Highly diastereoselective arylations of substituted piperidines

Article abstract of DOI:10.1021/ja201008e

A highly diastereoselective methodology for the preparation of various substituted piperidines via Negishi cross-couplings with (hetero)aryl iodides was developed. Depending on the position of the C-Zn bond relative to the nitrogen (position 2 vs position

Full text of DOI:10.1021/ja201008e

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Highly Diastereoselective Arylations of Substituted Piperidines
Stephanie Seel,† Tobias Thaler,† Keishi Takatsu,§ Cong Zhang,† Hendrik Zipse,† Bernd F. Straub,‡
Peter Mayer,† and Paul Knochel*,†
†Department Chemie, Ludwig-Maximilians-Universit€at M€unchen, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
‡Organisch-Chemisches Institut, Universit€at Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
§Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S Supporting Information
b
procedures of Beak and Lee6 and Coldham and Leonori.3c To
ABSTRACT: A highly diastereoselective methodology for
the preparation of various substituted piperidines via
Negishi cross-couplings with (hetero)aryl iodides was de-
veloped. Depending on the position of the C-Zn bond
relative to the nitrogen (position 2 vs position 4), the
stereoselectivity of the coupling can be directed toward
either the trans- or cis-2,4-disubstituted products. Density
functional theory calculations on the relative stabilities of
the Zn and Pd intermediates were performed to explain the
high diastereoselectivities obtained. A novel 1,2-migration
of Pd further expands this method to the stereoselective
preparation of 5-aryl-2,5-disubstituted piperidines.
our delight, the Pd-catalyzed cross-coupling of 1a-e with various
aryl and heteroaryl iodides using 2% SPhos7 or 5% RuPhos8 and
2-5% Pd(dba)2 as the catalyst system furnished the desired
R-arylated products 3 in 54-84% yield with an exceptional level
of diastereoselectivity (d.r. of 95:5 to >99:1) (Table 1). Thus,
cross-coupling of the 4-methyl-substituted piperidinylzinc re-
agent 1a with electron-rich 4-iodoanisole using 2% Pd(dba)2 and
2% SPhos at 55 °C furnished exclusively the cis-configured
product 3a in 78% yield (entry 1 of Table 1).9
Coupling of 1a with electron-poor aryl iodides and 4-iodopyridine
under the same conditions gave the products 3b-f with d.r. from
95:5 to 98:2 (entries 2-6). Under slightly altered conditions (5%
Pd(dba)2 and 5% RuPhos at 55 °C), the piperidinylzinc reagent 1b
bearing a large phenyl ring instead of the smaller methyl substituent
provided the cis products 3g-i with comparable yields (64-79%)
and equally high diastereoselectivities (97:3 to >99:1) (entries 7-9).
Even the functionalized piperidinylzinc reagent 1c bearing an OSi
(i-Pr)3 (OTIPS) group at position 4 reacted smoothly, furnishing the
cis R-arylated products 3j-m in high yields (81-84%) with d.r.
between 95:5 and 97:3 (entries 10-13). The method also proved
applicable to the trans-decahydroisoquinolinyl scaffold. By using the
method of Beak and Lee,6 we were able for the first time to metalate
this heterocycle regioselectively at position 3. Cross-coupling of the
resulting organozinc species 1d led to the stereodefined 2,4,5-
trisubstituted products 3n-p in 54-69% yield with excellent d.r.
(97:3 to >99:1) (entries 14-16). In the case of the 5-methyl-
substituted reagent 1e, lower temperatures were necessary in order to
achieve high diastereoselectivities (Table 1). Thus, the trans-2,5-
disubstituted products 3q-r were obtained in moderate yields of
59-62% with a high d.r. of 95:5 (entries 17 and 18).
ubstituted piperidines are ubiquitous structural motifs pre-
S
sent in numerous bioactive alkaloids.1 In order to ensure
appropriate biological activity, many of them have to be prepared in a
stereodefined manner.1 Therefore, the development of efficient
methods for the diastereoselective construction of piperidines bearing
more than one stereocenter represents an important synthetic task.2
Still, procedures for the direct diastereoselective arylation of the
piperidine ring are scarce.3 Only one isolated example, involving the
diastereoselective coupling of a 6-methylpiperidin-2-yl organometallic
with 4-bromoveratrole to furnish the trans-2,6-disubstituted product,
has been reported.3c To date, the direct stereoselective synthesis of
2,4- and 2,5-disubstituted arylated piperidines via C(sp3)-C(sp2)
cross-coupling remains a challenging problem. We recently developed
highly diastereoselective couplings of several substituted cycloalkyl
derivatives mediated by Pd.4 Herein we report that Pd-catalyzed
cross-couplings can be efficiently used for a highly diastereoselective
preparation of various disubstituted or annulated piperidines.
We previously showed that cross-couplings of substituted
cyclohexylzinc reagents with diverse aryl halides result in the
stereoconvergent formation of the thermodynamically favored
arylpalladium intermediates, which upon reductive elimination
afford the desired arylated products with retention of configura-
tion (d.r. up to >99:1).4 Because of the structural importance of
piperidines, we envisioned performing diastereoselective cross-
couplings with the related substituted piperidinylzinc com-
pounds. By exploiting the pseudo-allylic strain induced by the
protecting group on N,5 we were able to prepare both the cis-
and trans-2,4-disubstituted piperidine derivatives with excellent
diastereoselectivity.
Complementary to the diastereoselective preparation of the cis-
2,4-disubstituted piperidines, we also report the synthesis of the
corresponding trans isomers by switching the positions of the
substituent and the C-Zn bond. Thus, in preliminary experiments,
we prepared the 2-substituted piperidin-4-ylzinc reagent 4a via
LiCl-promoted Zn insertion into iodide 5a10 and subjected it to
cross-coupling with 4-iodobenzonitrile and iodobenzene using 5%
TMPP2PdCl2 as the catalyst (Table 2).4 The trans coupling
11
products 6a and 6b were obtained in 50-74% yield with d.r. of 91:9
and 92:8, respectively (entries 1 and 2 of Table 2).12 By examining
the NMR spectra of 6a and 6b, we found that both revealed the
presence of two Boc conformers at room temperature. These
First, we generated various piperidin-2-ylzinc reagents of type
1 starting from the respective piperidines 2a-e according to the
Received: February 1, 2011
Published: March 09, 2011
r
2011 American Chemical Society
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Table 1. Diastereoselective Cross-Coupling of Substituted
Piperidin-2-ylzinc Reagents
Table 2. Diastereoselective Cross-Coupling of 2-Substituted
Piperidin-4-ylzinc Reagents
a Isolated yield. b Determined by GC and/or 1H/13C NMR analysis.
6b together with the corresponding data for the Zn and Pd
intermediates were analyzed at the B3LYP/631SVP level
(Scheme 1 and Table 3).14 From our former studies,4 it was
clear that the relative stabilities of the Pd intermediates represent
the crucial factor for the determination of the final diastereo-
selectivity of the cross-coupling.
The stabilities of the products (3g and 6b) and the corre-
sponding Zn intermediates were calculated to refine our mecha-
nistic picture. In contrast to the corresponding cyclohexanes,
in which an overall equatorial substitution pattern is thermo-
dynamically preferred,4 the pseudo-allylic strain in N-Boc piper-
idines caused by the partial double-bond character of the amide
bond forces the substituent vicinal to the nitrogen into an axial
orientation.5 Therefore, cis isomer 3g was found to be much less
stable (by 13.4 kJ/mol) than trans isomer 6b. Detailed DFT
conformational analysis (chair vs twist boat) showed that the
energy difference between the chair and twist-boat confor-
mations is negligible for 3g but large for 6b, confirming our
observations on 6a and 6b by 1H and 13C NMR spectroscopy.
The stabilities of the respective Pd and Zn intermediates involved
in the formation of the cross-coupling products 3g and 6b were
calculated using the same model as in our recent study of the
analogous cyclohexyl systems.4 Whereas the diastereomeric substi-
tuted cyclohexylzinc complexes possessed very similar energies, large
differences in the stabilities of the corresponding piperidinylzinc
species were found. In the case of piperidin-2-ylzinc reagent 1b, the
equatorial orientation of the C-Zn bond is stabilized by its
coordination to the carbonyl oxygen atom of the Boc group, leading
to a pentacoordinated Zn center. This results in an energetic
preference for eq-1b by 15.4 kJ/mol (entry 1 of Table 3). Since
pseudo-allylic strain in the 4-zincated piperidinyl species 4a dictates
an axial position of the substituent at C2, the axial orientation of the
C-Zn bond is hampered by 1,3-diaxial repulsions, causing ax-4a to
be the most stable conformer (entry 2). This underlines the “Janus-
like” nature of the Boc group, which shows its sterically demanding,
repulsive character toward vicinal substituents yet turns into an
electrostatically attractive neighbor with Lewis acidic metal centers
a Isolated yield. b Determined by GC and/or 1H/13C NMR analysis. c 2%
Pd(dba)2, 2% SPhos, THF, 55°C, 12h. d 5% Pd(dba)2, 5% RuPhos, THF,
f
55 °C, 12 h. e 5% Pd(dba)2, 5% RuPhos, THF, 55°C, 60 h. 5%Pd(dba)2,
5% RuPhos, THF, 0 °C (6 h), then rt (12 h), then 40 °C (12 h).
findings were supported by DFT analysis.13 Furthermore, the X-ray
structures of the previously prepared N-Boc-protected piperidines
3d and 3h9 (entries 6 and 8 of Table 1) showed a twisted ring
conformation, whereas the structures of the N-Ts-protected piper-
idines 3na and 3qa9 displayed an almost perfect chairlike structure.
Thus, we prepared the corresponding N-tosylated zinc reagent 4b.
Cross-coupling of 4b with 4-iodobenzonitrile under the same
reaction conditions led to the exclusive formation of the trans isomer
6c in 70% yield (entry 3). Remarkably, the couplings of the zinc
reagent 4c bearing only a small methyl group in position 2 also gave
the corresponding trans isomers 6e and 6f with excellent diaster-
eoselectivity (d.r. = 97:3; entries 5 and 6).
In order to explain the distinct stereochemical outcomes of
these couplings, the cis/trans stability differences between 3g and
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Scheme 1. DFT Conformational Analysis of Cis Isomer 3g
and Trans Isomer 6b
Scheme 2. 1,2-Migration of Pd in the Diastereoselective
Cross-Coupling of N-Boc 6-Methylpiperidin-2-ylzinc
Chloride
lithiation step.3c,f,g,6 The thermodynamic preference for the Zn com-
plexes with all substituents in equatorial positions may also contribute
to the observed high diastereomeric ratios through dynamic thermo-
dynamic resolution (DTR) processes.15 For the piperidin-4-ylzinc
iodides (4), the stereoselectivity is most likely introduced via a
selective transmetalation step between the Zn reagent and the aryl-
Pd complex, leading to the thermodynamically most stable inter-
mediate, as proposed for the cyclohexyl systems,4 although DTR
processes on the Zn intermediates are also conceivable.
Table 3. DFT-Calculation-Based Conformational Analysis of
the Diastereomeric Zinc and Palladium Complexes
In continuation of our study, we found that arylations with the
6-methyl-substituted piperidin-2-ylzinc reagent 9 in the presence of
Pd(dba)2/RuPhos8 as the catalyst system consistently resulted in
the highly stereoselective formation of the 5-arylated, trans-config-
ured products of type 11 (d.r. = 93:7 to 96:4),16 whereas the
expected trans-2,6-disubstituted products (10)3c were not obtained
(Scheme 2). It is noteworthy that the coupling proceeded equally
well with electron-rich (11b) and electron-poor (11c-e) aryl
iodides. We assume that this reaction proceeds via β-hydride
elimination of the Pd moiety.17 The resulting ArPdL2H18 complex
stays bound to the same side of the tetrahydropyridinyl ring, and its
subsequent syn addition19 places the Pd in the sterically less
hindered position 5. Rapid reductive elimination furnishes the
observed δ-arylated, 2,5-disubstituted coupling products (11). This
Pd 1,2-migration/cross-coupling sequence seems to be a function of
the nature and stoichiometry of the phosphine ligand. In our case, a
Pd/RuPhos ratio of 1:1 was used. Coldham and Leonori3c reported
the use of Pd(OAc)2/t-Bu3P with a ratio of 1:2 as the catalyst
system, which may lead to a better stabilization of Pd(0) and thus
prevent β-hydride elimination.
In conclusion, we have established a powerful methodology for the
preparation of various substituted piperidines via highly diastereose-
lective Negishi cross-couplings20 with (hetero)aryl iodides. Depend-
ing on the position of the C-Zn bond relative to the nitrogen (C2 vs
C4), we were able to direct the stereoselectivity of the coupling
toward either the trans- or cis-2,4-disubstituted products. A novel 1,2-
migration of Pd expands our method to the synthesis of 5-arylated,
2,5-disubstituted piperidines. Investigations of the mechanism of this
migration as well as further stereoselective arylations of saturated
N-heterocycles are currently underway in our laboratory.
a Ar: 4-CF3C6H4. Preferred conformations are indicated as twist-boat
(TB) or chair (C). b Calculated energetic differences (B3LYP/631SVP)
between the thermodynamically lowest conformers of the two diaster-
eomers; L = PMe3.
present at the same position. As in the cyclohexyl systems, the Pd
moiety shows a preference for the equatorial position in all cases. In
the piperidin-2-ylpalladium intermediates eq-7 and ax-7 (entry 3),
where the square-planar coordination sphere of Pd is not perturbed,
this natural preference is magnified by a close contact between the Pd
center and the carbonyl oxygen of the Boc group. However, when C2
is occupied by an aryl/alkyl substituent, 1,3-allylic strain5 takes effect
and results in an axial orientation (ax-8 vs eq-8; entry 4). Without
this interaction, diaxial repulsions dictate an equatorial orientation
of the aryl/alkyl substituent (eq-7 vs ax-7; entry 3).4 In view of
the energetic differences of the organometallic intermediates,
the diastereoselectivity in the couplings of the piperidinylzinc
reagents (1 and 4) may be determined at the stage of the respective
Zn and Pd complexes. In the case of the couplings of the piperidin-
2-ylzinc chlorides (1), there is strong evidence that the diastereo-
selectivity may already be introduced into the molecule via the
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and computational
b
details, NMR spectra, and CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
paul.knochel@cup.uni-muenchen.de
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’ ACKNOWLEDGMENT
(7) Dicyclohexyl(20,60-dimethoxy-[1,10-biphenyl]-2-yl)phosphine. See:
Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2004, 43, 1871.
The research leading to these results received funding from
the European Research Council under the European Commu-
nity’s Seventh Framework Programme (FP7/2007-2013), ERC
grant agreement n° 227763. We also thank the SFB 749 and the
Fonds der Chemischen Industrie for financial support. We are
grateful to BASF AG, W. C. Heraeus GmbH, Chemetall GmbH,
and Solvias AG for the generous gifts of chemicals.
(8) Dicyclohexyl(20,60-diisopropoxy-[1,10-biphenyl]-2-yl)phosphine. See:
Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965.
(9) The relative configurations of 3d and 3h were directly deter-
mined via X-ray analysis, and those of 3n and 3q were determined via
acidic removal of the Boc protecting group and subsequent tosylation.
The crystals of the tosylates (3na and 3qa) proved suitable for X-ray
analysis. See the Supporting Information for details.
(10) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040.
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