Consecutive cyclization of allylaminoalkene by intramolecular aminolithiation-carbolithiation

Article abstract of DOI:10.1021/ol801397v

(Chemical Equation Presented) Consecutive cyclization of allylaminoalkenes by tandem aminolithiation-carbolithiation proceeded smoothly by using a lithium amide as a lithiating agent as well as protonating agent to give bicyclic amines, octahydroindolizine and hexahydro-1H-pyrrollzine, in reasonably high yield and diastereoselectivity.

Full text of DOI:10.1021/ol801397v

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3635-3638
Consecutive Cyclization of
Allylaminoalkene by Intramolecular
Aminolithiation-Carbolithiation
Susumu Tsuchida, Atsunori Kaneshige, Tokutaro Ogata, Hiromi Baba,
Yasutomo Yamamoto, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received June 20, 2008
ABSTRACT
Consecutive cyclization of allylaminoalkenes by tandem aminolithiation-carbolithiation proceeded smoothly by using a lithium amide as a
lithiating agent as well as protonating agent to give bicyclic amines, octahydroindolizine and hexahydro-1H-pyrrolizine, in reasonably high
yield and diastereoselectivity.
The prevalence of cyclic amines in natural products and
biologically active compounds necessitates the development of
novel methods for their syntheses.1 Although brilliant syntheses
of these compounds have been reported by using the method-
ologies of alkylation and hydrogenation of C-N double
bonds,2,3 approaches toward amination of C-C double bonds
have begun only recently. Conjugate hydroamination of C-C
double bonds activated by an electron-withdrawing group
has met some successes through the reaction of lithium amide
as a nitrogen nucleophile.4,5 On the other hand, direct
hydroamination6,7 of simple C-C double bonds8 has re-
mained in a relatively undeveloped stage.
of lithiated intermediates. In the conjugate additionapproach,
the alkylation of a lithium enolate intermediate provided
N-C and C-C bonds in one pot.9c,d In the hydroamination
approach, the aminolithiation intermediate is an organo-
lithium 3 (Scheme 1). If this intermediate 3 is capable of
being involved in carbolithiation with an intramolecular
carbon-carbon double bond,11,12 another organolithium 4
would be generated to give a bicyclic amine 5 upon
protonation. We describe herein the realization of an
aminolithiation-carbolithiation tandem process of 1 to
provide a method of one-pot formation of bicyclic amine 5
(Scheme 1).
We have already reported the chiral ligand-controlled
asymmetric conjugate amination reaction of enoates with
lithium amides.9 Quite recently, we also reported the lithium-
catalyzed asymmetric intramolecular amination of aminoalk-
enes.10 These reactions are characteristic of the involvement
(5) Alkoxyamination and azidation: (a) Guerin, D. J.; Miller, S. J. J. Am.
Chem. Soc. 2002, 124, 2134–2136. (b) Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 16178–16179. (c) Sibi, M. P.;
Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem. Soc. 2003,
125, 11796–11797. (d) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.;
Go´mez-Bengoa, E.; Garc´ıa, J. M. J. Am. Chem. Soc. 2004, 126, 9188–
9189. (e) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka,
M. Org. Lett. 2004, 6, 1861–1864. (f) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313–
1317. Aza-Michael reaction: (g) Enders, D.; Narine, A. A.; Toulgoat, F.;
Bisschops, T. Angew. Chem., Int. Ed. 2008, early view.
(1) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576. (b) France,
S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103, 2985–
3012. (c) Lee, H.-S.; Kang, S. H. Synlett 2004, 1673–1685.
(2) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169–196. (b)
Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Nat. Aca. Sci. U.S.A. 2004,
(6) Reviews: (a) Müller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675–
703. (b) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth.
Catal. 2002, 344, 795–812. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H.
Angew. Chem., Int. Ed. 2004, 43, 3368–3398. (d) Hartwig, J. F. Pure Appl.
Chem. 2004, 76, 507–516. (e) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004,
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101, 5356–5362
.
(3) (a) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000,
122, 12055–12056. (b) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.;
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.
.
10.1021/ol801397v CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society

Scheme 1
.
Aminolithiation of 2 to Monocyclic Organolithium 3
and Its Carbolithiation to Bicyclic Amine 4
Table 1. Aminolithiation-Carbolithiation of 1a
6a,
7a,
BuLi
entry (equiv)
time yield yield
7a
amine
none
DIA
none
DIA
pyrrolidine
TMP
t-Bu(Tr)NH 1.5
t-Bu(Tr)NH 1.5
equiv (h)
(%)
(%)
ratioa
1
2
3
4
5
6
7
8c
0.1
0.2
1.5
1.5
1.5
1.5
1.5
1.5
0
0.2
0
1.5
1.5
1.5
1
2
92
95
0
1
nd
nd
1:4:0
6:1:0
nd
2
3
1
5
33
74
0
15
29/55b
In THF allylaminoalkene 1a was treated with 0.1 equiv
of butyllithium for 1 h at room temperature smoothly to
give hydroamination product 6a in 92% yield and 7a was
not detected (Table 1, entry 1). With 0.2 equiv of lithium
diisopropylamide (LDA) for 2 h at room temperature, 6a
was isolated in 95% yield along with 1% yield of bicyclic
amine 7a (entry 2). Contrary to these disappointing results,
the reaction with 1.5 equiv of butyllithium for 2 h at room
temperature gave 33% yield of 7a as a 1:4 mixture of
two diastereomers and 6a in 5% yield (entry 3). With 1.5
equiv of LDA, 7a was isolated in 74% yield as a 6:1
mixture of two diastereomers along with 6a in 15% yield
(entry 4).
2
2
14
9
0
0
53 30:10:1
88 6:3:1
85 >30:1:0
a 7a:trans,trans-isomer:cis,trans-isomer. b Yield of deallylated amine
of 6a. c The reaction was conducted in a 1:7 mixture of THF and toluene.
Consideration of competitive steps between protonation
and carbolithiation of 3 led us to screening of amine as a
proton source (entries 3-7). It was impressive to find that
lithium pyrrolidide gave hydroamination product 6a in 29%
yield along with its deallylated amine in 55% yield without
formation of carbolithiation product 7a (entry 5). A bulkier
lithium tetramethylpiperidide (TMP) gave 7a in 53% yield
and 6a in 9% yield (entry 6). The most bulky tert-
butyltritylamine13 gave only 7a in 88% yield without
detective amount of 6a (entry 7). These dependencies of
formation of 7a and 6a on the bulkiness of amine rationalize
the preferred carbolithiation of 3 and protonation of less
crowded 4 with a bulky amine, and protonation of 3 with a
less bulky amine.
(7) (a) Beller, M.; Breindl, C. Tetrahedron 1998, 54, 6359–6368. (b)
Seijas, J. A.; Va´zquez-Tato, M. P.; Entenza, C.; Mart´ınez, M. M.; Onega,
M. G.; Veiga, S. Tetrahedron Lett. 1998, 39, 5073–5076. (c) Ates, A.;
Quinet, C. Eur. J. Org. Chem. 2003, 1623–1626. (d) Trost, B. M.; Tang,
W. J. Am. Chem. Soc. 2003, 125, 8744–8745. (e) van Otterlo, W. A. L.;
Pathak, R.; de Koning, C. B.; Fernandes, M. A. Tetrahedron Lett. 2004,
45, 9561–9563. (f) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf,
A.; Arlt, M.; Heinrich, T.; Bo¨ttcher, H.; Beller, M. Chem. Eur. J. 2004, 10,
746–757. (g) Khedkar, V.; Tillack, A.; Benisch, C.; Melder, J.-P.; Beller,
M. J. Mol. Catal. A: Chem. 2005, 241, 175–183. (h) Ti: Bexrud, J. A.;
Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959–1962.
(i) Pd: Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644–8651.
(j) Group 3 metal: Kim, Y. K.; Livinghouse, T.; Horino, Y. J. Am. Chem.
Soc. 2003, 125, 9560-9561. (k) Ca: Crimmin, M. R.; Casely, I. J.; Hill,
M. S. J. Am. Chem. Soc. 2005, 127, 2042–2043. (l) Ln: Hao, J.; Marks,
T. J. Organometallics 2006, 25, 4763–4772.
Solvent effect is noteworthy to give an almost diastereomer
free 7a in 85% yield as a 30:1:0 diastereomer mixture in a
1:7 mixture of THF and toluene (entry 8). Major isomer was
determined to be trans,cis-7a as shown by NOE.
The competition of carbolithiation and protonation of 3
was further experimentally evidenced by the lower temper-
ature reaction. The reaction with 1.5 equiv of LDA at -20
°C for 6 h and further at rt for 3.5 h gave 6a in 94% yield
without production of 7a. On the other hand, the reaction
with 1.5 equiv of lithium tert-butyltritylamide at -20 °C
for 21 h gave 7a in 65% yield and 6a in 10% yield.
(8) (a) O’Shaughnessy, P. N.; Knight, P. D.; Morton, C.; Gillespie,
K. M.; Scott, P. Chem. Commun. 2003, 1770–1771. (b) Roesky, P. W.;
Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708–2710. (c) Hong, S.;
Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768–
14783. (d) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P.
Chem. Commun. 2004, 894–895. (e) Martinez, P. H.; Hultzsch, K. C.;
Hampel, F. Chem. Commun. 2006, 2221–2223. (f) Lebeuf, R.; Robert, F.;
Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755–4758. (g) Gribkov, D. V.;
Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748–3759. (h)
Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 1828–1839. (i) Zhang, J. L.; Yang, C. G.; He, C. J. Am.
Chem. Soc. 2006, 128, 1798–1799. (j) Watson, D. A.; Chiu, M.; Bergman,
R. G. Organometallics 2006, 25, 4731–4733. (k) Wood, M. C.; Leitch,
D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed.
2007, 46, 354–358. (l) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc.
2008, 130, 2786–2792.
The preferred production of 6a and trace amount of 7a
by the treatment with a catalytic amount of butyllithium and
(12) Recently reported impressive works: (a) Coldham, I.; Price, K. N.;
Rathmell, R. E. Org. Biomol. Chem. 2003, 1, 2111–2119. (b) Bailey, W. F.;
Jiang, X. L. Tetrahedron 2005, 61, 3183–3194. (c) Deng, K.; Bensari-
Bouguerra, A.; Whetstone, J.; Cohen, T. J. Org. Chem. 2006, 71, 2360–
2372. (d) Melero, C.; Guijarro, A.; Baumann, V.; Perez-Jimenez, A. J.;
Yus, M. Eur. J. Org. Chem. 2007, 5514–5526. (e) Hogan, A.-M. L.; O’Shea,
D. F. J. Org. Chem. 2008, 73, 2503–2509. (f) Tang, S.; Han, J.; He, J.;
Zheng, J.; He, Y.; Pan, X.; She, X. Tetrahedron Lett. 2008, 49, 1348–
1351.
(9) (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886–2887. (b) Doi, H.; Sakai, T.; Yamada, K.;
Tomioka, K. Chem. Commun. 2004, 1850–1851. (c) Sakai, T.; Kawamoto,
Y.; Tomioka, K. J. Org. Chem. 2006, 71, 4706–4709. (d) Sakai, T.; Yamada,
K.; Tomioka, K. Chem. Asian J. 2008, 3, in press.
(10) Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.;
Tomioka, K. Tetrahedron Lett. 2007, 48, 6648–6650.
(11) Review: Clayden, J. Organolithiums: SelectiVity for Synthesis;
Pergamon Press: Oxford, U.K. 2002; pp 273-335.
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2518.
3636
Org. Lett., Vol. 10, No. 16, 2008

LDA is also rationalized by the protonation of 3 by 1a itself
that is considered to be a relatively less bulky amine (entries
1 and 2).
bicyclic amines 7b-d in reasonably high yield and diaste-
reoselectivity.14 Not only octahydroindolizines 7a-c but also
hexahydro-1H-pyrrolizine 7d were produced.
The intermediacy of 3 was evidenced by the production
of 1a and 7a from 6a (Scheme 2). Treatment of 6a with 1.5
Scheme 2. Intermediacy of 3
Figure 1. Stereochemical models 8 and 9.
equiv of LDA in THF at reflux for 17 h gave 1a in 31%, 6a
in 12%, and 7a (17:1:0) in 37% yield. Lithiation at the
benzylic position of 6a in forming 3 seems to require a high
refluxing temperature.
Having established the aminolithiation-carbolithiation
tandem cyclization conditions, other allyl- and homoally-
laminoalkenes 1b-f were examined. As shown in Scheme
3, terminal primary alkyllithium producing tandem
aminolithiation-carbolithiation proceeded smoothly to give
The structural limitation became apparent from the at-
tempted cyclization of 1e that produces Li-C bond at the
tertiary carbon center through carbolithiation. The reaction
stopped at the stage of aminolithiation to produce 6e. Another
limitation was 6-exo carbolithiation giving octahydro-1H-
quinolizine. The reaction stopped at the aminolithiation stage
to afford 6f.
The model proposed by Bailey, and recently by Cohen
and Jordan, rationalized stereochemistry in the intramolecular
carbolithiation.15 Thus, the model 8 fits for the preferencial
production of trans,cis-7a-c. Although the model 9 predicts
the formation of trans,cis-7d, involvement of lithiophilic
THF in the transition state allows formation of trans,trans-
7d.15b,16
Scheme 3
.
Successful Aminolithiation-Carbolithiation of 1b-d
and Unsuccessful Carbolithiation of 1e,f
A substoichiometric amount of lithium amide was found
to give tandem aminolithiation-carbolithiation product 7a.
Portionwise addition of allylaminoalkene 1a in THF to 0.36
equiv of t-BuTrNLi in THF during three 2 h intervals at room
temperature gave 7a in 64% yield along with 6a in 17%
yield.
In summary, we have demonstrated the double cycli-
zation of allylaminoalkenes through tandem amino-
lithiation-carbolithiation providing ready access to bi-
cyclic octahydroindolizine and hexahydro-1H-pyrroli-
zine skeletons. A catalytic amount of lithium amide was
also shown to give tandem aminolithiation-carbolithiation
product. Extension to other types of bicyclic amines and
asymmetric reactions is the focus of future studies.
(14) It is obvious from Table 1 that the relative stereochemistry
between azomethine carbon and benzyl methine carbon is highly
controlled even with THF alone. Indeed, the reaction of 1b gave a single
diastereoisomer. The reaction of 1d in toluene-THF mixed solvent
system was not examined.
(15) (a) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 5720–
5727. (b) Liu, H.; Deng, K.; Cohen, T.; Jordan, K. D. Org. Lett. 2007, 9,
1911–1914.
(16) Metallo-ene cyclizations are well known to yield cis products:
Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 38–52. Specifically
for Li-ene cyclizations: Cheng, D.; Zhu, S.; Liu, X.; Norton, S. H.; Cohen,
T. J. Am. Chem. Soc. 1999, 121, 10241–10242. Cheng, D.; Knox, K. R.;
Cohen, T. J. Am. Chem. Soc. 2000, 122, 412–413. Krief, A.; Kenda, B.;
Remacle, B. Tetrahedron 1996, 52, 7435–7463. Krief, A.; Kenda, B.;
Maertens, C.; Remacle, B. Tetrahedron 1996, 52, 7465–7473. We thank
the reviewer for good suggestions
.
Org. Lett., Vol. 10, No. 16, 2008
3637

Acknowledgment. This research was partially supported
by the 21st Century COE (Center of Excellence) Program
“Knowledge Information Infrastructure for Genome Sci-
ence”, a Grant-in-Aid for Scientific Research, and a Grant-
in-Aid for Scientific Research on Priority Areas “Ad-
vanced Molecular Transformations” from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
Note Added after ASAP Publication. There was an error
in the abstract/toc graphic, the corrected version was
published on August 7, 2008.
Supporting Information Available: Experimental details
and characterization of data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL801397V
3638
Org. Lett., Vol. 10, No. 16, 2008