Tandem directed lithiations of N-boc-1,2-dihydropyridines toward highly functionalized 2,3-dihydro-4-pyridones

Article abstract of DOI:10.1021/ol052313a

(Chemical Equation Presented) Sequential tandem directed lithiations of an N-Boc-4-methoxy-1,2-dihydropyridine have been achieved, leading to C-5,C-6 disubstituted dihydropyridones on acidic workup. The chlorine atom of the dihydropyridone products can in

Full text of DOI:10.1021/ol052313a

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5661-5664
Tandem Directed Lithiations of
N-Boc-1,2-dihydropyridines toward
Highly Functionalized
2,3-Dihydro-4-pyridones
Damian W. Young and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received September 23, 2005
ABSTRACT
Sequential tandem directed lithiations of an N-Boc-4-methoxy-1,2-dihydropyridine have been achieved, leading to C-5,C-6 disubstituted
dihydropyridones on acidic workup. The chlorine atom of the dihydropyridone products can in turn be substituted giving rise to diverse
substituents at C-6.
Nitrogen-containing heterocycles are profoundly represented
among natural products and pharmaceutically relevant small
molecules.1 Methods aimed at achieving such compounds
with strict control of regio- and stereochemistry continue to
stand as a prominent objective in synthetic organic chemistry.
In this vane, the 2,3-dihydro-4-pyridone 1 has been revealed
as an important synthetic building block in the synthesis of
several classes of azaheterocycles (Figure 1).2
These dihydropyridones have proficiently served as pre-
cursors to piperidine, perhydroquinoline, quinolizidine, and
indolizidine skeletons.2,3 Moreover, the value of these
Figure 1. Synthetic utility of dihydropyridones 1.
compounds is significantly enhanced by the facility to
(1) (a) Cordell, G. A. The Alkaloids: Chemistry and Biology; Elsevier
Science: San Diego, CA, 2003; Vol. 60. (b) Hesse, M. Alkaloids: Nature’s
Curse or Blessing?; Wiley-VCH: Weinheim, Germany, 2003. (c) Southon,
I. W.; Buckingham, J. Dictionary of Alkaloids; Chapman & Hall: London,
ongoing efforts to illustrate the versatility of dihydropyri-
UK, 1989.
construct them enantiomerically pure (1b) invoking methods
emanating from our laboratories and others.4 As part of our
(2) (a) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen Hetero-
cycles; Moody, C. J., Ed.; JAI Press Inc.: Greenwich, CT, 1996; Vol. 2, p
251. (b) Comins, D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic
Chemistry, 2nd ed.; McKillop, A., Ed.; Pergamon Press: Oxford, England,
1996; Vol. 5, p 37. (c) Comins, D. L. J. Heterocycl. Chem., 1999, 36, 1491.
(d) Joseph, S. P.; Comins, D. L. Curr. Opin. Drug DiscoVery DeV. 2002,
5, 870.
(4) Through chiral 1-acylpyridinium salts, see: (a) Comins, D. L.;
Goehring, R. R.; Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55, 2574.
(b) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994,
116, 4719. (c) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1994,
35, 7343. (d) Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am.
Chem. Soc. 1999, 121, 2651. (e) Ege, M.; Wanner, K. T. Org. Lett. 2004,
6, 3553 and references therein. (f) For examples of asymmetric hetero
Diels-Alder reactions, see: (g) Josephsohn, N. S.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 4018. (h) Waldmann, H. Synthesis
1994, 535.
(3) For recent examples and leading references, see: (a) Kuethe, J. T.;
Comins, D. L. J. Org. Chem. 2004, 69, 2863. (b) Kuethe, J. T.; Comins, D.
L. J. Org. Chem. 2004, 69, 5219. (c) Comins, D. L.; Kuethe, J. T.; Miller,
T. M.; Fe´vrier, F. C.; Brooks, C. A. J. Org. Chem. 2005, 70, 5221.
10.1021/ol052313a CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/08/2005

dones toward the generation of more elaborate natural and
biologically active substances, we desired a means for a facile
entry into more highly substituted derivatives. To address
this goal, we describe herein the preparation of 5,6-
disubstituted 2,3-dihydro-4-pyridones emanating from a
sequence of tandem directed lithiations of N-Boc-1,2-
dihydropyridines.
The directed ortho metalation (DoM) reaction is an
effective platform for functionalization of aromatic com-
pounds with controlled regiochemical outcomes.5 Utilized
to a lesser extent is the related DoM of nonaromatic
substrates. One example of such is the R-lithiation of N-Boc-
1,4-dihydropyridines that was first reported by us.6 This
methodology provides an expedient and controlled access
to substituted 1,4-dihydropyridines and pyridines. These
seminal studies led to application of the lithiation methodol-
ogy to the related N-Boc-4-methoxy-1,2-dihydropyridines,
which are effectively converted to 2,3-dihydro-4-pyridones
on acidic workup.7 In this case, treatment of the N-Boc-1,2-
dihydropyridine 2 with n-BuLi generates the C-6 lithiated
intermediate 3 (Scheme 1). Quenching of this anion with I2,
its well-documented aptitude for such reactivity in aromatic
systems,5b a chlorine atom was elected as a suitable candidate
at the C-6 position to appropriately confer this directing
ability.
To test this tandem lithiation hypothesis, dihydropyridine
7 was prepared through formation of an N-acylpyridinium
salt with 4-methoxypyridine and phenyl chloroformate fol-
lowed by treatment with isobutylmagnesium bromide (Scheme
2). A carbamate exchange to the more hindered N-Boc
Scheme 2
Scheme 1
derivative was effected with t-BuOK in THF to furnish
dihydropyridine 9.8,9 This expedient route to 7 belies direct
administration to our preparation of enatiomerically pure
dihydropyridones.4 Utilization of this asymmetric technology
necessarily proceeds through the dihydropyridone first to
allow facile removal of the chiral auxiliary. We therefore
optimized conditions to obtain 7 via O-methylation of the
dihydropyridone itself. After some effort, it was discovered
that treatment with dimethyl sulfate following enolization
of dihydropyridone 8 with KHMDS at -78 °C in THF
rendered dihydropyridine 7 in good yield. This reaction can
suitably be used to generate enantiomerically pure 4-meth-
oxy-1,2-dihydropyridines from nonracemic dihydropyridones
1b. The C-6 directed lithiation and chlorination sequence
was executed by treatment of 9 with n-BuLi followed by
hexachloroethane to afford the 6-chlorodihydropyridine 10
in 81% yield (Scheme 2). This transformation was particu-
larly valuable given that other chlorinating agents examined
in this reaction (N-chlorosuccinimide, trifluoromethylsulfonyl
chloride) rendered extensive decomposition. Accordingly,
through this directed lithiation, we were able to install the
directing group of choice and pave the way for a potential
second reaction of this type at C-5.
followed by mild acidic hydrolysis of the enol ether, gives
the 6-iodo-2,3-dihydro-4-pyridone 5.
These 6-iodo derivatives were found by us to be effective
coupling partners in Sonogashira reactions.8 We sought to
build upon these methodologies to gain a facile entry into
more elaborately functionalized dihydropyridones. We sur-
mised that if a suitable directing group was affixed at the
C-6 position of the dihydropyridine by the previous protocol,
a second lithiation event at C-5 might then be feasible by
addition of another equivalent of an alkyllithium base.
Although the C-5 position of a 1,2-dihydropyridine is
electron rich, potentially abrogating deprotonation there, it
was rationalized that the directing pressure of two adjacent
groups would render this lithiation possible. On the basis of
Efforts were now directed at the C-5 metalation and
functionalization of 10. Deprotonation of the chlorodihy-
dropyridine was first probed by a deuterium quenching
experiment (Scheme 3). In the initial attempt, dihydropyri-
dine 10 was treated with n-BuLi at -78 °C, quenched with
deuterium oxide, and then warmed to ambient temperature.
Gratifyingly, a mild hydrolysis of the reaction mixture with
(5) Directed ortho metalation: (a) Gwensh, H. W.; Rodriguez, H. R. Org.
React. 1979, 26, 1. (b) Sniekus, V. Chem. ReV. 1990, 90, 879.
(6) (a) Comins, D. L. Tetrahedron Lett. 1983, 24, 2807. (b) Comins, D.
L.; Weglarz, M. A. J. Org. Chem. 1988, 53, 4437.
(7) (a) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30,
5053. (b) For a related metalation, see: Comins, D. L.; Weglarz, M. A.;
O’Connor, S. Tetrahedron Lett. 1988, 29, 1751.
(8) Comins, D. L.; Williams, A. L. Org. Lett. 2001, 3, 3217.
(9) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836.
Org. Lett., Vol. 7, No. 25, 2005
5662

established on quenching with excess methyl chloroformate
(entry 1). Heteroatoms and acyl groups (entries 2-5, 7, and
8) were implemented on treatment with the appropriate
electrophiles. Reaction of anion 11 with benzaldehyde (entry
6) resulted in 13f as a mixture of diastereomers. Relatively
unreactive electrophiles such as iodoethane gave a good yield
of the ethyl-substituted dihydropyridone. As a general trend,
times required for hydrolysis from 11 to 13 lengthened
according to the strength of the electron-withdrawing po-
tential of the C-5 substituent.
Scheme 3
Intrinsic to our design of selecting the Cl atom as a
directing group was its dual ability to serve as a handle for
substitution reactions. In this system, the chlorine atom is a
proficient enabling element for substitution under a variety
of reaction conditions. Substitution of nucleophilic reagents
can proceed through a Michael addition with concomitant
expulsion of chloride to give the appropriately substituted
products (Scheme 4). The addition of NaOMe in methanol
aqueous oxalic acid resulted in isolation of 12 as the only
product. The complete incorporation of deuterium into C-5
indicated that the DoM was complete and highly regiose-
lective.
Regarding the mechanism of this transformation, we
conjecture that a kinetic and synergistic directing influence
of both the C-4 methoxy and C-6 chloro groups in 10
attribute to the selective lithiation at C-5. It cannot be ruled
out, however, that deprotonation initially occurs elsewhere
and then equilibrates to C-5 owing to the thermodynamic
charge stabilizing effect of situating the anion between two
positively polarized carbon atoms.10 This reaction, to the best
of our knowledge, constitutes the first demonstration of a
C-5 directed metalation on dihydropyridine substrates.
Encouraged by these preliminary results, we moved to
apply this methodology toward the installation of a range of
functional groups at C-5 (Table 1).
Scheme 4
Table 1. Preparation of Dihydropyridones 13 from
Dihydropyridine 10
entrya
electrophile (E+)
product, E
yieldb (%)
1
2
3
4
5
6
7
8
9
ClCO2Me (4.0 equiv)
MeSSMe (1.5 equiv)
PhSeSePh (1.5 equiv)
I2 (1.5 equiv)
C2Cl6 (1.5 equiv)
PhCHO (1.5 equiv)
DMF (1.5 equiv)
13a, CO2CH3
13b, SMe
13c, SePh
13d, I
77
87
62
91
88
67c
43
71
56
providing the C-6 methoxy derivative 14 and the alkyation
at C-6 with a lower ordered cyanocuprate yielding 15 both
fall under this mechanistic domain.
13e, Cl
Alternatively, substitution at C-6 can also be achieved
through the use of Pd(0) catalysis. Our initial screening of
several coupling reactions with Pd(PPh3)4, Pd2(dba)3, and Pd-
(dppf)2 was met with no success as these catalysts all resulted
in recovery of the starting material. We then employed
conditions reported by Fu, utilizing Pd(Pt-Bu3)2, which
proved to be highly effective in this system.11 A Negishi
coupling using phenylzinc chloride gave 16, and a Stille
coupling reaction with vinyltributylstannane rendered 17
under the auspices of this catalyst. The highly functionalized
heterocycles shown in Scheme 4 are achieved in good yields
and with exclusive control of regiochemistry in four synthetic
steps.
13f, CH(OH)Ph
13g, CHO
13h, COCH3
13i, CH2CH3
Ac2O (1.5 equiv)
CH3CH2I (5.0 equiv)
a The reactions were generally performed on a 1-3.0 mmol scale. b Yield
of products obtained from radial preparative-layer chromatography. c Product
is a mixture of diastereomers.
Given the reactivity of sp2-hybridized organolithiums, a
wide range of substituents can be installed in yields ranging
from good to excellent. A C-5 carbomethoxy group was
(10) For a contemporary mechanistic discussion on directed lithiations
relating to kinetic versus thermodynamic arguments, see: Gros, P.; Choppin,
S.; Fort, Y. J. Org. Chem. 2003, 68, 2243.
(11) Littke, A. F.; Scjwarz, Z. L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 6343.
Org. Lett., Vol. 7, No. 25, 2005
5663

In summary, we have disclosed a new route for the
preparation of highly functionalized and diversified 2,3-
dihydro-4-pyridones. The methodology uses sequential lithia-
tions: first at C-6 and then at C-5 of 1,2-dihydropyridines
as a means toward these dihydropyridones. The selection of
chlorine as a substituent at the C-6 position facilitates the
second lithiation event at C-5 with concomitant trapping of
electrophiles. Finally, the chloride additionally allows for the
substitution of a range of groups at C-6. Extension of this
methodology toward other heterocycles and natural products
of interest is currently underway and will be reported in due
course.
also like to thank the NIH for a research training supple-
mental Minority Graduate Research Assistantship.
Note Added after ASAP Publication. Compounds 16 and
17 were incorrectly labeled in the paragraph below Scheme
4 in the version published ASAP November 8, 2005; the
corrected version was published ASAP November 8, 2005.
Supporting Information Available: General experimen-
tal procedure for 13, experimental procedures for 10 and 14-
17, and spectroscopic characterization data and NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
National Institutes of Health (Grant GM 34442). D.Y. would
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Org. Lett., Vol. 7, No. 25, 2005