Intramolecular cyclization manifolds of 4-Alkylpyridines bearing ambiphilic side chains: Construction of spirodihydropyridines or benzylic cyclization via anhydrobase intermediates

Article abstract of DOI:10.1021/jo301247c

4-Alkylpyridines possessing nucleophilic β- dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(OⁱPr)₄. Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.

Full text of DOI:10.1021/jo301247c

Article
pubs.acs.org/joc
Intramolecular Cyclization Manifolds of 4‑Alkylpyridines Bearing
Ambiphilic Side Chains: Construction of Spirodihydropyridines or
Benzylic Cyclization via Anhydrobase Intermediates
Sharavathi G. Parameswarappa and F. Christopher Pigge*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
S
* Supporting Information
ABSTRACT: 4-Alkylpyridines possessing nucleophilic β-
dicarbonyl side chains have been converted to spirodihy-
dropyridines upon treatment with ethyl chloroformate and
sub-stoichiometric amounts of Ti(OiPr)4. Alternatively,
inclusion of mild base in the reaction medium was found to
facilitate generation of anhydrobase intermediates. Subsequent
aldol-like condensations with electrophilic side chain moieties
followed by hydrolysis delivered benzylically cyclized pyridines
in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.
The spirocyclization protocol described above proved to be
effective when β-amido ester groups served as pro-nucleophilic
components. We have subsequently attempted to expand the
scope of this transformation to include 4-alkylpyridines
possessing substituted β-keto amide and β-keto ester side
chains. During the course of these investigations a second
intramolecular cyclization reaction manifold available to these
pyridine substrates was uncovered that appears to proceed via
generation of nucleophilic anhydrobase intermediates. Under
these modified reaction conditions, cyclization between the
benzylic position of the pyridine and an electrophilic carbonyl
group of the side chain occurs to afford new pyridyl-substituted
hetero- and carbocyclic ring systems. Thus, judicious choice of
reaction conditions allows structurally similar pyridine deriva-
tives to be converted to either spirodihydropyridines or
polycylic pyridyl lactams in good yield. Notably, each of
these heterocyclic frameworks possesses pharmacological
significance.24,25
INTRODUCTION
■
Pyridines and pyridine derivatives are ubiquitous heterocyclic
motifs that are encountered in numerous natural products,
pharmaceutical agents, and functional materials.1−4 Developing
preparative methods suitable for construction of substituted
pyridines5−7 and further defining synthetic approaches for
manipulation of preformed pyridine substrates8−12 are
important objectives. Continued success in research along
these lines has potential to significantly impact many diverse
areas within the field of contemporary organic chemistry.
A convenient and well-established means of functionalizing
simple pyridine derivatives entails activation of the pyridine ring
system via N-alkylation or N-acylation followed by regiose-
lective nucleophilic addition to either the α or γ pyridine
carbon.8,13−15 The resulting dihydropyridine products can then
be further processed to afford substituted piperidines or
rearomatized to yield substituted pyridines. Intramolecular
variants of this strategy, however, have not been extensively
developed despite their potential to deliver concise entry to a
variety of polycyclic heterocyclic frameworks.16−22 In this
context we recently reported efficient spirocyclization reactions
of 4-alkylpyridines possessing β-amido ester groups in the side
chain (e.g., eq 1).23 In this manner several diazaspiro[4.5]-
RESULTS AND DISCUSSION
■
We previously reported that exposure of simple β-keto amide-
substituted pyridines 1 and 3 to the reaction conditions
illustrated in eq 1 gave the corresponding spirocyclic products 2
and 4 in greatly diminished yields as compared to reactions
involving closely related β-amido ester analogues (Scheme 1).23
The reactivity of several additional 4-alkylpyridines with β-keto
amide side chains was screened under these conditions, and the
results are depicted in Table 1. The reaction was found to be
sensitive to the nature of the amide N-substituent (allyl and
benzyl amides returned dihydropyridine products in signifi-
cantly lower yield, entries 1 and 2) as well as substitution at the
decane and diazaspiro[5.5]undecane derivatives were obtained
from 4-aminomethyl and 4-aminoethyl pyridine precursors via
acylation of the pyridine ring followed by Ti-mediated
nucleophilic addition of the dicarbonyl side chain.
Received: June 20, 2012
Published: August 30, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2
Table 1. Spirocyclization of 4-Alkylpyridines with β-Keto
Amide Side Chains
substrates (Table 1) were not efficiently cyclized under these
conditions.
An interesting observation was recorded when a crude
CH2Cl2 reaction mixture (Scheme 1 conditions) of 5h was
briefly heated to reflux. In this instance, the expected spirocycle
6h was obtained in 39% along with a byproduct identified as
the relatively stable anhydrobase 7 in 15% yield (eq 2).The
a
entry
substrate
R
R1
R2
product (% yield)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
allyl
Bn
Et
H
H
H
H
F
Me
Me
Et
6a (12)
6b (18)
6c (53)
6d (43)
6e (10)
Et
Ph
Et
Me
Me
Me
b
Et
allyl
np
b
5g
Et
propargyl
np
5h
Et
-CH2CH2CH2-
6h (51)
a
b
Isolated yield. No product.
formation of 7 is attributed to facile benzylic deprotonation of
5h upon acylation of the pyridine, perhaps assisted by the
activated methylene group of the β-dicarbonyl moiety (entries
5−7). An exception to this trend was observed in cyclizations
involving an oxoamide cyclopentanone side chain (entry 8).
Notably, cyclizations of analogous cyclopentanone amides
derived from 4-aminoethyl pyridine precursors were also
much more efficient compared to simpler acyclic β-keto
amide congeners.23b In all cases, however, pyridines with β-
amido ester side chains (as in eq 1) proved to be superior
substrates for this transformation.
i
presence of dissociated PrO− ligands. Condensation with the
pendant ketone carbonyl and elimination of water give rise to
the observed lactam ring. While anhydrobases of pyridine are
certainly well-established species,26 their use as synthetic
intermediates is relatively rare.27 Recent reports, however,
have described the ability of 2-picolines to participate in
intermolecular condensation reactions with activated electro-
philes catalyzed by Lewis acids,28 Brønsted acids,29 or simply
upon thermal activation30 via anhydrobase (enamine)-like
intermediates. Accordingly, we became interested in further
developing this second intramolecular reaction manifold
potentially available to the 4-alkylpyridine derivatives in hand.
We began these studies by examining the effect of added base
in established spirocyclization procedures. The inclusion of 1.5
Some effort was briefly directed toward enhancing the
reactivity of β-keto amide substrates by variation of reaction
conditions. For example, reactions of 1 were performed in
several other solvents (DMF, THF, acetone, toluene), but no
cyclized products were observed. In addition, the ability of
different Lewis acids to mediate the cyclization of 1 in the
presence of ethyl chloroformate was probed. Of the acids
examined (InCl3, Mg(OTf)2, Cu(OTf)2, TMSOTf), only InCl3
proved effective but was still inferior to the action of Ti(OiPr)4.
Likewise, the reactivity of pyridine 5h was also examined in the
presence of alternative Lewis acids. Once again Ti(OiPr)4
proved to be the additive of choice, although spirocyclization
was also observed in comparable yield using MgBr2. Other
Lewis acids (CuSO4, SnCl4, TiCl4) were ineffective. Interest-
ingly, both 1 and 5h were found to undergo spontaneous
spirocyclization when treated with ClCO2Et in trifluoroethanol
(TFE) solvent. While the isolated yield of 2 under these
conditions was modest, tricyclic dihydropyridine 6h was
obtained in higher yield compared to reactions performed in
the presence of Lewis acid (Scheme 2). We speculate that the
strong hydrogen bonding ability of TFE helps to promote
enolization of the dicarbonyl side chain, thereby facilitating
spirocyclization. The effect was not universal, however, as other
i
equiv of Pr2NEt along with the other reagents indicated in
Scheme 1 to reaction mixtures of 1, however, failed to produce
any products emanating from anhydrobase intermediates
(although the yield of spiro-adduct 2 was increased to 44%).
Changing the solvent to DMF and heating to 100 °C further
increased the yield of 2 to 49%, but again no products formed
from benzylic deprotonation were detected. Better results were
obtained with keto amide substrates 8 and 9. Indeed, exposure
of these pyridine derivatives to ClCO2Et/Ti(OiPr)4/iPr2NEt in
DMF (100 °C) cleanly afforded cyclized anhydrobase products
(10 and 11) in good yield (Scheme 3). These materials were
isolated and spectroscopically characterized in crude form after
aqueous workup of the reaction mixtures as both 10 and 11
proved to be unstable to silica gel, neutral alumina, and basic
alumina flash column chromatography (EtOAc/hexane eluent).
In considering procedures whereby a stable and tractable
product may be obtained from this process, we reasoned that in
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Scheme 3
Table 2. Benzylic Cyclization of 5f
a
entry
solvent
Lewis acid
T
% yield 13
1
2
3
4
5
6
7
8
9
CH2Cl2
DMF
PhCH3
THF
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
TiCl4
reflux
100 °C
reflux
reflux
reflux
reflux
reflux
reflux
reflux
12
40
65
94
0
THF
THF
InCl3
22
48
62
0
THF
TMSOTf
BF3·OEt2
Cu(OTf)2
situ protonation of 10/11 should generate an acyl pyridinium
species that might be prone to subsequent hydrolysis to give a
rearomatized pyridine moiety. To test this notion, crude 10 in
THF was combined with excess TFA and heated to reflux for 5
min. Water was then added, and reflux was maintained for an
additional ∼10 min. Gratifyingly, stable pyridine derivative 12
was isolated from the reaction upon cooling in ∼50% overall
yield from 8 (eq 3).
THF
THF
a
Isolated yield.
pyridinium salt 14. In the presence of Hunig’s base 14 is
̈
converted to neutral anhydrobase 15. Intramolecular cyclization
of the anhydrobase with the ketone carbonyl (activated by the
Lewis acid additive) then gives 16. Loss of H2O and a second
benzylic deprotonation afford anhydrobase 17 (analogous to 10
and 11, see Scheme 3). At this stage addition of TFA
reprotonates 17, and the resulting acyl pyridinium cation then
suffers hydrolysis upon addition of H2O to furnish the observed
product.
With a reasonably efficient one-pot procedure in hand for
conversion of 5f to 13, the generality of the reaction was next
assayed using several 4-aminomethyl- and 4-aminoethyl-
substituted pyridines. The results of this study are illustrated
in Table 3. Each transformation was performed using the
conditions indicated in entry 4 of Table 2. Substrates featuring
activated methine groups in the β-dicarbonyl moiety were
employed since 1 (with an unsubstituted β-dicarbonyl
methylene group) was observed to undergo spirocyclization
exclusively irrespective of reaction conditions. Pyridyl-sub-
stituted lactam products were obtained in each case in
moderate to good isolated yield. Entries 1−7 show the
successful construction of pyridyl-substituted pyrrolidinone
derivatives from pyridines possessing acyclic and cyclic β-
dicarbonyl side chains, including examples incorporating
potentially removable N-amide protecting groups (allyl, benzyl,
entries 6 and 7). Entries 8 and 9 illustrate the successful use of
4-aminoethyl pyridines as substrates to afford the correspond-
ing pyridyl-substituted piperidinone products in good yield.
The reaction depicted in entry 10 was performed in order to
probe the possibility of diastereoselective cyclization. Pyridine
( )-32 bearing an α-methyl-p-methoxybenzyl substitutent on
the amide nitrogen was subjected to optimized benzylic
cyclization conditions to give the expected pyridyl lactam 33
as a 2.7:1 mixture of inseparable diastereomers. Thus, the
presence of a remote stereogenic center seems to have limited
influence on reaction diastereoselectivity. Finally, allyl-sub-
stituted β-amido ester 34 was also found to undergo smooth
benzylic cyclization under the optimized reaction conditions. In
this case the initial tetramic acid product was isolated as the
enol carbonate after acylation by excess ethyl chloroformate or
by an acyl pyridinium intermediate analogous to 18 (see
Scheme 4).
The conversion of 8 to 12 via 10 represents a potentially
convenient means of assembling pyridyl-substituted lactams,
especially if the sequence of transformations could be reduced
to an efficient one-pot process. Toward this end, pyridine 5f
was selected as a substrate for screening of reaction conditions
since, unlike 1, 5f fails to undergo potentially competing
spirocyclization. Initially, 5f was exposed to ClCO2Et, Ti-
i
(OiPr)4, and Pr2NEt in refluxing CH2Cl2. After 20 min TLC
indicated disappearance of 5f, and an excess (10 equiv) of TFA
was added. After an additional 5 min water was added, and
reflux was continued for another 5−10 min. After cooling the
reaction mixture was neutralized with Na2CO3, followed by
aqueous workup and chromatography to afford the anticipated
pyridyl pyrrolidinone 13, albeit in only 12% isolated yield
(Table 2, entry 1). Control experiments established that
i
chloroformate, Lewis acid (Ti(OiPr)4), and Pr2NEt were all
required for cyclization to be observed. Consequently, reaction
conditions were screened in which the solvent and Lewis acid
were varied to identify the optimal combination (Table 2). In
each case TFA was added after 20 min, followed by H2O in
order to effect rearomatization of the pyridine group. These
experiments revealed THF to be the best solvent for this
transformation. Several Lewis acids were investigated (Table 2,
entries 5−9), but Ti(OiPr)4 gave the highest yields of 13.
Optimized conditions for this transformation are indicated in
Table 2 entry 4 and provided 13 in excellent 94% isolated yield.
A straightforward mechanistic rationale to account for the
conversion of 5f to 13 via a putative anhydrobase intermediate
is illustrated in Scheme 4. Acylation of 5f with ClCO2Et gives
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Scheme 4
a
Table 3. Synthesis of Pyridyl-Substituted Lactams via Benzylic Cyclization
a
b
c
Reactions performed according to conditions given in Table 2, entry 4. Isolated yield. 2.7:1 mixture of diastereomers.
We have also briefly examined the reactivity of substrates in
was observed to participate only in the spirocyclization reaction
manifold.23a Exposure of the ester analogue (36) to the
reaction conditions indicated in eq 4, however, produced the
corresponding cyclized anydrobase product 37 in 77% crude
yield. For reasons that remain obscure, 37 appears to be
which the amide linkage in the pyridine side chain has been
replaced with an ester group or removed altogether. Exchange
of the amide linkage for an ester group resulted in significantly
altered reactivity. For example, 1 is a keto amide substrate that
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direct route to piperidine-pyrrolidinone and piperidine-
piperidinone ring systems. Notably, products exhibiting this
latter framework may serve as precursors to bis(piperidine)
derivatives, a structural motif encountered in numerous marine
alkaloid natural products (Figure 1).32 Toward this end,
resistant to rearomatization via protonation/hydrolysis. Purifi-
cation of 37 by chromatography resulted in some decom-
position, but the anhydrobase was still isolated in 41% yield,
and the structural assignment was confirmed by X-ray
crystallography.31 In contrast, 38 was converted to the spiro-
dihydropyridine 39 in good yield under the same reaction
conditions (eq 5).
Figure 1. Representative bis(piperidine) alkaloids.
substrate 5f was treated with ClCO2Et/Ti(OiPr)4/iPr2NEt in
refluxing THF until TLC indicated complete conversion of the
starting material to a highly colored and less polar material
(presumably 17, Scheme 6). The reaction mixture was then
Carbocyclic ring construction via anhydrobase intermediates
was probed using substrates 40−42. The β-keto ester 40,
previously found to be unreactive toward spirocyclization,23a
was equally unreactive toward benzylic cyclization when
exposed to the optimized conditions indicated in Table 2.
We attribute this failure to inappropriate positioning of the
electrophilic ketone carbonyl with respect to the benzylic
carbon. Consequently, substrates 41 and 42 possessing an
electrophilic center four carbons removed from the benzylic
carbon were prepared using the route shown in Scheme 5.
Scheme 6
Treatment of these pyridines with ClCO Et and Hunig’s base
̈
2
in the presence of Ti(OiPr)4, however, gave only trace amounts
of the expected product. Much better results were obtained
when the Lewis acid additive was changed to TMSOTf, and the
desired cyclopentene products were isolated in excellent yield.
Perhaps Ti(OiPr)4 is better able to activate dicarbonyl side
chains via formation of chelated structures, whereas TMSOTf is
better suited to activate the monocarbonyl side chains
encountered in 41 and 42.
The manipulations above all involve rearomatization of
putative anhydrobase intermediates via protonation, ultimately
leading to restoration of a pyridine ring. In an effort to enhance
the versatility of these cyclizations, we have also explored
alternative methods for processing these intermediates.
Specifically, hydrogenation of anhydrobases would offer a
allowed to cool to room temperature and quickly filtered
through a plug of basic alumina. Catalytic hydrogenation of the
Scheme 5. Carbocyclization of 4-Alkylpyridines
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rotamers/tautomers) δ: 202.3, 167.8, 167.4, 150.6, 150.3, 145.9, 145.5,
135.6, 129.4, 129.2, 129.0, 128.3, 128.0, 126.8, 126.6, 122.7, 121.5,
86.8, 51.5, 50.6, 50.0, 49.9, 48.9, 47.9, 30.7, 22.3. HRMS (ESI):
calculated for C17H19N2O2 [M + H]+, 283.1447; found 283.1462.
5c. Yield 1.01 g, 59%, yellow-brown oil. 1H NMR (300 MHz,
CDCl3, mixture of rotamers/tautomers) δ: 14.71−14.62 (m,0.2H),
8.62−8.55 (m, 2H), 7.23−7.13 (m, 2H), 4.61−4.50 (m, 2H), 3.66 (s,
1.2H), 3.48−3.41 (m, 1.1H), 3.33−3.26 (m, 1.5H), 2.67−2.55 (m,
1.6H), 2.31−2.24 (m, 0.4H), 1.20−1.03 (m, 6H). 13C NMR (75 MHz,
CDCl3, mixture of rotamers/tautomers) δ: 205.1, 180.6, 167.2, 150.6,
150.2, 146.6, 122.5, 121.5, 85.1, 50.5, 49.0, 48.5, 47.4, 43.3, 41.7, 36.8,
29.2, 14.0, 12.7, 7.8. HRMS (ESI): calculated for C13H19N2O2 [M +
filtrate (Pd/C, 100 psi H2) then afforded 49. Evidently, the
tetrasubstituted conjugated olefin is resistant to hydrogenation
under these conditions. In similar fashion, 4-aminoethyl
pyridine 28 was converted to the corresponding anhydrobase
48. In situ reduction of 48 then provided 3,4′-bis(piperidine)
derivative 50 in reasonable overall yield.
CONCLUSIONS
■
This work demonstrates that simple 4-alkylpyridines imbued
with ambiphilic (nucleophilic and electrophilic) side chains can
be converted to either spiro(dihydropyridines) or pyridyl (or
piperidine)-substituted lactams as a function of reaction
conditions. In addition, benzylic cyclization of pyridines bearing
ketone side chains has been shown to afford pyridyl-substituted
cyclopentenes in good yield. These methods provide
convenient and direct access to diverse heterocyclic structures
of pharmacological relevance. In the future we hope to expand
this general strategy to include catalytic transformations and
alternative modes of cyclization involving additional electro-
philic and nucleophilic components. We are also seeking
reaction conditions suitable for manipulation of 2-substituted
pyridines, substrates that have thus far been unwilling
participants in these types of intramolecular transformations.
Finally, applications of this chemistry in the stereoselective
construction of bis(piperidine) alkaloids (Figure 1) is also
under active investigation.
+
H] , 235.1447; found 235.1460.
5d. Yield 1.24 g, 60%, brown oil. H NMR (300 MHz, CDCl3,
1
mixture of rotamers/tautomers) δ: 15.27−15.18 (m, 0.5H), 8.61−8.54
(m, 2H), 8.05−7.95 (m, 1H), 7.82−7.37 (m, 4H), 7.25−7.13 (m, 2H),
5.86 (s, 0.3H), 5.58 (s, 0.1H), 4.68−4.61 (m, 2H), 4.23 (s, 0.8H), 4.04
(s, 0.3H), 3.57−3.31 (m, 2H), 1.27−1.13 (m, 3H). 13C NMR (75
MHz, CDCl3, mixture of rotamers/tautomers) δ: 194.2, 172.5, 167.5,
150.6, 150.2, 147.1, 146.6, 136.3, 135.0, 134.1, 131.1, 129.04, 129.0,
128.8, 128.7, 126.2, 122.6, 122.5, 121.6, 84.8, 84.5, 50.6, 50.2, 47.9,
47.5, 46.1, 45.8, 43.4, 43.0, 41.7, 14.0, 12.6. IR (film): 1683, 1638
cm−1. HRMS (ESI): calculated for C17H19N2O2 [M + H] +, 283.1447;
found 283.1462.
5e. A reaction mixture containing 1 (0.30 g, 1.36 mmol, 1 equiv) in
acetonitrile (10 mL) was cooled to 0 °C, and Selectfluor (0.48 g, 1.36
mmol, 1 equiv) was added. The resulting mixture was warmed to room
temperature, stirred for 18 h, quenched with satd aq NaHCO3 solution
(10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined
organics were dried over anhydrous Na2SO4, filtered, and evaporated
in vacuo. The crude product was purified by silica gel column
chromatography using 50−90% ethyl acetate in hexanes to obtain 5e
as a brown oil (0.23 g, 71%). 1H NMR (300 MHz, CDCl3, mixture of
rotamers) δ: 8.63−8.55 (m, 2H), 7.16−7.12 (m, 2H), 5.65 (s, 0.3H),
5.50−5.48 (m, 0.4H), 5.33−5.31 (m, 0.3H), 4.73−4.50 (m, 2H),
3.58−3.30 (m, 2H), 2.44−2.36 (m, 3H), 1.22 (t, J = 7.2 Hz, 2.1H),
1.13 (t, J = 7.2 Hz, 0.9H). 13C NMR (75 MHz, CDCl3, mixture of
EXPERIMENTAL SECTION
■
General Information. All commercially available starting materials
and reagents were used as received unless otherwise noted. All
reactions were performed under an argon atmosphere. Solvents were
dried and purified by passage through activated alumina or activated
1
molecular sieves. H NMR and 13C NMR spectra were recorded at
2
2
rotamers) δ: 202.5 (d, JC−F = 24.9 Hz), 164.5 (d, JC−F = 20.2 Hz),
300 or 500 MHz and 75 or 125 MHz, respectively. Chemical shifts (δ)
are reported in parts per million (ppm) relative to tetramethylsilane
for NMR spectra obtained in CDCl3 or residual undeuterated solvent
for all other spectra not obtained in CDCl3. IR spectra were recorded
on a FT-IR spectrophometer as thin films on sodium chloride discs.
High resolution mass spectra were obtained using electron spray
ionization (ESI) on a double-focusing magnetic sector mass
spectrometer. Melting points were recorded using a capillary melting
point apparatus and are uncorrected.
150.6, 150.3, 145.7, 145.5, 122.4, 121.7, 92.1 (d, J1
= 196.2 Hz),
C−F
91.4 (d, 1JC−F = 194.7 Hz), 53.6, 49.3, 48.1, 47.8, 42.6, 42.0, 26.5, 26.4,
+
14.1, 12.3. HRMS (ESI): calculated for C12H16N2O2F [M + H]
,
239.1196; found 239.1206.
1
5f. Yield 1.13 g, 59%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotomers) δ: 8.60 (d, J = 6.1 Hz, 0.5H), 8.54 (d, J = 6.0 Hz,
1.5H), 7.15−7.11 (m, 2H), 5.85−5.59 (m, 1H), 5.20−5.02 (m, 2H),
4.80−4.42 (m, 2H), 3.77−3.72 (m, 0.7H), 3.65−3.42 (m, 1.3H),
3.37−3.24 (m, 1H), 2.83−2.59 (m, 2H), 2.23 (s, 2.2H), 2.17 (s, 0.8H),
1.19 (t, J = 7.2 Hz, 2.2H), 1.13 (t, J = 7.1 Hz, 0.8H). 13C NMR (75
MHz, CDCl3, mixture of rotomers) δ: 204.7, 204.5, 169.0, 168.5,
150.4, 150.1, 146.6, 146.1, 134.5, 134.3, 122.5, 121.4, 118.0, 58.2, 57.6,
49.8, 48.0, 42.8, 42.0, 33.8, 33.6, 27.5, 27.1, 14.3, 12.6. HRMS (ESI):
Experimental Procedures and Characterization Data for 4-
Alkyl Pyridine Substrates. General procedure for the preparation of
4-alkylpyridines with amide side chains: These substrates were
prepared by treatment of an N-alkyl (aminomethyl)pyridine or N-
alkyl (aminoethyl)pyridine (1.00 g) with the appropriate β-keto
methyl ester in refluxing toluene (∼20 mL) for 36 h. Crude products
were purified by silica gel flash column chromatography using 50−70%
EtOAc in hexanes as eluent. 4-Alkylpyridines 1, 3, and 34 have been
previously reported.23
+
calculated for C15H21N2O2 [M + H] , 261.1603; found 261.1612.
1
5g. Yield 1.19 g, 63%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.61 (d, J = 6.1 Hz, 0.5H), 8.55 (d, J = 6.0 Hz,
1.5H), 7.18 (d, J = 6.1 Hz, 2H), 4.83−4.56 (m, 2H), 3.96−3.91 (m,
0.7H), 3.69−3.35 (m, 2.3H), 2.89−2.79 (m, 2H), 2.25 (s, 2.2H), 2.17
(s, 0.8H), 2.08 (t, J = 2.7 Hz, 0.7H), 2.06−2.04 (m, 0.3H), 1.26 (t, J =
7.2 Hz, 2.2H), 1.15 (t, J = 7.1 Hz, 0.8H). 13C NMR (75 MHz, CDCl3,
mixture of rotamers) δ: 202.4, 168.6, 167.9, 150.5, 150.1, 146.4, 146.0,
122.6, 121.5, 80.8, 71.1, 56.5, 55.8, 50.0, 48.1, 43.1, 42.2, 27.6, 27.1,
19.0, 14.3, 12.5. HRMS (ESI): calculated for C15H19N2O2 [M + H] +,
259.1447; found 259.1454.
1
5a. Yield 0.88 g, 56%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers/tautomers) δ: 14.58−14.50 (m, 0.25H), 8.62−
8.55 (m, 2H), 7.23−7.11 (m, 2H), 5.82−5.70 (m, 1H), 5.29−5.15 (m,
2H), 4.61 (s, 1.4H), 4.51−4.47 (m, 0.6H), 4.04−4.02 (m, 0.5H),
3.85−3.82 (m, 1.5H), 3.65 (s, 1H), 3.52 (s, 0.4H), 2.31−2.28 (m,
2.2H), 1.98−1.90 (m, 0.8H). 13C NMR (75 MHz, CDCl3, mixture of
rotamers/tautomers) δ: 202.4, 167.6, 150.6, 150.2, 146.2, 132.2, 132.0,
122.6, 121.5, 118.5, 117.8, 86.9, 50.7, 50.0, 49.8, 48.6, 47.9, 30.7, 22.2.
HRMS (ESI): calculated for C13H17N2O2 [M + H] +, 233.1290; found
233.1308.
5h. Yield 1.65 g, 91%, yellow-brown oil. 1H NMR (300 MHz,
CDCl3, mixture of rotamers) δ: 8.64−8.52 (m, 2H), 7.19−7.14 (m,
2H), 5.05−4.95 (m, 1H), 4.47 (d, J = 18.4 Hz, 0.3H), 4.26 (d, J = 16.1
Hz, 0.7H), 3.81−3.67 (m, 1H), 3.57−3.51 (m, 0.7H), 3.31−3.11 (m,
1.3H), 2.62−2.49 (m, 1H), 2.39−2.04 (m, 4H), 1.96−1.83 (m, 1H),
1.22−1.11 (m, 3H). 13C NMR (75 MHz, CDCl3, mixture of rotamers)
δ: 214.7, 169.3, 150.5, 150.1, 146.9, 122.3, 121.5, 52.3, 52.0, 49.9, 47.9,
42.9, 42.1, 38.7, 27.7, 21.3, 14.3, 12.8. IR (film): 1735, 1628 cm−1.
1
5b. Yield 1.01 g, 71%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers/tautomers ) δ: 14.69−14.57 (m,0.3H), 8.61−8.53
(m, 2H), 7.41−7.07 (m, 7H), 5.29 (s, 0.2H), 5.03 (s, 0.1H), 4.64−4.60
(m, 2H), 4.44−4.41 (m, 2H), 3.71 (s, 0.9H), 3.58 (s, 0.5H), 2.30 (s,
2H), 1.96−1.92 (m, 1H). 13C NMR (75 MHz, CDCl3, mixture of
8043
dx.doi.org/10.1021/jo301247c | J. Org. Chem. 2012, 77, 8038−8048

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Article
HRMS (ESI): calculated for C14H19N2O2 [M + H] +, 247.1447; found
237.1462.
δ: 207.6, 170.3, 169.9, 159.4, 159.2, 150.3, 150.0, 148.5, 147.5, 129.3,
128.3, 127.8, 124.5, 124.3, 114.6, 114.2, 55.5, 54.7, 54.5, 51.5, 47.8,
47.6, 47.4, 42.1, 42.0, 34.4, 33.4, 30.5, 27.1, 23.8. IR (film): 1704, 1642
cm−1. HRMS (ESI): calculated for C22H27N2O3 [M + H] +, 367.2022;
found 367.2040.
8. Yield 1.10 g, 63%, brown oil. 1H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.61−8.54 (m, 2H), 7.19−7.12 (m, 2H),
5.88−5.70 (m, 1H), 5.27−4.99 (m, 3H), 4.49−4.37 (m, 1.3H), 4.14−
4.09 (m, 0.7H), 3.80−3.72 (m, 0.7H), 3.66−3.59 (m, 0.3H), 3.52−
3.46 (m, 0.7H), 3.31−3.25 (m, 0.3H), 2.63−2.38 (m, 1H), 2.36−2.14
(m, 4H), 1.96−1.80 (m, 1H). 13C NMR (75 MHz, CDCl3, mixture of
rotamers) δ: 214.8, 169.6, 150.6, 150.2, 146.4, 132.8, 132.2, 122.3,
121.4, 117.9, 117.1, 52.3, 50.0, 49.5, 48.9, 48.3, 38.7, 27.5, 21.2. IR
(film): 1735, 1641 cm−1. HRMS (ESI): calculated for C15H19N2O2 [M
1
32. Yield 0.88 g, 66%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.56−8.39 (m, 2H), 7.25−7.02 (m, 3H),
6.96−6.78 (m, 3H), 6.21−6.08 (m, 0.4H), 5.30−5.19 (m, 0.6H),
4.79−3.90 (m, 2.6H), 3.81−3.76 (m, 3H), 3.33−3.22 (m, 0.4H), 2.25
(d, J = 9.4 Hz, 1.7H), 2.15 (d, J = 6.0 Hz, 1.3H), 1.54−1.48 (m, 4H),
1.42−1.32 (m, 2H). 13C NMR (75 MHz, CDCl3, mixture of rotamers)
δ: 205.7, 204.9, 171.3, 171.0, 159.5, 150.4, 150.2, 149.9, 149.8, 148.1,
148.0, 132.4, 131.9, 131.1, 129.2, 128.8, 128.6, 127.9, 122.2, 122.13,
121.1, 121.0, 114.5, 114.3, 114.2, 114.1, 55.7, 55.6, 55.5, 52.8, 52.4,
52.1, 51.8, 51.6, 46.1, 45.7, 45.4, 27.7, 27.6, 27.2, 19.2, 17.2, 17.1, 14.5,
14.1. IR (film): 1722, 1637 cm−1. HRMS (ESI): calculated for
+
+ H] , 259.1447; found 259.1461.
9. Yield 1.45 g, 76%, yellow-brown oil 1H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.61−8.54 (m, 2H), 7.30−7.29 (m, 1.6H),
7.13−7.11 (m, 0.4H), 5.04 (d, J = 16.5 Hz, 0.8H), 4.52 (d, J = 18.1 Hz,
0.2H), 4.36 (d, J = 18.1 Hz, 0.2H), 4.23 (d, J = 16.2 Hz, 0.8H), 3.68−
3.61 (m, 1H), 3.36−3.04 (m, 2H), 2.64−1.69 (m, 8H), 1.15 (t, J = 7.2
H, 3H). 13C NMR (75 MHz, CDCl3, mixture of rotamers) δ: 207.6,
169.9, 150.5, 150.1, 146.8, 146.6, 122.4, 121.5, 54.6, 54.5, 49.9, 47.5,
42.4, 42.2, 41.9, 41.7, 30.6, 30.4, 27.1, 26.9, 23.9, 23.5, 14.3, 12.6.
HRMS (ESI): calculated for C15H21N2O2 [M + H] +, 261.1603; found
261.1616.
+
C20H25N2O3 [M + H] , 341.1865; found 341.1883.
36. A reaction mixture containing 4-(hydroxymethyl) pyridine
(2.20 g, 20.16 mmol, 1 equiv) and tert-butyl acetoacetate (4.78 g,
30.24 mmol, 1.5 equiv) in toluene (50 mL) was refluxed for 36 h. The
reaction mixture was cooled to room temperature and concentrated in
vacuo. The crude product was purified by silica gel column
chromatography using 70−100% ethyl acetate in hexanes to afford
the desired β-keto ester 36 (2.10 g, 54%) as a yellow liquid. 1H NMR
(300 MHz, CDCl3, mixture of tautomers) δ: 11.89 (s, 0.1H), 8.62−
8.59 (m, 2H), 7.29−7.24 (m, 2H), 5.20−5.19 (m, 2H), 5.11 (s, 0.1H),
3.58 (s, 1.8H), 2.29 (s, 2.7H), 2.00 (s, 0.3H). 13C NMR (75 MHz,
CDCl3, mixture of tautomers) δ: 200.1, 166.8, 150.3, 144.4, 122.1,
65.2, 50.0, 30.5. IR (film): 1744, 1708 cm−1. HRMS (ESI): calculated
1
19. Yield 1.10 g, 64%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.63−8.54 (m, 2H), 7.17−7.12 (m, 2H),
4.78−4.70 (m, 1H), 4.49−4.42 (m, 1H), 3.77−3.70 (q, J = 7.0 Hz,
0.7H), 3.67−3.60.(m, 0.3H), 3.50−3.38 (m, 1H), 3.34−3.22 (m, 1H),
2.24−2.13 (m, 3H), 1.47 (d, J = 7.0 Hz, 2.1H), 1.37 (d, J = 7.0 Hz,
0.9H), 1.21 (t, J = 7.1 Hz, 2.1H), 1.15 (t, J = 7.1 Hz, 0.9H). 13C NMR
(75 MHz, CDCl3, mixture of rotamers) δ: 205.4, 170.7, 170.4, 150.6,
150.2, 146.7, 146.3, 122.5, 121.3, 52.2, 51.5, 50.0, 47.7, 42.8, 42.0, 27.5,
27.1, 14.3, 12.6. IR (film): 1722, 1637 cm−1. HRMS (ESI): calculated
+
for C10H12NO3 [M + H] , 194.0817; found 194.0834.
38. Prepared from 4-hydroxymethylpyridine (2.00 g) and cyclo-
pentanone-2-carboxylate methyl ester using the procedure given for
36. Isolated yield (yellow oil) 1.84 g, 46%. 1H NMR (300 MHz,
CDCl3) δ: 8.61 (d, J = 6.1 Hz, 2H), 7.29 (d, J = 5.9 Hz, 2H), 5.28−
5.14 (m, 2H), 3.29 (t, J = 9.3 Hz, 1H), 2.59−1.85 (m, 6H). 13C NMR
(75 MHz, CDCl3) δ: 212.0, 169.0, 150.1, 144.7, 121.8, 65.0, 54.8, 38.2,
27.4, 21.1. IR (film): 1757, 1726 cm−1. HRMS (ESI): calculated for
+
for C13H19N2O2 [M + H] , 235.1447; found 235.1471.
1
24. Yield 1.39 g, 69%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.62−8.53 (m, 2H), 7.18−7.14 (m, 2H),
4.92−4.80 (m, 1H), 4.46−4.32 (m, 1H), 3.78−3.73 (m, 0.7H), 3.59−
3.44 (m, 1.3H), 3.27−3.17 (m, 1H), 2.89−2.80 (m, 1H), 2.61−2.42
(m, 1H), 2.24−1.90 (m, 6H), 1.57−1.37 (m, 3H), 1.22−1.09 (m, 3H).
13C NMR (75 MHz, CDCl3, mixture of rotamers) δ: 211.1, 170.8,
170.2, 150.4, 150.1, 146.9, 146.6, 122.3, 121.5, 57.2, 56.5, 50.0, 47.7,
43.3, 42.9, 41.9, 30.4, 28.5, 28.4, 27.8, 25.8, 25.5, 14.4, 12.7. IR (film):
1699, 1642 cm−1. HRMS (ESI): calculated for C16H23N2O2 [M + H]
+, 275.1760; found 275.1776.
+
C12H13NO3 [M + H] , 220.0974; found 220.0995.
General Procedure for the Synthesis of Spiro-
(dihydropyridine)s. The preparation of 2 is representative. Keto
amide 1 (0.10 g, 0.45 mmol, 1 equiv) in ∼3 mL CH2Cl2 was cooled to
0 °C. Ti(OiPr)4 (61 μL, 0.23 mmol, 0.5 equiv) was added, and the
reaction was stirred for 2 min. Ethyl chloroformate (83 μL, 0.68 mmol,
1.5 equiv) was then added, and the resulting mixture was stirred for
∼10−15 min. The reaction was then directly subjected to silica gel
flash column chromatography eluting with 70−80% EtOAc in hexanes.
1
26. Yield 1.18 g, 76%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.60−8.54 (m, 2H), 7.41−7.08 (m, 7H),
5.26−4.94 (m, 2H), 4.42−4.33 (m, 1H), 4.18−4.01 (m, 1H), 3.56−
3.51 (m, 0.7H), 3.36−3.31 (m, 0.3H), 2.66−2.54 (m, 1H), 2.39−2.33
(m, 2H), 2.26−2.15 (m, 2H), 1.92−1.79 (m, 1H). 13C NMR (75
MHz, CDCl3, mixture of rotamers) δ: 214.8, 169.9, 150.6, 150.3,
146.2, 136.5, 136.2, 129.3, 129.0, 128.1, 128.0, 126.4, 122.4, 121.4,
52.4, 51.0, 49.5, 48.4, 38.8, 27.5, 21.2. IR (film): 1739, 1646 cm−1.
HRMS (ESI): calculated for C19H21N2O2 [M + H] +, 309.1614; found
309.1615.
1
Dihydropyridine 2 was obtained as a yellow oil (43 mg, 33%). H
NMR (300 MHz, CDCl3, mixture of tautomers) δ: 12.32 (s, 0.3H),
6.99−6.88 (m, 2H), 4.94−4.89 (m, 2H), 4.28 (q, J = 7.2 Hz, 2H),
3.48−3.29 (m, 3.3H), 3.23−3.15 (m, 1.4H), 2.26 (s, 2H), 1.83 (s, 1H),
1.37−1.31 (m, 3H), 1.16−1.11 (m, 3H). 13C NMR (75 MHz, CDCl3)
δ: 204.0, 171.4, 168.8, 167.4, 151.4, 151.2, 124.9, 122.9, 121.3, 110.2,
105.9, 69.8, 63.3, 63.2, 61.0, 39.7, 37.4, 36.6, 33.4, 17.5, 14.6, 12.6,
12.5. IR (film): 3435, 1659, 1632 cm−1. HRMS (ESI): calculated for
28. Yield 1.22 g, 87%, yellow-brown oil. 1H NMR (300 MHz,
CDCl3, mixture of rotamers) δ: 8.55−8.48 (m, 2H), 7.19−7.04 (m,
4H), 6.91−6.85 (m, 2H), 4.73−4.68 (m, 0.3H), 4.52−4.44 (m, 1H),
4.31−4.26 (m, 0.7H), 3.80−3.78 (m, 3H), 3.76−3.71.(m, 0.6H), 3.63
(q, J = 6.9 Hz, 0.7H), 3.57−3.44 (m, 1.7H), 2.87−2.77.(m, 2H), 2.12−
2.11 (m, 3H), 1.37 (d, J = 7.0 Hz, 2H), 1.32 (d, J = 6.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3, mixture of rotamers) δ: 205.1, 171.0, 170.4,
159.6, 150.4, 150.1, 148.0, 146.9, 129.6, 129.3, 128.2, 127.8, 124.4,
124.2, 114.7, 114.4, 55.5, 52.1, 51.9, 51.6, 48.2, 47.5, 34.5, 33.4, 27.4,
27.0, 14.2. IR (film): 1726, 1633 cm−1. HRMS (ESI): calculated for
+
C15H21N2O4 [M + H] , 293.1501; found 293.1492.
Using the procedure given above the spiro(dihydropyridine)s 4,
6a−e, and 6h were prepared starting from 100 mg of 2, 5a−e, and 5h,
respectively.
1
Spiro(dihydropyridine) 4. Pale yellow liquid, 22 mg, 18%. H
NMR (300 MHz, CDCl3) δ mixture of tautomers: 16.0 (s, 0.2H),
7.27−7.18 (m, 2H), 6.95−6.82 (m, 4H), 4.77−4.49 (m, 4H), 4.30−
4.22 (m, 2H), 3.81−3.80 (m, 3H), 3.59 (s, 0.8H), 3.32−3.12 (m, 2H),
2.31 (s, 2.4H), 2.26−2.17 (m, 1H), 2.00 (s, 0.6H), 1.77−1.62 (m, 1H),
1.35−1.29 (m, 3H). 13C NMR (75 MHz, CDCl3, mixture of
tautomers) δ: 205.5, 176.7, 165.3, 159.3, 151.3, 129.6, 129.4, 129.2,
128.9, 123.9, 123.1, 120.9, 114.3, 109.6, 107.9, 67.1, 63.2, 55.5, 49.8,
41.7, 41.1, 40.4, 37.0, 35.4, 34.7, 33.8, 21.5, 14.6. IR (film): 1722, 1686,
1628 cm−1. HRMS (ESI): calculated for C22H27N2O5 [M + H]+,
399.1920; found 399.1934.
+
C20H25N2O3 [M + H] , 341.1865; found 341.1858.
1
30. Yield 0.64 g, 42%, brown oil. H NMR (300 MHz, CDCl3,
mixture of rotamers) δ: 8.54−8.48 (m, 2H), 7.28−7.24 (m, 2H),
7.04−7.01 (m, 2H), 6.89−6.86 (m, 2H), 4.96−4.91 (m, 0.3H), 4.37−
4.29 (m, 1H), 4.11−4.05 (m, 0.7H), 3.94−3.87 (m, 0.7H), 3.80−3.79.
(m, 3H), 3.56−3.47 (m, 0.7H), 3.38−3.18 (m, 1.6H), 2.91−2.73 (m,
2H), 2.57−2.52 (m, 1H), 2.35−1.98 (m, 5H), 1.83−1.76 (m, 1H),
1.65−1.46 (m, 1H). 13C NMR (75 MHz, CDCl3, mixture of rotamers)
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Article
1
Spiro(dihydropyridine) 6a. Brown liquid, 16 mg, 12%. 1H NMR
(500 MHz, CDCl3, mixture of tautomers) δ: 12.27 (s, 0.3H), 7.00−
6.88 (m, 2H), 5.78−5.70 (m, 1H), 5.28−5.19 (m, 2H), 4.97−4.81 (m,
2H), 4.30 (q, J = 7.0 Hz, 2H), 4.00−3.89 (m, 2H), 3.47−3.45 (m,
1.3H), 3.21 (s, 0.7H), 3.16−3.14 (m, 0.7H), 2.28 (s, 2H), 1.86 (s, 1H),
1.37−1.33 (m, 3H). 13C NMR (125 MHz, CDCl3, mixture of
tautomers) δ: 203.9, 171.6, 167.9, 151.2, 132.2, 131.9, 118.8, 118.5,
brown oil (18 mg, 15% isolated yield). H NMR (300 MHz, CDCl3)
δ: 7.22 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.32 (d, J = 9.0
Hz, 1H), 6.29 (d, J = 9.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.88 (q, J
= 7.2 Hz, 2H), 2.86−2.81 (m, 2H), 2.59−2.54 (m, 2H), 2.41−2.34 (m,
2H), 1.38 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ: 166.9, 152.4, 150.4, 137.4, 127.5, 125.0, 112.7, 109.6,
64.3, 37.2, 31.8, 28.3, 25.4, 15.9, 14.5. HRMS (ESI): calculated for
+
109.9, 69.8, 63.7, 63.4, 63.2, 61.3, 45.4, 44.7, 39.8, 36.7, 33.4, 29.9,
C17H21N2O3 [M + H] , 301.1552; found 301.1569.
+
17.6, 14.6. HRMS (ESI): calculated for C16H21N2O4 [M + H]
305.1501; found 305.1511.
,
Procedure for the Preparation of Anhydrobases 10 and 11.
The preparation of 11 is representative. Titanium isopropoxide (58
μL, 0.2 mmol, 0.5 equiv) and diisopropylethylamine (95 μL, 0.58
mmol, 1.5 equiv) were added to a solution of 9 (0.10 g, 0.38 mmol, 1
equiv) in DMF (3 mL) and the reaction was placed in a preheated 100
°C oil bath for 2 min. Ethyl chloroformate (55 μL, 0.58 mmol, 1.5
equiv) was added to the warm reaction mixture, causing the reaction to
immediately turn dark brown. Heating was maintained for 20 min,
after which time the reaction was allowed to cool to room
temperature. The reaction was made basic by addition of satd aq
Na2CO3 solution and then extracted with ethyl acetate (3 × 5 mL).
The combined organic layer was washed with water (10 mL) and brine
(5 mL). The organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo to yield the crude anhydrobase product 11
(0.10 g, 83%, crude yield). Attempted purification by flash column
chromatography resulted in decomposition. 1H NMR (300 MHz,
CDCl3) δ: 7.20 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.36 (d, J
= 8.6 Hz, 1H), 6.30 (d, J = 8.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.84
(q, J = 7.1 Hz, 2H), 2.56−2.54 (m, 2H), 2.36−2.34 (m, 2H), 1.77−
1.65 (m, 4H), 1.38 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 171.1, 150.4, 141.9, 128.2, 127.6, 126.4,
125.0, 116.8, 112.4, 110.7, 64.1, 37.7, 27.0, 23.6, 21.8, 21.3, 15.2, 14.5.
IR (film): 1731, 1642 cm−1. HRMS (ESI): calculated for C18H23N2O3
[M + H] , 315.1709; found 315.1731. Using the same procedure 8
(0.10 g) was converted to 10 (isolated as a brown oil, 97 mg, 80%
crude yield). H NMR (300 MHz, CDCl3) δ: 7.16−7.12 (m, 2H),
6.35−6.27 (m, 2H), 6.01−5.89 (m, 1H), 5.23−5.11 (m, 2H), 4.44−
4.42 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 2.89−2.84 (m, 2H), 2.62−2.58
(m, 2H), 2.43−2.36 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ: 166.8, 152.6, 150.3, 136.8, 135.0, 127.2, 125.3, 124.1,
117.6, 116.1, 112.5, 109.6, 64.2, 44.7, 31.7, 28.3, 25.5, 14.5. HRMS
(ESI): calculated for C18H21N2O3 [M + H] +, 313.1552; found
313.1566.
Spiro(dihydropyridine) 6b. Yellow liquid, 23 mg, 18%. 1H NMR
(300 MHz, CDCl3, mixture of tautomers) δ: 12.32 (s, 0.4H), 7.38−
7.22 (m, 5H), 6.95−6.83 (m, 2H), 4.82−4.75 (m, 2H), 4.51−4.48 (m,
1H), 4.44 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.49 (s, 0.6H), 3.33 (d, J =
9.9 Hz, 0.6H), 3.11 (s, 0.8H), 3.02 (d, J = 9.9 Hz, 0.6H), 2.28 (s, 2H),
1.85 (s, 1H), 1.35−1.29 (m, 3H). 13C NMR (75 MHz, CDCl3, mixture
of tautomers) δ: 203.9, 171.7, 168.1, 151.4, 151.1, 136.2, 135.9, 129.0,
128.33, 128.3, 128.0, 127.9, 122.9, 110.0, 69.7, 63.3, 63.2, 60.1, 46.8,
46.1, 39.7, 36.6, 33.5, 17.6, 14.6. HRMS (ESI): calculated for
+
C20H23N2O4 [M + H] , 355.1658; found 355.1675.
Spiro(dihydropyridine) 6c. Yellow liquid, 69 mg, 53%. H NMR
1
(300 MHz, CDCl3, mixture of tautomers) δ: 12.40 (s, 0.2H), 6.95 (br
s, 2H), 4.90 (br s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.51 (d, J = 9.7 Hz,
0.8H), 3.44−3.28 (m, 2.8H), 3.21 (s, 0.4H), 3.14 (d, J = 9.7 Hz,
0.8H), 2.72−2.43 (m, 1.6H), 2.16 (q, J = 7.4 Hz, 0.4H), 1.37−1.31 (m,
3H), 1.16−1.08 (m, 3H), 1.06−1.00 (m, 3H). 13C NMR (75 MHz,
CDCl3, mixture of tautomers) δ: 206.4, 171.7, 169.1, 151.2, 124.7,
122.5, 121.1, 110.5, 105.8, 69.5, 63.5, 63.3, 63.2, 61.1, 39.6, 37.5, 36.7,
24.4, 14.6, 12.5, 11.0, 7.1. HRMS (ESI): calculated for C16H23N2O4
+
[M + H] , 307.1658; found 307.1675.
Spiro(dihydropyridine) 6d. Brown liquid, 54 mg, 43%. 1H NMR
(300 MHz, CDCl3, mixture of rotamers) δ: 7.93−7.91 (m, 2H), 7.59−
7.54 (m, 1H), 7.48−7.43 (m, 2H), 6.97−6.76 (m, 2H), 5.08 (br s,
2H), 4.88 (br s, 1H), 4.30 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.65 (d, J
= 9.7 Hz, 1H), 3.53−3.33 (m, 2H), 3.23 (d, J = 9.8 Hz, 1H), 1.31−
1.26 (m, 3H), 1.19 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3,
mixture of rotamers) δ: 196.0, 169.6, 151.1, 137.6, 133.7, 129.1, 128.7,
124.6, 122.3, 110.5, 106.1, 65.4, 63.2, 61.4, 40.2, 37.5, 14.5, 12.5. IR
(film): 1723, 1678, 1669 cm−1. HRMS (ESI): calculated for
+
1
+
C20H23N2O4 [M + H] , 355.1658; found 355.1679.
Spiro(dihydropyridine) 6e. Pale yellow liquid, 13 mg, 10%. H
1
NMR (500 MHz, CDCl3, mixture of rotamers) δ: 7.11−7.01 (m, 2H),
4.88−4.79 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.50 (d, J = 9.5 Hz, 1 H),
3.48−3.30 (m, 2H), 3.12 (d, J = 9.6 Hz, 1H), 2.30 (d, JHF = 5.8 Hz,
3H), 1.34 (t, J = 7.2 Hz, 3H). 1.16 (t, J = 7.3 Hz, 3H). Insufficient
sample for 13C NMR spectrum. HRMS (ESI): calculated for
General Procedure for the Preparation of Pyridyl-Substi-
tuted Lactams (Tables 2 and 3). The preparation of 13 is
representative. Titanium isopropoxide (57 μL, 0.19 mmol, 0.5 equiv)
and diisopropylethylamine (0.10 mL, 0.58 mmol, 1.5 equiv) were
added to a solution of 5f (0.10 g, 0.38 mmol, 1 equiv) in THF (2 mL)
and heated to reflux in a preheated 80 °C oil bath for 2 min. Ethyl
chloroformate (55 μL, 0.58 mmol, 1.5 equiv) was added to the
refluxing reaction mixture, which immediately turned dark brown.
Reflux was maintained for 20 min, then TFA (10 equiv) was added,
and reflux was continued for an additional 5 min. Water (2 mL) was
then added and reflux continued for 10−15 min before allowing the
reaction to cool to room temperature. The mixture was made basic by
addition of satd aq Na2CO3 solution and then extracted with ethyl
acetate (3 × 5 mL). The combined organic layer was washed with
water (10 mL) and brine (5 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation of the solvent gave a residue that was
purified via flash column chromatography (70−90% EtOAc in
+
C15H20FN2O4 [M + H] , 311.1407; found 311.1415.
Spiro(dihydropyridine) 6h. Pale yellow oil, 66 mg, 51%. 1H
NMR (300 MHz, CDCl3, mixture of rotamers) δ: 6.98 (br s, 2H), 4.85
(br s, 1H), 4.66 (br s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.76 (d, J = 9.5
Hz, 1H), 3.44−3.28 (m, 2H), 3.02 (d, J = 9.5 Hz, 1H), 2.37−2.24 (m,
2H), 2.12−2.06 (m, 3H), 0.1.90−1.87 (m, 1H), 1.34 (t, J = 7.1 Hz,
3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3, mixture of
rotamers) δ: 216.0, 171.0, 151.1, 125.9, 123.2, 108.2, 105.1, 69.0, 63.2,
59.1, 43.8, 39.8, 37.6, 28.6, 19.9, 14.5, 12.5. HRMS (ESI): calculated
+
for C17H22N2O4Na [M + Na] , 341.1477; found 341.1459.
Procedure for Spirocyclization in Trifluoroethanol (TFE).
Ethyl chloroformate (78 μL, 0.81 mmol, 2 equiv) was added to a
solution of 5h (0.10 g, 0.41 mmol, 1 equiv) in TFE (2 mL) at room
temperature. The resulting mixture was stirred for 15−20 min and
then directly loaded onto a silica gel column and purified using 70−
80% ethyl acetate in hexanes to give 6h (85 mg, 66%). In a similar
fashion 1 (0.10 g) was converted to 2 (yellow oil, 25 mg, 19% isolated
yield).
Anhydrobase 7. This compound was obtained as a minor
byproduct when pyridine 5h was subjected to the spirocyclization
reaction conditions described previously except that the CH2Cl2
reaction mixture was heated to reflux before purification by flash
column chromatography. From 100 mg of 5h, the expected spirocycle
6h was obtained (50 mg, 39% isolated yield) accompanied by 7 as a
1
hexanes) to afford 13 as a brown oil (87 mg, 94%). H NMR (300
MHz, CDCl3) δ: 8.62 (d, J = 5.9 Hz, 2H), 7.1 (d, J = 6 Hz, 2H), 5.96−
5.82 (m, 1H), 5.09−5.02 (m, 2H), 4.78 (s, 1H), 3.87−3.75 (m, 1H),
3.09 (d, J = 6.2 Hz, 2H), 2.88−2.76 (m, 1H), 1.74 (s, 3H), 1.05 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 171.7, 150.5, 150.1,
145.9, 134.3, 131.0, 122.5, 115.8, 66.6, 35.3, 27.9, 13.8, 12.1. IR (film):
+
1681 cm−1. HRMS (ESI): calculated for C15H19N2O [M + H]
,
243.1497; found 243.1520. Substituted pyridines shown in Table 3
were prepared starting from 0.10 g of the corresponding 4-alkyl
pyridine.
1
Pyridyl-dehydropyrrolidinone 20. Brown oil, 54 mg, 59%. H
NMR (300 MHz, CDCl3) δ: 8.62 (d, J = 5.5 Hz, 2H), 7.08 (d, J = 5.9
8045
dx.doi.org/10.1021/jo301247c | J. Org. Chem. 2012, 77, 8038−8048

The Journal of Organic Chemistry
Article
Hz, 2H), 4.73 (s, 1H), 3.88−3.76 (m, 1H), 2.86−2.74 (m, 1H), 1.87
(s, 3H), 1.72 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ: 172.5, 150.6, 148.5, 146.0, 129.3, 122.6, 66.5, 35.3, 13.9,
12.1, 8.9. IR (film): 1685 cm−1. HRMS (ESI): calculated for
Pyridyl-dehydropyrrolidinone 33. Brown oil, 34 mg, 36%, 2.7:1
mixture of diastereomers. 1H NMR (300 MHz, CDCl3) δ Major
diastereomer: 8.56 (d, J = 5.7 Hz, 2H), 7.08−7.00 (m, 2H), 6.95 (d, J
= 6.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.54 (q, J = 7.3 Hz, 1H), 4.26
(s, 1H), 3.82 (s, 3H), 1.88−1.86 (m, 3H), 1.52 (s, 3H), 1.17 (d, J = 7.3
Hz, 3H). Minor diastereomer: 8.35 (d, J = 5.7 Hz, 2H), 7.08−7.00 (m,
2H), 6.78 (d, J = 5.8 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 5.08 (q, J = 7.2
Hz, 1H), 4.64 (s, 1H), 3.71 (s, 3H), 1.88−1.86 (m, 3H), 1.66 (d, J =
7.2 Hz, 3H), 1.59 (s, 3H). 13C NMR (75 MHz, CDCl3) δ mixture of
diastereomers: 173.4, 173.2, 159.2, 159.0, 150.4, 150.0, 149.6, 149.1,
147.8, 146.5, 133.4, 132.8, 129.4, 128.9, 128.8, 122.9, 122.7, 114.0,
113.6, 66.3, 65.5, 55.5, 51.4, 50.6, 18.8, 18.3, 12.1, 12.0, 9.0, 8.96. IR
(film): 1668 cm−1. HRMS (ESI): calculated for C20H23N2O2 [M + H]
+, 323.1760; found 323.1780.
+
C13H17N2O [M + H] , 217.1341; found 217.1371.
Pyridyl-dehydropyrrolidinone 21. Brown oil, 80 mg, 86%. H
1
NMR (300 MHz, CDCl3) δ: 8.64 (d, J = 5.9 Hz, 2H), 7.1 (d, J = 6.1
Hz, 2H), 4.78 (s, 1H), 3.87−3.75 (m, 1H), 3.29−3.28 (m, 2H), 2.88−
2.76 (m, 1H), 2.04 (t, J = 2.8 Hz, 1H), 1.88 (s, 3H), 1.06 (t, J = 7.2
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 170.6, 151.1, 150.7, 145.2,
127.9, 122.5, 79.9, 69.2, 66.6, 35.3, 13.8, 13.5, 12.2. IR (film): 1681
+
cm−1. HRMS (ESI): calculated for C15H17N2O [M + H] , 241.1341;
found 241.1361.
1
Pyridyl-dehydropyrrolidinone 22. Brown oil, 58 mg, 63%. H
1
NMR (300 MHz, CDCl3) δ: 8.62 (d, J = 5.9 Hz, 2H), 7.11 (d, J = 6.0
Hz, 2H), 4.97 (s, 1H), 3.88−3.76 (m, 1H), 2.90−2.79 (m, 1H), 2.61−
2.12 (m, 6H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ:
168.6, 164.3, 150.6, 145.1, 142.3, 122.0, 62.2, 35.6, 28.2, 27.5, 26.0,
14.0. IR (film): 1685 cm−1. HRMS (ESI): calculated for C14H17N2O
Pyridyl-dehydropyrrolidinone 35. Brown oil, 68 mg, 62%. H
NMR (300 MHz, CDCl3) δ: 8.63 (d, J = 6.0 Hz, 2H), 7.14 (d, J = 6.1
Hz, 2H), 5.95−5.82 (m, 1H), 5.36 (m, 1H), 5.17−5.06 (m, 2H), 4.2
(q, J = 7.2 Hz, 2H),3.85−3.73 (m, 1H), 3.10−3.07 (m, 2H), 2.91−
2.79 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 169.6, 158.5, 151.1, 150.8, 143.5, 133.1,
+
[M + H] , 229.1341; found 229.1368.
Pyridyl-dehydropyrolidinone 23. Brown oil, 63 mg, 68%. H
1
122.9, 120.4, 116.9, 66.0, 61.9, 35.3, 27.0, 14.1, 13.8. IR (film): 1766,
+
1690 cm−1. HRMS (ESI): calculated for C17H21N2O4 [M + H]
317.1501; found 317.1501.
,
NMR (300 MHz, CDCl3) δ: 8.61 (d, J = 5.9 Hz, 2H), 7.08 (d, J = 6.0
Hz, 2H), 4.80 (s, 1H), 3.89−3.77 (m, 1H), 2.89−2.78 (m, 1H), 2.30−
2.11 (m, 3H), 1.82−1.59 (m, 5H), 1.06 (t, J = 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ: 171.8, 152.9, 150.7, 145.9, 132.2, 122.3, 65.7,
35.1, 23.0, 22.2, 21.8, 20.4, 14.0. IR (film): 1681 cm−1. HRMS (ESI):
Anhydrobase 37. Using the procedure given for the preparation
of 13, 37 (52 mg) was isolated from 0.10 g of 36 as an orange-brown
1
crystalline solid (41%, 77% crude yield). Mp 157−162 °C (dec), H
+
calculated for C15H19N2O [M + H] , 243.1497; found 243.1515.
Pyridyl-dehydropyrrolidinone 25. Brown oil, 39 mg, 42%. H
NMR (300 MHz, CDCl3) δ: 7.37 (d, J = 6.5 Hz, 1H), 7.35 (d, J = 6.4
Hz, 1H), 6.54 (dd, J = 8.4, 2.2 Hz, 1H), 6.34 (dd, J = 8.5, 2.2 Hz. 1H),
5.70 (d, J = 1.08 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.3 (s, 3H), 1.40 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 169.7, 151.4, 150.2,
137.4, 128.2, 127.8, 119.8, 113.0, 110.4, 108.2, 64.7, 15.9, 14.4. IR
(film): 1717, 1650 cm−1. HRMS (ESI): calculated for C13H14NO4 [M
1
NMR (300 MHz, CDCl3) δ: 8.61 (d, J = 5.1 Hz, 2H), 7.09 (d, J = 5.9
Hz, 2H), 4.73 (s, 1H), 3.83−3.72 (m, 1H), 2.83−2.72 (m, 1H), 2.57−
2.50 (m, 2H), 2.28 (m, 2.20 9 m, 1H), 2.05−1.94 (m, 1H), 1.76−1.71
(m, 2H), 1.64−1.61 (m, 3H), 1.43−1.35 (m, 1H), 1.04 (t, J = 7.3 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ: 172.2, 154.8, 150.5, 145.7, 135.2,
122.8, 66.1, 35.3, 30.9, 28.7, 27.2, 27.1, 25.0, 13.9. IR (film): 1681
+
+ H] , 248.0923; found 248.0931.
Spiro(dihydropyridine) 39. Using the procedure given for the
+
cm−1. HRMS (ESI): calculated for C16H21N2O [M + H] , 257.1654;
preparation of 13, 39 was obtained from 0.10 g of 38 as pale yellow oil
1
found 257.1661.
(81 mg, 61%). H NMR (300 MHz, CDCl3, mixture of rotamers) δ:
1
Pyridyl-dehydropyrrolidinone 12. Brown oil, 41 mg, 44%. H
7.05 (br s, 2H), 4.80−4.72 (m, 2H), 4.52 (d, J = 8.7 Hz, 1H), 4.30 (q,
J = 7.1 Hz, 2H), 4.07 (d, J = 8.7 Hz, 1H), 2.45−2.33 (m, 2H), 2.26−
2.06 (m, 3H), 1.97−1.88 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3, mixture of rotamers) δ: 212.8, 173.8, 151.0, 127.2,
124.2, 106.3, 102.4, 67.4, 63.6, 47.4, 39.8, 29.3, 19.9, 14.5. IR (film):
1775, 1734, 1685 cm−1. HRMS (ESI): calculated for C15H17NO5 Na
NMR (300 MHz, CDCl3) δ: 8.61 (d, J = 6.1 Hz, 2H), 7.07 (d, J = 6.0
Hz, 2H), 5.80−5.67 (m, 1H), 5.14−4.93 (m, 3H), 4.56−4.49 (m, 1H),
3.22 (dd, J = 15.6, 7.7 Hz, 1H), 2.62−2.14 (m, 6H). 13C NMR (75
MHz, CDCl3) δ: 168.7, 164.9, 150.7, 145.1, 142.3, 133.6, 122.3, 118.1,
62.3, 43.5, 28.4, 27.6, 26.2. IR (film): 1685 cm−1. HRMS (ESI):
+
+
[M + Na] , 314.1004; found 314.1022.
calculated for C15H17N2O [M + H] , 241.1341; found 241.1362.
Pyridyl-dehydropyrrolidinone 27. Brown oil, 45 mg, 48%. H
1
Ethyl 5-(4-Pyridyl)-pentadienoate 43. LHMDS (1.0 M
solution, 26.4 mL, 1.1 equiv) was added to a solution of triethyl 4-
phosphonocrotonate (6.00 g, 24.0 mmol, 1 equiv) in THF at 0 °C and
stirred for 45 min. 4-Pyridine carboxaldehyde (2.57 g, 24.0 mmol, 1
equiv) was added, and the reaction mixture was allowed to warm to
room temperature and maintained overnight. The reaction was
quenched with satd aq NH4Cl and extracted with EtOAc (3 × 50
mL), and the combined organic layer was washed with water (50 mL)
and brine (25 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by silica gel flash column chromatography using 50−70%
EtOAc in hexanes to yield 43 as a brown liquid, (4.3 g, 88%). 1H NMR
(300 MHz, CDCl3) δ: 8.60 (d, J = 4.6 Hz, 2H), 7.43 (dd, J = 15.3, 11.0
Hz, 1H), 7.31 (d, J = 4.5 Hz, 2H), 7.03 (dd, J = 15.6, 10.9 Hz, 1H),
6.81 (d, J = 15.6 Hz, 1H), 6.09 (d, J = 15.2 Hz, 1H), 4.25 (q, J = 7.2
Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ:
166.7, 150.6, 143.3, 143.2, 137.3, 130.6, 124.3, 121.3, 60.8, 14.5. IR
(film): 1694 cm−1. HRMS (ESI): calculated for C12H14NO2 [M + H]
+, 204.1025; found 204.1050.
NMR (300 MHz, CDCl3) δ: 8.61 (d, J = 5.9 Hz, 2H), 7.29−7.25 (m,
3H), 7.12−7.09 (m, 2H), 7.01 (d, J = 6.1 Hz, 2H), 5.20 (d, J = 15 Hz,
1H), 4.70 (s, 1H), 3.65 (d, J = 15.1 Hz, 1H), 2.65−2.58 (m, 2H),
2.46−2.26 (m, 3H), 2.19−2.11 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ: 168.8, 165.0, 150.8, 144.8, 142.1, 137.5, 128.9, 128.4, 127.7, 122.3,
61.9, 44.5, 28.4, 27.6, 26.2. IR (film): 1690 cm−1. HRMS (ESI):
+
calculated for C19H19N2O [M + H] , 291.1497; found 291.1494.
Pyridyl-dehydropiperidinone 29. Brown oil, 45 mg, 48%. H
1
NMR (300 MHz, CDCl3) δ: 8.44 (d, J = 5.9 Hz, 2H), 6.96 (d, J = 6.1
Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 4.61 (d, J
= 14.5 Hz, 1H), 4.22 (d, J = 14.5 Hz, 1H), 3.81−3.68 (m, 4H), 3.28 (s,
br, 1H), 3.14 (dd, J = 12.4, 2.8 Hz, 1H), 2.04 (s, 3H), 1.78 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ: 165.5, 159.1, 150.2, 149.0, 141.5, 129.6,
128.9, 128.4, 123.3, 113.9, 55.4, 50.4, 49.6, 45.4, 19.5, 12.9. IR (film):
+
1659 cm−1. HRMS (ESI): calculated for C20H23N2O2 [M + H]
323.1760; found 323.1760.
,
1
Pyridyl-dehydropiperidinone 31. Brown oil, 65 mg, 68%. H
NMR (300 MHz, CDCl3) δ: 8.44 (d, J = 5.9 Hz, 2H), 6.98 (d, J = 6.0
Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 4.62 (d, J
= 14.5 Hz, 1H), 4.23 (d, J = 14.5 Hz, 1H), 3.78−3.72 (m, 4H), 3.23−
3.22 (m, 1H), 3.16 (dd, J = 12.3, 2.9 Hz, 1H), 2.66−2.58 (m, 1H),
2.44−2.31 (m, 1H), 2.11−2.05 (m, 1H), 1.95−1.88 (m, 1H), 1.76−
1.53 (m, 4H). 13C NMR (75 MHz, CDCl3) δ:165.3, 158.9, 150.1,
149.2, 143.8, 129.9, 129.5, 128.8, 123.2, 113.8, 55.4, 50.5, 49.3, 44.1,
29.4, 23.8, 22.4, 22. IR (film): 1659 cm−1. HRMS (ESI): calculated for
Ethyl 5-(4-Pyridyl)-pentanoate 44. Substrate 43 (4.0 g) was
dissolved in ethanol (5 mL), and 10% Pd/C was added (10 mg). The
resulting mixture was hydrogenated at 100 psi for 14 h and then
filtered through a bed of Celite. The filtrate was evaporated in vacuo
and dried to afford 44 as a brown liquid (4.0 g, 99%), which was used
1
in the next step without further purification. H NMR (300 MHz,
CDCl3) δ: 8.49 (d, J = 6.1 Hz, 2H), 7.10 (d, J = 5.9 Hz, 2H), 4.13 (q, J
= 7.1 Hz, 2H), 2.65−2.61 (m, 2H), 2.35−2.31 (m, 2H), 1.70−1.65 (m,
+
C22H25N2O2 [M + H] , 349.1916; found 349.1923.
8046
dx.doi.org/10.1021/jo301247c | J. Org. Chem. 2012, 77, 8038−8048

The Journal of Organic Chemistry
Article
4H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 173.6,
151.2, 149.9, 124.0, 60.5, 35.1, 34.2, 29.8, 24.6, 14.4. IR (film): 1654
90%). 1H NMR (300 MHz, CDCl3) δ: 8.39 (d, J = 5.9 Hz, 2H), 7.27−
7.19 (m, 3H), 7.17−7.13 (m, 3H), 7.02 (d, J = 6.2 Hz, 2H), 2.93−2.88
(m, 4H), 2.07 (p, J = 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ:
150.1, 149.7, 146.0, 142.6, 137.8, 134.7, 128.6, 128.1, 127.5, 122.9,
40.0, 38.1, 22.2. HRMS (ESI): calculated for C16H16N [M + H] ,
222.1283; found 222.1291.
+
cm−1. HRMS (ESI): calculated for C12H18NO2 [M + H] , 208.1338;
found 208.1366.
+
Weinreb Amide 45. AlMe3 (2.80 mL, 56 mmol, 4 equiv) was
added dropwise to a reaction mixture containing N,O-dimethyl
hydroxylamine hydrochloride (5.46 g, 56 mmol, 4 equiv) in THF at
−78 °C, and the resulting mixture was stirred for 45 min. Substrate 44
(2.90 g, 14 mmol, 1 equiv) was added, and the reaction mixture was
stirred for 16 h. The reaction was quenched with satd aq NH4Cl and
then extracted with EtOAc (3 × 50 mL). The combined organic layer
was washed with water (100 mL) and brine (50 mL). The organic
layer was dried over anhydrous NaSO4, filtered and concentrated in
vacuo. The crude product was purified by silica gel flash column
chromatography using 50−70% EtOAc in hexanes to yield 45 as a
Piperidine-dehydropyrrolidinone 49. Titanium isopropoxide
(57 μL, 0.19 mmol, 0.5 equiv) and diisopropylethylamine (99 μL, 0.57
mmol, 1.5 equiv) were added to a solution of 5f (0.10 g, 0.38 mmol, 1
equiv) in THF (5 mL), and the reaction was placed in a preheated 80
°C oil bath for 2 min. Ethyl chloroformate (54 μL, 0.57 mmol, 1.5
equiv) was added to the refluxing reaction mixture, causing the color
to immediately turn dark brown. The mixture was refluxed for 20 min
and then removed from the oil bath and allowed to cool to room
temperature. The mixture was then passed through a short plug of
basic alumina. Ten milligrams of 10% Pd/C was added to the filtrate,
and the mixture was placed under H2 (100 psi) for 24 h. The reaction
was then filtered through a bed of Celite and concentrated in vacuo.
The crude product was purified by silica gel flash column
chromatography using 70% EtOAc in hexanes to afford 49 as a
1
brown oil (2.6 g, 82%). H NMR (300 MHz, CDCl3) δ: 8.48 (d, J =
6.0 Hz, 2H), 7.12 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 3.18 (s, 3H),
2.66−2.62 (m, 2H), 2.47−2.44 (m, 2H), 1.69 (quintet, J = 3.6 Hz,
4H). 13C NMR (75 MHz, CDCl3) δ: 174.3, 151.3, 149.8, 124.0, 61.3,
35.2, 32.3, 31.7, 30.1, 24.3. IR (film): 1654 cm−1. HRMS (ESI):
1
+
brown oil (53 mg, 43%). H NMR (300 MHz, CDCl3) δ: 4.25−4.17
calculated for C12H19N2O2 [M + H] , 223.1447; found 223.1470.
(m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.91−3.84 (m, 1H), 3.82 (s, 1H),
3.15−3.03 (m, 1H), 2.70−2.62 (m, 2H), 2.29−2.12 (m, 2H), 2.02−
1.91 (m, 4H), 1.52−1.45 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H), 1.13 (t, J =
7.2 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ:
172.2, 155.6, 148.1, 134.6, 66.1, 61.5, 44.7, 44.5, 37.9, 35.5, 27.4, 25.7,
22.0, 14.8, 14.1, 13.9. HRMS (ESI): calculated for C18H31N2O3 [M +
6-(4-Pyridyl)-2-hexanone 41. Methyl magnesium bromide (3.0
M solution in THF, 1.1 mL, 3.3 mmol, 1.5 equiv) was added dropwise
to a reaction mixture containing Weinreb amide 45 (0.50 g, 2.2 mmol,
1 equiv) in THF (25 mL) at 0 °C. The reaction mixture was warmed
to room temperature and stirred for 16 h. The reaction was quenched
with satd aq NH4Cl solution and then extracted with EtOAc (3 × 15
mL), and the combined organic layer was washed with water (10 mL)
and brine (5 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and evaporated. The crude product was purified by
silica gel flash column chromatography using 50−70% EtOAc in
hexanes to give 41 as a brown oil (0.34 g, 88%). 1H NMR (300 MHz,
CDCl3) δ: 8.48 (d, J = 5.8 Hz, 2H), 7.10 (d, J = 5.8 Hz, 2H), 2.62 (t, J
= 7.0 Hz, 2H), 2.46 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H), 1.63 (quintet, J =
3.6 Hz, 4H). 13C NMR (75 MHz, CDCl3) δ: 208.7, 151.2, 149.9,
124.0, 43.5, 35.2, 30.1, 29.9, 23.4. IR (film): 1708 cm−1. HRMS (ESI):
+
H] , 323.2335; found 323.2350.
Piperidine-dehydropiperidinone 50. Using the procedure given
above, 28 (0.10 g, 0.29 mmol) was converted to 50 (brown oil, 64 mg,
54%). 1H NMR (300 MHz, CDCl3) δ: 7.25−7.12 (m, 2H), 6.88−6.78
(m, 2H), 4.94−4.88 (m, 1H), 4.21−4.01 (m, 4H), 3.94−3.92 (m,
1.4H), 3.81−3.72 (m, 3.6H), 3.40 (dd, J = 12.9, 4.7 Hz, 1H), 3.12 (dd,
J = 12.8, 1.4 Hz, 1H), 2.54−2.45 (m, 1H), 2.28−2.20 (m, 1H), 2.00 (s,
0.4H), 1.90 (s, 2.6H), 1.86 (s, 3H), 1.72−1.69 (m, 1H), 1.46−1.39 (m,
2H), 1.29−1.10 (m, 4H), 0.91−0.78 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ: 165.5, 159.3, 155.5, 144.3, 130.4, 129.8, 126.5, 114.1, 61.3,
55.5, 49.5, 45.3, 45.1, 44.3, 44.1, 37.6, 30.7, 29.7, 21.6, 14.9, 13.0. IR
(film): 1690, 1655 cm−1. HRMS (ESI): calculated for C23H33N2O4 [M
+
calculated for C11H16NO [M + H] , 178.1232; found 178.1262.
1-Phenyl-5-(pyridin-4-yl)-pentan-1-one 42. Weinreb amide 45
(0.60 g, 2.7 mmol) was treated with phenyl magnesium bromide
according the procedure given above to afford 42 (0.63 g, 97%) as a
+
+ H] , 401.2440; found 401.2438.
1
brown oil. H NMR (300 MHz, CDCl3) δ: 8.48 (d, J = 6.3 Hz, 2H),
ASSOCIATED CONTENT
7.97−7.94 (m, 2H),7.59−7.54 (m, 1H), 7.49−7.44 (m, 2H), 7.12 (d, J
= 6.3 Hz, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H),
21.83−1.69 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 200.1, 151.2,
149.9, 137.0, 133.2, 128.8, 128.2, 124.0, 38.3, 35.3, 30.1, 23.9. IR
(film): 1681 cm−1. HRMS (ESI): calculated for C16H18NO [M + H] +,
240.1388; found 240.1415.
■
S
* Supporting Information
1H/13C NMR spectra and X-ray crystal structure of 37. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1-Methyl-2-(pyridin-4-yl)-cyclopentene 46. TMSOTf (52 μL,
0.28 mmol, 0.5 equiv) and diisopropylethylamine (0.14 mL, 0.85
mmol, 1.5 equiv) were added to a solution of 46 (0.10 g, 0.56 mmol, 1
equiv) in THF (2 mL). The reaction mixture was placed in an oil bath
preheated to 80 °C for 2 min. Ethyl chloroformate (81 μL, 0.85 mmol,
1.5 equiv) was added to the refluxing reaction mixture, which
immediately turned dark brown. The reaction was refluxed for 20 min,
after which time TFA (10 equiv) was added. The reaction was refluxed
for an additional 10 min and then H2O (2 mL) was added. After 5 min
the reaction was removed from the oil bath and allowed to cool to
room temperature. The mixture was made basic by addition of satd aq
Na2CO3 and extracted with EtOAc (3 × 5 mL). The combined
organic layer was washed with water (10 mL) and brine (5 mL) and
dried over anhydrous Na2SO4. Filtration and evaporation of the
solvent gave a residue that was purified using silica gel flash column
chromatography using 70−90% EtOAc in hexanes to afford 46 (80
mg, 89%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ: 8.54 (d, J =
4.9 Hz, 2H), 7.18 (d, J = 6.0 Hz, 2H), 2.78−2.69 (m, 2H), 2.55−2.50
(m, 2H), 1.96−1.86 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 149.7,
146.2, 140.3, 132.7, 122.4, 40.6, 36.5, 21.9, 15.8. HRMS (ESI):
AUTHOR INFORMATION
Corresponding Author
*E-mail: chris-pigge@uiowa.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Roy J. Carver Charitable Trust for generous
financial support (Grant No. 09-3279) and Drs. Dale C.
Swenson and Pradeep P. Kapadia for assistance with X-ray
crystallography.
REFERENCES
■
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