, 2.40 mmol), HMPA (1.60 g,
8.93 mmol), indole derivative 1 (273 mg, 1.00 mmol), and benzyl bromide
(1.00 g, 5.88 mmol) furnished after purification by column chromatogra-
phy on silica gel (Hex/EtOAc 4:1, 1:1, EtOAc) compound 2 f (255 mg,
70%) as a colorless solid. M.p. 190–1928C; 1H NMR (500 MHz, CDCl3):
d=1.19 (s, 3H; 9-CH3), 1.86 (ddd, J=3.6, 7.7, 13.3 Hz, 1H; 8-H), 1.97
(ddd, J=7.7, 10.4, 13.3 Hz, 1H; 8-H), 2.53 (ddd, J=7.7, 10.4, 18.3 Hz,
1H; 7-H), 2.66 (ddd, J=3.6, 7.7, 18.3 Hz, 1H; 7-H), 3.34 (d, J=13.7 Hz,
1H; 10-CH2), 3.68 (d, J=13.7 Hz, 1H; 10-CH2), 3.71 (s, 3H; OCH3), 3.91
(s, 1H; OH), 4.35 (s, 1H; 9a-H), 6.94–6.98 (m, 3H, 1-H; Ar), 7.04 (dt, J
ꢀ0.9, 7.7 Hz, 1H; 2-H), 7.18–7.22 (m, 3H; Ar), 7.29 (dt, Jꢀ1.3, 7.7 Hz,
1H; 3-H), 8.23 ppm (d, J=8.2 Hz, 1H; 4-H); 13C NMR (100 MHz,
CDCl3): d=20.7 (q, 9-CH3), 30.9, 37.8, 46.2 (3t; C-7, C-8, 10-CH2), 53.1
(q; OCH3), 58.5, 70.8 (2s; C-10, C-9), 73.0 (d; C-9a), 116.5, 123.3, 126.2,
127.3*, 128.3* (5d; C-4, C-2, C-1, Ar), 129.0 (s; Ar), 129.0, 131.1 (2d;
C-3, Ar), 135.0, 142.6, 167.9, 175.5 ppm (4s; 2Ar, C-6, CO2Me) (*double
À
À
À
intensity); IR (KBr): n˜ =3385 (O H), 3065–2880 (=C H, C H), 2255
(CꢁN), 1730, 1660–1640 (C=O), 1595 cmÀ1 (C=C); MS (ESI-TOF): m/z:
calcd for C23H22N2O4: 391.1658 [M+H]+, 413.1477 [M+Na]+, 429.1217
[M+K]+; found: 391.1666 [M+H]+, 413.1481 [M+Na]+, 429.1225
[M+K]+; elemental analysis: calcd (%) for C23H22N2O4 (390.4): C 70.75,
H 5.68, N 7.17; found: C 70.20, H 5.58, N 7.31.
À
À
intensity); IR (ATR): n˜ =3495 (O H), 3060–3000 (=C H), 2945–2870
À1
À
(C H), 1710, 1660 (C=O), 1595 cm (C=C); MS (ESI-TOF): m/z: calcd
for C22H23NO4: 388.1519 [M+H]+, 404.1259 [M+Na]+; found: 388.1511
[M+H]+, 404.1254 [M+Na]+.
Methyl (9S*,9aR*,10S*)-9-hydroxy-9-methyl-6-oxo-10-[3-(trimethylsilyl)-
Benzyl (9R*,9aR*,10S*)-9-[2-(tert-butyldimethylsiloxy)ethyl]-10-(cyano-
prop-2-ynyl]-6,7,8,9,9a,10-hexahydropyrido
G
methyl)-9-hydroxy-6-oxo-6,7,8,9,9a,10-hexahydropyridoACTHNGUTER[NNUG 1,2-a]indole-10-
(2i): According to GP3, SmI2 solution (24.0 mL, 2.40 mmol), HMPA
(1.90 g, 10.6 mmol), indole derivative 1 (280 mg, 1.03 mmol), and (3-bro-
moprop-1-ynyl)trimethylsilane (800 mg, 4.34 mmol) provided after purifi-
cation by column chromatography on silica gel (Hex/EtOAc 4:1, 1:1,
EtOAc) compound 2i (340 mg, 86%) as a colorless solid. M.p. 132–
carboxylate (23c): According to GP3, SmI2 solution (12.0 mL,
1.20 mmol), HMPA (2.00 g, 11.2 mmol), indole derivative 22c (500 mg,
1.00 mmol), and bromo acetonitrile (1.00 g, 8.34 mmol) afforded after pu-
rification by column chromatography on silica gel (Hex/EtOAc 9:1, 4:1,
1:1) 23c (460 mg, 86%) as a colorless solid. M.p. 98–1018C; 1H NMR
1
1338C; H NMR (500 MHz, CDCl3): d=0.05 (s, 9H; SiCH3), 1.22 (s, 3H;
(500 MHz, CDCl3): d=0.09 (s, 6H; SiCH3), 0.90 (s, 9H; SiCACHTNGUTERNNU(G CH3)3), 1.60
9-CH3), 1.88 (ddd, J=2.3, 7.7, 13.1 Hz, 1H; 8-H), 2.01 (dt, Jꢀ7.3,
12.3 Hz, 1H; 8-H), 2.51–2.62 (ddd, J=7.7, 11.6, 18.5 Hz, 1H; 7-H), 2.72
(ddd, J=2.2, 7.7, 18.5 Hz, 1H; 7-H), 2.96 (d, J=16.9 Hz, 1H; 10-CH2),
3.19 (d, J=16.9 Hz, 1H; 10-CH2), 3.62 (s, 1H; OH), 3.70 (s, 3H; OCH3),
4.31 (s, 1H; 9a-H), 7.09 (dt, Jꢀ 0.6, 7.6 Hz, 1H; 2-H), 7.30 (dt, Jꢀ0.8,
7.9 Hz, 1H, 3-H), 7.46 (dd, J=0.6, 7.6 Hz, 1H; 1-H), 8.27 ppm (d, J=
8.2 Hz, 1H; 4-H); 13C NMR (100 MHz, CDCl3): d=À0.2 (q; SiCH3), 20.1
(q; 9-CH3), 30.8, 31.8, 37.8 (3t; C-7, C-8, 10-CH2), 53.0 (q; OCH3), 56.4,
70.4 (2s; C-10, C-9), 74.3 (d; C-9a), 89.4, 101.9 (2s; CꢁCTMS), 116.6,
124.0, 124.7, 129.1 (4d; C-4, C-1, C-2, C-3), 130.0, 142.4, 167.4, 173.9 ppm
(td, Jꢀ2.2, 14.5 Hz, 1H; 9-CH2), 1.71 (dt, Jꢀ4.9, 15.0 Hz, 1H; 9-CH2),
1.97 (dt, Jꢀ5.7, 13.6 Hz, 1H; 8-H), 2.19 (ddd, J=1.6, 6.3, 13.6 Hz, 1H; 8-
H), 2.32 (ddd, J=6.3, 13.6, 18.5 Hz, 1H; 7-H), 2.67 (ddd, J=1.6, 6.3,
18.5 Hz, 1H; 7-H), 3.43 (d, J=17.2 Hz, 1H; 10-CH2), 3.46 (d, J=17.2 Hz,
1H; 10-CH2), 3.56 (ddd, Jꢀ2.2, 4.9, 10.5 Hz, 1H; CH2OTBS), 3.74 (dt, J
ꢀ2.2, 11.5 Hz, 1H; CH2OTBS), 4.36 (s, 1H; OH), 4.48 (s, 1H; 9a-H),
5.03, 5.06 (AB system, JAB =12.4 Hz, 2H; OCH2Ph), 7.01–7.05 (m, 2H;
Ar), 7.14 (dt, Jꢀ0.8, 7.7 Hz, 1H; 2-H), 7.22–7.26 (m, 4H; Ar, 1-H), 7.37
(dt, Jꢀ1.2, 7.6 Hz, 1H; 3-H), 8.31 ppm (d, J=8.1 Hz, 1H; 4-H);
13C NMR (100 MHz, CDCl3): d=À5.7, À5.6 (2q; SiCH3), 17.9 (s; SiC-
À
À
(4s; 2Ar, C-6, CO2Me); IR (ATR): n˜ =3380 (O H), 3250–3010 (=C H),
G
ACHTUGNTERN(NUNG CH3)3), 30.9, 31.0, 32.8 (3t; C-7,
À1
À
2990–2895 (C H), 2175 (CꢁC), 1735, 1630 (C=O), 1595 cm (C=C); el-
Chem. Eur. J. 2011, 17, 9720 – 9730
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9727

H.-U. Reissig et al.
C-9a), 74.2 (s; C-9), 117.6, 122.1, 124.8 (3d; C-4, C-1, C-2), 127.7*, 128.3,
128.4* (3d; Ar), 129.9 (s; Ar), 130.1 (d; C-3), 134.2, 142.9, 167.0,
170.3 ppm (4d; 2Ar, C-6, CO2Bn) (*double intensity); IR (KBr): n˜ =
0.26 mmol), Boc2O (80 mg, 0.37 mmol), and Raney-Ni (ca. 200 mg) were
stirred in MeOH (20 mL) under an atmosphere of hydrogen for 1 d. Fil-
tration of the mixture and flash column chromatography on silica gel
(Hex/EtOAc 5:1, 1:1, EtOAc) yielded compound 28 (100 mg, 94%) as a
colorless solid. M.p. 78–798C; 1H NMR (400 MHz, CDCl3): d=1.12 (s,
À
À
À
3445 (O H), 3065–3035 (=C H), 2950–2855 (C H), 2250 (CꢁN), 1730,
1665–1645 (C=O), 1600 cmÀ1 (C=C); MS (ESI-TOF): m/z: calcd for
C30H38N2O5Si: 557.2442 [M+Na]+; found: 557.2441 [M+Na]+.
3H; 9-CH3), 1.32 (s, 9H; OCACHTNURGTNEUNG(CH3)3), 1.81 (ddd, J=2.6, 7.6, 12.4 Hz, 1H;
8-H), 1.91–1.96 (td, Jꢀ6.5, 12.4 Hz, 1H; 8-H), 2.35 (ddd, J=4.6, 9.7,
14.2 Hz, 1H; 10-CH2), 2.40–2.50 (m, 1H; 10-CH2), 2.55 (ddd, J=6.5, 7.6,
18.6 Hz, 1H; 7-H), 2.63 (ddd, J=2.6, 7.6, 18.6 Hz, 1H; 7-H), 2.95–3.05
(m, 1H; CH2NHBoc), 3.10–3.20 (m, 1H; CH2NHBoc), 3.57 (s, 3H;
OCH3), 3.82 (s, 1H; OH), 4.36 (s, 1H; 9a-H), 4.70 (s, 1H; NH), 7.01 (t, J
ꢀ7.5 Hz, 1H; 2-H), 7.09 (d, J=7.5 Hz, 1H; 1-H), 7.20 (t, Jꢀ7.7 Hz, 1H;
3-H), 8.19 ppm (d, J=8.1 Hz, 1H; 4-H); 13C NMR (100 MHz, CDCl3):
Further transformations
Methyl
(9S*,9aR*,10S*)-9-hydroxy-9-methyl-10-(oxiran-2-ylmethyl)-6-
[1,2-a]indole-10-carboxylate (24):
oxo-6,7,8,9,9a,10-hexahydropyridoACHTUNGTRENNNUG
Compound 2a (80 mg, 0.25 mmol) was dissolved in CH2Cl2 (5 mL) and
m-CPBA (150 mg, 70 wt.%, 0.60 mmol) was added. The mixture was
stirred overnight and then diluted with CH2Cl2 (10 mL) and washed with
sat. aq. NaHCO3 (10 mL) and brine (10 mL). The aqueous phase was ex-
tracted with CH2Cl2 and the combined organic phases were dried with
MgSO4 and evaporated. Purification by column chromatography on silica
gel (Hex/EtOAc 4:1 to 1:1) furnished compound 24 as a colorless oil
(60 mg, 73%); 1H NMR (500 MHz, CDCl3): d=1.18 (s, 3H; 9-CH3),
1.86–1.94 (m, 2H; 8-H), 2.18 (dd, J=9.5, 15.6 Hz, 1H; 10-CH2), 2.46–2.55
(m, 1H; 7-H), 2.56 (dd, J=2.7, 4.7 Hz, 1H; OCH2), 2.65 (ddd, J=2.6,
6.7, 18.4 Hz, 1H; 7-H), 2.72 (t, Jꢀ4.4 Hz, 1H; OCH2), 2.73–2.80 (m, 2H;
OCH, 10-CH2), 3.13 (s, 1H; OH), 3.53 (s, 3H; OCH3), 4.60 (s, 1H; 9a-
H), 7.06 (d, J=7.5 Hz, 1H; 1-H), 7.09 (t, Jꢀ6.7 Hz, 1H; 2-H), 7.26 (t,
Jꢀ7.5 Hz, 1H; 3-H), 8.25 ppm (d, J=8.1 Hz, 1H; 4-H); 13C NMR
(100 MHz, CDCl3): d=19.8 (q; 9-CH3), 31.1, 38.6, 38.7 (3t; C-7, 10-CH2,
C-8), 46.5 (s; C-10), 48.7 (t; CHOCH2), 52.7 (d; 10-CH2CHOCH2), 55.7
(q; OCH3), 70.3 (s; C-9), 73.1 (d; C-9a), 117.3, 123.1, 124.3, 129.2 (4d; C-
4, C-1, C-2, C-3), 130.1, 143.2, 167.6, 173.5 ppm (4s; 2Ar, C-6, CO2Me);
d=20.1, 28.3 (2q; 9-CH3, OC
10-CH2, CH2NHBoc), 52.9 (q; OCH3), 55.5, 70.5 (2s; C-10, C-9), 72.9 (d;
C-9a), 79.5 (s; OC(CH3)3), 116.9, 124.1, 124.3 (3d; C-4, C-1, C-2), 128.9
(s; Ar), 129.7 (d; C-3), 142.6, 155.9, 167.8, 174.5 ppm (4s; Ar, COtBu, C-
ACHTUGNERTN(NUNG CH3)3), 30.9, 36.5, 37.9, 38.2 (4t; C-7, C-8,
AHCTUNGTRENNUNG
À
À
6, CO2Me); IR (KBr): n˜ =3350 (O H), 3070–3045 (=C H), 2975–2880
À1
À
(C H), 1730, 1710–1690, 1660–1640 (C=O), 1595 cm (C=C); MS (ESI-
TOF): m/z: calcd for C22H30N2O6: 441.2002 [M+Na]+; found: 441.1996
[M+Na]+.
(3’S*,9S*,9aR*)-9-Hydroxy-9-methyl-7,8,9,9a-tetrahydro-6H-spiro
ACHTUNGTRENNUNG[pyrido-
AHCTUNGTERG[NNUN 1,2-a]indole-10,3’-pyrrolidine]-2’,6-dione (29): According to GP4, indole
derivative 2j (70 mg, 0.22 mmol) and Raney-Ni (ca. 100 mg) were stirred
in MeOH (20 mL) for 1 d under an atmosphere of hydrogen. Filtration
of the mixture furnished compound 29 (59 mg, 92%) as a colorless solid.
1
M.p. >2008C; H NMR (500 MHz, CD3OD/DMSO 3:1): d=1.28 (s, 3H;
9-CH3), 1.72 (ddd, J=2.1, 6.6, 12.3 Hz, 1H; 8-H), 1.91 (td, Jꢀ6.6,
12.3 Hz, 1H; 8-H), 2.35–2.39 (m, 1H; 4’-H), 2.42 (ddd, J=6.6, 12.3,
18.5 Hz, 1H; 7-H), 2.45–2.50 (m, 1H; 7-H), 2.66 (td, Jꢀ8.8, 13.0 Hz, 1H;
4’-H), 3.29 (brt, Jꢀ9.0 Hz, 1H; 5’-H), 3.58 (q, Jꢀ8.2 Hz, 1H; 5’-H), 4.12
(s, 1H; 9a-H), 7.07 (t, Jꢀ7.5 Hz, 1H; 2-H), 7.21 (t, Jꢀ7.5 Hz, 1H; 3-H),
7.23 (d, J=7.2 Hz, 1H; 1-H), 7.85 (s, 1H; NH), 8.09 ppm (d, J=8.0 Hz,
1H; 4-H); 13C NMR (100 MHz, CD3OD/CDCl3 3:1): d=20.5 (q; 9-CH3),
31.0, 33.6, 38.23, 38.27 (4t; C-7, C-4’, C-5’, C-8), 53.5 (s; C-3’), 68.9 (s; C-
9), 76.6 (d; C-9a), 115.9, 122.3, 123.8, 127.7 (4d; C-4, C-1, C-2, C-3),
135.0, 142.7, 167.0, 174.9 ppm (4s; 2Ar, C-6, C-2’); IR (ATR): n˜ =3310,
À
À
À
IR (ATR): n˜ =3410 (O H), 3030–3000 (=C H), 2950–2940 (C H), 1725,
1635 (C=O), 1595 cmÀ1 (C=C); MS (ESI-TOF): m/z: calcd for
C18H21NO5: 354.1312 [M+Na]+; found: 354.1309 [M+Na]+.
Methyl (9S*,9aR*,10S*)-10-[(E)-4-tert-butoxy-4-oxobut-2-enyl]-9-(tert-
butyldimethylsiloxy)-9-methyl-6-oxo-6,7,8,9,9a,10-hexahydropyrido
a]indole-10-carboxylate (27): Under an atmosphere of argon compound
25 (100 mg, 0.17 mmol) was dissolved in CH2Cl2 (10 mL) followed by ad-
dition of tert-butyl acrylate (300 mg, 2.34 mmol) and GII-catalyst (30 mg,
35 mmol). After stirring at 408C overnight the solvent was evaporated
and the crude mixture subjected to column chromatography on silica gel
(Hex/EtOAc 10:1, 7:1, 1:1) yielding 27 (110 mg, 89%) as a colorless oil;
1H NMR (500 MHz, CDCl3): d=0.15, 0.19 (2s, each 3H; SiCH3), 0.93 (s,
ACHTUNGTNER[NUNG 1,2-
ACHTUNGTRENNUNG
À
À
3260 (NH), 3110–3040 (=C H), 2980–2865 (C H), 1700–1680, 1655
AHCTUNGTRENNUNG
(C=O), 1595 cmÀ1 (C=C); MS (ESI-TOF): m/z: calcd for C16H18N2O3:
309.1215 [M+Na]+; found: 309.1217 [M+Na]+.
9H; SiCACHTUNGTRENNUNG(CH3)3), 1.32 (s, 3H; 9-CH3), 1.41 (s, 9H; OCACHUTGNTREN(NUGN CH3)3), 1.92–2.04
(3’R*,9S*,9aR*)-9-Hydroxy-9-methyl-7,8,9,9a-tetrahydro-6H-spiro-
ACHUTNGRENUN[G pyridoACHUTNGTREN[NUGN 1,2-a]indole-10,3’-pyrrolidine]-5’,6-dione (30): According to GP4,
(m, 2H; 8-H), 2.50 (ddd, J=7.7, 11.5, 18.3 Hz, 1H; 7-H), 2.66 (ddd, J=
3.0, 5.7, 18.3 Hz, 1H; 7-H), 3.17 (ddd, J=1.7, 5.5, 15.3 Hz, 1H; 10-CH2),
3.28 (dd, J=9.4, 15.3 Hz, 1H; 10-CH2), 3.51 (s, 3H; OCH3), 4.20 (s, 1H;
9a-H), 5.85 (dd, J=1.7, 15.6 Hz, 1H; CH=CHCO2tBu), 6.60 (ddd, J=5.5,
9.4, 15.6 Hz, 1H; CH=CHCO2tBu), 7.02 (d, J=7.6 Hz, 1H; 1-H), 7.07 (t,
Jꢀ7.4 Hz, 1H; 2-H), 7.26 (dt, Jꢀ1.4, 8.1 Hz, 1H; 3-H), 8.26 ppm (d, J=
8.1 Hz, 1H; 4-H); 13C NMR (100 MHz, CDCl3): d=À1.8, À1.6 (2q;
indole derivative 4b (50 mg, 0.15 mmol) and Raney-Ni (ca. 100 mg) were
stirred in MeOH (20 mL) under an atmosphere of hydrogen for 1 d. Fil-
tration and flash column chromatography on silica gel (EtOAc, EtOAc/
MeOH 3:1) furnished compound 30 (40 mg, 92%) as a colorless solid.
M.p. >2008C; 1H NMR (400 MHz, CD3OD/CDCl3 3:1): d=1.35 (s, 3H;
9-CH3), 1.85 (ddd, J=2.8, 7.8, 12.9 Hz, 1H; 8-H), 1.91 (s, 1H; NH), 2.00
(ddd, J=7.8, 10.5, 12.9 Hz, 1H; 8-H), 2.58 (ddd, J=7.8, 10.5, 18.4 Hz,
1H; 7-H), 2.66 (d, J=16.6 Hz, 1H; 4’-H), 2.70 (ddd, J=2.8, 7.8, 18.4 Hz,
1H; 7-H), 2.84 (d, J=16.6 Hz, 1H; 4’-H), 3.24 (d, J=10.0 Hz, 1H; 2’-H),
3.35 (s, 1H; OH), 4.21 (s, 1H; 9a-H), 4.43 (d, J=10.0 Hz, 1H; 2’-H), 7.12
(dt, Jꢀ1.0, 7.6 Hz, 1H; 2-H), 7.26 (dt, Jꢀ1.3, 7.8 Hz, 1H; 3-H), 7.37 (dd,
J=0.8, 7.6 Hz, 1H; 1-H), 8.17 ppm (d, J=8.0 Hz, 1H; 4-H); 13C NMR
(100 MHz, CD3OD:CDCl3 3:1): d=21.0 (q; 9-CH3), 31.8, 39.6, 46.5 (3t;
C-7, C-8, C-4’), 51.4* (t, s; C-2’, C-3’), 71.6 (s; C-9), 73.9 (d; C-9a), 117.4,
122.3, 126.0, 129.5 (4d; C-4, C-1, C-2, C-3), 137.7, 141.4, 170.1, 178.1 ppm
SiCH3), 18.1 (s; SiC
(CH3)3), 31.0, 36.5, 39.0 (3t; C-8, C-7, 10-CH2), 52.1 (q; OCH3), 55.6 (s;
C-10), 73.6 (s; C-9), 73.7 (d; C-9a), 80.2 (s; OC(CH3)3), 117.4, 122.7,
ACHTUNGTRENNUNG(CH3)3), 20.7, 25.9, 27.9 (3q; 9-CH3, SiCCAHTUNGTREN(NUGN CH3)3, OC-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
124.4, 127.2, 128.8 (5d; C-4, C-1, C-2, CH=CHCO2tBu, C-3), 131.0 (s;
Ar), 142.1 (d; CH=CHCO2tBu), 143.0, 165.2, 167.2, 172.2 ppm (4s; Ar,
CO2Me, CO2tBu, C-6); IR (ATR): n˜ =3070 (=C H), 2950–2850 (C H),
1730, 1715, 1665 (C=O), 1595 cmÀ1 (C=C); MS (ESI-TOF): m/z: calcd for
C29H43NO6Si: 552.2752 [M+H]+; found: 552.2801 [M+H]+.
À
À
General procedure for hydrogenation with Raney-Ni (GP4): Raney Ni
(50 wt% in H2O) was washed with MeOH prior to use. A mixture of
Raney-Ni in MeOH (5 mL per 0.5 mmol indole derivative) was saturated
with hydrogen for 30 min. After addition of a solution of the indole de-
rivative and if required Boc2O (1.5 equiv) in MeOH (2 mL per 0.5 mmol
indole derivative), hydrogen was conducted through the mixture for
30 min. The mixture was stirred at RT under an atmosphere of hydrogen
until completion of the reaction was monitored by TLC. The solid resi-
due was filtered off, the residue thoroughly washed with MeOH, and the
solvents were removed in vacuo.
À
(4s; 2Ar, C-6, C-5’) (*double intensity); IR (ATR): n˜ =3260–3100 (N H,
À1
À
À
O H), 3000–2850 (C H), 1675, 1640 (C=O), 1590 cm (C=C); MS (ESI-
TOF): m/z: calcd for C16H18N2O3: 309.1215 [M+Na]+, 595.2533
[2M+Na]+; found: 309.1246 [M+Na]+, 595.2579 [2M+Na]+.
Acknowledgements
Methyl
droxy-9-methyl-6-oxo-6,7,8,9,9a,10-hexahydropyrido
boxylate (28): According to GP4, indole derivative 2j (80 mg,
(9S*,9aR*,10S*)-10-[2-(tert-butoxycarbonylamino)ethyl]-9-hy-
G
Support of this work by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie, the Studienstiftung des deutschen Volkes (fel-
9728
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 9720 – 9730

Samarium Diiodide Induced Cyclizations of Indolyl Ketones
FULL PAPER
lowships for C.B.), and the Bayer Schering Pharma AG is most gratefully
acknowledged. We thank Dr. S. Gross for the initial experiments, A. Ka-
malakumar and S. Mçhl for experimental assistance and Dr. R. Zimmer
for his help during the preparation of this manuscript. The help of C.
Groneberg for HPLC separations and the NMR service team for numer-
ous NOE experiments is also gratefully acknowledged.
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www.chemeurj.org
9729

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Received: March 30, 2011
Published online: July 8, 2011
9730
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