Bronsted acid catalyzed intramolecular benzylic cyclizations of alkylpyridines

Article abstract of DOI:10.1039/c3ob42039f

Aldehyde and ketone electrophiles incorporated into the side chains of 2- and 4-alkylpyridines participate in intramolecular aldol-like condensations with pyridine benzylic carbons in the presence of Bronsted acid catalysts. Pyridines featuring β-ketoamid

Full text of DOI:10.1039/c3ob42039f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Brønsted acid catalyzed intramolecular benzylic
cyclizations of alkylpyridines†
Cite this: Org. Biomol. Chem., 2014,
12, 1090
Ashabha I. Lansakara, Daniel P. Farrell and F. Christopher Pigge*
Aldehyde and ketone electrophiles incorporated into the side chains of 2- and 4-alkylpyridines participate
in intramolecular aldol-like condensations with pyridine benzylic carbons in the presence of Brønsted
acid catalysts. Pyridines featuring β-ketoamide side chains undergo cyclization in the presence of 10 mol%
TfOH to afford pyridyl-substituted hydroxy lactams in good yield. These products were found to be resist-
ant to further dehydration under a variety of conditions, however treatment with thionyl chloride elicited
an unusual dehydration/oxidation reaction sequence. In contrast, acid-catalyzed cyclization of pyridines
tethered to aliphatic aldehydes with amine linkers gives pyridyl-substituted dehydro-piperidine products.
Similarly, intramolecular condensation of salicylaldehyde- and salicylketone-substituted pyridines affords
pyridyl-substituted benzofurans.
Received 11th October 2013,
Accepted 13th December 2013
DOI: 10.1039/c3ob42039f
www.rsc.org/obc
Introduction
Aza-heterocyclic structural motifs are important components
of numerous natural products, bio-active pharmaceutical
agents, and functional organic materials. Pyridine and related
aza-arenes in particular are commonly encountered in many
diverse types of organic compounds that display wide-ranging
and desirable physical properties.1–4 Consequently, preparative
methods for the synthesis of substituted pyridines,5,6 along
with methods suitable for manipulation of pre-formed pyri-
dine derivatives,7–11 are valuable tools in the synthetic organic
and medicinal chemistry communities.
Recently, several reports have described condensation reac-
tions of 2-methyl(aza-arenes) that proceed in the presence of
Brønsted or Lewis acid catalysts. For example, treatment of a
2-alkyl(aza-arene) such as 2,6-lutidine with sulfonyl imines in
the presence of a Cu(II) Lewis acid additive affords products of
Mannich-type reactions (Scheme 1a).12 In addition to Cu,13
other Lewis acidic metals such as Sc,14,15 Fe,16 and Yb17 have
proven effective in promoting reaction between 2-methyl(aza-
arenes) and activated imines, ketones, aldehydes, and Michael
acceptors. Similarly, Brønsted acids have also been employed
as catalysts capable of mediating reaction between 2-methyl-
(aza-arenes) and activated aldehydes,18 ketones,19,20 and
Michael acceptors21 (Scheme 1b).
Scheme 1 Acid catalysed condensation reactions of 2-alkyl(aza-
arenes).
enamine tautomers of the 2-methyl(aza-arene) substrate. Reac-
tion of the enamine tautomer with added electrophile then
leads to the observed products (Scheme 1c). In some instances
thermal activation alone has been shown to be effective in pro-
moting similar reactions, presumably by also providing access
to reactive enamine-like tautomers.22–24 The activating effects
observed under these reaction conditions, however, generally
do not extend to 4-substituted aza-arenes, such as 4-pico-
line.12,14,18 Thus, the proximity of the alkyl substituent to an
aza-arene nitrogen atom appears to be an important structural
feature.25
In each of these transformations the acid additive is envi-
sioned to facilitate interconversion between imine and
We recently reported Lewis acid-promoted intramolecular
condensation reactions involving 4-alkylpyridines possessing
attached carbonyl electrophiles.26 These reactions were con-
ducted by first acylating the pyridine with ethyl chloroformate
in the presence of iPr2NEt. Under these conditions the
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.
E-mail: chris-pigge@uiowa.edu; Fax: +1-319-335-1270; Tel: +1-319-335-3805
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, copies of 1H and 13C NMR spectra. See DOI: 10.1039/c3ob42039f
1090 | Org. Biomol. Chem., 2014, 12, 1090–1099
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Acid catalysed cyclization of 4
Entry
Catalysta
% Yield 5b
1
2
3
4
5
6
None
TfOH
TFA
AcOH
p-TSA
CSAd
0c
97
90
78
70
72
Scheme 2 4-Alkylpyridine benzylic cyclization via anhydrobase inter-
mediates.26
a Reactions performed on 100 mg scale, [4] ∼ 0.3 M in dioxane.
b Isolated yield after purification by chromatography, ∼2 : 1 dr of
products in each case. c Recovered starting material (93%).
d Camphorsulfonic acid.
pyridine substrate is converted to the corresponding anhydro-
base, which then reacts with the activated carbonyl
(Scheme 2). Subsequent processing under aqueous conditions
afforded substituted pyridine products that had undergone
formal benzylic cyclization.
Given the similarity of acyl anhydrobase intermediates 1
and 2 to enamine tautomers of alkyl pyridines, we became
intrigued by the possibility of using an acid catalyst to effect
intramolecular alkylpyridine condensation reactions analo-
gous to that depicted in Scheme 2. If successful, then the need
for pyridine activation with stoichiometric quantities of an acy-
lating agent would be circumvented, resulting in greatly sim-
plified cyclization procedures. With this goal in mind, we
initiated a study examining the efficiency of Brønsted acid
catalysed benzylic cyclization of 4- and 2-alkylpyridines.27
The reaction conditions outlined in Table 1, entry 2 rep-
resent a greatly simplified experimental protocol for achieving
intramolecular alkylpyridine functionalization as compared to
our original procedure (see Scheme 2).26 To explore the gener-
ality of acid catalyzed cyclization, several other 4- and 2-alkyl-
pyridines structurally related to 4 were also subjected to the
reaction conditions illustrated in Table 1, and the results are
shown in Table 2. The alkylpyridine substrates for this study
were each prepared by condensation of the corresponding
N-alkyl aminomethyl- or aminoethylpyridine with the appro-
priate β-ketoester to install the indicated β-amidocarbonyl side
chains.26 Cyclization reactions involved heating a solution of
the substrate (∼0.3 M) and 10 mol% TfOH in dioxane to
120 °C for 12 h. Crude reaction mixtures were then directly
purified by silica gel flash column chromatography to afford
the isolated products as mixtures of diastereomers. Diastereo-
Results and discussion
1
mer ratios were estimated on the basis of H NMR spectra. In
The 4-alkylpyridine derivative 4 was selected as a test substrate
for initial investigations (Table 1) due to its straightforward
preparation from commercially available N-ethyl-4-amino-
methylpyridine and ethyl-3-oxo-valerate.26 Dioxane was chosen
as the reaction solvent as it features a reasonably high boiling
point and has been used as a reaction medium in several
related intermolecular alkyl(aza-arene) condensation reac-
tions.15,17,19,20 As a control experiment, 4 alone in dioxane was
heated to 120 °C to determine if thermal activation would
result in cyclization.22 No reaction was observed after 12 h
(Table 1, entry 1). Next, 4 was heated (dioxane, 120 °C) in the
presence of various Brønsted acid catalysts (10 mol%). Gratify-
ingly, an aldol-like condensation was observed in each case,
and pyridine derivative 5 was isolated as a ∼2 : 1 mixture of
diastereomers inseparable by flash column chromatography
(Table 1, entries 2–6). Reaction in the presence of TfOH
afforded the highest isolated yield of 5. Notably, however, all
the Brønsted acids screened in this assay were effective to
varying degrees in promoting benzylic cyclization.
particular, signals for the benzylic hydrogens of the individual
diastereomers were sufficiently separated in most cases so as
to allow determination of stereoisomer ratios.
As shown in Table 2, entries 1–4, TfOH acid catalysis was
effective in converting 6a–9a to the corresponding pyridine-
substituted γ-lactams in good to excellent yield, and in all
cases cyclized products 6b–9b were isolated as mixtures of dia-
stereomers inseparable by flash column chromatography. In
the case of 7b and 8b (entries 2 and 3), two diastereomers were
evident in the NMR spectra, which we attribute to formation of
cis-ring fusions in the 5,5- and 6,5-bicyclic moieties. Com-
pounds 6b and 9b (Table 2, entries 1 and 4) however, were
obtained as mixtures of all possible diastereomers. Due to
overlapping signals for many of the hydrogens, the relative
stereochemistry for individual diastereomers could not be
assigned. In similar fashion, this procedure was effective for
inducing cyclization of aminoethylpyridine derivatives as
revealed in Table 2, entries 5 and 6. The pyridyl-substituted
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1090–1099 | 1091

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 2 TfOH catalyzed benzylic cyclization of alkylpyridinesa
Table 2 (Contd.)
Entry
9
Substrate
Product
n.p.e
% Yieldb
Entry
1
Substrate
Product
% Yieldb
g
97% (3.4 : 2.6 : 2.3 : 1)
—
a Reactions performed on 100 mg scale, [substrate] ∼ 0.3 M in dioxane.
b Isolated yield, diastereomeric ratio of products indicated in
parentheses. c Diastereomeric ratio could not be determined due to
overlapping signals in the 1H NMR spectrum. d Based on 20%
recovered 12a. e No cyclized product was obtained. f 60% recovered
starting material. g 68% recovered starting material.
2
3
60% (3.9 : 1)
δ-lactams 10b and 11b also were isolated as mixtures of dia-
stereomers in good yield. Table 2, entry 7, illustrates the suc-
cessful conversion of 2-alkylpyridine substrate 12a to the
corresponding cyclized product 12b in reasonable yield. This
transformation represents an expansion of substrate scope
compared to our original cyclization procedure (Scheme 2),
under which 2-substituted pyridines are unreactive.26 Unfortu-
nately, two other 2-alkylpyridine substrates examined in this
study failed to undergo benzylic cyclization, and only
unreacted starting material was recovered (Table 2, entries 8
and 9). At present, factors responsible for the differing reactiv-
ity of 2-substituted pyridines remain obscure.
98% (9.0 : 1)
4
89% (3.0 : 1.6 : 1.3 : 1)
The results in Table 2 demonstrate the utility of Brønsted
acid catalysis in promoting intramolecular aldol-type reactions
of alkylpyridines. It is additionally noteworthy that 4-alkylpyri-
dines are good substrates for this reaction, in contrast to
related Lewis and Brønsted acid catalyzed intermolecular con-
densation reactions of methyl-substituted aza-arenes.15,17,19,20
We were somewhat surprised, however, to isolate tertiary alcohol
products exclusively as we anticipated the initial aldol-like pro-
ducts would undergo facile elimination of H2O under the acidic
reaction conditions.28 Dehydration of initial cyclization products
would produce the added benefit of greatly simplified product
mixtures by removing the possibility of diastereoisomers. Conse-
quently, we briefly explored reaction conditions designed to
effect dehydration of selected cyclized products.
5
6
97%c
70% (7.5 : 1)
Lactam 6b was selected as the initial substrate for these
studies. Unexpectedly, however, we found 6b to be remarkably
resistant to dehydration under a variety of reaction conditions.
For example, in separate experiments 6b was exposed to
BF3·OEt2, MsCl–Et3N, Ac2O–Et3N, P2O5, H2SO4, H3PO4, HCl,
KOtBu, or NaH, and in each case none of the anticipated unsatu-
rated lactam was observed (in some cases unreacted 6b was
recovered while in others substrate decomposition occurred). A
reaction was observed upon treatment of 6b with POCl3–Et3N,
but transformation of the amide group occurred concomitantly
with elimination of the tertiary alcohol to afford chloropyrrole
15 (eqn (1)).
7
8
59%d (1.5 : 1.2 : 1 : 1)
f
n.p.e
—
1092 | Org. Biomol. Chem., 2014, 12, 1090–1099
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
19 and 20.31 Subsequently, the presence of excess SOCl2 may
result in further reaction at the lactam carbonyl and/or the
pyridine ring to give species such as 21a,b and 22a,b. Addition
of H2O then leads to 16 while loss of H+ leads to 18. As a test
of this mechanistic formulation, the known lactam 1926 was
treated with SOCl2–Et3N. Oxidized lactam 16 was obtained in
57% isolated yield (eqn (2)).
ð1Þ
Several substrates (in addition to 6b) were examined for
their reactivity toward thionyl chloride (SOCl2) as a putative
dehydration agent (Scheme 3). While loss of the 3° alcohol did
occur in the presence of SOCl2, oxidation of the lactam ring
was also observed. Thus, 6b and 8b were converted to 16 and
17, respectively, in moderate to good yield. The δ lactam 10b
also suffered dehydrative oxidation in the presence of SOCl2 to
afford 18, albeit in modest yield. While oxidation was not the
anticipated outcome, the use of SOCl2 as an oxidizing agent is
not unprecedented.29 Moreover, a somewhat related SOCl2-
mediated oxidation has been studied in some detail by
Cushman and co-workers.30
ð2Þ
Two additional types of cyclization substrates distinct from
the β-amido carbonyl starting materials discussed thus far
were also examined. An approach to pyridyl-substituted piper-
idines was explored through preparation of (aminoethyl)pyri-
dine derivatives featuring pendant aldehyde electrophiles as
depicted in Scheme 5. 4-(Aminoethyl)pyridine was converted
to the corresponding benzoyl or tosyl amide. Allylation of the
amide nitrogen followed by hydroboration/oxidation provided
primary alcohols 23 and 24 in good yield. Swern oxidation of
the benzoyl amide derivative afforded aldehyde 25. Exposure
of 25 to acid catalyzed cyclization reaction conditions,
however, failed to generate the expected cyclized product, and
only substrate decomposition was observed. Cyclization of 25
to 27 could be achieved in good yield via discrete anhydrobase
intermediates using our previously reported procedure.26 In
contrast, the tosyl amide derivative 26 proved stable to acid
catalysis, and 28 was obtained in reasonable isolated yield
(52%). Thus, in this reaction elimination of the secondary
alcohol intermediate readily occurs to deliver the conjugated
olefin. Tosyl amide 26 could also be cyclized in slightly higher
yield upon activation with EtO2CCl and iPr2NEt in the presence
of Ti(OiPr)4.26
Based on this previous work,30 a plausible mechanistic
rationale to account for these transformations is illustrated in
Scheme 4. Initial loss of H2O may give the unsaturated lactams
Reactions of cyclization substrates based on derivatives of
salicylaldehyde were also examined. We envisioned that alkyl-
ation of salicylaldehyde with appropriate aza-arenes would
afford precursors to heterocycle-substituted benzofurans
Scheme 3 Lactam elimination/oxidation with SOCl2.
Scheme 5 Acid catalyzed pyridine benzylic cyclization with aldehyde
Scheme 4 Mechanistic rationale for SOCl2-mediated oxidation.
electrophiles.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1090–1099 | 1093

View Article Online
Paper
Organic & Biomolecular Chemistry
Conclusions
An experimentally simple Brønsted acid catalyzed procedure
effective for inducing intramolecular aldol-like condensations
of alkylpyridine derivatives has been developed. Positioning of
carbonyl electrophiles in the side chain of 4-alkylpyridines in
particular affords viable cyclization precursors across a range
of substrate types. Appropriately functionalized 2-alkylpyri-
dines also gave the reaction, especially those featuring salicyl-
aldehyde-derived side chains. Other 2-alkylpyridines, however,
were resistant to acid catalyzed benzylic cyclization for reasons
that remain under investigation. An unusual SOCl2-mediated
oxidation of pyridyl-substituted lactams has also been un-
covered. The construction of intriguing heterocyclic ring
systems of relevance to medicinal, natural product, and
materials chemistry has been demonstrated. Continuing
research seeks to expand upon these results by harnessing the
reactivity of putative enamine-like anhydrobase intermediates
available to pyridine and related aza-arenes in additional and
novel bond-forming processes.34
Scheme 6 Synthesis of pyridyl-substituted benzofurans.
which could be assembled through subsequent intramolecular
benzylic cyclization. Benzofurans in general possess a wealth
of desirable activities in both biological and materials
settings,32 and incorporation of an aza-arene substituent
(e.g., pyridine) provides a handle for further molecular and
supramolecular (e.g., H-bonding, metal ion binding)
elaboration.
Experimental
General procedure for intramolecular acid catalyzed benzylic
cyclization
To begin, alkylation of salicylaldehyde with 4- and 2-picolyl
chloride yielded precursors to functionalized benzofurans in
straightforward fashion (Scheme 6).33 As anticipated, exposure
of 29 and 30 to acid catalyzed benzylic cyclization reaction con-
ditions returned the corresponding benzofuran products (31,
32) in good to excellent yield. Notably, the 2-substituted pyri-
dine proved to be a suitable substrate for this transformation.
In each case, elimination of H2O was observed during the
course of cyclization, undoubtedly facilitated by formation of
the aromatic benzofuran ring system. This approach also
proved amenable to construction of 2,3-disubstituted benzo-
furans. Addition of Grignard reagents to 29 and 30 followed by
oxidation with the Dess–Martin periodinane gave ketones
33–36. Acid catalyzed cyclization proceeded smoothly with
each of these substrates, and benzofurans 37–40 were isolated
in good yield.
This transformation also has been extended to include
incorporation of a quinoline moiety as a benzofuran substitu-
ent, as shown in eqn (3). Similar to pyridine analogues,
exposure of 41 to TfOH (10 mol%) in dioxane at 120 °C pro-
duced benzofuran 42 in 73% isolated yield. The successful
cyclization of 41 indicates that this acid catalyzed procedure
may be applicable to transformations of aza-arenes other than
pyridine.
The preparation of pyridine derivative 5 is representative. Reac-
tion mixtures were prepared open to air. Pyridine 4 (100 mg,
0.40 mmol, 1 equiv.) was placed in a scintillation vial equipped
with a Teflon-lined screw cap and dissolved in 1,4-dioxane
(1 mL). Trifluoromethanesulfonic acid (TfOH) (4 µL,
0.04 mmol, 0.1 equiv.) was added and the reaction was heated
to 120 °C. The reaction was maintained at this temperature for
12 h, then allowed to cool to room temperature. The solvent
was removed under vacuum and the crude product was puri-
fied by silica gel flash column chromatography using 70–100%
EtOAc in hexanes as eluent. N,4-Diethyl-4-hydroxy-5-(pyridin-4-
yl)pyrrolidin-2-one 5 (∼2 : 1 mixture of diastereomers, 96 mg,
1
96%) was isolated as a yellow oil. H NMR (300 MHz, CDCl3) δ
8.55 (d, J = 5.4 Hz, 0.7H), 8.46 (d, J = 5.7 Hz, 1.3H), 7.18 (d, J =
5.9 Hz, 1.3H), 7.09 (d, J = 4.9 Hz, 0.7H), 4.55 (s, 0.35H), 4.47 (s,
0.65H), 3.93–3.67 (m, 1H), 3.48 (s, 1H), 2.81–2.60 (m, 1H),
2.60–2.39 (m, 2H), 1.77 (q, J = 7.4 Hz, 1H), 1.39–1.29 (m, 1H),
1.09–1.02 (m, 3H), 0.99 (t, J = 7.2 Hz, 2H), 0.93–0.88 (m, 1H).
13C NMR (75 MHz, CDCl3) δ 173.7, 173.4, 150.2, 149.4, 146.7,
145.0, 124.0, 77.3, 75.5, 73.8, 70.0, 43.3, 36.3, 35.8, 33.1, 30.6,
12.4, 12.1, 8.2, 8.1. IR (film) 3350, 2972, 2936, 2874,
1672 cm−1. HRMS (ESI) C13H19N2O2 [M + H]+, calculated
235.1447; found 235.1434.
Cyclized products 6b–12b (Table 2) were prepared from
100 mg of the corresponding pyridine substrates using the pro-
cedure given above.
N-Ethyl-4-hydroxy-3,4-dimethyl-5-(pyridin-4-yl)pyrrolidin-2-
one (6b). Mixture of diastereomers, 97 mg, 97%, yellow oil. 1H
NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.9 Hz, 0.7H), 8.50–8.41
(m, 1.3H), 7.22 (d, J = 5.3 Hz, 0.5H), 7.16 (d, J = 5.1 Hz, 0.9H),
ð3Þ
1094 | Org. Biomol. Chem., 2014, 12, 1090–1099
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
7.11 (d, J = 3.8 Hz, 0.5H), 7.06 (d, J = 4.2 Hz, 0.1H), 4.61 (s, 6H), 7.19–6.92 (m, 1H), 4.95–4.26 (m, 2H), 3.99–2.77 (m, 4H),
0.1H), 4.50 (s, 0.3H), 4.43 (s, 0.2H), 4.34 (m, 0.4H), 3.96–3.68 2.76–2.67 (m, 0.1H), 2.67–2.54 (m, 0.2H), 2.54–2.38 (m, 0.7H),
(m, 1H), 3.41 (s, 1H), 2.86–2.59 (m, 1H), 2.59–2.49 (m, 0.4H), 1.50–1.29 (m, 3H), 1.26 (s, 0.3H), 1.18 (s, 0.2H), 1.10–0.81 (m,
2.49–2.33 (m, 0.6H), 1.38 (d, J = 7.2 Hz, 2H), 1.29–1.21 (m, 1H), 2.5H). 13C NMR (75 MHz, CDCl3) δ 173.4, 171.2, 149.6, 149.5,
1.21–1.12 (m, 2.5H), 1.07–0.96 (m, 3H), 0.93 (t, J = 7.1 Hz, 149.4, 149.2, 148.2, 147.9, 137.0, 136.9, 136.8, 129.2, 128.8,
0.5H). 13C NMR (125 MHz, CDCl3) δ 176.8, 176.7, 175.8, 175.5, 128.77, 128.74, 128.4, 128.2, 127.9, 127.8, 127.4, 126.3, 125.0,
150.2, 149.8, 149.4, 149.3, 146.8, 145.8, 145.4, 143.9, 124.5, 124.9, 124.5, 124.4, 72.3, 71.7, 51.7, 50.4, 50.2, 50.08, 50.02,
123.6, 123.1, 77.1, 76.9, 76.1, 74.9, 72.1, 71.4, 69.8, 69.6, 60.5, 49.2, 48.4, 47.6, 47.2, 47.1, 44.6, 25.7, 25.2, 16.3, 10.1. IR (film)
49.9, 48.1, 46.6, 45.3, 36.4, 36.0, 35.6, 24.2, 23.4, 23.3, 20.7, 3419, 2983, 2928, 1697, 1625, 1617 cm−1
14.3, 12.5, 12.3, 11.9, 11.3, 9.6, 7.8, 7.2. IR (film) 3368, 2976, C19H23N2O2 [M + H]+, calculated 311.1760; found 311.1764.
. HRMS (ESI)
2939, 2870, 1683, 1657 cm−1
[M + H]+, calculated 235.1447; found 235.1466.
.
HRMS (ESI) C13H19N2O2
N-Benzyl-4a-hydroxy-4-(pyridin-4-yl)octahydroisoquinolin-
1(2H)-one (11b). Mixture of diastereomers, 70 mg, 70%,
N-Ethyl-3a-hydroxy-3-(pyridin-4-yl)hexahydrocyclopenta[c]- yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 5.9 Hz,
pyrrol-1(2H)-one (7b). Mixture of diastereomers, 60 mg, 60%, 1.8H), 8.39 (dd, J = 4.6, 1.4 Hz, 0.2H), 7.41–7.19 (m, 6.8H), 7.00
yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.55–8.43 (m, 0.4H), (d, J = 6.1 Hz, 0.2H), 4.86 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.4
8.38 (d, J = 5.9 Hz, 1.6H), 7.12 (d, J = 6.0 Hz, 2H), 4.52 (s, 0.3H), Hz, 0.1H), 4.37 (d, J = 14.9 Hz, 0.9H), 3.83–3.68 (m, 1H), 3.23
4.49 (s, 0.7H), 3.81 (dq, J = 14.6, 7.4 Hz, 1H), 3.27 (dd, J = 14.0, (dd, J = 11.8, 6.0 Hz, 1H), 2.98 (dd, J = 12.2, 6.0 Hz, 1H), 2.71
6.8 Hz, 0.4H), 2.85 (dd, J = 9.6, 4.3 Hz, 0.2H), 2.76 (dd, J = 9.0, (s, 1H), 2.37 (dd, J = 13.9, 2.3 Hz, 1H), 2.29 (dd, J = 12.5,
2.8 Hz, 0.8H), 2.65 (dq, J = 14.1, 7.1 Hz, 0.6H), 2.21–1.80 (m, 3.8 Hz, 1H), 1.93–1.78 (m, 1H), 1.66–1.47 (m, 2H), 1.47–1.34
5H), 1.80–1.58 (m, 1H), 1.11–0.90 (m, 3H). 13C NMR (75 MHz, (m, 1H), 1.34–1.06 (m, 3H). 13C NMR (125 MHz, CDCl3)
CDCl3) δ 176.0, 149.8, 149.5, 146.8, 123.3, 83.8, 69.1, 52.9, 42.3, δ 170.1, 149.8, 147.2, 137.2, 128.79, 128.72, 128.0, 127.5, 124.7,
36.3, 27.6, 24.8, 12.2. IR (film) 3367, 2958, 2872, 1667, 124.0, 71.0, 50.2, 50.2, 50.0, 48.9, 35.9, 25.3, 22.4, 20.6. IR
1601 cm−1. HRMS (ESI) C14H19N2O2 [M + H]+, calculated (film) 3386, 2928, 2852, 1630, 1625 cm−1
247.1447; found 247.1436.
.
HRMS (ESI)
C21H25N2O2 [M + H]+, calculated 337.1916; found 337.1907.
N-Ethyl-3a-hydroxy-3-(pyridin-4-yl)octahydro-1H-isoindol-1-
3a-Hydroxy-2-methyl-3-(pyridin-2-yl)hexahydrocyclopenta[c]-
one (8b). Mixture of diastereomers, 98 mg, 98%, yellow oil. 1H pyrrol-1(2H)-one (12b). Mixture of diastereomers, 47 mg, 59%
1
NMR (300 MHz, CDCl3) δ 8.45 (d, J = 5.9 Hz, 0.2H), 8.28 (d, J = (based on 20% recovery of unreacted 12a), yellow oil. H NMR
6.0 Hz, 1.8H), 7.19 (d, J = 6.0 Hz, 0.2H), 7.08 (d, J = 6.0 Hz, (400 MHz, CDCl3) δ 8.64–8.57 (m, 0.8H), 8.57–8.50 (m, 0.2H),
1.8H), 4.52 (s, 0.1H), 4.20 (s, 0.9H), 3.98–3.79 (m, J = 14.6, 7.3 8.30 (s, 0.2H), 8.19 (s, 0.2H), 7.80–7.63 (m, 1H), 7.31–7.14 (m,
Hz, 1H), 3.70 (s, 1H), 2.77 (dq, J = 14.1, 7.0 Hz, 1H), 2.56 (d, J = 2H), 4.85 (s, 0.3H), 4.66 (s, 0.4H), 4.53 (s, 0.5H), 4.50 (s, 0.3H),
5.8 Hz, 0.1H), 2.49–2.36 (m, 0.9H), 2.01–1.83 (m, J = 15.9, 5.3 3.43–3.06 (m, 0.4H), 2.99 (s, 0.6H), 2.97–2.90 (m, 0.6H), 2.85 (s,
Hz, 2H), 1.80–1.48 (m, 4H), 1.43–1.29 (m, 2H), 1.06 (t, J = 7.2 0.7H), 2.83 (s, 0.8H), 2.72 (s, 0.9H), 2.60–2.25 (m, 0.5H),
Hz, 2.7H), 0.96 (t, J = 7.1 Hz, 0.3H). 13C NMR (75 MHz, CDCl3) 2.24–2.07 (m, 1H), 2.07–1.80 (m, 1.5H), 1.80–1.60 (m, 0.7H),
δ 174.4, 149.2, 145.6, 123.3, 74.7, 68.8, 46.1, 36.11, 36.08, 22.7, 1.60–1.44 (m, 0.3H), 1.44–1.29 (m, 0.5H), 1.29–1.08 (m, 0.6H).
21.46, 21.42, 12.3. IR (film) 3404, 2939, 2859, 1676, 1665, 13C NMR (101 MHz, CDCl3) δ 177.0, 176.4, 163.3, 162.8, 157.2,
1603 cm−1. HRMS (ESI) C15H21N2O2 [M + H]+, calculated 157.0, 156.3, 156.1, 150.1, 150.0, 149.7, 149.4, 137.4, 137.2,
261.1603; found 261.1594.
137.1, 136.9, 123.4, 123.2, 123.0, 123.0, 122.7, 122.4, 121.5,
N-Ethyl-3a-hydroxy-3-(pyridin-4-yl)octahydrocyclohepta[c]- 86.0, 84.1, 74.8, 73.3, 55.3, 55.0, 53.8, 49.9, 42.4, 38.2, 34.9,
pyrrol-1(2H)-one (9b). Mixture of diastereomers, 89 mg, 89%, 30.1, 29.5, 29.0, 28.2, 28.1, 25.3, 25.0. IR (film) 3404, 2965,
yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 4.9 Hz, 2885, 1665, 1643 cm−1. HRMS (ESI) C13H17N2O2 [M + H]+,
0.8H), 8.54–8.41 (m, J = 5.9 Hz, 1.2H), 7.26–7.13 (m, J = 5.5 Hz, calculated 233.1290; found 233.1286.
1.5H), 7.14–6.94 (m, 0.5H), 4.61 (s, 0.1H), 4.46 (s, 0.2H), 4.44
4-(5-Chloro-N-ethyl-3,4-dimethyl-1H-pyrrol-2-yl)pyridine (15).
(s, 0.5H), 4.40 (s, 0.2H), 4.02–3.59 (m, 1H), 3.39–2.85 (m, 1H), Pyridine substrate 6b (100 mg, 0.4 mmol, 1 equiv.) was dis-
2.85–2.38 (m, 2H), 2.26–1.93 (m, 2H), 1.93–1.12 (m, 8H), solved in 1,4-dioxane (1 mL). POCl3 (0.12 mL, 1.3 mmol, 3
1.12–1.00 (m, 1H), 1.00–0.76 (m, 2H). 13C NMR (75 MHz, equiv.) was added dropwise. The reaction was maintained for
CDCl3) δ 177.2, 176.9, 176.3, 175.4, 174.4, 150.2, 150.2, 149.5, 10 min, then Et3N (0.24 mL, 1.7 mmol, 4 equiv.) was added
149.3, 147.5, 146.8, 144.4, 143.8, 143.5, 124.5, 124.3, 124.2, and the reaction was heated to 120 °C for 12 h. After cooling to
79.6, 79.4, 78.5, 77.9, 73.9, 73.0, 70.3, 70.0, 58.3, 56.4, 50.5, room temperature the solvent was removed under vacuum.
47.7, 42.7, 39.5, 38.4, 37.9, 37.8, 36.4, 36.2, 35.7, 31.2, 31.1, The residue was combined with saturated aqueous Na2CO3
30.9, 30.0, 29.9, 28.0, 26.2, 26.1, 25.5, 25.4, 24.7, 22.7, 20.8, solution and extracted with EtOAc (3 × 10 mL). The combined
12.6, 12.2, 12.0. IR (film) 3364, 2932, 2849, 1683, 1661 cm−1
.
organic layer was concentrated under vacuum and purified via
HRMS (ESI) C16H23N2O2 [M + H]+, calculated 275.1760; found flash column chromatography (SiO2, 70–100% EtOAc–hexanes)
1
275.1755.
to afford 15 (30 mg, 30%) as a brown oil. H NMR (300 MHz,
N-Benzyl-4-hydroxy-3,4-dimethyl-5-(pyridin-4-yl)piperidin-2- CDCl3) δ 8.64 (d, J = 4.5 Hz, 2H), 7.19 (dd, J = 4.5, 1.6 Hz, 2H),
one (10b). Mixture of diastereomers, 97 mg, 97%, yellow oil. 3.90 (q, J = 7.1 Hz, 2H), 2.01 (s, 3H), 1.99 (s, 3H), 1.15 (t, J =
1H NMR (300 MHz, CDCl3) δ 8.54–8.31 (m, 2H), 7.48–7.19 (m, 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 150.0, 140.6, 126.9,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1090–1099 | 1095

View Article Online
Paper
Organic & Biomolecular Chemistry
124.6, 118.3, 116.2, 115.4, 39.9, 16.2, 10.4, 9.35. IR (film) 1654, (5.1 mL, 36 mmol, 1.5 equiv.) was added. The reaction was
1636, 1632 cm−1. HRMS (ESI) C13H16N2Cl [M + H]+, calculated cooled to 0 °C and benzoyl chloride (3.1 mL, 27 mmol,
235.1002; found 235.1017.
1.1 equiv.) dissolved in CH2Cl2 (50 mL) was added dropwise
via addition funnel. Once the addition was complete, the reac-
tion was maintained at 0 °C for an additional 20 min, then
quenched with H2O (100 mL). The layers were separated and
General procedure for SOCl2-mediated oxidation of hydroxy
lactams
The preparation of 16 is representative. Compound 6b the aqueous was re-extracted with CH2Cl2 (2 × 100 mL). The
(100 mg, 0.4 mmol, 1 equiv.) was dissolved in CH2Cl2 (5 mL) combined organic layer was dried over anhydrous Na2SO4, fil-
and the resulting solution cooled to 0 °C. Thionyl chloride tered, and concentrated to afford the crude benzamide deriva-
1
(100 μL, 1.3 mmol, 3 equiv.) was added dropwise. After stirring tive (4.4 g, 80%, H NMR (300 MHz, CDCl3) δ 8.37 (dd, J = 4.4,
at 0 °C for 10 min, Et3N (0.30 mL, 2.2 mmol, 5 equiv.) was 1.6 Hz, 2H), 7.76 (dd, J = 7.1, 1.5 Hz, 2H), 7.54–7.27 (m, 3H),
added dropwise over 5 min. The reaction was maintained at 7.08 (dd, J = 4.5, 1.5 Hz, 2H), 3.67 (dd, J = 13.0, 6.9 Hz, 2H),
0 °C for 12 h, and then quenched by addition of saturated 2.90 (t, J = 7.0 Hz, 2H) 13C NMR (75 MHz, CDCl3) δ 167.9,
aqueous Na2CO3 solution. After warming to room temperature 149.6, 148.5, 134.4, 131.5, 128.5, 127.0, 124.3, 40.4, 35.0).
the layers were separated and the aqueous was re-extracted Without further purification/characterization, the benzamide
with CH2Cl2 (2 × 10 mL). The combined organic layer was (4.4 g, 19.5 mmol, 1 equiv.) was dissolved in THF (100 mL) and
dried over anhydrous Na2SO4, filtered, and concentrated under cooled to −78 °C. A solution of KHMDS (0.5 M in THF, 98 mL,
vacuum. The residue was purified via flash column chromato- 49 mmol, 2.5 equiv.) was added dropwise. After stirring at
graphy (SiO2, 70–100% EtOAc–hexanes as eluent) to give −78 °C for 1 h, allyl bromide (5.1 mL, 59 mmol, 3 equiv.) was
N-ethyl-5-hydroxy-3,4-dimethyl-5-(pyridin-4-yl)-1H-pyrrol-2(5H)- added and the reaction was maintained an additional 1 h at
one 16 (45 mg, 45%) as a brown oil. 1H NMR (500 MHz, −78 °C, and then allowed to warm to room temperature and
CDCl3) δ 8.53 (d, J = 4.3 Hz, 2H), 7.35 (d, J = 4.3 Hz, 2H), stirred overnight. The reaction was quenched with H2O and
5.52–4.86 (m, 1H), 3.42 (dq, J = 14.4, 7.2 Hz, 1H), 3.02 (dq, J = extracted with EtOAc (3 × 100 mL). The combined organic layer
14.3, 7.2 Hz, 1H), 1.82 (s, 3H), 1.66 (s, 3H), 1.00 (t, J = 7.2 Hz, was dried over anhydrous Na2SO4, filtered, and concentrated.
3H). 13C NMR (125 MHz, CDCl3) δ 171.4, 151.9, 149.6, 148.5, The residue was purified via flash column chromatography
128.9, 121.6, 91.6, 34.5, 14.7, 9.9, 8.6. IR (film) 3436, 1659, (SiO2, 50–100% EtOAC–hexanes as eluent) to afford the desired
1638, 1630 cm−1. HRMS (ESI) C13H17N2O2 [M + H]+, calculated N-allyl amide as a brown oil (4.0 g, 77%, mixture of rotamers,
233.1290; found 233.1313.
1H NMR (300 MHz, CDCl3) δ 8.70–8.32 (m, 2H), 7.56–7.03
Compound 16 (0.15 g, 57%) was also obtained when the (m, 6.6H), 7.00–6.54 (m, 0.5H), 6.06–5.51 (m, 1H), 5.40–5.01
known lactam26 19 (0.24 g, 1.1 mmol) was subjected to the (m, 2H), 4.37–3.96 (m, 0.6H), 3.94–3.31 (m, 3.5H), 3.16–2.61
conditions described above (see eqn (2)).
(m, 2H) 13C NMR (75 MHz, CDCl3) δ 171.9, 149.9, 148.2, 136.2,
N-Ethyl-3-hydroxy-3-(pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H- 133.2, 129.7, 128.5, 126.4, 124.3, 117.8, 52.5, 45.9, 32.9).
isoindol-1-one (17). Using the procedure given for the prepa- Without further characterization, the allyl amide (4.0 g,
ration of 16, 8b (100 mg, 0.4 mmol) was converted to 17 15 mmol, 1 equiv.) was dissolved in THF (100 mL) and cooled
1
(65 mg, 70%, yellow oil). H NMR (300 MHz, CDCl3) δ 8.50 (d, to 0 °C. 9-BBN (30 mL, 45 mmol, 3 equiv.) was added via
J = 6.0 Hz, 2H), 7.36 (d, J = 6.0 Hz, 2H), 5.97 (s, 1H), 3.44 (dd, syringe and the reaction was stirred at 0 °C overnight. After
J = 14.2, 7.2 Hz, 1H), 3.02 (dd, J = 14.2, 7.2 Hz, 1H), 2.37–2.06 this time, a solution prepared from 10 mL 1 M aq. NaOH and
(m, 4H), 1.72–1.43 (m, 4H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR 10 mL 30% aq. H2O2 was added and the reaction was allowed
(75 MHz, CDCl3) δ 170.8, 156.0, 149.6, 148.6, 132.0, 121.5, to warm to room temperature. The reaction was then quenched
91.2, 34.2, 22.0, 21.8, 20.62, 20.1, 14.8. IR (film) 3383, 2983, with additional H2O and extracted with EtOAc (3 × 100 mL).
2925, 2848, 1667 cm−1. HRMS (ESI) C15H19N2O2 [M + H]+, cal- The combined organic layer was dried over anhydrous Na2SO4,
culated 259.1447; found 259.1455.
filtered, and concentrated. Purification via flash column
N-Benzyl-[3,4′-bipyridin]-6(1H)-one (18). Using the pro- chromatography (SiO2, 50–100% EtOAc–hexanes as eluent)
1
cedure for the preparation of 16, compound 18 (27 mg, 30%) gave 23 as a yellow oil (3.9 g, 92%). H NMR (300 MHz, CDCl3,
was isolated as a yellow oil from 100 mg of 10b. 1H NMR mixture of rotamers) δ 8.56–8.36 (m, 2H), 7.47–7.07 (m, 6H),
(300 MHz, CDCl3) δ 8.61 (dd, J = 4.5, 1.6 Hz, 2H), 7.38–7.28 (m, 6.91–6.72 (m, 1H), 3.84–3.57 (m, 3H), 3.56–3.34 (m, 2H), 3.25
5H), 7.14 (dd, J = 4.4, 1.6 Hz, 2H), 7.08 (s, 1H), 5.18 (s, 2H), (m, 1H), 3.13–2.89 (m, 1H), 2.89–2.66 (m, 2H), 1.97–1.79 (m,
2.22 (s, 3H), 2.08 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.0, 1H), 1.79–1.55 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 173.1,
150.0, 145.8, 143.7, 136.5, 132.9, 129.0, 128.3, 128.2, 127.7, 149.9, 146.7, 136.0, 129.7, 128.7, 126.2, 124.1, 58.6, 49.8, 41.4,
124.6, 120.5, 52.6, 17.9, 13.6. IR (film) 1654, 1639, 1625 cm−1
.
34.6, 30.5. IR (film) 3266, 3063, 2928, 2867, 1607 cm−1. HRMS
H]+, calculated 285.1603; found
HRMS (ESI) C19H19N2O [M + H]+, calculated 291.1497; found (ESI) C17H21N2O2 [M
+
291.1512.
285.1598.
Tosylamide 24 was prepared in similar fashion starting
N-(3-Hydroxypropyl)-N-(2-(pyridine-4-yl)ethyl)benzamide (23)
and N-(3-hydroxypropyl)-N-(2-(pyridine-4-yl)ethyl)toluenesulfo- from 4-(2-aminoethyl)pyridine and tosyl chloride (90%, 1H
namide (24). 4-(2-Aminoethyl)pyridine (2.9 mL, 24 mmol, NMR (300 MHz, CDCl3) δ 8.41 (dd, J = 4.4, 1.6 Hz, 2H), 7.70 (d,
1.0 equiv.) was dissolved in CH2Cl2 (100 mL) and Et3N J = 8.3 Hz, 2H), 7.37–7.21 (m, 2H), 7.03 (dd, J = 4.5, 1.5 Hz,
1096 | Org. Biomol. Chem., 2014, 12, 1090–1099
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
2H), 5.32 (t, J = 6.2 Hz, 1H), 3.23 (q, J = 6.8 Hz, 2H), 2.78 (t, J =
N-Benzoyl-1,2,5,6-tetrahydro-3,4′-bipyridine (27). Cyclization
6.9 Hz, 2H), 2.43 (s, 3H) 13C NMR (75 MHz, CDCl3) δ 150.0, of 25 (100 mg) was achieved by application of previously
147.3, 143.7, 137.0, 129.9, 127.2, 124.3, 43.4, 35.6, 21.7). Allyla- reported reaction conditions26 to yield 27 (68 mg, 73%) as a
tion was performed as described above (70%, 1H NMR yellow oil. H NMR (300 MHz, CDCl3, mixture of rotamers) δ
1
(300 MHz, CDCl3) δ 8.50 (d, J = 5.8 Hz, 2H), 7.68 (d, J = 8.2 Hz, 8.71–8.41 (m, 2H), 7.54–6.90 (m, 7H), 6.55–6.43 (m, 1H),
2H), 7.30 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 5.6 Hz, 2H), 5.60 (ddt, 4.72–4.44 (m, 1.4H), 4.44–4.18 (m, 0.6H), 4.02–3.73 (m, 0.6H),
J = 16.4, 9.8, 6.5 Hz, 1H), 5.26–5.11 (m, 2H), 3.78 (d, J = 6.4 Hz, 3.73–3.27 (m, 1.4H), 2.62–2.25 (m, 2H). 13C NMR (126 MHz,
2H), 3.46–3.20 (m, 2H), 2.98–2.75 (m, 2H), 2.43 (s, 3H) 13C CDCl3) δ 171.2, 150.3, 145.8, 136.0, 132.8, 130.1, 128.8, 127.0,
NMR (75 MHz, CDCl3) δ 150.1, 147.6, 143.7, 136.7, 133.1, 125.7, 119.6, 44.1, 43.2, 26.5. IR (film) 3060, 3027, 2921, 2893,
129.9, 127.3, 124.3, 119.4, 51.4, 47.9, 35.0, 21.7). Hydrobora- 2852, 1626 cm−1. HRMS (ESI) C17H17N2O [M + H]+, calculated
tion/oxidation of the allyl tosylamide afforded 24 (90%) as a 265.1341; found 265.1334.
yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.7 Hz, 2H),
N-Tosyl-1,2,5,6-tetrahydro-3,4′-bipyridine (28). This material
7.70–7.63 (m, 2H), 7.31 (dd, J = 8.5, 0.6 Hz, 2H), 7.11 (d, J = 5.9 was obtained as a yellow oil in 72% isolated yield under pre-
Hz, 2H), 3.68 (t, J = 5.7 Hz, 2H), 3.39–3.31 (m, 2H), 3.27 (t, J = viously reported reaction conditions,26 and in 52% isolated
6.7 Hz, 2H), 2.89 (dd, J = 8.8, 6.9 Hz, 2H), 2.43 (s, 4H), yield using the TfOH-catalyzed procedure given above for the
1.77–1.61 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 150.0, 147.6, preparation of 5. 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.6,
143.8, 136.2, 130.0, 127.2, 124.3, 58.9, 49.7, 45.8, 35.3, 31.4, 1.6 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),
21.7. IR (film) 3291, 2925, 2870 cm−1
C17H23N2O3S [M + H]+, calculated 335.1429; found 335.1422.
.
HRMS (ESI) 7.18 (dd, J = 4.6, 1.7 Hz, 2H), 6.35 (tt, J = 4.0, 1.9 Hz, 1H), 3.93
(dd, J = 4.6, 2.5 Hz, 2H), 3.24 (dt, J = 6.9, 4.0 Hz, 2H), 2.48–2.38
N-(3-Oxopropyl)-N-(2-(pyridine-4-yl)ethyl)benzamide (25). (m, 5H). 13C NMR (125 MHz, CDCl3) δ 150.3, 145.7, 144.0,
Dichloromethane (40 mL) was cooled to −78 °C. Oxalyl chlor- 133.4, 131.4, 130.0, 127.8, 126.0, 119.5, 45.6, 42.3, 25.9, 21.7.
ide (0.6 mL, 7.0 mmol, 2 equiv.) and DMSO (1 mL, 14 mmol, 4 IR (film) 3026, 2917, 2852 cm−1. HRMS (ESI) C17H19N2O2S
equiv.) were added dropwise while maintaining the tempera- [M + H]+, calculated 315.1167; found 315.1170.
ture below −70 °C. After 10 min, a solution of 23 (1.0 g,
General procedure for the preparation of 2-pyridylbenzofurans
3.5 mmol, 1 equiv.) in CH2Cl2 (10 mL) was added dropwise.
Once the addition was complete the reaction was stirred an Benzofuran derivatives shown in Scheme 6 were prepared
additional 15 min followed by addition of Et3N (2 mL, using the TfOH-catalyzed procedure given for the preparation
14 mmol, 4 equiv.). The reaction was allowed to warm to 0 °C of 5. Reactions were performed using 100 mg of alkylated sali-
and stirred for 10 min. The solvent was then evaporated and cylaldehyde substrates.
the residue was purified by flash column chromatography
2-(Benzofuran-2-yl)pyridine (31).35 Yellow solid, 58%. 1H
(SiO2, 50–100% EtOAc–hexanes as eluent) to give 25 (0.4 g, NMR (300 MHz, CDCl3) δ 8.67 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H),
40%) as a yellow oil. 1H NMR (500 MHz, CDCl3 mixture of rota- 7.87 (dt, J = 8.0, 1.0 Hz, 1H), 7.78–7.70 (m, 1H), 7.64 (ddd, J =
mers) δ 9.93–9.47 (m, 1H), 8.65–8.19 (m, 2H), 7.48–6.96 (m, 7.6, 1.4, 0.7 Hz, 1H), 7.60–7.53 (m, 1H), 7.42 (d, J = 0.9 Hz, 1H),
6H), 6.96–6.53 (m, 1H), 4.02–3.22 (m, 4H), 3.15–2.43 (m, 4H). 7.37–7.28 (m, 1H), 7.28–7.17 (m, 2H). 13C NMR (75 MHz,
13C NMR (125 MHz, CDCl3) δ 200.5, 172.0, 170.5, 149.8, 149.4, CDCl3) δ 155.5, 155.2, 150.1, 149.4, 136.9, 129.0, 125.4, 123.4,
146.7, 135.9, 129.6, 128.5, 126.8, 126.2, 124.1, 123.5, 50.6, 42.6, 123.1, 121.9, 120.0, 111.7, 105.0. IR (film) 3056, 3007, 2921,
39.4, 34.6. IR (film) 2921, 2856, 1726, 1636 cm−1. HRMS (ESI) 2844, 1610, 1556 cm−1. HRMS (ESI) C13H10NO [M + H]+, calcu-
C17H19N2O2 [M + H]+, calculated 283.1447; found 283.1452.
N-(3-Oxopropyl)-N-(2-(pyridine-4-yl)ethyl)toluenesulfonamide
lated 196.0762; found 196.0754.
4-(Benzofuran-2-yl)pyridine (32). Colorless solid, 96%, 1H
(26). To a solution of 24 (1.0 g, 3.0 mmol, 1 equiv.) in CH2Cl2 NMR (300 MHz, CDCl3) δ 8.66 (d, J = 4.3 Hz, 2H), 7.67 (d, J =
(50 mL) was added the Dess–Martin periodinane (1.9 g, 5.6 Hz, 2H), 7.64–7.48 (m, 2H), 7.35 (ddd, J = 8.3, 7.3, 1.4 Hz,
4.5 mmol, 1.5 equiv.) at room temperature. After 30 min the 1H), 7.30–7.17 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 155.3,
reaction was quenched with 1 M aqueous NaOH solution 152.9, 150.3, 137.4, 128.5, 125.7, 123.4, 121.6, 118.7, 111.5,
(20 mL) and the layers were separated. The aqueous layer was 105.0. IR (film) 3081, 3034, 2928, 2852, 1610, 1541. HRMS
extracted with CH2Cl2 (2 × 30 mL) and the combined organic (ESI) C13H10NO [M + H]+, calculated 196.0762; found 196.0747.
layer was dried over anhydrous Na2SO4, filtered, and concen-
4-(3-(4-Methoxyphenyl)benzofuran-2-yl)pyridine (37). Yellow
1
trated. Purification by flash column chromatography (SiO2, solid, 92%, Mp. 105–108 °C. H NMR (300 MHz, CDCl3) δ 8.53
50–100% EtOAc–hexanes as eluent) gave 26 (0.42 g, 42%) as a (d, J = 6.0 Hz, 2H), 7.60–7.51 (m, 3H), 7.48 (dd, J = 7.8, 0.6 Hz,
yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.49 (d, J = 1H), 7.44–7.34 (m, 3H), 7.25 (t, J = 7.5 Hz, 1H), 7.09–7.00 (m,
5.8 Hz, 2H), 7.68–7.63 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 2H), 3.89 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 159.9, 154.4,
(dd, J = 4.5, 1.5 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 3.39–3.31 (m, 149.9, 147.2, 138.4, 130.9, 130.3, 126.2, 123.9, 123.5, 121.6,
2H), 2.89–2.83 (m, 2H), 2.75 (td, J = 6.8, 0.6 Hz, 2H), 2.42 (s, 120.9, 120.4, 114.9, 111.6, 55.5. IR (film) 3065, 3040, 2960,
3H). 13C NMR (101 MHz, CDCl3) δ 200.1, 149.8, 147.2, 143.8, 2915, 2841, 1603, 1516. HRMS (ESI) C20H16NO2 [M + H]+, cal-
135.7, 129.9, 127.1, 124.2, 49.7, 43.7, 42.0, 34.7, 21.5. IR (film) culated 302.1181; found 302.1169.
3291, 2925, 2870 cm−1. HRMS (ESI) C17H21N2O3S [M + H]+,
calculated 333.1265; found 333.1284.
4-(3-Methylbenzofuran-2-yl)pyridine (38). Yellow solid, 75%,
Mp. 40–45 °C. H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 4.4 Hz,
1
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1090–1099 | 1097

View Article Online
Paper
Organic & Biomolecular Chemistry
1H), 7.66–7.57 (m, 1.9H), 7.55–7.46 (m, 1H), 7.46–7.37 (m, 1H),
7.33–7.24 (m, 1H), 7.24–7.13 (m, 1H), 2.46 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 154.3, 150.2, 147.7, 138.8, 130.8, 126.0,
123.0, 120.3, 120.1, 115.9, 111.5, 9.9. IR (film) 3036, 2929,
2852, 1609, 1540. HRMS (ESI) C14H12NO [M + H]+, calculated
210.0919; found 210.0913.
5 (a) M. D. Hill, Chem.–Eur. J., 2010, 16, 12052; (b) D.-S. Kim,
J.-W. Park and C.-H. Jun, Chem. Commun., 2012, 48, 11334;
(c) M. N. Khan, S. Pal, T. Parvin and L. H. Choudhury, RSC
Adv., 2012, 2, 12305.
6 G. D. Henry, Tetrahedron, 2004, 60, 6043.
7 (a) J. A. Bull, J. J. Mousseau, G. Pelletier and A. B. Charette,
Chem. Rev., 2012, 112, 2642; (b) H. Andersson, R. Olsson
and F. Almqvist, Org. Biomol. Chem., 2011, 9, 337.
8 (a) Y. Nakao, Synthesis, 2011, 3209; (b) Q. Xiao, L. Ling,
F. Ye, R. Tan, L. Tian, Y. Zhang, Y. Li and J. Wang, J. Org.
Chem., 2013, 78, 3879; (c) B.-T. Guan, B. Wang, M. Nishiura
and Z. Hou, Angew. Chem., Int. Ed., 2013, 52, 4418;
(d) B.-T. Guan and Z. Hou, J. Am. Chem. Soc., 2011, 133,
18086; (e) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem. Soc.,
2011, 133, 6964; (f) P. Guo, J. M. Joo, S. Rakshit and
D. Sames, J. Am. Chem. Soc., 2011, 133, 16338; (g) Y. Nakao,
Y. Yamada, N. Kashihara and T. Hiyama, J. Am. Chem. Soc.,
2010, 132, 13666.
2-(3-(4-Methoxyphenyl)benzofuran-2-yl)pyridine (39). Color-
less solid, 61%, Mp. 50–53 °C. 1H NMR (300 MHz, CDCl3) δ
8.69 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H),
7.60–7.42 (m, 5H), 7.37 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H),
7.29–7.21 (m, 1H), 7.16 (ddd, J = 7.2, 4.8, 1.4 Hz, 1H),
7.06–6.98 (m, 2H), 3.88 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
159.53, 154.48, 150.1, 149.9, 149.1, 136.2, 131.2, 130.2, 125.8,
124.6, 123.3, 122.8, 122.5, 120.8, 120.6, 114.6, 111.9, 55.5. IR
(film) 3052, 2997, 2925, 2828, 1598, 1581, 1556, 1507. HRMS
(ESI) C20H16NO2 [M
302.1163.
+
H]+, calculated 302.1181; found
4-(3-Methylbenzofuran-2-yl)pyridine (40). Colorless solid,
62%, Mp. 38–41 °C. 1H NMR (300 MHz, CDCl3) δ 8.67 (ddd, J =
4.8, 1.8, 0.9 Hz, 1H), 7.85 (dt, J = 8.0, 1.0 Hz, 1H), 7.70 (td, J =
9 T. J. Donohoe, J. F. Bower and L. K. M. Chan, Org. Biomol.
Chem., 2012, 10, 1322.
7.8, 1.8 Hz, 1H), 7.56 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 7.52–7.46 10 M. Schlosser and F. Mongin, Chem. Soc. Rev., 2007, 36, 1161.
(m, 1H), 7.35–7.27 (m, 1H), 7.27–7.20 (m, 1H), 7.13 (ddd, J = 11 (a) M. Jaric, B. A. Haag, S. M. Manolikakes and P. Knochel,
7.5, 4.8, 1.2 Hz, 1H), 2.70 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
154.1, 151.5, 149.7, 149.2, 136.6, 131.3, 125.4, 122.8, 122.1,
Org. Lett., 2011, 13, 2306; (b) M. R. Luzung, J. S. Patel and
J. Yin, J. Org. Chem., 2010, 75, 8330.
121.1, 120.2, 116.0, 111.4, 9.8. IR (film) 3048, 2928, 2863, 1603, 12 M. Rueping and N. Tolstoluzhsky, Org. Lett., 2011, 13,
1585 cm−1. HRMS (ESI) C14H12NO [M + H]+, calculated
210.0919; found 210.0906.
1095.
13 J.-J. Jin, H.-Y. Niu, G.-R. Qu, H. M. Guo and J. S. Fossey,
4-(3-(4-Methoxyphenyl)benzofuran-2-yl)quinoline (42). Brown
oil, 73%. H NMR (300 MHz, CDCl3) δ 8.98 (d, J = 4.6 Hz, 1H), 14 H. Komai, T. Yishino, S. Matsunaga and M. Kanai, Org.
RSC Adv., 2012, 2, 5968.
1
8.56 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.84–7.73 (m,
2H), 7.73–7.57 (m, 3H), 7.47–7.36 (m, 1H), 7.36–7.23 (m, 2H). 15 B. Qian, S. Guo, C. Xia and H. Huang, Adv. Synth. Catal.,
13C NMR (75 MHz, CDCl3) δ 155.4, 152.9, 150.1, 149.2, 135.9,
2010, 352, 3195.
130.5, 129.8, 128.7, 127.6, 125.8, 125.5, 125.00, 123.6, 121.8, 16 B. Qian, P. Xie, Y. Xie and H. Huang, Org. Lett., 2011, 13,
120.0, 111.7, 108.8. IR (film) 3060, 3027, 2962, 2917, 2856, 2580.
1593, 1561. HRMS (ESI) C17H12NO [M + H]+, calculated 17 V. B. Graves and A. Shaikh, Tetrahedron Lett., 2013, 54, 695.
Lett., 2011, 13, 1706.
246.0919; found 246.0914.
18 F.-F. Wang, C.-P. Luo, Y. Wang, G. Deng and L. Yang, Org.
Biomol. Chem., 2012, 10, 8605.
19 R. Niu, J. Xiao, T. Liang and X. Li, Org. Lett., 2012, 14, 676.
20 S. V. N. Vuppalapati and Y. R. Lee, Tetrahedron, 2012, 68,
8286.
21 H.-Y. Li, L.-J. Xing, T. Xu, P. Wang, R.-H. Liu and B. Wang,
Tetrahedron Lett., 2013, 54, 858.
22 Y. Yan, K. Xu, Y. Fang and Z. Wang, J. Org. Chem., 2011, 76,
6849.
23 N. N. Rao and H. M. Meshram, Tetrahedron Lett., 2013, 54,
1315.
Acknowledgements
We gratefully acknowledge support from the U. S. National
Science Foundation (CHE-1265488), the Department of Chem-
istry, University of Iowa, and the Iowa Center for Research by
Undergraduates (ICRU Summer Fellowship to DPF).
24 H. M. Meshram, N. N. Rao, L. C. Rao and N. S. Kumar,
Tetrahedron Lett., 2012, 53, 3963.
Notes and references
25 For examples of transition metal-mediated functionali-
zation of 2-alkyl(aza-arenes), see: (a) D. Best, S. Kujawa and
H. W. Lam, J. Am. Chem. Soc., 2012, 134, 18193; (b) B. Qian,
S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia and H. Huang,
J. Am. Chem. Soc., 2010, 132, 3650; (c) J.-Y. Liu, H.-Y. Niu,
S. Wu, G.-R. Qu and H.-M. Guo, Chem. Commun., 2012, 48,
9723; (d) P. M. Burton and J. A. Morris, Org. Lett., 2010, 12,
5359.
1 Comprehensive Heterocyclic Chemistry, II, ed. A. R. Katritzky,
C. W. Rees and E. F. V. Scriven, Pergamon, Oxford, 1996.
2 Progress in Heterocyclic Chemistry, ed. G. W. Gribble and
J. A. Joule, Elsevier, Amsterdam, 2009.
3 Topics in Heterocyclic Chemistry, Vol. 11 – Bioactive Hetero-
cycles V, ed. R. R. Gupta, Springer, New York, 2008.
4 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679.
1098 | Org. Biomol. Chem., 2014, 12, 1090–1099
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
26 S. G. Parameswarappa and F. C. Pigge, J. Org. Chem., 2012, 32 (a) I. Kim and J. Choi, Org. Biomol. Chem., 2009, 7,
77, 8038.
2788; (b) J. Verghese, A. Liang, P. P. S. Sidhu,
M. Hindle, Q. Zhou and U. R. Desai, Bioorg. Med.
Chem. Lett., 2009, 19, 4126; (c) M. Ono, H. Kawashima,
A. Nonaka, T. Kawai, M. Haratake, H. Mori, M.-P. Kung,
H. F. Kung, H. Saji and M. Nakayama, J. Med. Chem.,
2006, 49, 2725; (d) S. Anderson, P. N. Taylor and
G. L. B. Verschoor, Chem.–Eur. J., 2004, 10, 518;
(e) J. R. Hwu, K.-S. Chuang, S. H. Chuang and
S.-C. Tsay, Org. Lett., 2005, 7, 1545; (f) T. Zawadowski
and C. Wiercinska-Radzio, Acta Pol. Pharm., 1986, 43,
207.
27 For related intramolecular transformations of alkylpyri-
dines, see: (a) J. J. Klappa, A. E. Rich and K. McNeill, Org.
Lett., 2002, 4, 435; (b) H. Ohkura, D. O. Berbasov and
V. A. Soloshonok, Tetrahedron Lett., 2003, 44, 2417.
28 Inclusion of molecular sieves in acid-catalyzed cyclization
reactions had no effect on the outcome.
29 (a) G. Büchi and G. Lukas, J. Am. Chem. Soc., 1964, 86,
5654; (b) M. Cushman and L. Cheng, J. Org. Chem., 1978,
43, 3781; (c) S. Feng, C. A. Panetta and D. E. Graves, J. Org.
Chem., 2001, 66, 612; (d) V. Terrasson, J. G. Planas, D. Prim,
C. Vinas, F. Teixidor, M. E. Light and M. B. Hursthouse, 33 I. N. Nnamani, G. S. Joshi, R. Danso-Danquah,
J. Org. Chem., 2008, 73, 9140.
30 X. Xiao, A. Morrell, P. E. Fanwick and M. Cushman, Tetra-
hedron, 2006, 62, 9705.
O. Abdulmalik, T. Asakura, D. J. Abraham and M. K. Safo,
Chem. Biodiversity, 2008, 5, 1762.
34 For example, see: L. Pawar and F. C. Pigge, Tetrahedron
Lett., 2013, 54, 6067.
31 Attempts to stop the reaction at the putative conjugated
lactam stage by reducing the amount of SOCl2 employed 35 F. Mongin, A. Bucher, J. P. Bazureau, O. Bayh, H. Awad and
were unsuccessful.
F. Trécourt, Tetrahedron Lett., 2005, 46, 7989.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1090–1099 | 1099