Complexation promoted additions to N-benzoyliminopyridinium ylides. A novel and highly regioselective approach to polysubstituted piperidines

Article abstract of DOI:10.1021/ja0348647

Unprecedented regioselectivities were observed for the addition of different organometallic nucleophiles to N-benzoyliminopyridinium ylides. Even benzylic and branched aliphatic Grignard reagents, which usually give substantial amounts of 1,4-adducts, sho

Full text of DOI:10.1021/ja0348647

Published on Web 04/30/2003
Complexation Promoted Additions to N-Benzoyliminopyridinium Ylides. A
Novel and Highly Regioselective Approach to Polysubstituted Piperidines
Claude Legault and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, QC H3C 3J7, Canada
Received February 25, 2003; E-mail: andre.charette@umontreal.ca
The piperidine unit is widely found in many natural products
and biologically important pharmaceuticals. Extensive reviews
describing various strategies for their syntheses and their natural
occurrence have been published.1,2 One of the most expedient
methods to access piperidine subunits has been through addition
reactions of nucleophilic reagents to an activated pyridinium moiety.
However, this approach is complicated by the multiple electrophilic
Figure 1. X-ray crystal structure of 1. Selected bond lengths [Å] and angles
sites on the ring which generally translate into nonregioselective
nucleophilic additions. One way to circumvent this problem is
through the use of protecting groups to block undesired electrophilic
sites, a methodology that has been exploited by Comins.3 Another
approach involves the use of a directing group, allowing for
controlled addition to the 2 position. Pioneering work using this
strategy has been reported by Marazano.4 Recent work in our group
has led to the development of a new system for the regio- and
stereoselective synthesis of 2-substituted dihydropyridines and
piperidines.5 While these systems favor the regioselective addition
of various nucleophiles to the 2 position, the limitations of this
methodology include the incompatibility of 2-substituted pyridine
toward the activation conditions and poor regiocontrol with bulky
aliphatic and benzylic organometallic reagents. Herein, we report
a novel and highly regioselective approach to 2- and 2,6-disubsti-
tuted tetrahydropyridines from unsubstituted and 2-substituted
pyridinium moieties using N-benzoyliminopyridinium ylides.
All of the current successful systems rely on classical pyridinium
salts, having a dissociated counterion. This anion can serve as a
Lewis base to activate the organometallic nucleophile, making the
directing group on the pyridinium salt less effective. Conversely,
the ylides have the counterion directly linked to the pyridinium
moiety, and our postulate was that this counterion could serve both
as a Lewis base and as a directing group for the nucleophile.
Furthermore, an uncomplexed pyridinium ylide should possess a
lower electrophilicity due to the delocalization of the negative
charge in the pyridine ring. The complexation of the nucleophile
should enhance the electrophilicity of the ring, thus promoting the
addition (Scheme 1).
[deg]: C(12)-O(12) 1.247, C(12)-N(11) 1.335, N(1)-N(11)-C(12) 115.5,
C(6)-N(1)-N(11)-C(12), 59.3.
Compounds of this type have been used in various rearrangements
leading to novel heterocyclic compounds.7,8
An extensive study of the nature of the substituent on the
exocyclic nitrogen established that the use of a benzoyl group was
optimal. N-Benzoyliminopyridinium ylide (NAPBz) 1 is rapidly
synthesized in excellent yield by benzoylation of the commercially
available N-aminopyridinium iodide.9 The N-aminopyridinium salts
can also be prepared by direct amination of the corresponding
pyridine, encompassing a wide variety of pyridines, including
2-substituted ones.10,11 NAPBz shows interesting physical and
spectroscopic properties.12 The IR spectrum shows the carbonyl
stretching band at 1560 cm-1. This value is about 90 cm-1 lower
than a corresponding hydrazide. This provides strong evidence for
the delocalization of the negative charge into the carbonyl. Further
proof of this is illustrated by the X-ray crystal structure of 1 (Figure
1) with a C-O bond length of 1.247 Å, as compared to the
corresponding hydrazide (1.219 Å, see Supporting Information).13
Several Grignard reagents were then added to 1, and these results
are summarized in Table 1. The addition proceeds smoothly at room
temperature within 25 min. Because the dihydropyridines obtained
were found to be unstable, they were reduced in situ with a
methanolic solution of NaBH4 to afford the 1,2,5,6-tetrahydro-
pyridines in good to excellent yields. The level of regiocontrol was
excellent (>95:5), favoring the 1,2-adduct. Particular attention
should be given to entries 4, 5, 7, and 8, which are known to be
problematic, usually giving predominant 1,4-addition. To our
surprise, even the addition of t-BuMgCl (entry 5), a typical reagent
for 1,4-addition,14 gave a modest amount of the 1,2-adduct. Last,
and most importantly, is the high regioselectivity obtained in the
addition of a benzylic Grignard. It has been shown by Marazano
to be a reagent selective for 1,4-addition.4a
Scheme 1
This methodology can also be applied to 2-substituted pyridines.
There are reports of electrophilic activation of the former followed
by addition of a nucleophile; however, the addition is nondirected
and usually results in a mixture of regioisomers.15 Several Grignard
reagents were added to the 2-methyl-N-benzoyliminopyridinium
ylide 4, and the results are summarized in Table 2.
In all cases, the regioselectivity was complete, favoring the 1,2-
adduct. Following the addition, the resulting dihydropyridines were
reduced to afford the 2,6-disubstituted tetrahydropyridines, favoring
the cis isomer in moderate to excellent diastereoselectivities and
Our selection for the nature of X (Scheme 1) was based upon
the N-X bond strength and its directing ability. Also, following
addition, it is desirable that the N-X bond be easily cleaved,
affording the desired piperidines. Pyridine N-oxide was not
considered a suitable candidate due to a variety of reports showing
rearrangements following addition of a nucleophile.6 Instead, we
focused on N-iminopyridinium ylides (X ) NR), where modifica-
tions of R could tune the reactivity of the pyridinium moiety.
9
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J. AM. CHEM. SOC. 2003, 125, 6360-6361
10.1021/ja0348647 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Formation of 1,2,5,6-Tetrahydropyridinesa
In conclusion, we have shown that N-benzoyliminopyridinium
ylides are promising substrates for the synthesis of polysubstituted
piperidines, showing an unprecedented reactivity. The development
of an enantioselective version leading to nonracemic piperidines is
also currently underway and will be reported in due course.
entry
RMgX
2/3
yield (%)
products
Acknowledgment. This work was supported by the E. W. R.
Steacie Fund, the National Science and Engineering Research
Council (NSERC) of Canada, Merck Frosst Canada, Boehringer
Ingelheim (Canada), and the Universite´ de Montre´al. C.L. is grateful
to NSERC (PGS A and B) and FCAR (B2) for postgraduate
fellowships.
1
2
3
4
5
6
7
8
9
MeMgBr
EtMgBr
>95/5
>95/5
>95/5
>95/5
43/57
>95/5
>95/5
93/7
91
83
87
81
39, 28
77
79
71
85
2a
2b
2c
2d
2e, 3e
2f
2g
2h
2h
n-PrMgCl
i-PrMgBr
t-BuMgCl
VinylMgBr
AllylMgBr
BnMgCl
BnMgCl
>95/5
Supporting Information Available: Experimental procedures and
spectral data of selected compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
a See Supporting Information for details.
Table 2. Formation of 2,6-Disubstituted
1,2,5,6-Tetrahydropyridines
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lective system are encouraging. The addition of n-PrMgBr to chiral
pyridinium ylide 9 resulted in complete regioselectivity in the 2
position, providing the tetrahydropyridine 10 in 92% yield and 84:
16 dr (eq 2).
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J.; Declercq, J. P. Synthesis 1995, 1038-1050. Treatment of 5b with HCl/
Et2O afforded (()-cis-2-methyl-6-propylpiperidine hydrochloride 11
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