New insights into NIS-promoted aminocyclization. Synthesis of decahydroquinolines from 2-allylcyclohexylamines

Article abstract of DOI:10.1021/ol070770g

Equation Presented Bishomoallylic secondary amines embodying the 2-allyl-N-benzylcyclohexylamine unit react with NIS to undergo cyclization through 6-endo processes in either the cis or trans series. Nevertheless, when the resulting cis-3-iododecahydroqui

Full text of DOI:10.1021/ol070770g

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2633-2636
New Insights into NIS-Promoted
Aminocyclization. Synthesis of
Decahydroquinolines from
2-Allylcyclohexylamines‡
1
Fa ıza Diaba,* Eva Ricou, and Josep Bonjoch*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, UniVersitat de Barcelona,
AV. Joan XXIII s/n, 08028-Barcelona, Spain
josep.bonjoch@ub.edu
Received March 30, 2007
ABSTRACT
Bishomoallylic secondary amines embodying the 2-allyl-N-benzylcyclohexylamine unit react with NIS to undergo cyclization through 6-endo
processes in either the cis or trans series. Nevertheless, when the resulting cis-3-iododecahydroquinolines are treated with Al2O3, the exo
derivatives evolve into octahydroindoles and the endo derivatives keep the same backbone, the configuration being retained in the generated
alcohols.
noncyclic alkenylamines6 and the corresponding N-protected
The formation of functionalized nitrogen-containing rings
derivatives (amides or carbamates)7 has been profusely
is a constant endeavor in synthetic organic chemistry, giving
studied, usually resulting in five-membered rings through
access to building blocks that allow new approaches to many
5-endo and 5-exo cyclization processes.
naturally occurring and biologically interesting compounds.
In this work, we describe the results observed in the NIS-
Halocyclization of unsaturated derivatives with an intramo-
promoted cyclization in bishomoallylic secondary amines
lecular nucleophilic center plays an important role in the
embodying the 2-allyl-N-benzylcyclohexylamine unit (Scheme
stereoselective construction of cyclic structures1 and thus
constitutes a suitable tool for the synthesis of azacyclic com-
pounds. However, iodoaminocyclization of cyclic alkenyl-
amines to build azabicyclic motifs using iodine(I) reagents2,3
has received limited attention, even starting from N-pro-
tected derivatives4 or anilines.5 In contrast, the reaction upon
(3) Using NIS: (a) Blough, B. E.; Mascarella, S. W.; Rothman, R. B.;
Carroll, F. I. J. Chem. Soc., Chem. Commun. 1993, 758-760. (b) Faltz,
H.; Bender, C.; Liebscher, J. Synthesis 2006, 2907-2922. (c) Beshore, D.
C.; Smith, A. B., III J. Am. Chem. Soc. 2007, 129, 4148-4149.
(4) (a) Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M. R. S.;
Payret-Arru´a, M. E. Tetrahedron 1999, 55, 10915-10924. (b) Jones, A.
D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1, 2001,
1182-1203. (c) Marcotullio, M. C.; Campagna, V.; Sternativo, S.; Con-
stantino, F.; Curini, M. Synthesis 2006, 2760-2766. (d) For the t-BuOI-
promoted cyclization of N-alkenylamides: Minakata, S.; Morino, Y.;
Oderaoroshi, Y.; Komatsu, M. Org. Lett. 2006, 8, 3335-3337.
‡ Dedicated to Prof. Miguel Yus on his 60th birthday.
(1) (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408. (b)
French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. ReV. 2004, 33, 354-
362.
(2) Using iodine: (a) Tanner, D.; Selle´n, M.; Ba¨ckvall, J.-E. J. Org.
Chem. 1989, 54, 3374-3378. (b) Bowman, W. R.; Clark, D. N.; Marmon,
R. J. Tetrahedron 1994, 50, 1275-1294. (c) Bonjoch, J.; Diaba, F.; Puigbo´,
G.; Sole´, D.; Segarra, V.; Santamar´ıa, L.; Beleta, J.; Ryder, H.; Palacios,
J.-M. Bioorg. Med. Chem. 1999, 7, 2891-2897.
(5) (a) Francis, C. L.; Ward, A. D. Aust. J. Chem. 1994, 47, 2109-
2117. (b) Gataullin, R. R.; Minnigulov, F. F.; Khakimova, T. V.; Kazhanova,
T. V.; Fatykhov, A. A.; Spirikhin, L. V.; Abdrakhmanov, I. B. Russ. Chem.
Bull., Int. Ed. 2001, 50, 456-459. (c) Majumdar, K. C.; Kundu, U. K.;
Das, U.; Jana, N. K.; Roy, B. Can. J. Chem. 2005, 83, 63-67.
10.1021/ol070770g CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/06/2007

tively, at room temperature in CH2Cl2 solution. In series c,
the reaction starting from 2-methylcyclohexanone required
heating under Dean-Stark conditions for the preparation of
1c. Imines 1 were allylated using LDA as a base in THF at
-78 °C, and the resulting imines 2 were reduced with NaBH4
to give a mixture of secondary amines 3 and 4 (4:1 to 2:1
according to the series; see Scheme 2).8 At this point,
improving the diastereoselectivity of the reduction9 was not
a priority because the availability of all the diastereomers
would help evaluate the scope and limitations of the NIS-
promoted cyclization process. To our knowledge, the protocol
reported here for the synthesis of R-alkylated cyclohexyl-
amines by alkylation of a cycloalkylimine and subsequent
reduction of the imine is unprecedented because this type
of compound (i.e., 3, 4) is usually prepared by reductive
amination of the corresponding R-alkylated cyclohexanone.10
Treatment of cis-alkenylamine 3a with NIS in CH2Cl2,
using K2CO3 as the base, gave after filtration on a silica gel
pad the decahydroquinolines 5a and 6a. If the reaction
mixture was heated, the imide 711 (42%) was isolated
together with 6a (27%), but when 5a was heated in CH2Cl2
and NaI, it did not give the corresponding 2-iodomethyl
derivative and was recovered.12 Interestingly, when com-
pounds 5a and 6a were eluted separately through Al2O3,
alcohols 8a and 9a were isolated, respectively. Although it
is well documented that nucleophilic substitution of 3-halo-
piperidines and 2-halomethylpyrrolidines proceeds stereo-
specifically through an aziridinium salt intermediate11a,13
with retention of configuration, to our knowledge, the
stereospecific Al2O3-promoted formation of alcohols is
unprecedented.
Scheme 1. Possible Regio- and Stereochemical Outcomes for
Cyclization
1). Curiously, the iodoaminocyclization of 2-alkenylcyclo-
hexylamines has not been studied so far, the only related
precedent being the iodocyclization of a homoallylic
sulfonamide.4b Thus, the regio- and stereoselectivity of the
iodine(I)-promoted aminocyclization of the cyclic starting
materials reported here would give new insights into this
classical reaction and, in turn, open new perspectives for the
synthesis of decahydroquinoline derivatives.
The starting materials were prepared from the appropriate
cyclohexanone according to the following three-step se-
quence: (i) imine formation; (ii) R-allylation; and (iii)
reduction (Scheme 2). In series a and b, the imine was
Scheme 2. Synthesis of 2-Allylcyclohexylamines
Having established the optimal conditions for the cycliza-
tion, we were ready to do a one-pot procedure. Treatment
of amino alkene 3a with NIS in CH2Cl2 followed by column
chromatography upon alumina allowed the isolation of
alcohols 8a (43% for the two steps) and 9a (29% for the
two steps), constituting a 72% overall yield for the cyclization
and interconversion of the functional group (Scheme 3). The
13C NMR data14 (see Supporting Information) of these
(8) Of the cyclohexylamines 3a-c and 4a-c here described, only 3a
has been previously reported. This amine has been prepared by an
enantioselective reduction of imine 2a: Ros, A.; Magriz, A.; Dietrich, H.;
Ford, M.; Ferna´ndez, R.; Lassaletta, J. M. AdV. Synth. Catal. 2005, 347,
1917-1920.
(9) For a recent example of diastereoselective reduction of 2-substituted
iminocyclohexanes, see: Sanderson, J. M.; Findlay, J. B. C.; Fishwick, C.
W. G. Tetrahedron 2005, 61, 11244-11252. For a classic paper in this
field: Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y.
P. J. Org. Chem. 1983, 48, 3412. See also: Knupp, G.; Frahm, A. W. Arch.
Pharm. 1985, 318, 250-257.
(10) For another procedure to achieve 3-alkyl-2-allylcyclohexylamines,
starting from 2-cyclohexenone, see: Dijk, E. W.; Panella, L.; Pinho, P.;
Naasz, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2004,
60, 9687-9693.
(11) For nucleophilic ring opening of bicyclic aziridinium ions, see: (a)
Cossy, J.; Dumas, C.; Pardo, D. G. Eur. J. Org. Chem. 1999, 1693-1699.
(b) Graham, M. A.; Wadsworth, A. H.; Thornton-Pett, M.; Rayner, C. M.
Chem. Commun. 2001, 966-967.
(12) Hjelmgaard, T.; Tanner, D. Org. Biomol. Chem. 2006, 4, 1796-
1805.
formed by reaction of benzylamine with cyclohexanone and
the monoethyleneacetal of 1,4-cyclohexanedione, respec-
(6) (a) Wilson, S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 287-291.
(b) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989,
111, 1923-1925. (c) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett.
1996, 37, 1991-1994. (d) Bubnov, Y. N.; Misharin, M. A.; Ignatenko, A.
V. Tetrahedron Lett. 1997, 38, 6259-6262. (e) Hu¨gel, H. M.; Hugues, A.
B.; Khalil, K. Aust. J. Chem. 1998, 51, 1149-1155. (f) Verhelst, S. H. L.;
Martinez, B. P.; Timmer, M. S. M.; Lodder, G.; van der Marel, G. A.;
Overkleeft, H. S.; van Boom, J. H. J. Org. Chem. 2003, 68, 9598-9603.
(g) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Smith, A.
D. Synlett 2004, 901-903. (h) Kim, J. H.; Long, M. J. C.; Deo, W. D.;
Ryu, Y. B.; Yang, M. S.; Park, K. H. J. Org. Chem. 2005, 70, 4082- 4087.
(i) Fiorelli, C.; Marchioro, C.; Martelli, G.; Monari, M.; Savoia, D. Eur. J.
Org. Chem. 2005, 3987-3993.
(7) Inter alia, see: (a) Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida,
Z. Tetrahedron Lett. 1984, 25, 1063-1066. (b) Knight, D. W.; Redfern,
A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2001, 2874-2883. (c)
Hashihayata, T.; Sakoh, H.; Goto, Y.; Yamada, K.; Morishima, H. Chem.
Pharm. Bull. 2002, 50, 423-425. (d) Amjad, M.; Knight, D. W. Tetrahedron
Lett. 2006, 47, 2825-2828. (e) Davis, F. A.; Song, M.; Augustine, A. J.
Org. Chem. 2006, 71, 2779-2786.
(13) Hammer, C. F.; Weber, J. D. Tetrahedron 1981, 37, 2173-2180.
(14) For a classical conformational and configurational study on cis-
decahydroquinolines: Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977,
42, 51-62.
2634
Org. Lett., Vol. 9, No. 14, 2007

Scheme 3. Aminocyclization of 3a and Further
Scheme 5. Aminocyclization of Trans Derivatives 4
Transformations
compounds prove that the relative configuration of C-3 in
6a and 9a is the same.
Additionally, octahydroindole 8a was submitted to the
reaction conditions developed by Cossy for the ring enlarge-
ment of prolinol derivatives (TFAA, Et3N, THF, reflux; then
NaOH)15 to give the corresponding cis-decahydroquinoline
10, the epimer at C(3) of 9a. This enlargement under thermo-
dynamic reaction conditions clearly indicated that the ring
contraction (5a f 7) occurred under kinetic reaction condi-
tions.
Although decahydroquinolines 6, 9, and 10 showed the
same conformational preference, it is noteworthy that in the
8-methyl-substituted derivatives, 6c and 9c, the nitrogen atom
lone pair is located equatorially to avoid steric crowding
between the C(8)-Me and the N-benzyl group.
The iodoaminocyclization of 3b and 3c was further
examined, yielding the results shown in Scheme 4. Although
The regio- and diastereoselectivity observed in the reported
reactions from cis (3a-c) and trans compounds (4a-c) is
consistent with the following envisaged scenario. The
intramolecular C-N bond formation arises from the elec-
trophilic activation of the double bond by the iodinating
reagent.16,17 In cis derivatives, the observed diastereoselec-
tivity, i.e., the facial selectivity for the nitrogen atom
nucleophile addition to the π-bond, depends on substrate
control of the conformationally mobile compounds 3. As
shown in Scheme 6, the coordination in conformation I
occurs from the re face of the double bond and from the si
face on conformation II. Each intermediate (A or B) or
preassociative complex17 then undergoes a regioselective
attack by the nitrogen atom leading to a 6-endo process.18
Scheme 4. Aminocyclization of 3b and 3c
(15) For the application of this protocol to the synthesis of cis-
decahydroquinolines, see: Mena, M.; Bonjoch, J.; Gomez Pardo, D.; Cossy,
J. J. Org. Chem. 2006, 71, 5930-5935.
the reaction from 3b followed the same course as that from
3a, the diastereoselectivity changed when starting from 3c,
and after treatment with Al2O3, decahydroquinoline 9c was
the main compound.
Gratifyingly, the iodoaminocyclization of trans derivatives
4a-c with NIS installed a C(3) equatorial iodine atom in
the single regio- and diastereomer formed. The decahydro-
quinolines 11 thus obtained were converted into the corre-
sponding alcohols 12 with good yields (Scheme 5).
(16) For a semiempirical MO approach to the mechanism of the NIS-
mediated nucleophilic addition, see: Mota, A. J.; Castellanos, E.; Alvarez
de Cienfuegos, L.; Robles, R. Tetrahedron: Asymmetry 2005, 16, 1615-
1629.
(17) For the sake of clarity, we have drawn the iodonium species in
Scheme 6 as intermediates, although they might not actually have been
formed.
(18) Interestingly, the aminocyclization of 2-allyl-N-tosylcyclohexyl-
amines promoted by MCPBA oxidation always gives octahydroindole
derivatives irrespective of the cis or trans relationship of the bishomoallylic
amine used: Nuhrich, A.; Moulines, J. Tetrahedron 1991, 47, 3075-3088.
Org. Lett., Vol. 9, No. 14, 2007
2635

Scheme 6. Reaction Pathway of Compound 3a
Thus, the major compounds isolated from 3a and 3b, whose
a nucleophilic attack at the methine carbon. Under thermo-
dynamic reaction conditions, the ring opening of the aziri-
dinium ion coming from the exo derivative 5a follows a
different regioselectivity, giving the decahydroquinoline 10.
In summary, the first synthetic approach to decahydro-
quinolines using a N f π-cyclization promoted by NIS has
been reported. We are currently applying this procedure to
the synthesis of the marine alkaloid fasicularin.21
preferred conformation was I, were decahydroquinolines 5,19
which would then evolve into octahydroindole derivatives
8, whereas 3c, whose preferred conformation was II accord-
ing to the NMR data, primarily gave decahydroquinoline 6c
evolving into 9c. The process in the trans series is highly
regio- and stereoselective,20 according to the thermodynamic
control in the cyclization step and the kinetically controlled
ring opening at the methine carbon in the aziridinium
intermediate formed during the Al2O3-promoted functional
exchange (I f OH).
Acknowledgment. This research was supported by the
MEC (Spain)-FEDER through project CTQ2004-04701/
BQU. Thanks are also due to the DURSI (Catalonia) for grant
2005SGR-00442.
In conclusion, both cis- and trans-2-allyl-N-benzyl-cyclo-
hexylamine derivatives undergo 6-endo cyclizations leading
to 3-iododecahydroquinolines, but the resulting cis deriva-
tives behave differently. Thus, although the exo derivatives
5 with Al2O3 easily form aziridinium ions that evolve through
a kinetic-controlled ring opening to octahydroindoles 8, the
endo derivatives 6 undergo a different regioselective aziri-
dinium ring opening to give decahydroquinolines 9 through
Supporting Information Available: Experimental and
NMR data for all compounds reported, including tables of
13C NMR chemical shifts of octahydroindoles and decahy-
droquinolines described. Copies of 1H and 13C NMR spectra
of all new compounds as well as COSY and HSQC spectra
when available. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Unlike 6, compounds 5 are conformationally heterogeneous at rt
and showed very broad signals in their NMR spectra. Sharp and interpretable
spectra of 5b were obtained at -20 °C.
(20) The NIS-promoted oxacyclization of trans-2-allylcyclohexanol gives
an epimeric mixture of 2-iodomethylperhydrobenzofurane derivatives:
Tanikaga, R.; Matsumoto, Y.; Sakaguchi, M.; Koyama, Y.; Ono, K.
Tetrahedron Lett. 2003, 44, 6781-6783.
OL070770G
(21) (a) Weinreb, S. M. Chem. ReV. 2006, 106, 2531-2549. (b) Scha¨r,
P.; Cren, S.; Renaud, P. Chimia 2006, 60, 131-141.
2636
Org. Lett., Vol. 9, No. 14, 2007