2,2- and 2,6-diarylpiperidines by aryl migration within lithiated urea derivatives of tetrahydropyridines

Article abstract of DOI:10.1021/acs.orglett.5b00199

2-Aryltetrahydropyridines formed by anionic cyclization or ring-closing metathesis were converted to their N′-aryl urea derivatives. Depending on the position of the unsaturation within the tetrahydropyridine ring, metalation by deprotonative lithiation or carbolithiation led to migration of the N′-aryl substituent to the 2- or 6-position via intramolecular nucleophilic attack of a benzylic organolithium on the aryl ring. The products are a range of 2,2-, 2,2,3-, and 2,6-polysubstituted piperidine derivatives. Related chemistry was observed in pyrroline homologues.

Full text of DOI:10.1021/acs.orglett.5b00199

Letter
pubs.acs.org/OrgLett
2,2- and 2,6-Diarylpiperidines by Aryl Migration within Lithiated
Urea Derivatives of Tetrahydropyridines
Michael B. Tait,† Sam Butterworth,‡,§ and Jonathan Clayden*,†
†School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
‡AstraZeneca Ltd., Alderley Park, Cheshire, SK10 4TG, U.K.
S
* Supporting Information
ABSTRACT: 2-Aryltetrahydropyridines formed by anionic cyclization
or ring-closing metathesis were converted to their N′-aryl urea
derivatives. Depending on the position of the unsaturation within the
tetrahydropyridine ring, metalation by deprotonative lithiation or
carbolithiation led to migration of the N′-aryl substituent to the 2- or
6-position via intramolecular nucleophilic attack of a benzylic
organolithium on the aryl ring. The products are a range of 2,2-,
2,2,3-, and 2,6-polysubstituted piperidine derivatives. Related chemistry
was observed in pyrroline homologues.
2-Arylpiperidines are a valuable class of biologically active
saturated heterocycles1 and have found particular utility as orally
active NK1 receptor antagonists, PARP inhibitors, TGR5
agonists, and bradykinin B1 antagonists, and as treatments for
erectile dysfunction (tadalafil) and urinary incontinence
(solifenacin).2−4 Among the wide range of strategies that have
been employed for their synthesis,5 the organolithium chemistry6
of piperidines features highly because deprotonation adjacent to
nitrogen may be facilitated by N-acylation.7−13 Nonetheless,
lithiated piperidines typically suffer from the limitation of
reacting only with “polar” electrophiles: introduction of aryl or
vinyl substituents typically requires transmetalation to an
organozinc followed by Negishi coupling.10,14−17
Figure 1. Tetrahydropyridines used as starting materials for arylation.
We have previously reported that acyclic organolithiums may
be arylated18 or vinylated19 intramolecularly with a broad scope
of trigonal “electrophiles” if they are stabilized by a functional
In the other approaches to the starting materials, the
tetrahydropyridines were formed by ring-closing metathesis. A
vinylzinc addition34 to imines 7 gave a secondary amine that was
converted to the unsaturated urea 8, from which the Grubbs I
catalyst provided racemic 1,2,5,6-tetrahydropyridines 2. Alter-
natively, adding allylmagnesium bromide to a range of tert-butyl
sulfinimine derivatives35 9 gave the sulfonamides 10 in excellent
yield as single diastereoisomers. Hydrolysis of the sulfonamide
followed by conversion to the ureas 11 was achieved under
standard conditions. Ring closing metathesis with the Grubbs I
catalyst gave the 1,2,3,6-tetrahydropyridines 4 as single
enantiomers. Isomerization of the unsaturation in 4 using
RuHCl(CO)(PPh3)3 returned vinylurea 3 without loss of
enantiomeric purity.33 This regioisomer was surprisingly also
formed exclusively (as a racemic mixture) from 2 under the same
conditions; isomerization to 1 was achieved by deprotonation of
group XCONRAr (a urea X = NR;18,20 a carbamate X = O;21−23
a
thiocarbamate X = S24−26) that delivers the “electrophile”
intramolecularly. We now report the use of a similar organo-
lithium arylation, initiated by either deprotonation or carboli-
thiation, to the direct α-arylation of cyclic amines,27,28 allowing
the synthesis of otherwise synthetically challenging 2,2- and 2,6-
diaryl piperidine and 2,2-diarylpyrrolidine derivatives.
The intramolecular organolithium arylation has shown the
most generality when applied to allylic29,30 or benzylic18,20 ureas.
The N-carboxamidotetrahydropyridines 1−4 (Figure 1)31 were
thus made as suitable starting materials for the synthesis of the
arylated piperidines. The three strategies outlined in Scheme 1
and detailed in full in the Supporting Information were used. In
the first, 5-bromopentanenitrile 5 was treated with an aryllithium
to give imine 6.32 N-Acylation33 with a series of aryl isocyanates
and methylation gave the urea derivatives 1, in which a vinyl urea
is embedded within the tetrahydropyridine ring.
Received: January 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00199
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 1. Synthesis of the Starting Tetrahydropyridines
Scheme 3. 2- and 6-Arylation of Tetrahydropyridines 3 and 4
2 under conditions not promoting aryl migration (KHMDS at
−78 °C in THF).33
Each of the three substrates 1, 3, and 4 was deprotonated with
LDA to generate a urea-stabilized organolithium.
In 1, deprotonation by LDA at the 4-position of the
tetrahydropyridine ring in a mixture of THF and DMPU led to
migration of the aryl ring to the benzylic 2-position of the
piperidine system, presumably via the intermediate cinnamyl-
lithium 1Li,29 which selectively reacted at the position α to N
(Scheme 2).36 The 2,2-diaryltetrahydropyridine products 12
were readily solvolyzed under our standard conditions to yield
the 2,2-diaryl-1,2,5,6-tetrahydropyridines 13.37
principle also be formed from 3 by deprotonation at the 4-
position, it must be that the regioselectivities of the rearrange-
ment arise from kinetic control over the relative rates of
deprotonation at the three possible sites: allylic 2-CH > benzylic
2-CH > allylic 4-CH. Differing reactivities of equilibrating
organolithiums are not responsible for the selectivity because the
products 15 are formed stereospecifically: there is no
racemization at the benzylic carbon atom. An unoptimized
solvolysis of a representative example 15a gave the 2,6-
diaryltetrahydropyridine 16 in moderate yield.
The formation of the products 15 was also completely
diastereoselective (>95:5 by NMR).17 The relative configuration
of 15b was established by hydrogenation over Pd in isopropyl
alcohol39 to give the symmetrical 2,6-diphenylpiperidinyl urea
17. Its optical rotation [α]25D = +40.4 (c = 1.0, CHCl3) proved
this compound to be the chiral, rather than the meso,
diastereoisomer, and hence trans relative stereochemistry was
assigned to the entire series 15.40
Scheme 2. Arylation of Tetrahydropyridines 1 by
Rearrangement of Their Organolithium Derivatives
Rearrangement to the 2-position of 3 was however not
stereospecific: the products were formed as racemic mixtures.
We have previously noted41 that while rearrangements of acyclic
lithiated ureas proceed with high levels of stereospecificity,
rearrangements that pass through fused bicyclic transition states
tend to be poorly stereospecific.
Organolithiums may be generated connectively by carboli-
thiation of alkenes.6,42 We have previously reported a
carbolithiation−rearrangement sequence for the 1,2-difunction-
alization of acyclic vinyl ureas,43,44 and after considerable
optimization we found that the best way to form the 2,2,3-
trifunctionalized products 19 in good yield was to carbolithiate 1
in toluene or (for primary alkyllithiums, which deprotonate
toluene) cumene and then immediately to add DMPU to
In 3 and 4, there is potential competition for deprotonation
between the allylic position(s) and the benzylic position, and a
different outcome was observed with each of the two sets of
compounds. On lithiation with LDA, the 5,6-unstaturated
isomers 3 rearranged to the 2,2-diaryl-1,2,3,4-tetrahydro-
pyridines 14 via the benzylic organolithium 3Li (Scheme 3).
The 4,5-unsaturated isomers 4 by contrast gave the 2,6-diaryl-
1,2,3,6-tetrahydropyridines38 15 by rearrangement of the
intermediate allylic organolithium 4Li. Since 4Li could in
B
DOI: 10.1021/acs.orglett.5b00199
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Carbolithiation−Rearrangement of Ureas 1
Scheme 5. Arylation of Pyrrolines
yield.46 Also obtained was a small amount of the ring-
fragmentation product 27, which presumably arises from the
electrocyclic ring opening of the anionic derivative of 25.
Substituted analogues 30 were made by an analogous
metathesis strategy, this time forming the starting doubly allylic
urea 29 by addition of a vinyl nucleophile to the imine 28.
Pyrrolines 30 were rearranged to 31a−c by treatment with LDA
in DMPU and THF.
In summary, 2- and 6-arylated piperidine and pyrrolidine
derivatives containing unsaturation ripe for further functionaliza-
tion may be synthesized by anionic migration of aryl rings from
an N-aryl urea at the ring nitrogen.
a
b
Using cumene. 2:1 dr at the exocyclic center.
promote efficient rearrangement of the intermediate 18 on
warming (Scheme 4). Other conditions (including the use of
THF) led in various degrees to competing allylic deprotonation
in the manner of Scheme 2, or to incomplete rearrangement. The
products were typically formed in around 60% yield as single
diastereoisomers by NMR spectroscopy, and solvolysis of a
selection of ureas 19 by heating in n-BuOH gave 2,2-aryl-3-
alkylpiperidines 20, also as single diastereoisomers, in good yield.
It was difficult to ascertain the relative configuration of 19 or
20 directly. A series of related unsaturated ureas 21 were thus
made by N-acylation of imine 6 with aryl isocyanates.
Carbolithiation of these ureas with an excess of alkyllithium
gave the ureas 22 via 18 (Z = Li), which cannot undergo
rearrangement due to the anionic nitrogen adjacent to the ring.
Products 22 were formed as single diastereoisomers and their
relative configuration was deduced from the strong NOE
correlation between the protons of the new alkyl group and
the benzylic proton. N-Methylation of 22a followed by
deprotonation under the conditions used for carbolithiation
recreates 18 (Z = Me) with known configuration, which
rearranges to yield the same diastereoisomer of 19g as that
obtained directly from 1.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full details of experimental procedures and characterization of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clayden@man.ac.uk.
Present Address
§School of Clinical and Experimental Medicine, College of
Medical and Dental Sciences, University of Birmingham,
Edgbaston, Birmingham B15 2TT, UK.
Due to their structural relationship to nicotine, 2-arylpyrro-
lidines form another important group of valuable targets,14,16,45
and we extended the metathesis/rearrangement sequence as a
method for the 2-arylation of heterocycles to some 5-membered
cyclic substrates. The pyrrolinyl urea starting material 25 was
formed readily by metathesis of the N,N-diallylurea 24 (Scheme
5). Treatment with LDA in THF with DMPU as a cosolvent led
to rearrangement, accompanied by double bond migration
(presumably due to a second deprotonation of the first-formed
product of this reaction), to return the 2-arylpyrroline 26 in 65%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the EPSRC and AstraZeneca
through a CASE award.
■
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