Practical and highly regio- and stereoselective synthesis of 2-substituted dihydropyridines and piperidines: Application to the synthesis of (-)-coniine [17]

Full text of DOI:10.1021/ja017136x

J. Am. Chem. Soc. 2001, 123, 11829-11830
11829
Table 1. Addition of Organomagnesium Reagents to Pyridinium
Practical and Highly Regio- and Stereoselective
Synthesis of 2-Substituted Dihydropyridines and
Piperidines: Application to the Synthesis of
(-)-Coniine
Salts Derived from Amide 46
Andre´ B. Charette,* Michel Grenon, Alexandre Lemire,
Mehrnaz Pourashraf, and Jonathan Martel
De´partement de Chimie, UniVersite´ de Montre´al
P.O. Box 6128, Station Downtown
Montre´al, Que´bec, Canada H3C 3J7
ReceiVed September 21, 2001
The piperidine subunit is one of the most important pharma-
cophores that is widely found in biologically active molecules
and natural products. Many synthetic methodologies have been
developed to access these very useful heterocyclic compounds.1
One very attractive and cost-effective approach consists of
activating pyridine to generate either an N-alkyl- or an N-
acylpyridinium salt 1 or 2 (R1 and R2 ) H). A subsequent
nucleophilic attack by an organometallic reagent generates a
substituted dihydropyridine which can then be further derivatized.2
The drawback of this approach is the lack of regiocontrol when
an unsubstituted pyridinium salt is used. Typically, mixtures of
1,2- and 1,4-adducts which had to be separated were obtained.
To circumvent this problem, several systems in which directing
or blocking groups had to be included (such as in 2a and 2b) to
achieve high levels of regio- and stereocontrol were developed.
In this communication, we report a novel highly regio- and
stereoselective approach to 2-substituted dihydropyridines from
unsubstituted N-pyridinium salts. This approach relies on the
stereoselective formation of the (E)-isomer of N-pyridinium
imidate 3 from the corresponding amide in which the nitrogen
imidate lone pair is oriented in the proper position to direct the
addition of an organometallic reagent at the 2 position.
a Ratios determined by 1H NMR. b Combined yield of dihydropyri-
dines. c Organomagnesium reagent added at -30 °C.
magnesium reagents proceeds extremely well at low temperatures
to give the desired 1,2-dihydropyridines, 5, in good to excellent
isolated yields. The regioselectivity of addition was found to be
very high in general, favoring the 1,2-adduct in all cases. Although
the addition of methylmagnesium bromide occurred with the
exclusive formation of 5a (entry 1), the addition of more hindered
alkylmagnesium and functionalized Grignard reagents gave rise
to slightly lower regioselectivities (entries 4,7). In those cases, it
was found that the addition of the related cuprate reagents
proceeded with slightly higher regioselectivities (entries 5,8). The
regiochemical outcome with cuprates is in sharp contrast to what
is observed with N-acylpyridinium salts which give exclusively
1,4-addition with these reagents.5 The addition of phenyl-, vinyl-,
and furyl Grignard proceeded extremely well to provide the 1,2-
dihydropyridines in excellent yields.
To illustrate the synthetic utility of the 1,2-dihydropyridine
adducts, compounds 5b and 5f were oxidized upon treatment with
DDQ to afford the corresponding 2-substituted pyridines 7b and
7f in excellent yields (100 and 85% respectively) (eq 2).
We have recently reported that secondary or tertiary amides
could be activated toward nucleophilic attack upon treatment with
triflic anhydride (Tf2O) and pyridine. A subsequent addition of
several heteronucleophiles (ROH, RNH2, H2S, etc.) gave rise to
a variety of useful functional group transformations (eq 1).3
Having established that the imidate lone pair could effectively
direct the nucleophilic attack at the C-2, we then focused our
(1) For recent reviews on the stereoselective synthesis of piperidines, see:
(a) Laschat, S.; Dickner, T. Synthesis 2000, 1781. (b) Mitchinson, A.; Nadin,
A. J. Chem. Soc., Perkin Trans. 1 2000, 2862.
(2) From chiral N-alkylpyridinium salts, see; (a) Guilloteau-Berin, B.;
Compe`re, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000,
1391. (b) Ge´nisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58,
2052. From chiral N-acylpyridinium salts, see: (c) Comins, D. L.; Kuethe, J.
T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc. 1999, 121, 2651. (d) Comins,
D. L.; Zhang, Y. J. Am. Chem. Soc. 1996, 118, 12248. (e) Comins, D. L.;
Guerra-Weltzien, L. Tetrahedron Lett. 1996, 37, 3807. (f) Comins, D. L.;
Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994, 116, 4719.
(3) (a) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677. (b)
Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908 and references therein.
(4) Charette, A. B.; Grenon, M. Can. J. Chem. 2001. In press.
A spectroscopic investigation of the activation process has
shown that N-pyridinium intermediate 3 was formed in the
activation process.4 NOESY experiments have confirmed that the
(E)-imidate was formed as the only isomer when the appropriate
R1 and R2 groups were selected. Initial studies on the activation
of N-methylbenzamide, 4, confirmed that the (E)-imidate was
formed exclusively upon treatment with Tf2O and pyridine.
The results of the addition of organometallic reagents are
summarized in Table 1. As illustrated, the addition of organo-
(5) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315.
10.1021/ja017136x CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

11830 J. Am. Chem. Soc., Vol. 123, No. 47, 2001
Communications to the Editor
Scheme 1. Synthesis of (R)-(-)-Coniine 17a
Table 2. Addition of Organomagnesium Reagents to Pyridinium
Salts Derived from Chiral Amide 9
entry
RM
10/11a
>95/5 >95/5
75/25 >95/5
>95/5 >95/5
90/10
d.r.a
yield (%) product
1
2
3
4
5
6
7
MeMgBr
EtMgBr
77
79b
73c
74
89
68
65
10a
10b
10b
10c
10c
10d
12
Et2Zn
PhMgBr
PhMgBrc,d
2-FurylMgBr
>95/5
>95/5 >95/5
>95/5 >95/5
1-HexynylMgBr >95/5 >95/5
a Conditions: (a) i) Pyridine, Tf2O, CH2Cl2, -40 to 0 °C ii) 14, -78
to -30 °C, 61%; (b) H2, Pd(OH)2, EtOH, 25 °C then add cyclohexene
and AcOH, 100 °C; (c) (Boc)2O, THF, NaOH 2.0 M, 60% (two steps).
a Ratios determined by 1H NMR. b Combined yield of dihydro-
pyridines. c Added at -20 °C. d Prepared from PhLi.
attention to generation of enantiomerically enriched 2-substituted
piperidines. The stereoselective addition to unsubstituted pyri-
dinium salts is complicated by the fact that four electrophilic faces
(2- and 2′-position, 8) could be subjected to nucleophilic attack.
If, however, a bulky substituent is introduced at the R1 position,
nucleophilic attack at the 2′-position (in 8) may be suppressed.
Neither this substituent nor the N-substituent of the imidate should
preclude (E)-imidate formation. After extensive optimization, it
was found that the optimal R1 group was phenyl and that a
bidentate chiral auxiliary derived from valinol produced excellent
results in nucleophilic addition reactions.
(entry 3). The addition of aryl-, furyl- and alkynylmagnesium
bromides led to the adducts with excellent regio- and stereocontrol
(entries 4-7).8 To further demonstrate the synthetic potential of
this methodology, an expedient synthesis of the piperidine alkaloid
(R)-(-)-coniine starting from amide 13 is presented (Scheme 1).9
The addition of cis-1-propenylmagnesium bromide 14 proceeded
well to yield 1,2-dihydropyridine 15 in 61% isolated yield.
Hydrogenation of the three alkenes and hydrogenolysis of the
benzyl ether led to 16 which spontaneously cyclized under the
reaction conditions to the oxazoline 19 and to (R)-(-)-coniine
17 which was isolated as its N-Boc derivative 18 in 60% yield
for the two-step process.10
In summary, we have reported an expedient regio- and
stereoselective approach to 2-substituted dihydropyridines that
relies on the powerful directing ability of the imidate group.
Further applications of this methodology will be reported in due
course.
As shown in Table 2, amide 9 derived from (S)-valinol, in
which the alcohol was protected as a methyl ether,7 gave in most
cases excellent regio- and diastereoselectivities.
Acknowledgment. This work was supported by the E. W. R. Steacie
Fund, NSERC, Merck Frosst Canada, Boehringer Ingelheim, and the
Universite´ de Montre´al. A.L. thanks NSERC for a postgraduate fellowship.
J.M. thanks NSERC and FCAR (Que´bec) for a postgraduate fellowship.
Once again, although the addition of methylmagnesium bro-
mide proceeded very well to afford 10a, the addition of more
hindered alkylmagnesium reagents suffers from a lack of regio-
control (compare entries 1 and 2). For the introduction of alkyl
chains, we found that although organocuprates led to slightly
better regioselectivities, the diastereoselectivies were quite modest.
In contrast, addition of diethylzinc proceeded extremely well to
produce 10b in excellent yield, regio- and diastereoselectivities
Supporting Information Available: Experimental procedures and
spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA017136X
(8) The 1,2-dihydropyridine, 10e, proved unstable and was isolated as the
fully hydrogenated compound 12.
(6) Typical procedure: A solution of 4 in CH2Cl2 containing pyridine (3.0
equiv) was cooled to -40 °C and treated with Tf2O (1.2 equiv). The mixture
was then warmed to room temperature. After 1 h of stirring at room
temperature, the solution was cooled to -78 °C, and the nucleophile (2.5
equiv) was added. The reaction was stirred at -78 °C until TLC analysis
showed complete disappearance of the starting amide (ca. 3 h). Aqueous
workup, followed by chromatography, yielded the dihydropyridine. For further
details, see Supporting Information.
(9) Coniine is a common synthetic target for testing new piperidine synthesis
methodology. For selected examples, see; (a) Wilkinson, T. J.; Stehle, N. W.;
Beak, P. Org. Lett. 2000, 2, 155. (b) Reding, M. T.; Buchwald, S. L. J. Org.
Chem. 1998, 63, 6344. (c) Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J. J.
Org. Chem. 1998, 63, 6699. (d) Munchhof, M. J.; Meyers, A. I. J. Org. Chem.
1995, 60, 7084.
(10) The stereochemistry of the chiral center created in 15 was established
by comparing the optical rotation of 18 with the previously reported value
([R]23D ) -29.9 (c 0.67, CHCl3); [R]23D lit. ) -31.6 (c 0.86, CHCl3): Enders,
D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173.
(7) Meyers, A. I.; Poindexter, G. S.; Brich, Z. J. Org. Chem. 1978, 43,
892.