Samarium diiodide-induced diastereoselective synthesis of hexahydroquinoline derivatives

Article abstract of DOI:10.1055/s-2002-35599

Samarium diiodide-induced cyclization of aniline derivatives 5, 9, 12, 14, and 16 afforded hexahydroquinolines such as 6, 10, 13, 15, and 17 in moderate to good yields and excellent diastereoselectivities. Phenol was found to be a surprisingly effective proton source in some of these samarium-ketyl cyclizations. The influence of different substituents at nitrogen as well as at the aromatic ring of the aniline moiety was studied. Whereas para-donor-substituted aniline derivatives 19 and 21 provided the expected products 20 and 22, the corresponding para-cyano derivatives 23 and 26 took an alternative pathway. Ipso-substitution involving spiro intermediates 29 resulted in formation of rearranged products 24 and 28.

Full text of DOI:10.1055/s-2002-35599

LETTER
2027
Samarium Diiodide-Induced Diastereoselective Synthesis of Hexahydro-
quinoline Derivatives
D
iastereoselec
t
tive Sy
e
nthesis of
H
f
e
xahyd
f
r
oquinol
e
ine
s
n Gross, Hans-Ulrich Reissig*
Institut für Chemie - Organische Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 25 September 2002
We recently extended the scope of this reaction to aniline
derivatives, which yielded hexahydroquinoline deriva-
tives under the aforementioned reductive conditions
(Scheme 1, X = NR). Due to the nucleophilic character of
the ketyl, we anticipated that relatively electron-poor
aniline derivatives should be the most promising candi-
dates for this kind of cyclization reaction, and therefore
different substituents were attached to the nitrogen. The
required N-alkylated anilines were obtained using a palla-
dium(II)-catalyzed addition to methyl vinyl ketone5
whereas N-acylated derivatives were smoothly prepared
by Michael addition of aniline to methyl vinyl ketone in
refluxing ethanol followed by acylation under standard
conditions.
Abstract: Samarium diiodide-induced cyclization of aniline deriv-
atives 5, 9, 12, 14, and 16 afforded hexahydroquinolines such as 6,
10, 13, 15, and 17 in moderate to good yields and excellent diaste-
reoselectivities. Phenol was found to be a surprisingly effective pro-
ton source in some of these samarium-ketyl cyclizations. The
influence of different substituents at nitrogen as well as at the aro-
matic ring of the aniline moiety was studied. Whereas para-donor-
substituted aniline derivatives 19 and 21 provided the expected
products 20 and 22, the corresponding para-cyano derivatives 23
and 26 took an alternative pathway. Ipso-substitution involving
spiro intermediates 29 resulted in formation of rearranged products
24 and 28.
Key words: samarium diiodide, electron transfer, ketyl, radicals,
hexahydroquinolines
The reductive cyclizations were carried out routinely us-
ing 2.5 equivalents of samarium diiodide in the presence
of 10 equivalents of HMPA (hexamethylphosphoramide)
and 2.0 equivalents of tert-butanol in THF at room tem-
perature.6 The use of HMPA was essential for the success
of the reactions since its property as a donor ligand results
in drastic enhancement of the reduction potential of sa-
marium(II) species.7 Scheme 2 summarizes the results of
a series in which the N-substituent varied from an elec-
tron-donating methyl group in 1 via a phenyl substituent
with a slight electron-withdrawing mesomeric effect in 3
towards the strongly electron-withdrawing benzyloxycar-
bonyl and acetyl groups at nitrogen in 5 and 9.
6-trig-Cyclizations of -arylketones via ketyl radical ad-
dition to the aromatic substituent1 are of ongoing interest
in our group. This method benefits from the remarkable
properties of ‘Kagan’s reagent’2 samarium diiodide,
namely combination of its powerful reduction potential
with mild reaction conditions and high chemo- and stereo-
selectivity. Upon loss of its aromaticity the aryl group
serves as a C-6 building block, leading to functionalized
hexahydronaphthalene systems (Scheme 1, X = CH2).
Donor- and acceptor-substituted -arylketones and naph-
thyl derivatives were examined.3,4 The sequence starts
with formation of a ketyl radical anion by samarium diio-
dide-mediated electron transfer to the ketone, followed by
6-trig-cyclization to the aromatic ring, resulting in a pen-
tadienyl radical. This is reduced by a second equivalent of
samarium diiodide to provide the corresponding pentadi-
enyl anion. Regioselective protonation takes place simi-
larly to the related Birch reaction, furnishing 1,4-
cyclohexadiene units.
Compounds 1 and 3 afforded cyclized products with low
yield, however, rearomatized derivatives 2 and 4 were iso-
lated instead of the expected hexahydroquinolines. These
were probably formed by spontaneous oxidation during
work up.8 Carbamate 5 finally provided the desired cy-
clization product 6 in moderate yield along with rearoma-
tized 7 and anilide 8. Compound 8 was most likely
generated by base-induced retro-Michael reaction since
the anilide anion is a good leaving group in elimination
processes. The best result was obtained with substrate 9
yielding 39% of hexahydroquinoline derivative 10. No
rearomatized product was observed, only small amounts
of acetanilide 11 and the secondary alcohol 18 generated
by reduction of 9 were detected as side products. The
newly generated stereogenic centres of 6 and 10 exclu-
sively exhibit the depicted configuration.9 These first re-
sults demonstrate that the anticipated cyclization proceeds
in moderate yields with anilides such as 5 and 9, but even
rather electron-rich aniline derivatives 1 and 3 undergo a
reaction, although in low yield and followed by rearoma-
tization.
Scheme 1 X = CH2, NR
Synlett 2002, No. 12, 02 12 2002. Article Identifier:
1437-2096,E;2002,0,12,2027,2030,ftx,en;G28402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2028
S. Gross, H.-U. Reissig
LETTER
Scheme 2 Reagents and conditions: a) 2.5 equiv SmI2, 2.0 equiv tert-BuOH, 10 equiv HMPA, THF, r.t. b) Mixture of acetanilide 11 and
secondary alcohol 18.
We then checked the diastereoselectivity of this novel aryl cantly. The influence of the proton source was then inves-
carbonyl coupling reaction by introducing substituents tigated (Table 1). Entry 1 represents the result under
into the side chain. Syntheses of compounds 12, 14, and standard conditions. In the absence of a proton source (en-
16 in Scheme 3 were accomplished by an efficient one- try 2) a poor yield was obtained. Water (entry 3) was only
pot method10 using the corresponding aldehyde, aniline, a slightly worse proton source compared to tert-butanol
acetone and a catalytic amount of L-proline in DMSO fol- while methanol (entry 4) yielded almost the same amount
lowed by acylation with acetyl chloride. The samarium di- of 10 together with side products. Most remarkably, appli-
iodide-induced cyclizations of these substrates revealed cation of phenol (entry 5) dramatically increased the yield
that even the small methyl substituent of 12 induced an of 10 from 39% to 63%, and the amount of side products
excellent diastereoselectivity (10:1) in synthesis of 13, was reduced to traces. Possibly the generated phenolate
and that bulkier substituents such as phenyl in 14 or iso- anion causes less retro-Michael fragmentation of the start-
propyl in 16 caused formation of 15 and 17 as single dia- ing material due to its lower basicity.12 In contrast, use of
stereomers. The relative configuration of 17 was un- thiophenol (entry 6) led to exclusive isolation of 18, which
equivocally proven by X-ray analysis.11
indicates that the ketyl radical anion abstracts a hydrogen
atom from the thiol rather than adding to the aromatic
ring.
Table 1 Influence of the Proton Source on the Cyclization of Com-
pound 9
Entry
Proton source
10
11+18a
7%
1
2
3
4
5
6
tert-BuOH
39%
9%
__
8%
H2O
33%
38%
24%
3%
Scheme 3 Reagents and conditions: a) 2.5 equiv SmI2, 2.0 equiv
tert-BuOH, 10 equiv HMPA, THF, r.t. b) Two diastereomers (10:1).
MeOH
phenol
thiophenol
63%
< 1%
85%b
__
To generally improve the yield of the cyclizations model
substrate 9 was subjected to different reaction conditions
(Scheme 4). As mentioned above, use of HMPA is crucial
for the reaction but increasing the amount of this additive
from 10 to 18 equivalents did not raise the yield signifi-
a 11 and 18 were isolated as mixtures.
b 18 was formed exclusively.
Scheme 4 Reagents and conditions: a) 2.5 equiv SmI2, 2.0 equiv proton source, 10 equiv HMPA, THF, r.t.
Synlett 2002, No. 12, 2027–2030 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Synthesis of Hexahydroquinolines
2029
The influence of substituents at the aryl group was also in-
vestigated. Examples depicted in Scheme 5 demonstrate
that electron-donating substituents at the anilide ring are
suitable. Para-substituted substrates 19 and 21 (Y = CH3,
OCH3) exclusively afforded the desired bicyclic hexahy-
droquinolines 20 and 22 in approximately 50% yield.13
Surprisingly, acceptor-substituents at the anilide compli-
cate the reaction. Compound 23 with a para-cyano group
led to formation of the expected cyclization product 25
along with ipso-substitution product 24. This evidently
arises from a 5-exo-trig attack to the aromatic ring giving
the spirocyclic14 intermediate 29 in which the negative
charge is most favourably stabilized. Elimination of the
amide function is promoted by gain of aromaticity and
furnishes 24. The outcome of the reaction of the related
compound 26 was strongly dependent on the proton
source applied. Treating 26 under standard conditions
gave bicyclic product 27 in low yield. However, use of
phenol instead of tert-butanol furnished the ipso-substitu-
tion product 28 in good yield.
Acknowledgment
We are grateful to the Volkswagen-Stiftung and the Schering-Rese-
arch-Foundation (PhD fellowship for S. G.) for generous support.
We also thank the Fonds der Chemischen Industrie and the Schering
AG for general support.
References
(1) For related phenyl-carbonyl coupling reactions, see:
(a) Shiue, J.-S.; Lin, M.-H.; Fang, J.-M. J. Org. Chem. 1997,
62, 4643. (b) Kuo, Ch.-W.; Fang, J.-M. Synth. Commun.
2001, 31, 877. (c) Schmalz, H.-G.; Kiehl, O.; Gotov, B.
Synlett 2002, 1253. (d) ref.(14).
(2) Selected reviews on samarium diiodide promoted
chemistry: (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986,
42, 6573. (b) Molander, G. A.; Harris, C. R. Chem. Rev.
1996, 96, 307. (c) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321. (d) Krief, A.; Laval, A.-M.
Chem. Rev. 1999, 99, 745. (e) Steel, P. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2727. (f) Hölemann, A. Synlett 2001,
1497.
(3) Berndt, M.; Reissig, H.-U. Synlett 2001, 1290.
(4) (a) Dinesh, C. U.; Reissig, H.-U. Angew. Chem. Int. Ed.
1999, 38, 789; Angew. Chem. 1999, 111, 874 .
(b) Nandanan, E.; Dinesh, C. U.; Reissig, H.-U. Tetrahedron
2000, 56, 4267.
(5) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
(6) Typical procedure, cyclization of 16 to 17: Samarium
(0.329 g, 2.19 mmoL) and 1,2-diiodoethane (0.571 g, 2.02
mmol) were suspended in freshly distilled THF (30 mL)
under an argon atmosphere and stirred for 2 h at room
temperature. To the resulting dark blue solution HMPA
(1.45 g, 8.1 mmol) was added. Ketone 16 (200 mg, 0.81
mmol) and tert-butanol (0.15 mL, 1.62 mmol), dissolved in
THF (20 mL), were then added in one portion to the deep
violet solution. After 16 h the reaction was quenched with
saturated aqueous solution of sodium bicarbonate, the
organic layer was separated and the aqueous layer was
extracted with diethyl ether (3 × 25 mL). The combined ether
extracts were washed with brine (25 mL), dried over
anhydrous magnesium sulfate, filtered and evaporated. The
resulting crude product was purified by flash
chromatography on silica gel using hexane–ethyl acetate
(5:1 to 1:3) to give 17 (0.128 g, 63%) as a colourless solid.
Data for (2R*,4S*,4aS*)-1-acetyl-2-(iso-propyl)-4-
hydroxy-4-methyl-1,2,3,4,4a,7-hexahydroquinoline (17):
colourless crystals; mp 164 °C; 1H NMR (C6D6, 270 MHz):
= 0.82, 0.91 (2d, J = 6.6 Hz, 3 H each, CH3), 1.18 (s, 3 H,
4-CH3), 1.74 (mc, 2 H, 3-H, 2-CH), 2.05 (s, 3 H, COCH3),
2.05 (mc, 1 H, 3-H), 2.25 (s, 1 H, br, OH), 2.67 (mc, 1 H, 4a-
H), 2.28 (mc, 2 H, 7-H), 4.33 (dd, J = 6.6, 11.8 Hz, 1 H, 2-
H), 5.58 (s, 1 H, br, 8-H), 5.81 (mc, 2 H, 5-H, 6-H); 13C NMR
(CDCl3, 68 MHz): = 19.8, 20.3 (2q, CH3), 21.8 (q,
COCH3), 24.4 (q, 4-CH3), 27.1 (t, C-7), 28.7 (d, 2-CH), 40.4
(t, C-3), 48.9 (d, C-4a), 55.7 (d, C-2), 73.0 (s, C-4), 123.3 (d,
C-8), 123.9 (d, C-6), 124.4 (d, C-5), 134.6 (s, C-8a), 169.2
(s, CO); IR (KBr): = 3390 (OH), 3030 (=CH), 2975–2820
(CH), 1610 (CO) cm–1; Calcd. for C15H23NO2 (249.4): C
72.23, H 9.30, N 5.62; Found: C 72.49, H 9.10, N 5.50.
(7) (a) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett.
1987, 1485. (b) Shabangi, M.; Flowers, R. A. II Tetrahedron
Lett. 1997, 38, 1137. (c) Miller, R. S.; Sealy, J. M.;
Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A.
II J. Am. Chem. Soc. 2000, 122, 7718. (d) Knettle, B. W.;
Flowers, R. A. II Org. Lett. 2001, 3, 2321. (e) Prasad, E.;
Flowers, R. A. II J. Am. Chem. Soc. 2002, 124, 6895.
Scheme 5 Reagents and conditions: a) 2.5 equiv SmI2, 2.0 equiv
proton source, 10 equiv HMPA, THF, r.t. b) 4% of secondary alcohol
and 5% of acetanilide as side products. c) 14% of acetanilide isolated.
d) 69% of benzylalcohol isolated.
These last experiments indicate that a primary ipso-attack
of the ketyl can not rigorously be ruled out for all cycliza-
tion reactions. Spirocycles such as 29 may also be inter-
mediates in other reactions, but their rearrangement by
1,2-shift would finally generate identical products as the
direct ketyl addition to the ortho-position.
The reductive cyclization reactions presented here reveal
a new and stereoselective approach to highly functional-
ized nitrogen heterocycles. The enamide and alcohol
functions allow subsequent synthetic transformations
leading to natural product analogue structures. Other N-
heterocyclic aromatic compounds are currently investi-
gated to further explore scope and limitations of this re-
ductive cyclization method.
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S. Gross, H.-U. Reissig
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enantiomeric excess of these starting materials and the
resulting products was so far not determined..
(11) Brüdgam, I.; Hartl, H. Institut für Chemie, FU Berlin, 2002
unpublished results.
(12) When phenol was applied in related SmI2-induced
cyclizations yields were at least equivalent to those with tert-
butanol as proton source, however, so far no rule is
recognizable for which substrates phenol improves the
outcome. Other proton sources were also examined
(including 2,6-di-tert-butylphenol or 2,2,2-trifluoroethanol)
but no effect similar to that of phenol was discovered.
(13) The related ortho- and meta-substituted aromatic
compounds generally cyclize with considerably lower
efficiency. For cyano-substituted derivatives the yields are
particularly low.
(8) Since samarium(II/III) species are Lewis acids one might
assume a simple electrophilic substitution reaction for the
formation of 2 and 4. This possibility was excluded by
performing a test reaction with preformed samarium(III)
iodide under the same reaction conditions but no cyclization
product was observed (in the presence of HMPA as strong
donor ligand the Lewis acidity of the samarium salts is
effectively reduced).
(9) The relative configuration was determined by NOESY-
NMR spectroscopy. For 17 a crystal structure was obtained
to prove the relative configuration.
(10) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) Notz,
W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F. III
Tetrahedron Lett. 2001, 42, 199. (c) List, B.; Pojarliev, P.;
Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827; Basically, this Mannich reaction leads to optically
active compounds with considerable enantioselectivity, but
since our interest was focused on the chemo- and
diastereoselectivity of the cyclization reaction the
(14) For a recent report on related samarium diiodide induced
spirocyclizations to electron-deficient aromatic compounds,
see: Ohno, H.; Maeda, S.; Okumura, M.; Wakayama, R.;
Tanaka, T. Chem. Commun. 2002, 316.
Synlett 2002, No. 12, 2027–2030 ISSN 0936-5214 © Thieme Stuttgart · New York