One-pot catalytic enantioselective synthesis of tetrahydropyridines via a nitro-mannich/hydroamination cascade

Article abstract of DOI:10.1021/ol302459c

The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This approach utilizes an asymmetric organocatalytic nitro-Mannich reaction followed by a gold-catalyzed alkyne hydroamination/ isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities.

Full text of DOI:10.1021/ol302459c

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5290–5293
One-Pot Catalytic Enantioselective
Synthesis of Tetrahydropyridines via a
Nitro-Mannich/Hydroamination Cascade
David M. Barber,† Hitesh J. Sanganee,‡ and Darren J. Dixon*,†
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K., and AstraZeneca R&D, New Opportunities
iMed, Alderley Park, Cheshire, SK10 4GT, U.K.
darren.dixon@chem.ox.ac.uk
Received September 5, 2012
ABSTRACT
The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination
cascade is reported. This approach utilizes an asymmetric organocatalytic nitro-Mannich reaction followed by a gold-catalyzed alkyne
hydroamination/isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities.
Nitrogen-containing heterocycles such as pyrroles, pi-
peridines, and pyrrolidines are found in a wide variety of
biologically active natural products and pharmaceuticals.1
Due to the abundance of these chemical motifs, improved
resource efficient methods for their synthesis remains an
important challenge for the reaction designer. Some of the
most attractive methods in recent years for the construction
of single and polycyclic systems have employed reaction
cascades.2 These multi-reaction sequences are able to
efficiently unite readily available starting materials and
rapidly build up molecular complexity in the products,
without the need for laborious workup and purification
procedures of the intermediate compounds. To this end,
we recently reported a cascade synthesis of substituted
pyrroles via a nitro-Mannich/hydroamination cascade3
of 4-nitrobut-1-yne.3a This reaction cascade utilized a com-
bination of base and gold catalysis to furnish the desired
pyrrole products after an isomerization/nitro group elim-
ination sequence. To further advance this work, we postu-
lated that the union of a one-carbon homologue of the nitro-
alkyne starting material with N-protected aldimines pro-
moted by an appropriate catalyst combination could allow
rapid access to synthetically useful tetrahydropyridine4
motifs with high stereocontrol. Herein, we report our
findings.
† University of Oxford.
‡ AstraZeneca.
(1) For leading references on nitrogen-containing biologically active
compounds, see: (a) O’Hagen, D. Modern Alkaloids: Structure, Isola-
tion, Synthesis and Biology; Wiley-VCH: Weinheim, Germany, 2007. (b)
Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165 and earlier articles in this
series.
(2) For recent reviews of reaction cascades, see: (a) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993–3009. (b) Grondal1, C.;
Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178.
(3) (a) Barber, D. M.; Sanganee, H.; Dixon, D. J. Chem. Commun.
2011, 47, 4379–4381. For recent examples of one-pot cascades using
nitro-Mannich reactions, see: (b) Jakubec, P.; Helliwell, M.; Dixon, D. J.
Org. Lett. 2008, 10, 4267–4270. (c) Xie, J.; Yoshida, K.; Takasu, K.;
Takemoto, Y. Tetrahedron Lett. 2008, 49, 6910–6913. (d) Pelletier, S.
M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2009, 11, 4512–4515. (e)
Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131,
16632–16633. (f) Kyle, A. F.; Jakubec, P.; Cockfield, D. M.; Cleator, E.;
Skidmore, J.; Dixon, D. J. Chem. Commun. 2011, 47, 10037–10039. (g)
Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2011, 13, 6406–
6409. (h) Jakubec, P.; Kyle, A. F.; Calleja, J.; Dixon, D. J. Tetrahedron
Lett. 2011, 52, 6094–6097. (i) Jakubec, P.; Cockfield, D. M.; Helliwell,
M.; Raftery, J.; Dixon, D. J. Beilstein J. Org. Chem. 2012, 8, 567–578.
In our proposed concept (Scheme 1), we envisaged that
nitro alkyne II would undergo an enantioselective nitro-
Mannich5 reaction with a suitably protected aldimine I
(4) For recent examples of tetrahydropyridine synthesis, see: (a)
Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47, 5836–
5838. (b) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318–
6319. (c) Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830–3833.
(d) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2012, 134, 4064–4067.
r
10.1021/ol302459c
Published on Web 10/05/2012
2012 American Chemical Society

Table 1. Catalyst Optimization Studies in the Reaction of
Aldimine 1a and Nitro-alkyne 2a
Scheme 1. Proposed Enantioselective Synthesis of Tetrahydro-
pyridines Using a Nitro-Mannich/Hydroamination Cascade
under the control of a bifunctional organocatalyst.6 The
resulting β-nitroamine III would then be poised to cyclize via
a hydroamination7 reaction using an appropriate metal cata-
lyst to furnish piperidine V after protodemetalation. Sub-
sequent exo/endo isomerization of the alkene8 would lead to
tetrahydropyridine VI. In contrast to our previous study,3a
an elimination of HONO was not anticipated and accordingly
cascade product VI was expected to retain the contiguous
stereocenters created in the initial nitro-Mannich reaction.
a Isolated yield after flash column chromatography. b Determined by
c
HPLC analysis of the purified product. (2R,3S)-30 and (2R,3R)-40
obtained. d (2S,3R)-3 and (2S,3S)-4 obtained.
the reaction of N-Boc-protected aldimine 1a and nitro-
alkyne 2a to investigate the diastereo- and enantioselectivity
of the nitro-Mannich reaction (Table 1). Various conditions
including solvent, temperature, and concentration were
explored (for full optimization studies, see Table S1 in the
Supporting Information (SI)). Pleasingly, using Takemoto’s
catalyst D9eꢀg in toluene at ꢀ15 °C we were able to syn-
thesize β-nitroamines 3 and 4 in good yield (87%) and
diastereoselectivity (87:13), while also obtaining excellent
enantioselectivity (92%) for the major diastereomer 3
(Table 1, entry 6).
With high enantioselectivity achieved in the nitro-
Mannich step using catalyst D, our attention then turned to
Figure 1. Bifunctional organocatalysts screened in the nitro-
Mannich reaction of aldimine 1a and nitro-alkyne 2a (Table 1).
(8) For examples of gold catalyzed alkene isomerization, see: (a)
Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 10858–10859. (b) Ito, H.; Harada, T.; Ohmiya, H.; Sawamu, M.
Beilstein J. Org. Chem. 2011, 7, 951–959.
(9) For seminal work using cinchonine and cinchonidine derived bi-
functional organocatalysts, see: (a) McCooey, S. H.; Connon, S. J. Angew.
Accordingly a variety of bifunctional organocatalysts
introduced by us and others9 (Figure 1) were screened in
ꢀ
(5) For a recent review of the nitro-Mannich reaction, see: (a)
Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011,
111, 2626–2704. For selected examples of enantioselective nitro-Mannich
reactions, see: (b) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.;
Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606–8607. (c) Handa, S.;
Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 4925–4934. (d) Anderson, J. C.; Stepney, C. J.; Mills, M. R.;
Horsfall, L. R.; Blake, A. J.; Lewis, W. J. Org. Chem. 2011, 76, 1961–1971.
(e) Wei, Y.; He, W.; Liu, Y.; Liu, P.; Zhang, S. Org. Lett. 2012, 14, 704–707.
(6) For selected reviews of bifunctional organocatalysis, see: (a) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743. (b) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (c) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138–
6171. (d) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem.
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Chem., Int. Ed. 2005, 44, 6367–6370. (b) Vakulya, B.; Varga, S.; Csampai,
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A.; Soos, T. Org. Lett. 2005, 7, 1967–1969. (c) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun. 2005, 4481–4483. (d) Li, B.; Jiang, L.; Liu, M.; Chen,
Y.; Ding, L.; Wu, Y. Synlett 2005, 603–606. For seminal work using
Takemoto’s catalyst, including enantioselective nitro-Mannich reactions,
see: (e) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672–12673. (f) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625–627. (g) Xu, X.; Furukawa, T.; Okino, T.; Miyabe,
H.; Takemoto, Y. Chem.ꢀEur. J. 2006, 12, 466–476.
(10) For recent reviews of gold catalysis, see: (a) Shapiro, N.; Toste,
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F. D. Synlett 2010, 675–691. (b) Corma, A.; Leyva-Perez, A.; Sabater,
M. J. Chem. Rev. 2011, 111, 1657–1712. (c) Rudolph, M.; Hashmi,
A. S. K. Chem. Soc. Rev. 2012, 41, 2448–2462.
(11) For a recent review of one-pot reactions using organocatalysis
and gold catalysis, see: (a) Loh, C. C. J.; Enders, D. Chem.;Eur. J.
2012, 18, 10212–10225. For selected examples of one-pot reactions using
organocatalysis and gold catalysis combined with an acid additive, see:
(b) Belot, S.; Vogt, K. A.; Besnard, C.; Krause, N.; Alexakis, A. Angew.
Chem., Int. Ed. 2009, 48, 8923–8926. (c) Jensen, K. L.; Franke, P. T.;
(7) For selected reviews of hydroamination reactions, see: (a)
Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007,
5105–5118. (b) Hartwig, J. F. Nature 2008, 455, 314–322. For selected
examples of alkyne hydroaminations in reaction cascades, see: (c) Wang,
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Org. Lett., Vol. 14, No. 20, 2012
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after 8 h at 60 °C, albeit with low yield (11%).13 Further
optimization found that addition of diphenylphosphate
(10 mol %) prior to addition of the Au catalyst was
optimal for the reaction cascade and afforded the desired
product in high diastereoselectivity.14 Purification by
silica gel chromatography afforded 5a as a single diaste-
reomer15 in 65% yield and 93% ee after 6 h at 60 °C
(Table 2, entry 3). The use of triflate as the Au counterion
resulted in a reduction of the reaction efficiency; 5a was
isolated in 50% yield (Table 2, entry 5). Decreasing the
temperature of the hydroamination reaction to rt and
40 °C (Table 2, entries 8 and 9 respectively), led to longer
reaction times and slightly impaired yields. When the
reaction temperature was increased to 100 °C (Table 2,
entry 10) the yield (55%) and diastereoselectivity (crude
dr 91:9, purified dr 95:5) decreased, when compared to the
reaction cascade conducted at 60 °C (Table 2, entry 3).
A control experiment using only diphenylphosphate
(10 mol %) revealed that no cyclization took place even
after heating at 60 °C for 24 h (Table 2, entry 11), thus
highlighting the critical role of the Au catalyst in the
hydroamination process. Finally, a control experiment
using no acid additive yielded none of the desired 5a
(Table 2, entry 12), thus confirming the need for amine
protonation prior to the hydroamination stage.
Table 2. One-Pot Optimization Studies between Aldimine 1a
and Nitro-alkyne 2a Using Organocatalysis and Gold Catalysis
With optimal conditions identified, a range of substi-
tuted aromatic N-Boc-protected aldimines were subjected
to the enantioselective nitro-Mannich/hydroamination
cascade (Table 3). The reaction was found to tolerate both
o- and m-toluene derived N-Boc-protected aldimines, af-
fording the desired products in good yields and high
enantioselectivities (Table 3, entries 2 and 3). A range of
electron-poor o-, m- and p-halogen substituted aromatic
aldimines (Table 3, entries 4ꢀ7) all furnished the desired
tetrahydropyridines 5dꢀg in good yields (49ꢀ63%) and
high enantioselectivities (87ꢀ96%).
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield after flash column chromatography. c dr of the purified
product determined by HPLC analysis. d ee of the major diastereomer
determined by HPLC analysis. e AgOTf (10 mol %). f AgSbF6 (10 mol %).
g DPP (6 mol %). h No reaction observed. DPP = Diphenylphosphate;
Au(L1)SbF6 (Echavarren’s catalyst) = (Acetonitrile) [(2-biphenyl)di-tert-
butylphosphine]gold(I) hexafluoroantimonate; L2 = [P(tBu)2(o-biphenyl)].
the development of a one-pot cascade to access the desired
tetrahydropyridines. Our previous study3a demonstrated that
Au10 salts can very efficiently activate the alkyne func-
tionality toward intramolecular hydroamination reactions.
However, due to the known incompatibility of Au(I) cata-
lysts and bifunctional organocatalysts,11 we adopted the
tactic of adding a Brønsted acid to quench the basic
N-atom of the bifunctional catalyst prior to addition of
the Au salt. Our initial investigation used Echavarren’s
catalyst12 (5 mol %) with 4-nitrophenol (10 mol %) as the
quenching additive (Table 2, entry 1). Pleasingly, the desired
tetrahydropyridine 5a was afforded as a 85:15 mixture of
diastereomers in 88% ee (for the major diastereomer)
In contrast, more electron-rich m-substituted methoxy
and 2-thienyl derived aldimines (Table 3, entries 8 and 9)
afforded the products 5h and 5i in lower yields (31ꢀ54%)
while retaining good enantioselectivities (88ꢀ93%). The 1-
and 2-naphthyl derived aldimines (Table 3, entries 10 and 11)
(15) The enhancement in diastereomeric ratio on purification was a
result of epimerization of the less stable cis-isomer to the more stable
trans-isomer during silica gel chromatography. See SI for details.
(16) For details of the nitro-Mannich reaction diastereoselectivity for
compounds 5aꢀn, 3o, and 4o, see the SI.
(17) The absolute configuration of tetrahydropyridine 5f was deter-
mined to be (2S,3R) by single crystal X-ray diffraction. All other
compound structures were assigned by analogy to 5f assuming a uniform
reaction pathway. Data for 5f were collected at 150 K [Cosier, J.; Glazer,
A. M. J. Appl. Crystallogr. 1986, 19, 105ꢀ107] using an Enraf-Nonius
KCCD Diffractometer [Otwinowski, Z.; Minor, W. Processing of X-ray
Diffraction Data Collected in Oscillation Mode, Methods in Enzymology;
Carter, C. W., Jr., Sweet, R. M., Eds.; Academic Press: New York, 1997; Vol.
276, pp 307ꢀ326] solved with SIR92 [Altomare, A.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M.
J. Appl. Crystallogr. 1994, 27, 435] and refined using the CRYSTALS
software suite [Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout,
K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487. Cooper, R. I.;
Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100–
1107] as per the SI. CCDC-890291 contains the supplementary crystal-
lographic data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
ꢀ
(12) For recent examples using Echavarren’s catalyst, see: (a) Lopez-
Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292–9294.
(b) Solorio-Alvarado, C. R.; Wang, Y.; Echavarren, A. M. J. Am. Chem.
Soc. 2011, 133, 11952–11955.
(13) Very few examples of intramolecular 6-exo-dig hydroamination
reactions between N-Boc protected amines and alkynes have been
reported. For examples, see: (a) Ritter, S.; Horino, Y.; Lex, J.; Schmalz,
H.-G. Synlett 2006, 3309–3313. (b) Enomoto, T.; Obika, S.; Yasui, Y.;
Takemoto, Y. Synlett 2008, 1647–1650.
(14) The diastereoselectivity of the crude reaction mixture was typi-
cally higher than expected from the ratio of diastereomers in the nitro-
Mannich product due to both a slow rate of cyclization of 4 (relative to 3)
and a competing decomposition pathway. Evidence of this was provided
in the synthesis of tetrahydropyridine 5a. During purification of 5a
(Table 3, entry 1), unreacted β-nitroamine 4 was recovered in 6% yield
and 82% ee, while none of the β-nitroamine 3 was observed. See SI for
details.
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Org. Lett., Vol. 14, No. 20, 2012

Table 3. Scope of the One-Pot Enantioselective Nitro-Mannich/
Hydroamination Cascade16
Scheme 2. Synthetic Elaboration of Tetrahydropyridine 5a
variety of methods (Scheme 2). Firstly, reductive removal of
the nitro group using Ono’s conditions19 occurred smoothly
to give tetrahydropyridine 6 in 64% yield. A partially
chemoselective reduction of the nitro group was achieved
using in situ prepared nickel boride in chilled methanol,
furnishing the desired amine 7 in 68% yield with excellent
diastereoselectivity. The fully reduced piperidine 8 was also
isolated from the reaction mixture as a single diastereomer
in 28% yield. Increasing the equivalents of nickel boride,
reaction time, and temperature facilitated exhaustive reduc-
tion to piperidine 8, which was isolated in 74% yield as a
single diastereomer.
In summary, we have developed a novel one-pot enantio-
selective synthesis of N-Boc and N-Cbz-protected tetrahydro-
pyridine derivatives using a nitro-Mannich/hydroamination
cascade. The reaction utilizes readily available and easily syn-
thesized starting materials to generate a high level of mole-
cular complexity in a one-pot procedure. A total of 14
examples have been synthesized with yields ranging from
31 to 72% and enantioselectivities ranging from 86 to 96%.
Further investigation into the synthesis of other chemical
entities using nitro-Mannich/hydroamination cascades is cur-
rently underway, and the results will be reported in due course.
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield after flash column chromatography. c dr of the purified
product determined by 1H NMR analysis. d ee of the major diastereomer
determined by HPLC anaylsis. e Absolute and relative stereochemistry
of the major diastereomer was determined by single crystal X-ray
analysis.17 f No cyclization observed at 100 °C; nitro-Mannich adducts
3o and 4o were recovered.
gave rise to the desired tetrahydropyridine products in
good yields (55ꢀ62%) and enantioselectivities (86ꢀ88%).
N-Cbz aldimines were fully compatible with the devel-
oped nitro-Mannich/hydroamination cascade (Table 3,
entries12ꢀ14), and tetrahydropyridines 5lꢀnwere afforded
in good yields (50ꢀ62%) and high enantioselectivities
(93ꢀ95%). Phenyl substituted nitro-alkyne substrate 2b
(Table 3, entry 15) did undergo the nitro-Mannich reac-
tion but failed to perform the Au-catalyzed cyclization
even after heating at 100 °C for 72 h.18 The nitro-Mannich
adducts 3o and 4o were recovered as an inseparable mixture
of diastereomers in 63% combined yield with 90% ee being
obtained for the major diastereomer.
Acknowledgment. We gratefully acknowledge the
EPSRC (studentship to D.M.B. and Leadership Fellowship
to D.J.D.) and AstraZeneca (studentship to D.M.B.). We
thank Andrew Kyle of the Department of Chemistry for
X-ray structure determination and the Oxford Chemical
Crystallography Service for the use of the instrumentation.
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 1m, 2aꢀb, 3, 4,
5aꢀn, 3o, 4o, and 6ꢀ8 and the CIF file for compound 5f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
To highlight the synthetic potential of the tetrahydro-
pyridine cascade products, 5a was further elaborated by a
(18) It is possible that the phenyl substituted alkyne substrates 3o and
4o do not undergo 6-exo-dig cyclization due to 1,3-allylic strain arising in
the transition state. For a related gold catalyzed carbocyclization to an
alkyne, see: (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2004, 126, 4526–4527. (b) Staben, S. T.; Kennedy-Smith,
J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350–5352.
(19) For seminal work, see: (a) Ono, N.; Miyake, H.; Tamura, R.;
Kaji, A. Tetrahedron Lett. 1981, 22, 1705–1708. (b) Tanner, D. D.;
Blackburn, E. V.; Diaz, G. E. J. Am. Chem. Soc. 1981, 103, 1557–1559.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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