Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines

Article abstract of DOI:10.1021/acs.orglett.6b02667

Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.

Full text of DOI:10.1021/acs.orglett.6b02667

Letter
pubs.acs.org/OrgLett
Regio- and Stereoselective Alkylation of Pyridine‑N‑oxides: Synthesis
of Substituted Piperidines and Pyridines
Deepak Kumar Barange,† Magnus T. Johnson,‡ Andrew G. Cairns,† Roger Olsson,*,§
and Fredrik Almqvist*,†
†Department of Chemistry, Umea University, 90187 Umea, Sweden
̊
̊
‡Centre for Analysis and Synthesis, Lund University, 22100 Lund, Sweden
§Chemical Biology & Therapeutic Unit, Department of Experimental Medical Science, Lund University, 22100 Lund, Sweden
S
* Supporting Information
ABSTRACT: Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-
1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These
intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or
piperidines, respectively. These reactions have a broad substrate scope and short reaction times.
Gratifyingly, in this more extensive test we were able to
alkylate efficiently. These room-temperature additions were
followed by aromatization to access 2-alkyl, 2,6-disubstituted,
and 2,3,5-trisubstituted pyridines in good yields from readily
accessible pyridine-N-oxides (Scheme 2).
Foregoing the aromatization step, alkyl Grignard addition to
pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahy-
dropyridines, allowing the efficient synthesis of 2-alkylpiper-
idines and trans-2,3-dihydropiperidines. Addition of n-propyl
Grignard to pyridine-N-oxide and subsequent reduction with
NaBH4 gave 2-alkylated product 4a in a moderate yield
(Scheme 3). This improved to 60−70% when long-chain or
cyclic Grignard reagents 4b−d were used and further to 84%
when benzylmagnesium choride was used to give the alkylated
product 4e.
The presence of a C4-phenyl substituent improved the
isolated yield of the alkylation products. Short-chain alkyl
Grignards afforded moderate yields, with allyl and vinyl
Grignards comparable (4n and 4o). Significant improvement
was observed when longer chains were used, affording products
4k−m in good yields. This trend suggests that the chain length,
rather than electronic factors, determined the isolated yield.
iperidines and pyridines are recurring motifs in natural
Pproducts and drugs, and they show a range of biological
properties.1,2 Despite the prevalence of these privileged
structures, the synthesis of alkylpyridines4 and alkyl-substituted
piperidines remains challenging (Scheme 1).3 Many approaches
use directing or blocking groups to achieve stereoselectivity,
resulting in longer routes, or utilize expensive reagents, which
can limit the substrate scope.5 Nucleophilic addition to
activated pyridines represents an efficient alternative approach.3
However, substrate synthesis is required, and the regioselectiv-
ity can be problematic.3a,5a We herein report a one-pot strategy
utilizing regioselective alkyl Grignard additions to cheap, readily
available pyridine-N-oxides. The diastereoselectivity resulting
from successive Grignard addition is leveraged to generate C2-
alkylated N-hydroxy-1,2,5,6-tetrahydropyridines, trans-2,3-dis-
ubstituted analogues, and the corresponding piperidines in a
stereo- and regioselective manner.
Our previous research accessed aryl-substituted heterocycles
using aryl Grignard reagents,6,7 but analogous alkylation
resulted in poorer yields. Other researchers have demonstrated
nitro- and halo-directed pyridine-N-oxide alkylation,8a,b aryla-
tion of related scaffolds,8c,d different metal systems,8d,e and
nitro substitution.8f However, alkylation of simple pyridine-N-
oxides remains challenging. We have screened sp3 Grignard
reagents to investigate how these differ from sp2 examples.
Received: September 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02667
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Benzyl and phenethyl Grignard reagents worked especially well,
giving yields of 92% and 88% for 4p and 4q, respectively, while
addition to 4-chloropyridine-N-oxide also gave 2-alkylated
product 4r. The structure of 4p was confirmed by X-ray
crystallography.12 The moderate yields observed for 4a, 4f, and
4k likely result from isolation losses due to the low molecular
weight of the analogues. The ortho-substituted 2-phenyl-
pyridine-N-oxides or 2-methylpyridine-N-oxides reacted well
with cyclohexyl Grignard to afford products 4s−u in good
yields with diastereoselectivities of 99:1 cis:trans, as confirmed
by NMR spectroscopy (see the Supporting Information).
The N-hydroxy-1,2,5,6-tetrahydropyridine derivatives were
reduced with Raney nickel to give substituted piperidines in
excellent yields regardless of the substitution pattern (5a−g)
(Scheme 4). The facial preference of the heterogeneous catalyst
Scheme 1. Stereoselective Synthesis of Alkyl Piperidines
Scheme 4. Reduction of N-Hydroxy-1,2,5,6-
tetrahydropyridines to Substituted Piperidines
a b
,
a b
,
Scheme 2. Synthesis of 2-Alkylpyridine Derivatives
a
b
Isolated yields of products are shown. The reactions were performed
c
on a 0.5 mmol scale. The cis diastereomer was confirmed by NMR
spectroscopy (see the Supporting Information).
was controlled by the steric influence of the existing
stereocenters, allowing substituted alkenes to be reduced
selectively to the all-cis products in good yields (5f and 5h).
The route allows the efficient synthesis of racemic coniine 5a, a
toxic alkaloid found in hemlock (Conium maculactum).9
To investigate the scope and generality of the protocol, we
introduced substituents at C2, C3, and C6 of pyridine-N-oxide.
These di- and trisubstituted piperidines often display interesting
biological properties.10 Initial C2-alkylation of pyridine-N-oxide
followed by electrophilic trapping of the reactive intermediate
gave 2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines.
Using n-propylmagnesium chloride and benzaldehyde as an
electrophile gave 7a in 86% yield with 91:9 diastereoselectivity
(Scheme 5). However, only one C2/C3 configuration was
observed, later confirmed as trans by X-ray crystal analysis of
7p, and the diastereomeric mixture arose solely from the
secondary alcohol.13
a
b
Isolated yields of products are shown. The reactions were performed
on a 1.0 mmol scale.
Scheme 3. Regiospecific C2-Alkylation of Pyridine-N-oxides
via Grignard Addition
a b
,
Primary dodecylmagnesium chloride and secondary cyclo-
hexylmagnesium chloride nucleophiles gave good yields of 7b
and 7c (Scheme 5). Larger Grignard reagents did not give
higher yields in these examples; the opposite pattern was
observed (propyl > cyclohexyl > dodecyl), as evidenced by
comparison of 7a−c and 7g−j. This is likely due to steric
inhibition of electrophilic trapping. 7a was isolated in higher
yield than was previously observed for the C2-alkylation (2a),
suggesting that this earlier result represented isolation
difficulties. Phenethylmagnesium bromide gave 7j in high
yield (81%), while methyl and chloro substituents at C4 gave
a
b
Isolated yields of products are shown. The reactions were performed
c
on a 0.5 mmol scale. The cis diastereomer was confirmed by NMR
spectroscopy.
B
DOI: 10.1021/acs.orglett.6b02667
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Letter
treated with phenylmagnesium chloride to obtain 10 with high
diastereoselectivity. Compound 10 was reduced to trisubsti-
tuted piperidine 11, the structure of which was confirmed by X-
ray crystallography.12
Scheme 5. Synthesis of trans-2,3-Di- and 2,3,4-Trisubstituted
N-Hydroxy-1,2,5,6-tetrahydropyridines
ab c
, ,
In order to rapidly access trisubstituted piperidines, we
applied the alkylation−electrophilic trapping protocol to
commercial 2-phenylpyridine-N-oxide. This sequence pro-
ceeded in good yield, and the N-oxide intermediates 12a and
12b were subsequently reduced to 2,3,6-trisubstituted piper-
idines 13 and 11, respectively, with excellent diastereoselectivity
(Scheme 7).
Scheme 7. Synthesis of 2,3,6-Trisubstituted Piperidines from
Pyridine-N-oxides
a
The reactions were performed on a 1.0 mmol scale using Grignard
b
reagent, NaBH4 (3 equiv), and electrophile (2 equiv). The
diastereomeric ratios were determined by 1H NMR analysis with
reference to the secondary alcohol, and the trans configuration was
c
assigned from X-ray crystallography. Combined yields of two
diastereomers are shown.
moderate yields of 7e and 7f, respectively. Thiophene-2-
carboxaldehyde was used as the electrophile with only a small
loss of yield. We then explored butyraldehyde and cyclo-
hexanone as electrophiles together with n-propyl Grignard
reagent in the 2,3-addition. Rewardingly, these gave 7n and 7o
in 42−48% isolated yield despite the acidic α protons in the
electrophiles.
The diastereoselectivities trended lower with a C4 aryl
substituent but appear to be dependent on the specific
combination of Grignard and electrophile. Some di- and
trisubstituted N-hydroxy-1,2,5,6-tetrahydropyridines were re-
duced to the corresponding piperidines 8a−e (Scheme 6), with
The C6-phenyl of 13 has a cis orientation with respect to the
C2-propyl of the trisubstituted piperidine, despite the bulky C3
substituent, on the face of which the metal would approach.
This may reflect a haptophilic contribution from the hydroxyl
group.11
These complementary approaches allow both diverse
analogue production and rapid, high-yielding syntheses of
focused libraries and single products.
a b
,
Scheme 6. Synthesis of Di- and Trisubstituted Piperidines
Polysubstituted piperidines are valuable, complex drug-like
frameworks.12 Our procedure was extended to allow the
efficient synthesis of 2,3,4,6-tetrasubstituted piperidines
(Scheme 8). The 2-alkylated trans-2,3-dihydropyridine-N-
oxide 14 was synthesized in good yield and diastereoselectivity.
Scheme 8. Synthesis of Tetrasubstituted Piperidines
a
b
Isolated yields are shown. The reactions were performed on a 1.0
mmol scale.
the less hindered C4-unsubstituted piperidines 8a−c formed
faster and in better yields and diastereoselectivity. A
protection−oxidation sequence can also be used to access the
corresponding ketones with high diastereoselectivity (see the
Supporting Information).
To demonstrate the scope of the transformation, we
sequentially alkylated pyridine-N-oxide to give 2,3,6-trisubsti-
tuted piperidines. 2,3-Addition gave N-oxide 9, which was
C
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Org. Lett. XXXX, XXX, XXX−XXX

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M. Adv. Synth. Catal. 2014, 356, 2375. (e) McGrath, N. A.; Brichacek,
M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348.
Further Grignard addition to this C4-substituted substrate was
highly stereoselective but gave a different stereochemical
outcome to that observed in the C4-unsubstituted example,
affording tetrasubstituted N-hydroxy-1,2,5,6-tetrahydropyridine
15. Subsequent reduction gave piperidine 16 with excellent
diastereoselectivity (99:1), as confirmed through 2D NOESY
NMR spectroscopy and crystal structure analysis (see the
Supporting Information).
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In summary, we have demonstrated an efficient and
regiospecific alkyl Grignard addition to pyridine-N-oxides to
afford C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and
trans-2,3-disubstituted analogues in good to excellent yields.
These products were stereoselectively reduced to 2,3,4-tri- and
2,3,4,6-tetrasubstituted piperidine derivatives. We were also
able to use C-alkylation of pyridine-N-oxides to synthesize
valuable substituted pyridine derivatives from cheap and readily
available pyridine-N-oxide starting materials in a regiospecific
manner. Further investigations into the scope of this reaction
are currently underway in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02667.
Experimental procedures and spectroscopic and X-ray
crystallographic data for all new compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fredrik.almqvist@umu.se.
*E-mail: roger.olsson@med.lu.se.
ORCID
Fredrik Almqvist: 0000-0003-4646-0216
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Swedish Research Council (F.A., M.T.J., and
R.O.), the Knut and Alice Wallenberg Foundation (F.A.), the
Goran Gustafsson Foundation (F.A.), and the Swedish
Foundation for Strategic Research (F.A.) for financial support.
D.K.B. thanks the Kempe Foundation for Scientific Research
for providing a postdoctoral fellowship. We also thank Mattias
̈
Hedenstorm (Umea University) for the NMR study. This study
̊
made use of the “NMR for Life” infrastructure, which is
supported by the Knut and Alice Wallenberg Foundation, the
University of Gothenburg, and Umea University.
̊
(13) Crystallographic data for 2p, 7p, 11, 13, and 16 have been
deposited with the Cambridge Crystallographic Data Centre as CCDC
numbers 1479099, 1479111, 1479100, 479102, and 1487575,
respectively. These data can be obtained free of charge from the
CCDC via www.ccdc.cam.ac.uk/data_request/cif.
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