Synthesis and asymmetric hydrogenation of (3E)-1-benzyl-3-[(2-oxopyridin- 1(2H)-yl)methylidene]piperidine-2,6-dione

Article abstract of DOI:10.1039/c2cc36807b

The synthesis of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methylidene] piperidine-2,6-dione 4 from N-benzylglutarimide was achieved in three steps. The asymmetric hydrogenation of 4 gave either the product of partial reduction (10) or full reduction (13), depending on the catalyst which was employed, in high ee in each case. Attempts at asymmetric transfer hydrogenation (ATH) of 4 resulted in formation of a racemic product. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc36807b

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COMMUNICATION
Synthesis and asymmetric hydrogenation of (3E)-1-benzyl-3-
[(2-oxopyridin-1(2H)-yl)methylidene]piperidine-2,6-dionew
Alexander A. Bisset,a Akira Shiibashi,b Jasmine L. Desmond,a Allan Dishington,c
Teyrnon Jones,c Guy J. Clarkson,a Takao Ikariyab and Martin Wills*a
Received 18th September 2012, Accepted 25th October 2012
DOI: 10.1039/c2cc36807b
The synthesis of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)-
methylidene]piperidine-2,6-dione 4 from N-benzylglutarimide was
achieved in three steps. The asymmetric hydrogenation of 4 gave
either the product of partial reduction (10) or full reduction (13),
depending on the catalyst which was employed, in high ee in each
case. Attempts at asymmetric transfer hydrogenation (ATH) of 4
resulted in formation of a racemic product.
characterised and their structures were confirmed by X-ray
crystallography (Fig. 1 and 2 respectively) confirming an
E-geometry of the double bond in each case. This geometry
may be favoured in order to minimize unfavourable steric
interactions. The geometries of 6 and 7 are not known however
both are formed as single diastereoisomers, in the former case
due to stabilization by an internal hydrogen bond.
The reduction of 4 using transfer hydrogenation was investi-
gated, using Ru–arene complexes 9a/b, together with formic acid/
triethylamine (FA/TEA) as the hydrogen source.5 Although these
catalysts have been most commonly applied to CQO and CQN
reduction, some examples have been reported of asymmetric CQC
reduction.6 The racemic catalyst 9a successfully reduced 4 to
1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methyl]-piperidine-2,6-dione 10
with full chemoselectivity for the CQC bond over any of the CQO
bonds. Racemic 10 was additionally prepared by Pd/C reduction of
4 (1 atm, rt, 30 min). The reduction was also successful using 3
mol% of homochiral catalyst 9b in a range of solvents (Table 1).5
However the product was racemic (determined by HPLC analysis
of 10), indicating a mechanism in which conjugate reduction of the
CQC bond (possibly assisted by protonation of the imide CQO)
initially leads to formation of enamine 11, which subsequently
Chiral diamines of general structure 1 have valuable biological
properties and represent useful synthetic building blocks.1 Alkenes
of type 2, containing a (1-aminomethylene) function at the
3 position of a six-membered imide, are potential precursors to
structure 1, via reduction to 3. In this paper we report the
synthesis and reduction of a derivative of 2, including studies
of its asymmetric reduction.
We found that 4 could be prepared via the sequence shown in
Scheme 1.2,3 Starting with N-benzylglutarimide 5, addition of a
hydroxymethylene group was achieved through the use of sodium
hydride followed by ethyl formate to form 6.2 Tosylation of 6 to
give 7 was completed using TsCl and triethylamine.2
The reaction of 7 with 2-hydroxypyridine at reflux in toluene
led to a substitution to form 4, together with a quantity of the
O-linked by-product 8. However it was found that 8 isomerised
to 4 upon extended heating, and that 4 could be formed in
higher yields using longer reaction times. In one example, after
10 h 4 and 8 were formed in isolated yields of 32% and 12%
respectively, however by running the same reaction for 20 h
under reflux, 4 was formed exclusively in 62% yield.2f,g,4 Both 4
and 8, which had formed as single diastereoisomers, were fully
Scheme 1 Synthesis of (3E)-1-benzyl-3-[(2-oxopyridin-1(2H)-yl)methyl-
idene]piperidine-2,6-dione 4.
a Department of Chemistry, The University of Warwick, Coventry,
CV4 7AL, UK. E-mail: m.wills@warwick.ac.uk;
Fax: +44 (0)24 7652 3260; Tel: +44 (0)24 7652 4112
b Department of Applied Chemistry, Graduate School of Science and
Engineering, Tokyo Institute of Technology, 2-12-1-E4-1
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
c AstraZeneca, Oncology Innovative Medicines, Alderley Park,
Macclesfield, Cheshire, England, SK10 4TG, UK
w Electronic supplementary information (ESI) available: Experimental
details, X-ray structure and NMR spectra. CCDC 873751 and 873752.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc36807b
Fig. 1 X-ray crystallographic structure of 4.
c
11978 Chem. Commun., 2012, 48, 11978–11980
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The method for the determination of the absolute configuration is
described later in this paper.
The use of dichloromethane (DCM) as solvent was compatible
with the formation of 10; an attempt to perform hydrogenations
in methanol resulted in over-reduction to 13.
A series of ligands, 14–18, supplied by Solvias, were evaluated in
complexes formed upon their in situ combination with
[Rh(COD)Cl]2. These gave varying degrees of reduction to 10
and 13. In the case of Taniaphos 17, a very high ee of 98% was
recorded for the fully reduced product 13, the sole product. The ee
of 13 was determined by chiral HPLC, against an authentic
racemic sample prepared by direct hydrogenation of 4 to 13 using
Pd/C as a catalyst (5 atm, rt, 12 h). Compound 10 could also be
hydrogenated to 13 using Pd/C as catalyst, and this method was
used in cases where inseparable mixtures of 4 and 10 were formed,
in order to obtain an indirect measure of the ee of 10.
Fig. 2 X-ray crystallographic structures of 8.
Table 1 Reduction of 4 by Ru(II)-catalysed transfer hydrogenationa
Entry Cat/mol%
Solvent
EtOH
T
Conv./Yieldb
1
2
3
4
5
6
9a 2 mol%
28 1C >99% conv. 89% yield
The pyrrolidine-substituted product 19 was formed from tosylate
7 in 35% yield Attempts to reduce the double bond in 19 using
Rh/phosphine catalysts were unsuccessful, indicating that the
heterocyclic group in 4 performs an important directing role in
the reaction, analogous to the directing effect of the acylamino
function in a-acylamino acrylate precursors of a-amino acids.7–9
However the electron-donating nature of the pyrrolidine may also
have an influence on the reactivity of this derivative.
(R,R)-9b 2 mol% MeOH rt
(S,S)-9b 3 mol% EtOH rt
>99% conv.
>99% conv. 81% yield
(S,S)-9b 3 mol% tBuOH 30 1C >99% conv.
(S,S)-9b 3 mol% iPrOH 30 1C >99% conv.
(R,R)-9b 3 mol% EtOH
rt
>99% conv.
a
b
[S] = 0.06 M, Product was not isolated in all cases.
protonates non-enantioselectively at the 3-position. An alternative
explanation is that an initial product of high ee may be racemised
under the reaction conditions. This possibility was eliminated in a
separate experiment, in which a sample of enantiomerically-
enriched 10 (vide infra, 95% ee) did not exhibit significant
racemisation after stirring in FA/TEA/methanol at rt for 5 days.
Better results were achieved in asymmetric hydrogenation reac-
tions of substrate 4.7,8 Initial studies using [Rh((R,R)-EtDuPHOS)-
COD]BF4 12 led to full reduction in over 90% ee, predominantly
to 10 although over-reduction to 1-benzyl-3-[(2-oxopiperidin-1-yl)-
methyl]piperidine-2,6-dione 13 was observed in some cases
(Table 2). The highest ee of 94.5% was recorded under conditions
where some 11% over-reduction to 13 was observed. A product of
90% ee was obtained in a case where no over-reduction was seen.
Confirming the absolute configuration of 10 (and 13) was
achieved by reduction of a sample of 10 prepared using the
DuPHOS catalyst 12 (Table 2, entry 2, 90% ee) to known amide
204 via intermediate 21 in ca. 3 : 1 regioselectivity over its
Table 2 Asymmetric hydrogenation of 4 using Rh(I) complexes
Entry
Catalyst
T
Conv./ratio 10 : 13
Ee/% 10/13 (R/S)
1
2
[Rh((R,R)-EtDuPHOS)COD]BF4 12
[Rh((R,R)-EtDuPHOS)COD]BF4 12
30 1C
rt
100% conv. 89 : 11
100% conv. 100 : 0
96% yield
94.5 (S)a (10)
90 (S)b (10)
3
4
5
6
7
[Rh(COD)Cl]2/SL-J001-1 Josiphos 14
[Rh(COD)Cl]2/SL-J003-1 Josiphos 15
[Rh(COD)Cl]2/SL-M001-1 Mandyphos 16
[Rh(COD)Cl]2/SL-TOO2-1 Taniaphos 17
[Rh(COD)Cl]2/SL-W001-1 Walphos 18
rt
rt
rt
rt
rt
42% conv. 42 : 0
56% conv. 56 : 0
100% conv. 40 : 60
100% conv. 0 : 100
47% conv. 27 : 20
76 (R)b (10)
87 (S)b (10)
17 (R)a (13)
98 (R)c (13)
13 (R)a (13)
a
b
Indirect determination of ee of 10 via Pd/C reduction of mixture to 13. Direct ee determination of 10. Direct ee determination of 13.
c
c
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regioisomer 22.10 Comparison of the optical rotation of our
sample of 20 to that reported4 allowed its configuration to be
assigned as R. Hence the precursor imide of this sample, 10, was of
S configuration. This sequence was accompanied by partial
racemisation, confirmed by reduction of our sample of 20 to the
saturated compound 23 which was shown to be of 20% ee by
chiral HPLC. A standard of racemic 23 was prepared by reducing
racemic 13 through the same sequence as for 10; 28% of the
required regioisomer 23 was obtained, along with 20% of the
minor isomer 24.
K. M. Kutterer, X. Liu, R. Nilakantan, M. A. Otteng, Z. Tang,
A. Zask, T. Tran, S. C. Mayer, A. L. Banker and M. Reich,
U. S., Patent, US 7713994 B2 20100511, 2010.
4 (a) D. Gray and T. Gallagher, Angew. Chem., Int. Ed., 2006, 45,
2419–2423; (b) C. Botuha, C. M. S. Galley and T. Gallagher,
Org. Biomol. Chem., 2004, 2, 1825–1826; (c) C. Hirschhauser,
C. A. Haseler and T. Gallagher, Angew. Chem., Int. Ed., 2011,
50, 5162–5165.
5 (a) T. Ikariya, K. Murata and R. Noyori, Org. Biomol. Chem., 2006,
4, 393–406; (b) S. Gladiali and E. Alberico, Chem. Soc. Rev., 2006, 36,
226–236; (c) T. Ikariya and A. J. Blacker, Acc. Chem. Res., 2007, 40,
1300–1308; (d) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya and
R. Noyori, J. Am. Chem. Soc., 1996, 118, 2521–2522; (e) K. J. Haack,
S. Hashiguchi, A. Fujii, T. Ikariya and R. Noyori, Angew. Chem., Int.
Ed. Engl., 1997, 36, 285–288; (f) P. Brandt, P. Roth and P. G.
Andersson, J. Org. Chem., 2004, 69, 4885–4890; (g) D. J. Morris,
A. M. Hayes and M. Wills, J. Org. Chem., 2006, 71, 7035–7044;
(h) A. M. Hayes, D. J. Morris, G. Clarkson and M. Wills, J. Am.
Chem. Soc., 2005, 127, 7318–7319; (i) F. K. Cheung, C. Lin,
F. Minissi, A. Lorente Criville, M. A. Graham, D. J. Fox and
´
M. Wills, Org. Lett., 2007, 9, 4659–4662; (j) F. K. Cheung,
A. J. Clarke, G. J. Glarkson, D. J. Fox, M. A. Graham, C. Lin,
´
A. Lorente Criville and M. Wills, Dalton Trans., 2010, 39, 1395–1402.
6 (a) D. Xue, Y.-C. Chen, X. Cui, Q.-W. Wang, J. Zhu and
J.-G. Deng, J. Org. Chem., 2005, 70, 3584–3591; (b) M. Saburi,
M. Ohnuki, M. Ogasawara, T. Takahashi and Y. Uchida, Tetra-
hedron Lett., 1992, 33, 5783–5786; (c) Y.-C. Chen, D. Xue,
J.-G. Deng, X. Cui, J. Zhu and Y.-Z. Jiang, Tetrahedron Lett.,
2004, 45, 1555–1558; (d) X. Li, L. Li, Y. Tang, L. Zhong, L. Cun,
J. Zhu, J. Liao and J. Deng, J. Org. Chem., 2010, 75, 2981–2988.
7 (a) D. Heller, J. Holz, I. Komarov, H.-J. Drexler, J. You, K. Drauz and
In conclusion, we have developed a concise route to either
racemic or enantiomerically-enriched N-benzyl-(3-aminomethyl
glutarimide) derivatives starting from N-benzylglutarimide
using a selective condensation/reduction strategy.
We thank the EPSRC and AstraZeneca for funding (to AAB).
The X-ray Diffraction instrument was obtained through the
Science City Project with support from the AWM and part funded
by the ERDF. Johnson Matthey are thanked for supplying
samples of Ru catalyst used in this project. Dr Hans-Ulrich Blaser
and colleagues at Solvias AG are thanked for the donation of a
Solvias ligand kit for evaluation in the reduction reactions. We
thank Dr Reddys for the donation of a sample of the
Ru(EtDuPHOS) complex 12. We acknowledge the use of the
EPSRC Chemical Database Service.11 TI and AS acknowledge
the MEXT for Grant-in-Aid for the G-COE program.
A. Borner, Tetrahedron: Asymmetry, 2002, 13, 2735–2741; (b) D. Heller,
¨
J. Holz, H.-J. Drexler, J. Lang, K. Drauz, H.-P. Krimmer and
A. Borner, J. Org. Chem., 2001, 66, 6816–6817; (c) M. T. Reetz and
¨
X. Li, Tetrahedron, 2004, 60, 9709–9714; (d) Y. Hsiao, N. R. Rivera,
T. Rosner, S. W. Krska, E. Njolito, F. Wang, Y. Sun, J. D. Armstrong
III, E. J. J. Grabowski, R. D. Tillyer, F. Spindler and C. Malan, J. Am.
Chem. Soc., 2004, 126, 9918–9919; (e) W. D. Lubell, M. Kitamura and
R. Noyori, Tetrahedron: Asymmetry, 1991, 2, 543–554; (f) Y. Wada,
T. Imamoto, H. Tsuruta, K. Yamaguchi and I. D. Gridnev, Adv. Synth.
Catal., 2004, 346, 777–788; (g) M. J. Burk, M. F. Gross and
J. P. Martinex, J. Am. Chem. Soc., 1995, 117, 9375–9376.
Notes and references
1 (a) R. Potter, A. G. Horti, H. T. Ravert, D. P. Holt, P. Finley,
U. Scheffel, R. F. Dannais and R. L. Wahl, Bioorg. Med. Chem.,
2011, 19, 2368–2372; (b) J. F. Miller, E. M. Turner, K. S. Gudmundsson,
S. Jenkinson, A. Spaltenstein, M. Thomson and P. Wheelan, Bioorg.
Med. Chem. Lett., 2010, 20, 2125–2128; (c) J. L. M. Hernando, J. M.
Ontoria, S. Malancona, B. Attenni, F. Fiore, F. Bonelli, U. Koch, S. Di
Marco, S. Colarusso, S. Ponzi, N. Gennari, S. E. Vignetti, M. R. R.
Ferreira, J. Habermann, M. Rowley and F. Narjes, ChemMedChem,
2009, 4, 1695–1713; (d) I. Stansfield, M. Pompei, I. Conte, C. Ercolani,
G. Migliaccio, M. Jairaj, G. Giuliano, M. Rowley and F. Narjes, Bioorg.
Med. Chem. Lett., 2007, 17, 5143–5149; (e) M. C. Lanier, M. Feher,
N. J. Ashweek, C. J. Rueter, D. H. Slee, J. P. Williams, Y.-F. Zhu,
S. K. Sullivan and M. S. Brown, Bioorg. Med. Chem., 2007, 17,
5590–5603; (f) P. B. Madrid, W. E. Polgar, L. Toll and M. J. Tanga,
Bioorg. Med. Chem. Lett., 2007, 17, 3014–3017; (g) J. A. Hermet,
D. W. Porter, M. J. Dearden, J. R. Harrison, T. Koplin, P. O’Brien,
J. Parmene, V. Tyurin, A. C. Whitwood, J. Gilday and N. M. Smith,
Org. Biomol. Chem., 2003, 1, 3977–3988.
2 (a) R. M. Coates and H.-Y. Kang, J. Org. Chem., 1987, 52, 2065–2074;
(b) K. Higashiyama, M. Toyama and H. Otomasu, Chem. Pharm.
Bull., 1986, 34, 3015–3019; (c) B. Latli and G. D. Prestwich, J. Org.
Chem., 1988, 53, 4603–4605; (d) D. C. Myles and M. H. Bigham, Org.
Synth., 1998, Coll. Vol. 9, 548; (e) J. Jayaselli, J. M. S. Cheemala,
D. P. Geetha Rani and P. Sarbani, J. Braz. Chem. Soc., 2008, 19,
509–515; (f) P. S. Mariano, E. R. B. Krochmal, R. Beamer,
P. L. Huesmann and D. Dunawa-Mariano, Tetrahedron, 1978, 34,
2609–2616; (g) A. McKillop, M. J. Ielesko and E. C. Taylor, Tetra-
hedron Lett., 1968, 48, 4945–4948.
8 (a) Y. Yamanoi and T. Imamoto, J. Org. Chem., 1999, 64, 2988–2989;
(b) I. D. Gridnev, Y. Yamanoi, N. Higashi, H. Tsuruta, M. Yasutake
and T. Imamoto, Adv. Synth. Catal., 2001, 343, 118–136; (c) A. Ohashi
and T. Imamoto, Org. Lett., 2001, 3, 373–375; (d) T. Miura and
T. Imamoto, Tetrahedron Lett., 1999, 40, 4833–4836; (e) R. Kuwano,
T. Uemura, M. Saitoh and Y. Ito, Tetrahedron Lett., 1999, 40,
1327–1330; (f) J. W. Scott, D. D. Keith, G. Nix Jr, D. R. Parrish,
S. Remington, G. R. Roth, J. M. Townsend, D. Valentine Jr and
R. Yang, J. Org. Chem., 1981, 46, 5086–5093; (g) A. M. Clausen,
B. Dziadul, K. L. Cappuccio, M. Kaba, C. Starbuck, Y. Hsiao and
T. M. Dowling, Org. Process Res. Dev., 2006, 67, 723–726.
9 (a) S. Feldgus and C. R. Landis, J. Am. Chem. Soc., 2000, 122,
12714–12727; (b) D. P. Steinhuebel, S. W. Krska, A. Alorati,
J. M. Baxter, K. Belyk, B. Bishop, M. Palucki, Y. Sun and
I. W. Davies, Org. Lett., 2010, 12, 4201–4203.
10 (a) R. T. Hsu, L. M. Chen, N. C. Chang and H. M. Tai, J. Org. Chem.,
2002, 67, 5044–5047; (b) W. N. Speckamp and H. Hiemstra, Tetra-
hedron, 1985, 41, 4367–4416; (c) J. C. Hubert, J. B. P. A. Wijnberg and
W. N. Speckamp, Tetrahedron, 1975, 31, 1437–1441; (d) R. F. Borch
and H. D. Durst, J. Am. Chem. Soc., 1969, 91, 3996–3997; (e) G. M.
P. Giblin, D. T. Kirk, L. Mitchell and N. S. Simpkins, Org. Lett., 2003,
5, 1673–1675; (f) J.-K. Chang, B.-R. Chang, Y.-H. Chuang and
N.-C. Chang, Tetrahedron, 2008, 64, 9685–9688; (g) L.-X. Liu,
Q.-L. Peng and P.-Q. Huang, Tetrahedron: Asymmetry, 2008, 19,
1200–1203; (h) I. R. Morgan, A. Yazici and S. G. Pyne, Tetrahedron,
2008, 64, 1409–1419; (i) P. Kuntiyong, S. Akkarasamiyo and
G. Eksinitkun, Chem. Lett., 2006, 35, 1008–1009; (j) B. F. Chen,
M. R. Tasi, C. Y. Yang, J. K. Chang and N. C. Chang, Tetrahedron,
2004, 60, 10223–10231; (k) P. Q. Huang, B. G. Wei and Y. P. Ruan,
Synlett, 2003, 1663–1667; (l) M. Ito, A. Sakaguchi, C. Kobayashi and
T. Ikariya, J. Am. Chem. Soc., 2007, 129, 290–291.
3 (a) D. Pe
1990, 31, 143–144; (b) O. S. Wolfbeis, I. Trummer and A. Knierzinger,
Liebigs Ann. Chem., 1981, 811–818; (c) D. Perez, G. Bures, E. Guitia
rez Meiras, E. Guitian and L. Castedo, Tetrahedron Lett.,
´ ´ ´
´
´
´
n
and L. Castedo, J. Org. Chem., 1996, 61, 1650–1654; (d) H.-R. Tsou,
S. Ayral-Kaloustian, G. H. Birnberg, M. B. Floyd, J. Kaplan,
11 D. A. Fletcher, R. F. McMeeking and D. J. Parkin, J. Chem. Inf.
Model., 1996, 36, 746–749.
c
11980 Chem. Commun., 2012, 48, 11978–11980
This journal is The Royal Society of Chemistry 2012