Efficient synthesis of medium-sized rings incorporating indole or pyrrole units by samarium diiodide induced cyclizations

Article abstract of DOI:10.1002/ejoc.200600743

Samarium diiodide promoted the intramolecular reductive couplings of N-alkylated indole and pyrrole derivatives 9-12 and 14 to afford products 15-19 that incorporate seven- and eight-membered rings. They were obtained in good yields and generally with exc

Full text of DOI:10.1002/ejoc.200600743

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600743
Efficient Synthesis of Medium-Sized Rings Incorporating Indole or Pyrrole
Units by Samarium Diiodide Induced Cyclizations
Virginie Blot[a] and Hans-Ulrich Reißig*[a]
Keywords: Samarium diiodide / Indoles / Pyrroles / Radical reactions / Medium-ring compounds
Samarium diiodide promoted the intramolecular reductive
couplings of N-alkylated indole and pyrrole derivatives 9–12
and 14 to afford products 15–19 that incorporate seven- and
eight-membered rings. They were obtained in good yields
and generally with excellent diastereoselectivities. Up to four
contiguous stereogenic centres are controlled in this transfor-
mation, which is explained by a highly ordered transition
structure with the samarium alcoholate moiety preferring an
equatorial position.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
structures are obviously “privileged”[7] since these heterocy-
cles are present in a myriad of pharmaceutically important
compounds.[8]
Introduction
Recent advances in the employment of samarium diio-
dide[1] have documented that this coupling reagent effec-
tively promotes a number of important and useful synthetic
reactions. Work in our laboratory has so far focused on the
stereoselective formation of five- and six-membered rings
by samarium ketyl cyclizations of suitably substituted β- or
γ-N-substituted indole and pyrrole derivatives,[2] which pro-
vided access to novel functionalized bi- and tricyclic com-
pounds (Scheme 1).[3–5] Herein we report the extension of
these studies in order to synthesize seven- and eight-mem-
bered rings[6] incorporating indole and pyrrole units. The
general importance of heterocyclic compounds derives from
their presence in numerous biologically active compounds.
Development of new methods for stereoselective synthesis
of heterocycles with complex functional groups is hence of
great value. More specifically, the indole and pyrrole sub-
Results and Discussion
The syntheses of the required precursor indoles or pyr-
roles started with the N-alkylation of commercially avail-
able indole or pyrrole derivatives 4 and 5 by employing so-
dium hydride followed by addition of alkyl iodides 6, 7 and
8 containing the protected carbonyl group;[9] these com-
pounds were obtained in three routine steps (ketaliz-
ation,[10] reduction[10] and iodination[11]) from correspond-
ing esters 1–3.[12] Hydrolysis of the ketals in the presence of
p-toluenesulfonic acid led to desired precursors 9–14 in
good overall yields (Scheme 2).[13]
We then studied the scope and limitations of the samar-
ium diiodide induced ketyl cyclization reactions by examin-
ing the feasibility of seven- and eight-membered ring forma-
tion with the precursors prepared. Substrates 9–14 were
generally subjected to 2.5 equiv. of samarium diiodide in
THF along with an excess of HMPA[14] (10 equiv.) and two
equiv. of phenol as a proton source.[15] The formation of
seven-membered rings (Scheme 3) was successful with in-
dole derivative 9 or pyrrole 12.[16] Expected bi- and tricyclic
products 15 and 16 were obtained in good yields and in a
diastereomerically pure form, which demonstrates that this
method allows for the generation of three contiguous ste-
reogenic centres with high selectivity. The relative configu-
rations of the products were determined by NOE experi-
ments. The mechanism of this type of reaction is usually
described[2,3] as a sequence of initial electron transfer to the
carbonyl group generating a radical anion (samarium ke-
tyl), formation of the new ring by intramolecular addition
of the samarium ketyl to the (het)aryl group, a second elec-
Scheme 1. Samarium diiodide induced cyclizations of hetaryl
ketones to bicyclic and tricyclic products containing indole and
pyrrole substructures.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
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V. Blot, H.-U. Reißig
SHORT COMMUNICATION
Scheme 4. Transition structure of the cyclization of 9 leading to
tricyclic product 15 (HMPA ligands are omitted for clarity and
simplicity).
also examined the possibility of cyclobutanol formation
and therefore prepared a precursor analogous to 9 but with
just one methylene group as a spacer unit between the in-
dole nitrogen and the carbonyl group. Not surprisingly, the
reaction failed to give the corresponding tricyclic com-
pound with an incorporated four-membered ring and only
the corresponding secondary alcohol that was formed by
reduction of the carbonyl group was isolated.
Scheme 2. Synthesis of precursor indoles 9–11 and pyrroles 12–14.
tron transfer and subsequent regioselective protonation
leading to the corresponding product.[17]
Scheme 5. Conversion of indole derivative 10 into tricyclic product
17 containing an azocin moiety.
The intramolecular samarium diiodide induced ketyl
couplings were also examined with precursors containing
a cycloalkanone moiety. Compounds 11 and 14 efficiently
furnished anticipated polycyclic products 18 and 19 in very
good yields (Scheme 6). In the case of indole derivative 18,
four contiguous stereogenic centres were established in a
highly selective manner (dr = 94:6), whereas the formation
of pyrrole derivative 19 proceeded less selectively (dr =
75:25). The structural assignments for the major dia-
stereomers as depicted in Scheme 6 are based on NOE ex-
Scheme 3. Formation of seven-membered heterocyclic compounds
15 and 16 by samarium diiodide induced cyclization of precursors
9 and 12.
We recently suggested[1b,2,3] that the high degree of dia-
stereoselectivity for this type of cyclization should be due
to a highly ordered cyclic transition structure of the ketyl
addition to the (het)aryl ring in which the samarium alco-
holate prefers the sterically more favourable equatorial po-
sition (Scheme 4). This model nicely explains the relative
configuration of the stereogenic centres within the seven-
membered ring. For compounds 15 and 16, the configura-
tion of the carbon bearing the alkoxycarbonyl group seems
to be governed by thermodynamic control, which (by de-
protonation/protonation) positions this substituent at the
convex face of the molecule.[18]
The synthesis of eight-membered rings (Scheme 5) is also
possible; however, only indole derivative 10 furnished ex-
pected product 17 in moderate yield, whilst pyrrole 13 gave
only traces (Ͻ5%) of a cyclized product together with small
Scheme 6. Ketyl couplings of cyclohexanone derivatives 11 and 14
leading to products 18 and 19 (only the major diastereomers are
amounts of starting material and unidentified products. We depicted, all compounds are racemic).
4990 Eur. J. Org. Chem. 2006, 4989–4992
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Medium-Sized Rings by Samarium Diiodide Induced Cyclizations
SHORT COMMUNICATION
tized products, see S.-C. Lin, F.-D. Yang, J.-S. Shiue, S.-M.
Yang, J.-M. Fang, J. Org. Chem. 1998, 63, 2909–2917.
For the formation of medium-sized carbocycles and heterocy-
cles by intramolecular samarium ketyl additions to alkene and
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C. U. Dinesh, A. L. Shaikh, R. Zimmer, Eur. J. Org. Chem.
2006, 4419–4428, and literature cited in this publication; b) A.
Hölemann, H.-U. Reißig, Synlett 2004, 2732–2735.
B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M.
Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. An-
derson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen,
P. J. Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J. Med.
Chem. 1988, 31, 2235–2246.
a) M. Somei, F. Yamada, Nat. Prod. Prep. 2005, 22, 73–103;
b) J. A. Joule in Science of Synthesis (Houben-Weyl, Methods
of Molecular Transformation) (Ed.: E. J. Thomas), Georg Thie-
me, Stuttgart, 2000; vol. 10, pp. 361–652; c) J. Bonjoch, J.
Bosch, Alkaloids 1996, 48, 75–189; d) R. J. Sundberg, Indoles,
Academic Press, London, 1996; e) J. E. Saxton, The Chemistry
of Heterocyclic Compounds, Academic Press, New York, 1994;
vol. 25, part IV; f) H. Döpp, U. Döpp, U. Langer, B. Gerding
in Methoden der Organischen Chemie (Houben-Weyl), Georg
Thieme, Stuttgart, 1994, vol. E6b1, pp 546–848 and vol. E6b2;
g) D. J. Chadwick, R. A. Jones, R. J. Sundberg in Comprehen-
sive Heterocyclic Chemistry (Eds.: A. R. Katritzky, C. W. Rees),
Pergamon, Oxford, 1984, vol. 4, pp. 155–376.
Compound 6: V. N. Odinokov, O. S. Kukovinets, V. G. Kas-
radze, E. Y. Tsyglintseva, E. P. Serebryakov, G. A. Tolstikov,
Chem. Nat. Compd. 1992, 28, 106–109; compound 7: G. A.
Molander, J. A. McKie, J. Org. Chem. 1994, 59, 3186–3192;
compound 8: D. Becker, Z. Harel, M. Nagler, A. Gillon, J. Org.
Chem. 1982, 47, 3297–3306.
periments and by analogy considering our earlier ketyl cyc-
lization experiments with cyclohexanone derivatives.[19] For
the major diastereomer of 19, an X-ray analysis unequivo-
cally proved the constitution and configuration of this com-
pound.[20] The minor diastereomers of 18 and 19 very likely
have cis-configuration of the substituents at the two indole
carbons; however, these assignments have to be confirmed
by additional experiments.
[6]
[7]
[8]
Conclusions
In summary, we have demonstrated that the intramolecu-
lar samarium ketyl addition to suitable indole and pyrrole
acceptors generates seven- and eight-membered rings con-
taining these heterocycles. Yields are moderate to very good
and excellent diastereoselectivities are observed. Up to four
contiguous stereogenic centres can be established in a
stereoselective fashion. Extension to other substrates to
further investigate the scope and limitations of this ring
forming process, as well as application of this method to the
synthesis of natural products or analogues, are in progress.
[9]
Acknowledgments
[10]
[11]
[12]
H. Takikawa, K.-i. Shimbo, K. Mori, Liebigs Ann./Recueil
1997, 821–824.
H. Maehr, M. R. Uskokovic, Eur. J. Org. Chem. 2004, 1703–
1713.
Compound 1 is commercially available; compound 2 was ob-
tained by esterification from the corresponding commercially
available carboxylic acid: R. A. Cavallaro, L. Filocamo, A. Ga-
luppi, A. Galione, M. Brufani, A. A. Genazzani, J. Med.
Chem. 1999, 42, 2527–2534; compound 3 was prepared by
Michael-type α-alkylation of cyclohexanone with methyl acry-
late: L. Cotarca, P. Delogu, P. Maggioni, A. Nardelli, R. Bian-
chini, S. Sguassero, Synthesis 1997, 328–332.
Support of this work by the Alexander von Humboldt Stiftung (Re-
search Fellowship to V. B.), the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie and the Schering AG is most
gratefully acknowledged. We also thank Dr. S. Yekta for her help
during preparation of this manuscript.
[1] For selected recent reviews on samarium diiodide promoted
reactions, see a) D. J. Edmonds, D. Johnston, D. J. Procter,
Chem. Rev. 2004, 104, 3371–3404; b) M. Berndt, S. Gross, A.
Hölemann, H.-U. Reißig, Synlett 2004, 422–438; c) H. B. Ka-
gan, Tetrahedron 2003, 59, 10351–10372; d) G. A. Molander,
C. R. Harris, Tetrahedron 1998, 54, 3321–3354.
[2] S. Gross, H.-U. Reißig, Org. Lett. 2003, 5, 4305–4307.
[3] For our group’s work concerning intramolecular samarium ke-
tyl additions to aryl groups, see a) M. Berndt, I. Hlobilová,
H.-U. Reißig, Org. Lett. 2004, 6, 957–960; b) S. Gross, H.-U.
Reißig, Synlett 2002, 2027–2030; c) M. Berndt, H.-U. Reißig,
Synlett 2001, 1290–1292; d) E. Nandanan, C. U. Dinesh, H.-
U. Reißig, Tetrahedron 2000, 56, 4267–4277; e) C. U. Dinesh,
H.-U. Reißig, Angew. Chem. 1999, 111, 874–876; Angew. Chem.
Int. Ed. 1999, 38, 789–791.
[4] For related aryl carbonyl couplings, see a) H. Ohno, M. Oku-
mura, S. I. Maeda, H. Iwasaki, R. Wakayama, T. Tanaka, J.
Org. Chem. 2003, 68, 7722–7732; b) H. Ohno, R. Wakayama,
S. I. Maeda, H. Iwasaki, M. Okumura, C. Iwata, H. Mikami-
yama, T. Tanaka, J. Org. Chem. 2003, 68, 5909–5916; c) J.-S.
Shiue, M.-H. Lin, J.-M. Fang, J. Org. Chem. 1997, 62, 4643–
4649; d) H.-G. Schmalz, S. Siegel, J. W. Bats, Angew. Chem.
1995, 107, 2597–2599; Angew. Chem. Int. Ed. Engl. 1995, 34,
2383–2385.
[5] a) Samarium diiodide induced intermolecular couplings of car-
bonyl compounds to indole derivatives: V. Blot, H.-U. Reißig,
Synlett 2006, in press; b) For a few inter- and intramolecular
indole carbonyl coupling reactions mainly providing rearoma-
[13]
Typical Procedure: Synthesis of 9: To a suspension of NaH
(120 mg, 2.96 mmol, 60% suspension in paraffin oil, 1.2 equiv.)
in DMF (8 mL) at room temp. was added
4 (432 mg,
2.47 mmol, 1 equiv.). After 30 min of stirring, alkyl iodide 6
(860 mg, 3.20 mmol, 1.3 equiv.) in DMF (2 mL) was added.
The mixture was stirred overnight, then diluted with Et2O
(10 mL), washed with water (3 times), the organic phase was
dried (MgSO4) and concentrated under reduced pressure. The
resulting oil was dissolved in a mixture of acetone/H2O (1:1,
8 mL) and PTSA (47 mg, 0.25 mmol, 0.1 equiv.) was added.
After completion of the reaction (TLC control), the solution
was diluted with Et2O (10 mL), washed with a saturated aq.
NaHCO3 solution, then the organic layer was dried (MgSO4)
and concentrated. Purification by chromatography on silica gel
(hexane/EtOAc, 2:1) gave corresponding ketone 9 (668 mg,
98%) as a colourless oil. 1H NMR (CDCl3, 500 MHz): δ =
1.55–1.61 (m, 2 H, CH2), 1.82–1.88 (m, 2 H, CH2), 2.08 (s, 3
H, CH3), 2.41 (t, J = 7.1 Hz, 2 H, CH2), 3.90 (s, 3 H, OCH3),
4.13 (t, J = 7.3 Hz, 2 H, NCH2), 7.24–7.29 (m, 2 H, Ar), 7.32–
7.36 (m, 1 H, Ar), 7.78 (s, 1 H, Ar), 8.15–8.19 (m, 2 H, Ar)
ppm. 13C NMR (CDCl3, 126 MHz): δ = 20.8, 29.2 (2 t, CH2),
29.8 (q, CH3), 42.7, 46.8 (2 t, CH2), 50.9 (q, OCH3), 106.9 (s,
Ar), 109.8, 121.7, 121.8, 122.6 (4 d, Ar), 126.7 (s, Ar), 134.0
(d, Ar), 136.3 (s, Ar), 165.4, 207.9 (2 s, CO) ppm. IR (KBr): ν
˜
= 3115, 3055 (=CH), 2995–2890 (CH), 1700 (CO), 1535 (C=C)
cm–1. MS (EI, 80 eV, 100 °C): m/z (%) = 273 (100) [M]+, 242
Eur. J. Org. Chem. 2006, 4989–4992
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4991

V. Blot, H.-U. Reißig
SHORT COMMUNICATION
(18) [M – OCH3]+, 188 (74) [M – CH3CO(CH2)4]+, 43 (64)
[CH3CO]+. HRMS (EI, 80 eV, 60 °C): calcd. for C16H19NO3
273.13651; found 273.13547.
(EI, 80 eV, 70 °C): calcd. for C16H21NO3 275.15213; found
275.15237.
Analytical data of diethyl 9-hydroxy-9-methyl-5,6,7,8,9,9a-
[14] The use of HMPA as an additive strongly raises the reducing
ability of samarium diiodide and is required for many ketyl
coupling reactions. See R. A. Flowers II, X. Xu, C. Timmons,
G. Li, Eur. J. Org. Chem. 2004, 2988–2990; E. Prasard, R. A.
Flowers II, J. Am. Chem. Soc. 2002, 124, 6895–6899; J. Inan-
aga, M. Ishikawa, M. Yamaguchi, Chem. Lett. 1987, 1485–
1486.
[15] For the use of phenol as a superior proton source rather than
the conventionally used tert-butyl alcohol, see refs.[2,3b] Also,
see R. Zriba, S. Bezzenine-Lafollée, F. Guibé, M.-G. Guillerez,
Synlett 2005, 2362–2366.
[16] General Procedure for Samarium Diiodide Coupling Reactions:
Samarium (2.7–2.8 equiv.) and 1,2-diiodoethane (2.5–
2.6 equiv.) were suspended in freshly distilled anhydrous THF
(10 mL per mmol of Sm) under an argon atmosphere and
stirred for 2 h at room temp., which provided a dark blue solu-
tion of samarium diiodide. The flask was then evacuated,
purged with argon and HMPA (10.0 equiv.) was added. After
stirring for 30 min., to the freshly prepared deep blue solution
of SmI2-HMPA, indole or pyrrole derivatives 9–14 (1.0 equiv.)
and phenol (3.0 equiv.), dissolved in THF (5 mL) were added
in one portion. After 30 min the reaction was quenched with
saturated aq. solution of NaHCO3, the organic layer was sepa-
rated and the aqueous layer was extracted with diethyl ether.
The combined ether extracts were washed with brine, dried
(MgSO4), filtered, and the solvents were evaporated. The re-
sulting crude product was purified by flash chromatography on
silica gel by using a hexane/ethyl acetate mixture (4:1).
hexahydro-1H-pyrrolo[1,2-a]azepine-1,2-dicarboxylate
(16):
colourless solid, m.p. 118–120 °C (Et2O). 1H NMR (CDCl3,
500 MHz): δ = 1.13 (s, 3 H, 9-CH3), 1.19 (t, J = 7.1 Hz, 3 H,
CH3), 1.24 (t, J = 7.1 Hz, 3 H, CH3), 1.31–1.41 (m, 1 H, 7-H),
1.50–1.55 (m, 1 H, 8-H), 1.56–1.65 (m, 1 H, 6-H), 1.74–1.88
(m, 3 H, 6-H, 7-H, 8-H), 2.14 (br. s, 1 H, OH), 3.27–3.39 (m,
2 H, 5-H), 3.86 (d, J = 6.4 Hz, 1 H, 9a-H), 3.93 (dd, J = 0.9,
6.4 Hz, 1 H, 1-H), 4.02–4.11 (m, 2 H, OCH2), 4.15 (q, J =
7.1 Hz, 2 H, OCH2), 7.07 (d, J = 0.9 Hz, 1 H, 3-H) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 14.1, 14.4 (2 q, CH3), 20.9 (q,
9-CH3), 22.3 (t, C-7), 27.3 (t, C-6), 44.2 (t, C-8), 48.7 (d, C-1),
49.1 (t, C-5), 58.9, 61.0 (2 t, OCH2), 74.3, 74.4 (d, s, C-9a, C-
9), 99.4 (s, C-2), 152.2 (d, C-3), 165.3, 174.7 (2 s, CO) ppm. IR
(KBr): ν = 3440 (OH), 3070 (=CH), 2980–2860 (CH), 1740
˜
(C=O), 1730, 1660 (C=O), 1595, 1445, 1375 (C=C) cm–1. MS
(EI, 80 eV, 70 °C): m/z (%) = 311 (10) [M]+, 266 (2) [M –
COOH]+, 192 (100), 43 (29) [CH3CO]+. C16H25NO5 (311.2):
calcd. C 61.72, H 8.09, N 4.50; found C 61.69, H 8.33, N 4.48.
[17] For rather electron-deficient hetaryl compounds such as indole
and pyrrole derivatives 9–14 as employed in this study we can-
not rigorously exclude an alternative mechanism. A Birch-type
reduction of the heteroaromatic ring followed by addition of
the resulting carbanion to the carbonyl group may also deliver
the observed products. For a recent example of the Birch re-
duction of pyrrole derivatives and subsequent reactions with
electrophiles, see: T. J. Donohoe, C. L. Rigby, R. E. Thomas,
W. F. Nieuenhuys, F. L. Bhatti, A. R. Cowley, G. Bhalay, I. D.
Linney, J. Org. Chem. 2006, 71, 6298–6301, and references cited
here. However, since we observe similar patterns of stereoselec-
tivity for the transformations presented here as for less elec-
tron-deficient aryl derivatives, we assume that the product de-
livering process follows the standard samarium ketyl coupling
mechanism.
Analytical
data
for
methyl
10-hydroxy-10-methyl-
7,8,9,10,10a,11-hexahydro-6H-azepino[1,2-a]indole-11-carbox-
ylate (15): pale yellow oil. 1H NMR (CDCl3, 500 MHz): δ =
1.06 (s, 3 H, 10-CH3), 1.41–1.48 (m, 1 H, CH2), 1.55–1.63 (m,
1 H, CH2), 1.74–2.05 (m, 4 H, CH2), 3.17 (ddd, J = 3.6, 5.1,
11.6 Hz, 1 H, 6-H), 3.34 (dt, J = 5.1, 11.6 Hz, 1 H, 6-H), 4.28,
4.19 (AB system, JA,B = 6.6 Hz, 2 H, 10a-H, 11-H), 6.37 (d, J
= 7.7 Hz, 1 H, Ar), 6.63 (dt, J = 1.0, 7.7 Hz, 1 H, Ar), 7.10–
7.14 (m, 1 H, Ar), 7.25 (d, J = 7.7 Hz, 1 H, Ar) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 20.3 (q, CH3-10), 23.4, 28.8 (2
[18] This assignment is in contrast to the relative configurations
presented in Scheme 1 of ref.[2] which have also been deter-
mined by NOE experiments. We shall discuss and eventually
correct the assignment of these compounds in a future full pub-
lication.
t, CH2), 45.8 (t, C-9), 48.4 (t, C-6), 48.5 (d, C-11), 52.4 (q, [19] For examples, see refs.[1b,3a,6a]
OCH3), 71.7 (d, C-10a), 75.2 (s, C-10), 106.5, 116.7, 124.5 (3
d, Ar), 124.6 (s, Ar), 128.8 (d, Ar), 152.1 (s, Ar), 173.6 (s, CO)
[20] I. Brüdgam, H. Hartl, Freie Universität Berlin, unpublished
results.
ppm. IR (KBr): ν = 3480 (OH), 3045 (=CH), 2930–2730 (CH),
Received: August 21, 2006
Published Online: October 5, 2006
˜
1740 (C=O), 1600, 1490 (C=C) cm–1. MS (EI, 80 eV, 70 °C):
m/z (%) = 275 (54) [M]+, 190 (100), 43 (94) [C2H3O]+. HRMS
4992
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