Synthesis and kinetic resolution of N-Boc-2-arylpiperidines

Article abstract of DOI:10.1039/c4cc04576a

The chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97:3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities.

Full text of DOI:10.1039/c4cc04576a

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Synthesis and kinetic resolution of
N-Boc-2-arylpiperidines†
Edward J. Cochrane,a Daniele Leonori,a Lorraine A. Hassallb and Iain Coldham*a
Cite this: Chem. Commun., 2014,
50, 9910
Received 16th June 2014,
Accepted 11th July 2014
DOI: 10.1039/c4cc04576a
www.rsc.org/chemcomm
The chiral base n-BuLi/(À)-sparteine or n-BuLi/(+)-sparteine surro-
gate promotes kinetic resolution of N-Boc-2-arylpiperidines by
asymmetric deprotonation. The enantioenriched starting material
was recovered with yields 39–48% and ers up to 97 : 3. On lithiation
then electrophilic quench, 2,2-disubstituted piperidines were
obtained with excellent yields and enantioselectivities.
Fig. 1 Some biologically active 2-arylpiperidines.
Piperidines substituted in the 2-position with at least one aryl group
are a class of molecules often possessing high biological activities
and are therefore of interest to synthetic organic, medicinal and
process chemists.1 For example, piperidine 1 is a poly ADP ribose
polymerase inhibitor (Fig. 1).2 Piperidine 2 is a lead compound for
orally active NK1 antagonists.3 Piperidine 2 was synthesised by Xiao
and co-workers as a mixture of diastereomers via the THF-mediated
lithiation-substitution of (Æ)-N-Boc-2-phenylpiperidine.3a The need
for a stereoselective synthesis is exemplified by the B50-fold
difference in activity between the HCl salt of the (R,R) and the
(R,S) diastereomers (IC50 0.3 nM and 415 nM, respectively).4
Scheme 1 Lithiation-substitution of piperidine 3a.
2-tributylstannane, itself formed by dynamic resolution of 2-lithiated
A general approach to the asymmetric synthesis of 2,2- N-Boc-piperidine,6 or directly by ‘catalytic dynamic resolution’,7
disubstituted piperidines continues to pose a problem for synthetic although the latter method was unsuccessful in our hands. We
chemists. Building on their expertise of lithiated nitrogen-containing therefore sought a simpler method and wondered if racemic N-Boc-
heterocycles, Coldham and O’Brien and co-workers reported that the 2-arylpiperidines were amenable to kinetic resolution. There is
Boc group in N-Boc-2-phenylpiperidine rotates rapidly, even at growing interest in the kinetic resolution of amines, mostly by
À78 1C, to allow high yields of lithiation at the benzylic position N-acylation.8 In contrast, the kinetic resolution of amines by depro-
and that the organolithium is configurationally stable at low tem- tonation has received very little study.9 The closest example is that
perature.5 This led to the synthesis of enantiomerically enriched from Beak and co-workers, who showed that the chiral base n-BuLi/
2-alkyl-2-phenylpiperidines, such as piperidine 4a, using enantio- (À)-sparteine can effect a kinetic resolution of an acyclic N-Boc-a-
merically enriched N-Boc-2-phenylpiperidine 3a (Scheme 1).
methylbenzylamine, albeit with fairly low selectivity (er up to 81 : 19
The enantioenriched N-Boc-2-phenylpiperidine (S)-3a was for 12% yield of recovered starting material).9a In this paper, we
obtained by an asymmetric reduction of the corresponding report that N-Boc-2-arylpiperidines are excellent substrates for highly
cyclic imine.5a An alternative approach is by Negishi reaction selective kinetic resolution by asymmetric deprotonation.
using the chiral organozinc species formed either from the
Racemic N-Boc-2-phenylpiperidine and related 2-aryl or 2-hetero-
aryl derivatives can be prepared by several different methods.10
We selected to extend the method used for racemic 3a,5a for the
preparation of a variety of N-Boc-2-arylpiperidines (Scheme 2).
Addition of the aryllithium, obtained by bromine–lithium exchange,
to 5-bromovaleronitrile, followed by reduction of the intermediate
cyclic imine with sodium borohydride and addition of Boc2O gave
a Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.
E-mail: i.coldham@sheffield.ac.uk
b AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c4cc04576a
9910 | Chem. Commun., 2014, 50, 9910--9913
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Table 1 Kinetic resolution to give 5a with n-BuLi and (À)-sparteinea
Entry
Time (min)
Yieldb 5a (%)
erc 5a
1
2
3
4
5
10
30
60
120
180
16
27
33
36
42
95 : 5
95 : 5
93 : 7
93 : 7
92 : 8
a
b
For yield and er of recovered 3a, see ESI. Yield of isolated product.
Determined by CSP HPLC.
c
significant decrease in yield. By increasing the reaction time to 3 h,
it was possible to obtain the product 5 with er 92 : 8 and a yield of
42% (entry 5).
To investigate the differences in reaction times for these
methods, we performed in situ IR spectroscopy to monitor the
stretching frequency of the carbonyl group (Fig. 2). When using
pre-mixed n-BuLi/(À)-sparteine (Fig. 2a), partial lithiation
occurs over about 15 min, as judged by the steady but partial
loss of ncQo 1691 cmÀ1 (CQO stretch for 3a) and formation of a
new peak at 1640 cmÀ1 (assigned to ncQo in the lithiated
intermediate). However, without pre-mixing, the lithiation
required several hours (Fig. 2b). The method chosen clearly
impacts on the selectivity, with the slower lithiation allowing a
Scheme 2 Synthesis of (Æ)-N-Boc-2-arylpiperidines 3a–g.
Scheme 3 Initial study of the kinetic resolution with pre-mixed n-BuLi/
(À)-sparteine.
the desired racemic piperidines 3a–g. Reasonable yields for the
three-step procedure were obtained, except with p-MeOC6H4Li
which gave significant amounts of methoxybenzene, perhaps due
to its propensity to abstract a proton alpha to the nitrile. The
corresponding organomagnesium reagent was no more successful.
For the kinetic resolution of these substrates, we initially
focused on developing conditions using the substrate 3a. A mixture
of 0.55 equiv. of n-BuLi and (À)-sparteine (pre-mixed for 5 min) in
PhMe was used for the lithiation of N-Boc-2-phenylpiperidine 3a
(Scheme 3). After 5 min, addition of iodomethane gave the product
4a in 30% yield with a promising er (79 : 21). With the electrophile
ethyl chloroformate, both the yield of the product 5a and the er
were improved. By changing the solvent to Et2O, a similar er
(87 : 13) of 5a was obtained but in reduced yield (see ESI† for yield
and er of recovered 3a). The er was determined by chiral stationary
phase (CSP) HPLC and the optical rotation of 4a (see ESI†) matched
that reported for the (S) enantiomer.5a These data predict, as
expected based on the lithiation of N-Boc-piperidine,11 that the
enantiomer (S)-3a is preferentially lithiated by n-BuLi/(À)-sparteine.
As an alternative, we investigated a different method of addi-
tion, whereby n-BuLi and (À)-sparteine were not premixed. n-BuLi
was added to a solution containing the piperidine 3a and (À)-spar-
teine in PhMe. After different time periods the electrophile
EtOCOCl was added (Table 1). A marked improvement in the er
of the product 5a was obtained, and this was associated with a
Fig. 2 In situ IR plots of the lithiation of 3a with n-BuLi/(À)-sparteine at
À78 1C in PhMe with time in h:min:s. (a) ncQo 3a (1691 cmÀ1), pre-mixed
n-BuLi/(À)-sparteine added at time 16 min, ncQo lithiated 3a (1640 cmÀ1);
(b) ncQo 3a (1691 cmÀ1) and (À)-sparteine then n-BuLi added at time
16 min, ncQo lithiated 3a (1640 cmÀ1).
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Table 2 Kinetic resolution of 3a with n-BuLi and (À)-sparteine
Equiv. n-BuLi
and (À)-sp
Yielda (%)
Yield (%)
Entry
and erb 3a (%)
and erb 5a (%)
1
2
3
4
0.55
0.7
0.8
1.0
50 (77 : 23)
45 (96 : 4)
31 (92 : 8)
13 (98 : 2)
42 (92 : 8)
51 (86 : 14)
56 (77 : 23)
74 (57 : 43)
a
b
Yield of isolated starting material. Determined by CSP HPLC.
more selective reaction. The faster reaction occurs with the pre-
mixed n-BuLi/(À)-sparteine complex that will have a higher
concentration of the dimeric aggregation state.12
With optimised conditions in-hand, we studied the use of other
electrophiles but these gave lower yields and ers (37% yield, er
82 : 18 using allyl bromide; 24% yield, er 74 : 26 using MeI). The
lower selectivities may be due to partial racemisation of the
lithiated intermediate prior to slower electrophilic quench.
Due to the variation in er dependent on the choice of electro-
phile, we decided to focus on obtaining a good yield and er for the
recovered starting material. This was investigated by varying the
number of equivalents of the chiral base (Table 2). The best
conditions that we found used 0.7 equiv. of n-BuLi and (À)-spar-
teine and gave an excellent yield and er of recovered 3a (entry 2).
A yield of 45% with er 96 : 4 (R:S) corresponds to a relative rate of
reaction for the two enantiomers krel B 22.13
The kinetic resolution was then tested with the different
2-arylpiperidines that were prepared as shown in Scheme 2. We
were pleased to find that high levels of selectivity could be achieved
with many of these compounds (Scheme 4). The yields and er values
of the recovered starting materials are given in Scheme 4 for the
different aromatic derivatives and it was found that both electron-
poor (p-chloro 3b, p-fluoro 3c) and electron-rich (p-methoxy 3e)
substituents are tolerated in the kinetic resolution. However, some
loss in selectivity occurs with the 3,5-bis-trifluoromethyl 3f and
2-pyridyl 3g derivatives. This may be due to a faster and therefore
less selective lithiation with these more acidic substrates.
(Scheme 5). This could enable a subsequent tin–lithium exchange
to recover the starting material after proton quench. The kinetic
resolution performed well using this electrophile to give the recov-
ered piperidine 3a in 42% yield and er 94 : 6. The er of the stannane
6a was not determined but this product was treated with n-BuLi in
THF followed by addition of acetic acid. When this reaction was
conducted at À78 1C, the piperidine (S)-3a was isolated with er
82 : 18, suggesting that tin–lithium exchange and protonation
occurs with retention of configuration. However, when the exchange
and protonation was conducted at room temperature, racemic 3a
was recovered in high yield. Therefore this approach allows recy-
cling of the undesired product to allow a further kinetic resolution.
Finally, we have performed THF-mediated lithiation then sub-
stitution on the enantioenriched recovered starting materials to
show that these are amenable to the formation of 2,2-disubstituted
piperidines without loss of enantioselectivity.5,15 Treatment of the
piperidine (R)-3b (er 96 : 4) with n-BuLi followed by MeI, EtOCOCl
or allyl bromide gave the products 4b, 5b, and 7b with good yields
In addition, we have demonstrated that the other enantiomer of
the 2-arylpiperidine can be formed by changing the chiral ligand to
O’Brien’s (+)-sparteine surrogate.14 This resulted in the formation
of (S)-3a (41% yield, er 91 : 9) and (S)-3b (42% yield, er 84 : 16).
This methodology is reliant on using ethyl chloroformate as a
sacrificial electrophile, consuming the undesired enantiomer. The
kinetic resolution was tested with Me3SnCl as the electrophile
Scheme 5 Kinetic resolution of N-Boc-2-phenylpiperidine with Me3SnCl
Scheme 4 Kinetic resolution of various N-Boc-2-arylpiperidines.
9912 | Chem. Commun., 2014, 50, 9910--9913
quench.
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The chiral base n-BuLi with (À)-sparteine or the (+)-sparteine
surrogate is effective for the kinetic resolution of racemic N-Boc-2-
arylpiperidines in PhMe. The recovered starting material can be
isolated with high enantiomer ratios, especially if n-BuLi and the
chiral ligand are not pre-mixed. Use of in situ IR spectroscopy
helped to optimise the conditions for the kinetic resolution. By
using a trialkyltin halide electrophile, the quenched product can be
recycled by tin–lithium exchange and protonation. After kinetic
resolution, the recovered enantioenriched N-Boc-2-arylpiperidines
can be deprotonated with n-BuLi in THF at À78 1C and quenched
with electrophiles without loss of enantiopurity to provide highly
enantioselective syntheses of 2,2-disubstituted piperidine products.
We thank the EPSRC, the University of Sheffield and Astra-
Zeneca for funding.
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Notes and references
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Chem. Commun., 2014, 50, 9910--9913 | 9913