Enantioselective synthesis of 2-aryl-4-piperidones via rhodium/ phosphoramidite-catalyzed conjugate addition of arylboroxines

Article abstract of DOI:10.1021/ol050734m

(Chemical Equation Presented) The highly enantioselective synthesis of 2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed conjugate addition of arylboroxines to 2,3-dihydro-4-pyridones is described. Both enantiomers of a variety of products with sterically and electronically different R substituents were obtained in high isolated yield and with excellent enantioselectivity up to 99%.

Full text of DOI:10.1021/ol050734m

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2433-2435
Enantioselective Synthesis of
2-Aryl-4-piperidones via Rhodium/
Phosphoramidite-Catalyzed Conjugate
Addition of Arylboroxines
Richard B. C. Jagt, Johannes G. de Vries,* Ben L. Feringa,* and
Adriaan J. Minnaard*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
j.g.de.Vries@rug.nl; b.l.feringa@rug.nl; a.j.minnaard@rug.nl
Received April 6, 2005
ABSTRACT
The highly enantioselective synthesis of 2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed conjugate addition of arylboroxines to
2,3-dihydro-4-pyridones is described. Both enantiomers of a variety of products with sterically and electronically different R substituents were
obtained in high isolated yield and with excellent enantioselectivity up to 99%.
The piperidine ring system is a frequently encountered
heterocyclic unit in natural compounds and drug candidates.1
Piperidine alkaloids exhibit a range of biological activities
and as such represent important synthetic targets. Piperidones
serve an important role as intermediates en route to substi-
tuted piperidines2 and can be found as a part of more complex
biologically active compounds.3 Therefore, the development
of short, enantioselective routes to substituted piperidones
is a major goal.4 An attractive catalytic route toward
enantiopure piperidones is based on the enantioselective
conjugate addition to readily accessible N-protected 2,3-
dihydro-4-pyridones,5 which are frequently used in alkaloid
synthesis.6 Until recently,7-9 however, no suitable procedures
had been developed.
Monodentate phosphoramidite ligands comprise a cheap
and easily tunable class of ligands that has already proven
to be successful in a variety of reactions, including rhodium-
catalyzed asymmetric hydrogenations,10 rhodium-catalyzed
conjugate additions of trifluoroborates11 and boronic acids,12
and copper-catalyzed asymmetric conjugate additions of
(4) (a) For a review of the recent developments in asymmetric routes to
substituted piperidines, see: Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun. 1998, 633-640. (b) For a review on the recent advances
in the synthesis of piperidines and piperidones, see: Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989.
(5) For the preparation of N-protected 2,3-dihydropyridones, see: (a)
Kozikowski, A. P.; Park, P.-U. J. Org. Chem. 1990, 55, 4668-4682. (b)
Comins, D. L.; Chung, G.; Foley, M. A. Heterocycles 1994, 37, 1121-
1140.
(1) For a general review on piperidines, see: Rubiralta, M.; Giralt, E.;
Diez, A. Piperidine: Structure, Preparation and Synthetic Applications of
Piperidine and its DeriVatiVes; Elsevier: Amsterdam, 1991.
(2) For some recent examples of the use of 4-piperidones in the synthesis
of biologically active 4-piperidines, see: (a) Tawara, J. N.; Lorenz, P.;
Stermitz, F. R. J. Nat. Prod. 1999, 62, 321-323. (b) Watson, P. S.; Jiang,
B.; Scott, B. Org. Lett. 2000, 2, 3679-3681. (c) Brooks, C. A.; Comins,
D. L. Tetrahedron Lett. 2000, 41, 3551-3553.
(6) For a review on the asymmetric preparation and synthetic utility of
2,3-dihydro-4-pyridones, see: Comins, D. L. J. Heterocycl. Chem. 1999,
36, 1491-1500.
(7) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240-6241.
(3) For an example, see: Mukhtar, T. A.; Wright, G. D. Chem. ReV.
2005, 105, 529-542.
(8) Sˇebesta, R.; Pizzuti, M. G.; Boersma, A. J.; Minnaard, A. J.; Feringa,
B. L. Chem. Commun. 2005, 1711-1713.
10.1021/ol050734m CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/17/2005

Scheme 1
Figure 1. Phosphoramidite L, a highly efficient ligand in the
rhodium-catalyzed conjugate addition of boronic acids.
We envisioned that introduction of aryl groups to 1
(Scheme 1), using the rhodium/phosphoramidite-catalyzed
conjugate addition of arylboronic acids, could provide a
pathway to 2-substituted 4-piperidones that is complementary
to our work with dialkylzinc reagents. During our studies,
Hayashi et al. reported the enantioselective addition of
arylzinc chlorides to 2,3-dihydro-4-pyridones.7 In that study,
it was noted also that this type of substrate is less reactive
toward 1,4-addition compared to other enones. The rhodium/
BINAP-catalyzed conjugate addition of phenylboronic acid
failed to proceed to full conversion, although the enantiose-
lectivity was excellent.
diorganozinc reagents.13 Recently, we have reported the
synthesis of 2-alkyl-4-piperidones with high enantiomeric
excess using the copper/phosphoramidite-catalyzed conjugate
addition of dialkylzinc reagents to N-protected 2,3-dihydro-
4-pyridones.8 It was noted that this type of substrate is less
reactive toward 1,4-addition than cyclic enones, e.g., 2-cy-
clohexenone.
Although highly enantioselective 1,4-addition of diphen-
ylzinc, using the same catalyst, has been reported for
2-cyclohexenone,14 the lack of readily available diarylzinc
reagents severely limits this method. A more convenient
method for the introduction of aryl and alkenyl moieties is
the asymmetric rhodium-catalyzed conjugate addition of
boronic acids pioneered by Hayashi and Miyaura.15 Excellent
levels of enantioselectivity have been achieved for a broad
range of enones using BINAP.15 Also phosphonites16 and
amidophosphines17 were successfully applied as chiral
ligands. It was shown by our group that phosphoramidites
(i.e., L, Figure 1) are exceptionally efficient ligands for this
reaction in terms of reaction rate, chemoselectivity, and
enantioselectivity.12
Initial screening of our catalyst system on substrate 1 was
performed under standard conditions in a mixture of dioxane/
water (10/1) at 100 °C with a catalyst generated from 3 mol
% Rh(acac)(C2H4)2 and 7.5 mol % L. As in the report of
Hayashi, with 3 equiv of phenylboronic acid, the reaction
1
did not go to completion according to H NMR (entry 1,
Table 1). The enantioselectivity was, however, excellent
Table 1. Optimization of the Reaction Conditions for the
Rhodium-Catalyzed Conjugate Addition to 1
(9) For related 1,4-additions to 2-piperidones, see: Pineschi, M.; Del
Moro, F.; Gini, F.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004,
1244-1245.
(10) (a) Van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; Van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539-11540. (b) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.;
Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552-12553. (c) Van den
Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.;
Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans,
C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G.
AdV. Synth. Catal. 2003, 345, 308-323.
entry
“PhB” (equiv)
conditionsa conversion %b ee (%)c
(11) (a) Duursma, A.; Boiteau, J.-G.; Lefort, L.; Boogers, J. A. F.; de
Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2004, 69, 8045-8052. (b) Duursma, A.; Lefort, L.; Boogers, J. A.
F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L.
Org. Biomol. Chem. 2004, 2, 1682-1684.
(12) (a) Boiteau, J.-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org.
Lett. 2003, 5, 681-684. See also: Bioteau, J.-G.; Imbos, R.; Minnaard, A.
J.; Feringa, B. L. Org. Lett. 2003, 5, 1385. (b) Boiteau, J.-G.; Minnaard,
A. J.; Feringa, B. L. J. Org. Chem. 2003, 68, 9481-9484. (c) Duursma,
A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org.
Lett. 2003, 5, 3111-3113.
(13) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Naasz,
R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed.
2001, 40, 927-930. (c) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 3700-3701.
(14) Pen˜a, D.; Lopez, F.; Harutyunyan, A. R.; Minnaard, A. J.; Feringa,
B. L. Chem. Commun. 2004, 1836-1837.
1
2
3
4
5
6
PhB(OH)2 (3.0)
(PhBO)3 (1.0)
(PhBO)3 (3.0)
(PhBO)3 (1.0)
(PhBO)3 (2.0)
(PhBO)3 (3.0)
A
B
B
C
C
C
80
60
75
84
92
96
99
99
99
99
99
100
a All reactions were performed on a 0.2 mmol scale with 3 mol %
Rh(acac)(C2H4)2 and 7.5 mol % (R)-L at 100 °C for 2 h. Conditions A:
0.55 mL of dioxane/H2O (10/1). Conditions B: 0.5 mL of dioxane, 1 equiv
of H2O with respect to boron. Conditions C: 0.5 mL of dioxane, slow
addition of water by syringe pump, 100 °C, 1 h. b Determined by 1H NMR.
c Determined by chiral HPLC.
(15) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229-4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
Miyaura, M. J. Am. Chem. Soc. 1998, 120, 5579-5581. (c) For a recent
review, see: Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-
2844.
(16) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083-
4085.
(96% ee). We then decided to generate phenylboronic acid
in situ from phenylboroxine ((PhBO)3)18 and water (one
(18) Arylboroxines are obtained by dehydration of arylboronic acids by
azeotropic removal of water from their xylene solution or heating at 300
°C in Vacuo. For a review, see: Lappert, M. F. Chem. ReV. 1956, 56, 959-
1064.
(17) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932-8939.
2434
Org. Lett., Vol. 7, No. 12, 2005

equivalent with respect to boron), providing mild reaction
conditions (entries 2-5).19 The use of this reagent did not
improve the conversion but did improve the enantioselectivity
to an excellent ee of 99%. Upon slow addition of water,
thereby preventing premature hydrolysis of the boroxine, the
reaction could be driven to 84% conversion using 1 equiv
of boroxine (entry 4) and to full conversion with retention
of 99% ee using 3 equiv of the reagent (entry 6).
Table 2. Scope of Arylboroxines in the Rhodium-Catalyzed
Asymmetric 1,4-Addition to 1a
To show the applicability of this reaction for synthesis on
a laboratory scale, it was performed on a 0.5 g (2.2 mmol)
scale. After flash chromatography, the product was isolated
in 86% yield with 99% ee.
entry
Ar
product
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
2f
86d
82d
92d
86d
85d
86d
71
99
24
98
95
96
98
94
96
o-MeC6H4
With these optimized conditions in hand, the scope of the
asymmetric conjugate addition of arylboroxines to 1 was
investigated. High ee values could be obtained with a variety
of sterically and electronically diverse arylboroxines (entries
1-8, Table 2). meta- and para-tolyl groups can be introduced
with high enantioselectivity and high yield (entries 3 and
4). A dramatic drop in enantioselectivity was observed for
the more sterically demanding ortho-tolyl group (entry 2),
illustrating a possible limitation of the catalytic method.
Products with one or two electron-donating substituents on
the aryl were obtained in high yield with high enantioselec-
tivity (entries 5 and 6). However, electron-withdrawing
groups such as choride or fluoride slow the reaction, leading
to incomplete conversions (entries 7 and 8). Despite this
observation, the enantioselectivity is largely independent of
the electronic properties of the substituents, and all para- or
meta-substituted products are obtained with excellent ee
values between 94 and 98%.
m-MeC6H4
p- MeC6H4
p-MeOC6H4
m,p-(MeO)2C6H3
p-FC6H4
2g
2h
p-ClC6H4
55
a All reactions were performed in duplicate with both enantiomers of
the ligand on a 0.2 mmol scale with 3 mol % Rh(acac)(C2H4)2 and 7.5 mol
% L at 100 °C for 2 h. (R)-L gave the (R)-enantiomer of the product in all
cases; see Supporting Information. b Isolated yield. c Determined by chiral
HPLC. d Thin-layer chromatography shows a spot to spot conversion in 2
h.
scope and applications of this method in the synthesis of
more complex heterocycles.
Acknowledgment. We thank Mrs. T. D. Tiemersma-
Wegman for the technical support. Financial support from
DSM, the Ministry of Economic Affairs, and NWO/CW,
administered through the CW/Combichem program, is grate-
fully acknowledged.
In summary, we have shown that conjugate addition of
arylboroxines with a rhodium/phosphoramidite catalyst can
be used to prepare 2-aryl-4-piperidones in high isolated yield
(82-92%) and with excellent enantioselectivity (up to 99%).
We are currently directing our efforts toward enhancing the
Supporting Information Available: Experimental details
and chromatographic and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(19) Use of arylboroxines was previously reported to have a beneficial
effect on both conversion and enantioselectivity in the conjugate addition
to highly deactivated 1-alkenylphosphonates; see: Hayashi, T.; Senda, T.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591-11592.
OL050734M
Org. Lett., Vol. 7, No. 12, 2005
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