Studies on reactive pyridylketones formed by Weinreb transformations

Article abstract of DOI:10.1002/jhet.836

A method has been developed to allow the preparation of reactive pure vinylpyridylketones and activated vinylketones, in general, to be used in further reactions, such as cycloadditions. The process is based on the Weinreb's amide transformation and includes a quarternary ammonium intermediate and subsequent elimination. Additionally, based on our previous results on the malonate alkylation of 3-nitropyridines and subsequent synthetic applications, we present the studies on the transformation of pyridyl malonate derivative 3 via the Weinreb's amide 4 and reactive methylpyridyl- (17) and allylpyridyl-ketone (6) into bis-heterocyclic products 18 and 19, and 8, 20, and 21, respectively.

Full text of DOI:10.1002/jhet.836

May 2012
Studies on Reactive Pyridylketones Formed
by Weinreb Transformations
613
Vegar Stockmann, Svein Jacob Kaspersen,
Alexander Nicolaisen, and Anne Fiksdahl*
Department of Chemistry, Norwegian University of Science and Technology, NTNU, N-7491
Trondheim, Norway
*
E-mail: anne.fiksdahl@chem.ntnu.no
Received October 1, 2010
DOI 10.1002/jhet.836
View this article online at wileyonlinelibrary.com.
A method has been developed to allow the preparation of reactive pure vinylpyridylketones and activated
vinylketones, in general, to be used in further reactions, such as cycloadditions. The process is based on the
Weinreb’s amide transformation and includes a quarternary ammonium intermediate and subsequent
elimination. Additionally, based on our previous results on the malonate alkylation of 3-nitropyridines and
subsequent synthetic applications, we present the studies on the transformation of pyridyl malonate
derivative 3 via the Weinreb’s amide 4 and reactive methylpyridyl- (17) and allylpyridyl-ketone (6) into
bis-heterocyclic products 18 and 19, and 8, 20, and 21, respectively.
J. Heterocyclic Chem., 49, 613 (2012).
INTRODUCTION
resonance effect and the electron-withdrawing pyridine
moiety.
Aromatic alkylation methods are essential in organic
synthesis since more complex carbon skeletons can be
constructed. We have previously reported the nucleophilic
aromatic substitution (NAS) [1–3] of the nitro group in
Our approach for the preparation of the seven-membered
cyclic products 7 and the tricyclic product 9 was based on
RCM of the vinyl-vinyl and vinyl-allyl moieties of
compounds 5 and 8, prepared from pyridyl malonate (2)
via diester 3, Weinreb’s amide 4 and subsequent Weinreb
ketone transformations (Scheme 1) [13,14]. 7-Allyl-6-
vinylisoquinolinolol 8 would be obtained by an intramo-
lecular regioselective aldol cyclization of diallylketone 6.
However, some challenging effects were observed by
the transformation of Weinreb’s amide 4 into the reactive
divinyl- and diallyl-ketones 5 and 6. Further investigations
were needed to identify the formed products and preferably
establish suitable methods for the handling and application
of such reactive pyridyl ketones. The results of the studies
are discussed below.
3
-nitropyridyl carboxylate (1) with malonate (Scheme 1).
The versatility of the 3-pyridylmalonate product 2 was
demonstrated by subsequent transformations to give new
fused bis-heterocycles.
The initial target of this project was the preparation
of the two potentially biological active pyridoisotropolone
analogue 7 and cyclopenta[g]isoquinolinol 9 from pyridyl
malonate 2 (Scheme 1). Tropolones are widespread natural
products with a broad range of anti-bacterial, anti-fungal,
anti-tumor, and insecticide effects [4,5], whereas cyclopen-
taisoquinoline compounds, similar to product 9, have
been prepared as cancer chemotherapeutic agents [6–9].
The acidity and properties of the cyclopentadienide ion
of similar cyclopentaphenanthrenes have been studied
RESULTS AND DISCUSSION
[10–12]. Thus, derivatives of compound 9 would show
Weinreb’s amides, N-methoxy-N-methyl amides,
pronounced acidity due to the strong anionic stabilizing
formed by ester aminolysis [15], are useful intermediates
©
2012 HeteroCorporation

6
14
V. Stockmann, S. J. Kaspersen, A. Nicolaisen, and A. Fiksdahl
Vol 49
Scheme 1
Scheme 3
in organic synthesis, as they react efficiently with organo-
metallic agents, such as Grignard reagents, to selectively
produce ketones. A corresponding two-step procedure
allowed a direct allylation of carboxylic acids [16]. We
applied a more efficient process, using the modified
studied. By the conversion of intermediate 12 with
vinylMgBr, the formed vinylketone 13 was directly
trapped in situ by the present amine leaving group and
the corresponding —N(OMe)Me Michael product (14a)
was isolated (70%).
Me AlCl/MeONHMeꢀHCl reagent system [17] for the
2
preparation of Weinreb’s amide 4 (74%) from homochin-
chomeric acid dimethyl ester 3, readily obtained (89%)
by microwave (MW) promoted mono-decarboxylation of
pyridyl malonate 2 (Scheme 1) [3].
Furthermore, the corresponding amine products 14b—d
(64—89%) were formed by in situ trapping of the vinyl-
ketone 13 with dibutylamine, piperidine, or morpholine,
respectively, added to the reaction mixture. To enable
the formation of a stable and pure solution of the reac-
tive vinylpyridylketone 13, the isolated amine products
Vinylpyridylketone.
The ketone transformation of
Weinreb’s amide 4 into divinylketone (5) intermediate for
the preparation of pyridoisotropolone 7 (Scheme 1) did
not take place. The reaction resulted in a tarry and hardly
soluble material, and no products were isolated or
identified. The highly reactive vinylpyridylketone 5 may
react in several ways. Because of pyridyl activation,
instant mono or double Michael additions of present
potential nucleophiles, such as the amine leaving group,
NHMe(OMe), to the vinylketone groups of 5 would lead
to a mixture of unwanted intermediates and products.
Compounds, such as 10a or 10b, were not observed, but
illustrate the potential reactivity of vinylpyridylketone 5
1
4a—d were converted into quarternary ammonium
intermediates (15a—d) by reaction with methyl iodide
Scheme 3). In situ amine elimination afforded the desired
(
vinylketone 13. The dibutylamine intermediate 14b gave
full conversion to the vinylketone 13 in 10 h, as shown
by NMR of the reaction mixture. A solution of vinylketone
1
1
3 in CDCl (61%, Scheme 4), pure by H-NMR, was
3
obtained after repeated washing with water and final
argon-flush to remove excess MeI. The yield was deter-
1
mined by H-NMR with 1,2,4,5-tetrachlorobenzene as an
(Scheme 2). The direct synthesis of such b-aminoketones
internal standard. Low to moderate conversion (5—55%)
of amines 14a,c,d into vinylketone 13 was obtained through
their respective quarternary ammonium compounds 15a,c,d.
To demonstrate the utility of the reactive vinylpyri-
dylketone 13 in subsequent synthetic transformations,
from Weinreb’s amides via sequential nucleophilic vinyl
substitution and Michael reaction is well known [18,19].
To develop a practical and selective preparation method
for reactive vinylpyridylketones and activated vinylketones
in general, the transformations of Weinreb’s amide 12,
obtained from methyl isonicotinate (11, Scheme 3), was
Scheme 4
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Studies on Reactive Pyridylketones Formed by Weinreb Transformations
615
Scheme 5
the stable and pure solution of vinylketone 13 was
treated with cyclopentadiene to undergo a Diels-Alder
cycloaddition (Scheme 4). The bicyclo[2.2.1]heptenyl
product 16 was isolated in excellent yield (92% from
vinylketone 13; 56% from amine 14b). The endo isomer
was exclusively formed, as confirmed by 2D NMR, as
NOESY effects between H2 and H7, and between pyri-
dine-H3/-H5 and H6, were observed, excluding the exo
product. No traces of the exo-isomer could be observed.
The developed method was not successful for the
generation of divinylketone 5 from Weinreb’s amide 4,
probably due to competing cyclization reactions, as dis-
cussed below for allylpyridylketone 6.
Allylpyridylketone. The transformation of Weinreb’s
amide 4 with allylmagnesium bromide (Scheme 5) gave a
mixture of cyclization products via the initially formed
diallylketone (6). To identify these new heterocyclic
compounds, the MeMgBr conversion of amide 4 and,
hence, the formation of dimethyldiketone intermediate
workup. Such cyclocondensations are well known from
the preparation of 2H- and 4H-pyran natural product
from 1,5-diketone precursors [20—22].
The reaction of Weinreb’s amide 4 with allylMgBr gave
a crude mixture mainly affording isoquinolinol 8 (13%),
analogues to compound 18 discussed above, and the
corresponding aldol precursor, the ethylidene compound
20, by adding NaOH (5M) to the solution and thus extrac-
tion from an alkalic solution. Product 8 (11%) was also
obtained by quenching with an NH Cl solution and final
4
extraction. The aldol precursor compound 20 (26%),
and minor amounts of the hemiketal 21 (6%), similar to
product 19 above, were isolated as well. The hemiketal
21 was later isolated in higher yield (21%) by quenching
with an ice-cold solution of NH Cl. The conjugated addi-
4
tion of a methoxy group to the exocyclic double bond in
0
product 20, giving methoxy-product 20 , confirmed the
keto-ethylidene structure of 20. Separate experiments
showed that aromatization and ethylidene-vinyl isomeriza-
tion and, hence, full conversion of 20 into 8 could be
1
7 (Scheme 5) was chosen as a less complex reaction to
study the Grignard transformations of Weinreb’s amide 4.
The formed cyclic products were dependant on the
workup procedures. The MeMgBr conversion of amide
performed by treatment of 20in CDCl with p-TsOH in
3
10 hours. Alternative treatments with HCl (1—5M) or
NaOH (3—5M) were not successful, mainly affording
the elimination product without any ethylidene-vinyl
isomerization. We were, however, not able to develop op-
timized conditions allowing direct conversion of Weinreb’s
amide 4 into the desired compound 8 as the major product.
The identity of the vinyl-allyl-isoquinolinol product
8 was confirmed by HMBC, HSQC, and NOESY NMR
4
afforded the isoquinolinol product 18 (56%), formed
by regioselective intramolecular aldol condensation of
diketone 17, by quenching the reaction with water and
subsequent alkalic treatment of the crude product. The
hemiketal 19 (64%), formed by O-acylation of diketone
1
7, was obtained as the main product after NH Cl
4
Journal of Heterocyclic Chemistry
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6
16
V. Stockmann, S. J. Kaspersen, A. Nicolaisen, and A. Fiksdahl
Vol 49
Scheme 6
experiments. In particular, the NOESY results supported
the regioselective aldol reaction and structure 8, as a
through-space proximity of H8 with both H1 and the
EXPERIMENTAL
General. Solvents: pro analysi quality. Dry solvents were
collected from a MB SPS-800 solvent purification system. All
air and moisture sensitive reactions were performed under argon
atmosphere in predried glassware. NMR: Bruker Avance DPX
allylic CH group was observed. The isolation of small
2
amounts of compound 8 was laborious, and the compound
was never isolated in sufficient amounts to permit a final
RCM for the preparation of 9 (Scheme 1).
1
13
3
00 and 400 MHz spectrometers. H and C chemical shifts
are reported in ppm downfield from TMS. J values are given in
Hz. ms: Finnigan MAT 95 XL (ei/70 eV). ESI-MS accurate
mass determination was performed on a waters QTOF II
instrument. IR: Nicolet 20SXC FT-IR spectrophotometer. IR
spectra were recorded using a Smart Endurance reflexion cell,
unless KBr or film is specified. All melting points are
uncorrected and were recorded on a Stuart apparatus. Flash
chromatography: SiO2 (sds, 60 Å, 40—63 mm). Dimethyl
homochinchomeric acid diester (3) was prepared from methyl
3-nitro-4-pyridinecarboxylate (1) according to the ref. 3.
The conclusive structure elucidations of isoquinolinol
8
and the cyclic diallylhemiketal 21 were based on com-
parative studies of the fully characterized products 18
and 19, respectively. In particular, the unambiguous
1
3
C-NMR data correlations in pairs between 8/18 and
9/21 were significant.
1
Attempts to develop a one-pot procedure for the for-
mation of allyl-vinyl-isoquinolinol 8, applying allyl-MgCl
both to generate the Me(MeO)NMgCl reagent [15] and
to convert the formed Weinreb’s amide 4 into di-allyl
product 6, were unsuccessful. Polyallylation of the
most reactive carbonyl group mainly took place (22
and 24, 24—32%, Scheme 6). Minor amount of the oxi-
dative nucleophilic substitution product 23 was also
observed [23].
N-Methoxy-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-N-
methylisonicotinamide (Weinreb’s amide 4). MeONHMeꢀHCl
ꢁ
(
2.30 g, 23.6 mmol) in CH Cl (80 mL) was cooled to 0 C and
2
2
2
added Me AlCl (23.6 mL, 23.6 mmol, 1M in hexanes) dropwise.
The mixture was stirred for 1.5 h before it was allowed to warm
to room temperature. The diester 3 (990 mg, 4.7 mmol) in CH Cl
20 mL) was added dropwise. The reaction mixture was stirred at
room temperature for 8 h, and then quenched with a borate buffer
pH 8, 100 mL). After extraction with CH Cl
(3ꢂ 60 mL),
drying over Na SO evaporation of solvent and flash
chromatography (5% MeOH/CH Cl ), the title compound 4 was
2
2
(
(
2
2
2
4
,
CONCLUSIONS
2
2
1
obtained as a transparent oil, 938 mg (74%), pure by H-NMR; IR
A method was developed to enable the preparation
of reactive pure vinylpyridylketones (e.g., 13) from
Weinreb’s amides (e.g., 4), including formation of a
b-aminoketone (e.g., 14a-d), quarternary ammonium
intermediates (e.g., 15a-d) and subsequent elimina-
tion. The utility of the reactive vinylketone 13 in
further synthesis was demonstrated by the application
in Diels-Alder cycloaddition with cyclopentadiene to
give the endo-bicyclo[2.2.1]heptenyl product (16, 92%
from 13).
The transformation of pyridyl malonate derivative 2
via diester 3, Weinreb’s amide 4 and the reactive
allylpyridylketone intermediate 6 into cyclization pro-
ducts was studied. The in situ formation of the cyclic
aldol products 8 and 20 and the O-acylation hemiketal
pyrano-compound 21 from diallylketone 6 took place.
The analogous dimethyldiketone 17 formed, correspond-
ingly, hemiketal 19 and the aldol cyclization product
(
9
film): 3535, 2972, 2938, 1672, 1592, 1493, 1419, 1385, 1177,
98, 844 cm ; H-NMR (400 MHz, CDCl ): d 8.55 (s, 1H,
3 H
ꢃ1
1
H2), 8.52 (d, J = 4.8 Hz, 1H, py-H6), 7.33 (d, J = 4.8 Hz, 1H,
py-H5), 3.93 (s, 2H, CH ), 3.77 (s, 3H, CH —CO—N—OCH ),
3.56 (s, br, 3H, py—CO—N—OCH
N—CH
CDCl ): d
2
2
3
), 3.26 (s, br, 3H, py—CO—
3
13
3
), 3.14 (s, CH
171.6 (CH
2
—CO—N—CH
3
); C-NMR (100 MHz,
—C=O), 152.4
3
C
2
—C=O), 168.2 (py—CH
2
(
(
C2), 148.1 (C6), 142.6 (C4), 128.5 (C3), 121.4 (C5), 61.8/61.4
2ꢂ N—OCH ), 34.0 (CH ), 32.6 (2ꢂ N—CH3); NMR
3
2
assignments are based on HSQC and HMBC experiments; ESI-
HRMS: calcd. for [M + H]
268.1293.
+
12 18 3 4
C H N O : 268.1297; observed
N-Methoxy-N-methylisonicotinamide (12).
compound was prepared as described above for Weinreb’s
amide 4, using MeONHMeꢀHCl (1.09 g, 11.2 mmol) in CH Cl
80 mL), Me AlCl (11.2 mL, 11.2 mmol, 1M in hexanes) and
ester 11 (1.02 g, 7.44 mmol) in CH Cl (10 mL). Product 12
was obtained after flash chromatography (2.5% CH Cl /MeOH)
The title
2
2
(
2
2
2
2
2
as a yellow oil (1.10 g, 89%), pure by NMR; R 0.15 (5%
MeOH/CH Cl ); IR: 2936w, 1644s, 1405m, 1382m, 980m,
8
f
2
2
ꢃ1
1
1
8, essential for the structure elucidation of the analo-
32m, 702m, 630m cm
3 H
; H-NMR (400 MHz, CDCl ): d
gous products 8 and 21.
8.71 (dd, 2H, J = 4.4, 1.6 Hz, H2/H6), 7.52 (dd, 2H, J = 4.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Studies on Reactive Pyridylketones Formed by Weinreb Transformations
617
1
.6 Hz, H3/H5), 3.54 (s, 3H, OMe), 3.36 (s, 3H, N—Me),
C-NMR (100 MHz, CDCl ): d 167.5 (C=O), 149.8 (C2, C6),
Hz, 2H, CO—CH ), 3.08 (t, J = 6.8 Hz, 2H, CH —N), 2.62
2 2
1
3
13
(s, 3H, NMe); C-NMR (100 MHz, CDCl ): dC 198.5 (C=O),
3
C
3
1
41.6 (C4), 121.9 (C3, C5), 61.3 (OMe), 33.0 (NMe); NMR
150.9 (py—C2/C6), 142.8 (py—C4), 121.0 (py—C3/C5), 59.8
assignments are based on HMBC and HSQC experiments ESI-
2 2
(OMe), 55.2 (CH —N), 45.0 (N—Me), 36.6 (CO—CH );
+
HRMS: calcd. for [M + H]
C
8
H
11
N
2
O
2
: 167.0815; observed
NMR assignments are based on HMBC and HSQC
+
1
67.0817.
-(Pyridin-4-yl)prop-2-en-1-one (13). Amine 14b (40 mg,
.152 mmol) in CDCl (5 mL) was added MeI (95 mL, 1.53
experiments; ESI-HRMS: calcd. for [M + H] C H N O
1
0
15
2
2
1
95.1128; observed 195.1126.
1
0
3
3-(Dibutylamino)-1-(pyridin-4-yl)propan-1-one (14b).
A
mmol) and stirred for 12 h at room temperature. The solution
stirred solution of Weinreb’s amide 12 (400 mg, 2.41 mmol) in
ꢁ
was washed with water (3ꢂ 3 mL) and dried over Na SO .
dry THF (15 mL) at ꢃ78 C was added vinylmagnesium
2
4
Argon was bobbled through the solution to remove excess of
MeI and the solution was used directly in the next step to form
Diels Alder adduct 16. Quantification was based on 1,2,4,5-
bromide (3.61 mL, 3.61 mmol, 1M in THF). The reaction was
allowed to warm to room temperature and stirred for 1 h.
Dibutylamine (4.1 mL, 24 mmol) was added to the mixture,
tetrachlorobenzene as internal standard; 13 was obtained in 61%
followed by the dropwise addition of H O (1 mL) over 10 min.
2
1
yield in a CDCl solution, pure by NMR; H-NMR (400 MHz,
Addition of water (50 mL), extraction with diethyl ether (3ꢂ 30
3
CDCl
dd, J = 4.4, 1.6 Hz, 2H, py—H3/H5), 7.07 (dd, J = 17.2, 10.8
Hz, 1H, CO—CH=), 6.48 (dd, J = 17.2, 1.2 Hz, 1H, =CH ),
.01 (dd, J = 10.8, 1.2 Hz, 1H, =CH H ); C-NMR (100 MHz,
3
): d
H
8.82 (dd, J = 4.4, 1.6 Hz, 2H, py—H2/H6); 7.70
2 4
mL), drying over Na SO , evaporation of solvent, and flash
(
3
chromatography [4% Et N in EtOAc/pentane (1:2)] afforded the
a
H
b
title compound 14b as a pale yellow oil, 453 mg (72%), pure by
NMR; R 0.24 [4% Et N in EtOAc/pentane (1:2)]; IR: 2955m,
1
3
6
a
b
f
3
ꢃ1
1
CDCl ): dC 190.5 (C=O), 150.8 (py—C2/C6), 143.3 (py—C4),
2930m, 1694s, 1407m, 1220w, 773w, 655m cm
(400 MHz, CDCl ): d 8.81 (dd, J = 4.4, 1.6 Hz, 2H, py—H2/
H6), 7.72 (dd, J = 4.4, 1.6 Hz, 2H, py—H3/H5), 3.10 (t, J =
7.6 Hz, 2H, CO—CH ), 2.90 (t, J = 7.6 Hz, 2H, CH —N), 2.43
(t, J = 7.2 Hz, 4H, Bu—H1), 1.39 (m, 4H, Bu—H2), 1.27 (m,
H, Bu—H3), 0.90 (t, J = 7.2 Hz, 6H, Bu—H4); C-NMR
100 MHz, CDCl ): d 199.4 (C=O), 150.9 (py—C2/C6), 142.9
(py—C4), 121.0 (py—C3/C5), 53.8 (Bu—C1), 48.9 (CH —N),
7.0 (CO—CH ), 29.2 (Bu—C2), 20.6 (Bu—C3), 14.0 (Bu—
; H-NMR
3
1
32.2 (—CH=), 131.7 (=CH
2
), 121.6 (py—C3/C5); NMR
3
H
assignments are based on HMBC and HSQC experiments; ESI-
+
HRMS: calcd. for [M + H]
34.0602.
endo-Bicyclo[2.2.1]hept-5-en-2-yl(pyridin-4-yl)methanone
16). To the stirred solution of vinylketone 13 in CDCl was
C
8
H
8
NO 134.0600; observed
2
2
1
13
4
(
3
C
(
3
ꢁ
2
added freshly distilled cyclopentadiene (100 mL) at ꢃ10 C. The
reaction was stirred for 2 h and allowed to warm to room
temperature. Evaporation of solvent and flash chromatography
3
2
C4); NMR assignments are based on HMBC and HSQC
+
experiments; ESI-HRMS: calcd. for [M + H]
263.2118; observed 263.2114.
16 27 2
C H N O
[
EtOAc/pentane (1:1)] afforded product 16 as a white solid, 17
ꢁ
mg (56% from 14b, 92% from 13), mp: 59—60 C, pure by
NMR; Rf 0.30 [EtOAc/pentane (1:1)]; IR: 2972w, 1681s,
3-(Piperidin-1-yl)-1-(pyridin-4-yl)propan-1-one (14c).
ꢃ1
1
1
411m, 1227m, 1218m, 848s, 717s, 685s, 654s cm
NMR (400 MHz, CDCl ): d 8.80 (dd, J = 4.4, 1.6 Hz, 2H,
py—H2/H6), 7.72 (dd, J = 4.4, 1.6 Hz, 2H, py—H3/H5), 6.20
dd, J = 5.6, 3.2 Hz, 1H, H5), 5.78 (dd, J = 5.6, 2.8 Hz, 1H,
H6), 3.79 (app. dt, J = 8.8, 4.0 Hz, 1H, H2), 3.25 (app. br s,
H, H1), 2.99 (app. br s, 1H, H4), 1.98 (ddd, J = 11.6, 8.8, 3.6
Hz, 1H, exo-H3), 1.62 (ddd, J = 11.6, 4.4, 2.4 Hz, 1H, endo-
;
H-
The title compound was prepared as described above for 14b,
using Weinreb’s amide 12 (106.6 mg, 0.641 mmol) in dry
THF (5 mL), vinylmagnesium bromide (1.22 mL, 1.22 mmol,
1M in THF) and piperidine (1.21 mL, 12.2 mmol). Flash
chromatography (5% MeOH/CH Cl ) afforded the title
3
H
(
2
2
1
compound 14c as a pale brown oil, 124.5 mg (89%), pure by
NMR; R 0.15 (5% MeOH/CH Cl ); IR (film): 3044w, 2935s,
2852m, 2799m, 1697s, 1555w, 1408s, 735m cm
(400 MHz, CDCl ): d 8.81 (d, J = 4.4, 1.6 Hz, 2H, py—
f
2
2
1
3
ꢃ1
1
H3), 1.50 (m, 2H, H7); C-NMR (100 MHz, CDCl
00.5 (C=O), 151.1 (py—C2/C6), 143.6 (py—C4), 137.9
C5), 131.6 (C6), 121.5 (py—C3/C5), 50.2 (C7), 48.2 (C2),
7.1 (C1), 43.1 (C4), 29.0 (C3); NMR assignments are
based on HSQC, HMBC, and NOESY experiments; ESI-
3
): d
C
; H-NMR
2
(
4
3
H
H2/H6), 7.73 (d, J = 4.4, 1.6 Hz, 2H, py—H3/H5), 3.18 (t, J
= 7.2 Hz, 2H, CO—CH ), 2.79 (t, J = 7.2 Hz, 2H, CH —
2
2
pip), 2.44 (s, 4H, pip—H2/H6), 1.58 (m, 4H, pip—H3/H5),
+
13
HRMS: calcd. for [M + H]
00.1065.
-(Methoxy(methyl)amino)-1-(pyridin-4-yl)propan-1-one
14a). A solution of Weinreb’s amide 12 (323 mg, 1.94
C
13
H
14NO 200.1070; observed
1.44 (m, 2H, pip—H4); C-NMR (100 MHz, CDCl
3 C
): d
2
198.9 (C=O), 150.9 (py—C2/C6), 142.8 (py—C4), 121.0
(
(
py—C3/C5), 54,6 (pip—C2/C6), 53.4 (CH —pip), 36.8
CO—CH2), 25.9 (pip—C3/C5), 24.2 (pip—C4); NMR
2
3
(
assignments are based on HMBC and HSQC experiments;
mmol) in dry THF (15 mL) was added vinylmagnesium
+
ESI-HRMS: calcd. for [M + H]
observed 219.1495.
13 19 2
C H N O: 219.1492;
bromide (3.89 mL, 3.89 mmol, 1M in THF) dropwise at
ꢁ
ꢃ78 C under argon atmosphere. The reaction mixture was
stirred for 60 min before it was allowed to warm to room
temperature, and stirred for an additional 2 h. Quenching with
3-(Morpholino)-1-(pyridin-4-yl)propan-1-one (14d). The
title compound was prepared as described above for 14b, using
Weinreb’s amide 12 (240 mg, 1.45 mmol) in dry THF (10 mL),
vinylmagnesiumbromide (2.12 mL, 2.17 mmol, 1M in THF)
and morpholine (1.26 mL, 14.5 mmol). After flash
an NH
4
Cl solution (15 mL, sat.), extraction with EtOAc (3ꢂ
5
0 mL), drying over Na SO , evaporation of solvent and flash
2
4
chromatography (5% MeOH/CH Cl ) afforded product 14a as
2
2
a light brown oil, 263 mg (70%), pure by NMR; R
MeOH/CH Cl ); IR: 2938w, 1694s, 1408m, 1209m, 1045s,
91m, 787m, 656m cm
.82 (dd, J = 4.4, 1.6 Hz, 2H, py—H2/H6), 7.74 (dd, J = 4.4,
.6 Hz, 2H, py—H3/H5), 3.45 (s, 3H, OMe), 3.24 (t, J = 6.8
f
0.24 (5%
chromatography (10% MeOH/CH
was obtained as a yellow oil, 229.3 mg (72%), pure by NMR;
0.30 (10% MeOH/CH Cl ); IR: 2953w, 2852w, 1694s,
2 2
Cl ), the title compound 14d
2
2
ꢃ1
1
9
8
1
;
H-NMR (400 MHz, CDCl
3
): d
H
R
f
2
2
ꢃ1
1
1408m, 1114s, 988m, 870m, 769m, 663m cm ; H-NMR (400
MHz, CDCl ): d 8.82 (dd, J = 4.4, 1.6 Hz, 2H, py—H2/H6),
3
H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

6
18
V. Stockmann, S. J. Kaspersen, A. Nicolaisen, and A. Fiksdahl
Vol 49
7
.72 (dd, J = 4.4, 1.6 Hz, 2H, py—H3/H5), 3.70 (t, J = 4.4 Hz,
chromatography [EtOAc/pentane (1:1)] allowed the isolation
4
H, morph-H2/H6), 3.19 (t, J = 7.2 Hz, 2H, CO—CH ), 2.83 (t,
of compounds 8, 20, and 21.
2
J = 7.2 Hz, 2H, CH
2
—N-morph), 2.50 (t, J = 4.0 Hz, 4H,
morph-H3/H5); C-NMR (100 MHz, CDCl ): d 198.4 (C=O),
50.9 (py—C2/C6), 142.6 (py—C4), 120.9 (py—C3/C5), 66.8
morph-C2/C6), 53.6 (morph-C3/C5), 53.0 (CH —N-morph),
7
-Allyl-6-vinylisoquinolin-5-ol (8).
The title compound
13
3
C
8
was obtained as a yellow oil, 31 mg (11%), pure by
H-NMR; R 0.26 [EtOAc/pentane (1:1)]; IR (KBr): 3074w,
2976w, 2922w, 2800w br, 1623m, 1579s, 1566m, 1394s,
1
1
(
f
2
ꢃ1
1
3
6.3 (CO—CH ); NMR assignments are based on HMBC and
2
1260s, 1180s, 1038s, 1024m, 921s, 847m cm
400 MHz, CDCl ): d 9.12 (s, 1H, H1), 8.49 (d, J = 5.6 Hz,
H, H3), 7.95 (d, J = 5.6 Hz, 1H, H4), 7.35 (s, 1H, H8), 6.84
(dd, J = 18.4, 11.6 Hz, 1H, vinyl; CH=CH ), 6.31 (br s, 1H,
OH), 6.01 (m, 1H, allyl; CH=CH ), 5.88 (dd, J = 11.6, 1.6
Hz, 1H, vinyl; CH=CH ), 5.71 (dd, J = 18.4, 1.6 Hz, 1H,
vinyl; CH=CH ), 5.14 (m, 1H, allyl; CH=CH ), 5.04 (m,
1H, allyl; CH=CH ), 3.49 (m, 2H, allyl —CH
(100 MHz, CDCl ): d 151.3 (C1), 147.3 (C5), 142.2 (C3),
137.8 (C7) 135.8 (allyl; CH=), 132.1 (vinyl; CH=), 128.5
(C8a), 125.7 (C4a), 122.4 (vinyl; =CH ), 122.2 (C6), 118.5
(C8), 116.8 (allyl; =CH ), 115.4 (C4), 38.2 (allyl; CH —);
; H-NMR
+
HSQC experiments; ESI-HRMS: calcd. for [M
221.1285; observed 221.1288.
-Methylisoquinolin-5-ol (18). To a stirred solution of
+ H]
(
1
3
H
12 17 2 2
C H N O
7
2
Weinreb’s amide 4 (60.0 mg, 0.224 mmol) in dry THF at
2
ꢁ
ꢃ78 C MeMgBr (1.0 mL, 1.0 mmol, 1M in butyl ether) was
a b
H
added dropwise. The reaction was allowed to heat to room
temperature and stirred for 2 h. Then, EtOAc (10 mL), brine (10
a
H
b
a b
H
1
3
H
); C-NMR
a
b
2
mL), and H O (5 mL) were added. After extraction with EtOAc
3
C
2
(
3ꢂ 10 mL), the combined organic phase was dried over
Na SO and concentrated under reduced pressure. An aqueous
2
2
4
solution of Na
and the mixture was stirred over night. Extraction with EtOAc
3ꢂ 10 mL), drying over Na SO , concentration under reduced
2
CO
3
(15 mL, sat.) was added to the brown oil
2
2
NMR assignments are based on NOESY, HSQC, and HMBC
experiments; EI-MS: m/z 212 (M , 100%).
+
(
2
4
pressure and flash chromatography (gradient; 2.5—5% MeOH/
7-Allyl-6-ethylidene-7-hydroxy-7,8-dihydroisoquinolin-5(6H)-
one (20). The title compound 20 was obtained as a red solid 80
mg (26%), pure by H-NMR; R 0.20 [EtOAc/pentane (1:1)]; IR
CH
2
Cl
2
) gave the title compound 18 as a white solid, 20 mg
ꢁ
1
(
56%), mp > 215 C (decomp), pure by NMR; R
f
0.18 (5%
f
MeOH/CH
2
Cl
2
); IR: 3400—2400br, 1588m, 1396s, 1350m,
(KBr): 3400br, 3074w, 2931w, 1678s, 1615m, 1416s, 1354m,
1247m, 1067m, 917m, 846m, 729m cm ; H-NMR (400 MHz,
ꢃ1
1
ꢃ1
1
1
1
281s, 1037m, 832s cm ; H-NMR (400 MHz, DMSO-d ): d
0.39 (s, 1H, OH), 9.10 (s, 1H, H1), 8.36 (d, J = 5.6 Hz, 1H,
6
H
CDCl ): d 8.65 (d, J = 5.2 Hz, 1H, H3), 8.60 (s, 1H, H1), 7.84
3
H
H3), 7.84 (d, J = 5.6 Hz, 1H, H4), 7.30 (s, 1H, H8), 6.93 (s,
(d, J = 5.2 Hz, 1H, H4), 6.63 (q, J = 7.2 Hz, 1H, =CH—CH3),
1
3
1
H, H6), 2.43 (s, 3H, —CH
3
); C-NMR (100 MHz, DMSO-
5.85—5.73 (m, 1H, CH=CH ), 5.19 (m, 1H, allyl =CH H ),
2
a b
d
6
): d 152.1 (C5), 151.1 (C1), 141.1 (C3), 137.7 (C7), 129.5
C
a b a b
5.06 (m, 1H, allyl =CH H ), 3.16 (br s, 1H, H8; CH H ), 3.15
(
(
C8a), 125.3 (C4a), 116.6 (C8), 114.8 (C4), 113.9 (C6), 21.6
a b 2
(br s, 1H, H8; CH H ), 2.4—2.2 (m, 2H, allyl—CH ), 2.17
13
—CH ); NMR assignments are based on HMBC, HSQC, and
(d, J = 7.2 Hz, 3H, CH3); C-NMR (100 MHz, CDCl ): dC
3
3
+
NOESY experiments; ESI-HRMS: calcd. for [M
10NO 160.0757; observed 160.0759.
+
H]
188.5 (C=O), 150.9 (C1), 148.7 (C3), 140.9/138.7/133.3 (C4a,
C
10
H
C6, C8a), 137.9 (=CH—CH ),132.1 (allyl—CH=CH ), 120.4/
3
2
1
19.6 (C4, allyl =CH
2
), 74.6 (C7), 43.9 (allyl—CH
2
—CH=),
1
,3-Dimethyl-1H-pyrano[4,3-c]pyridin-1-ol
(19).
A
3
9.7 (C8), 15.8 (=CH—CH
3
); NMR assignments are based on
solution of Weinreb’s amide 4 (36 mg, 0.14 mmol) in dry THF
2 mL) was added methylmagnesium bromide (0.4 mL, 0.4
HSQC and HMBC experiments.
(
ꢁ
mmol, 1M in butyl ether) dropwise at ꢃ78 C. The reaction
1,3-Diallyl-1H-pyrano[4,3-c]pyridin-1-ol (21).
The title
mixture was allowed to heat to room temperature and stirred for
compound 21 was obtained as a yellow oil, 20 mg (6%), pure
by H-NMR. Product 21 was, correspondingly, obtained in
1
3
h before a solution of NH
4
Cl (10 mL) was added. The
aqueous solution was extracted with diethyl ether (3ꢂ 15 mL).
21% by addition of a precooled NH
4
Cl solution to the reaction
ꢁ
After drying over Na SO , evaporation of solvent and flash
mixture kept at ꢃ78 C. R
f
0.40 [EtOAc/pentane (1:1)]; IR
(film): 3404br, 3076w, 2977w, 2918w, 1744w, 1638m,
2
4
chromatography (2.5% MeOH/CH Cl ), the title compound 19
2
2
1
was obtained as a yellow oil, 15 mg (64%), pure by NMR; H-
NMR (400 MHz, CDCl ): d 9.20 (s, 1H, py—H2), 8.63 (d, J
5.6 1H, py—H6), 7.81 (d, 1H J = 5.6 Hz, py—H5), 7.45 (s,
1618w, 1572s, 1481m, 1427w, 1376w, 1152w, 995m, 915s,
ꢃ1
1
859m cm ; H-NMR (400 MHz, CDCl ): d 9.24 (s, 1H,
3
H
3 H
=
py—H2), 8.62 (d, J = 6.0 Hz, 1H, py—H6), 7.85 (d, J = 6.0
Hz, 1H, py—H5), 7.49 (s, 1H, pyrano—H4), 6.2—6.1 (m, 2H,
13
1
H, pyran—CH=C), 2.94 (s, 3H, CH ), 2.71 (s, 3H, CH ); C-
3 3
NMR (100 MHz, CDCl ): d 158.0/152.4/131.2/127.4 (py—
C3, —C4, pyran—C1, —C3), 151.9 (py—C2), 143.7 (py—C6),
2ꢂ allyl CH=CH
4.07 (m, 2H, 1-pyrano-allyl; CH(OH)—CH
3.77 (m, 2H, 3-pyrano-allyl; =C—CH =CH); C-NMR
(100 MHz, CDCl ): d 159.2/154.6/131.5/127.4 (py—C3, —
2
), 5.25—5.15 (m, 4H, 2ꢂ allyl CH=CH
2
),
—CH=),
3
C
a b
H
1
3
1
17.6 (py—C5), 115.5 (pyran—CH=), 24.4 (Me), 21.7 (Me);
H
a b
NMR assignments are based on HMBC and HSQC
3
C
+
experiments; ESI-HRMS: calcd. for [M + H] H OꢀC H NO
C4, pyran—C1, —C3), 152.3 (py—C2), 143.9 (py—C6),
2
10 10
1
60.0757; observed 160.0758.
135.5/135.0 (2ꢂ allyl —CH=), 117.4 (py—C5), 117.2/117.1
(
2ꢂ allyl=CH
2
), 115.5 (pyran—CH=C), 42.5 (3-pyran-
Preparation of 8, 20, and 21.
A solution of Weinreb’s
allyl; =C—CH —CH=), 39.9 (1-pyran-allyl; CH(OH)—CH —
2
2
amide 4 (355 mg, 1.328 mmol) in dry THF (5 mL) was
ꢁ
CH=); NMR assignments are based on HSQC and HMBC
experiments.
cooled to ꢃ78 C, and allylmagnesium bromide (3.45 mL,
3
.45 mmol, 1M in ether) was added dropwise. The reaction
ꢁ
was stirred for 2 h at ꢃ78 C and allowed to heat to room
Formation of 8 by isomerization of 20. An NMR sample
of 20 (10 mg) in CDCl was added crystalline p-TsOH (2 mg)
3
temperature. NH
mixture was extracted with EtOAc (3ꢂ 40 mL). The
combined organic extracts were dried over Na SO , and the
solvent was removed under reduced pressure. Flash column
4
Cl (15 mL, sat.) was added and the
and left at room temperature. The isomerization was monitored
1
2
4
by H-NMR and TLC. Full conversion of 20 into 8, pure by
1
H-NMR, was obtained after 10 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Studies on Reactive Pyridylketones Formed by Weinreb Transformations
619
0
13
7
-Allyl-6-(1-methoxyethyl)isoquinolin-5-ol(20 ). A sample
3-py-side-chain; 2ꢂ C—CH ); C-NMR (100 MHz, CDCl3):
2
of 20 (20 mg, 0.08 mmol) in MeOH (5 mL) was added
crystalline NaOMe (∼30 mg) and stirred over night at room
temperature. Quenching with an NH Cl solution (15 mL),
4
d 155.6 (C=O), 152.1 (py—C2), 146.3 (py—C6), 139.9 (py—
C
C4), 135.6 (4-py-side-chain; CH=C), 133.2 (2-py-side-chain;
CH=C), 129.8 (3-py-side-chain; 2ꢂ CH=C), 125.3 (py—C3),
extraction with EtOAc (3ꢂ 20 mL), drying over Na
2 4
SO , and
119.3 (3-py-side-chain; 2ꢂ CH
2
=C), 118.5 (py—C5), 118.4 (2-
0
evaporation of solvent afforded product 20 (20 mg, 98%), pure
by NMR; IR (film): 3271br, 2928s, 1635m, 1581s, 1462m,
py-side-chain; CH =C), 118.4 (4-py-side-chain; CH =C), 96.5
2
2
(3-py—CH=), 81.6 (3-py—CH=C), 42.4 (3-py-side-chain; 2ꢂ
CH —CH=CH ), 38.8 and 39.2 (2- and 4-py-side-chain; CH
CH=CH ); NMR assignments are based on HMBC experiments;
ꢃ1
1
1
9
1
403s, 1286m, 1109m cm ; H-NMR (400 MHz, CDCl
.26 (br s, OH), 9.15 (s, 1H, H1), 8.50 (br s, 1H, H3), 8.00 (br s,
H, H4), 7.29 (s, 1H, H8), 6.0—6.1 (m, 1H, allyl—CH=), 5.17
): d
3 H
2
2
2
—
2
+
EI-MS: m/z 293 (M , 3%), 268 (2), 252 (100), 234 (3), 210 (5),
(
dd, J = 10.4, 1.6 Hz, 1H, allyl=CH H ), (d, J = 17.2, 1.6 Hz,
167 (9), 154 (5); EI-HRMS: calcd. for C H NO; 293.1780;
a
b
20 23
1
H, allyl—CH
a
H
b
), 4.91 (q, J = 6.8 Hz, 1H, CH—OMe), 3.48
), 3.41 (s, 3H, OMe), 1.58 (d, J
observed 293.1764.
(
d, J = 5.6 Hz, 2H, allyl—CH
2
4-(3-(2-Allyl-2-hydroxypent-4-enyl)pyridin-4-yl)hepta-1,6-dien-
1
3
=
6.8 Hz, 1H, CH—Me); C-NMR (100 MHz, CDCl
): d
3 C
4-ol (24).
IR: 3346m, 3000s (br), 3071w, 2976w, 2924w,
1
1
50.9 (C1), 141.9 (C3), 136.5 (allyl—CH=), 151,2/136.6/129.0/
27.2/122.6 (C4a, C5, C6, C7, C8a), 119.2 (C8), 116.9
2840w 1640s, 1598s, 1490w, 1438s, 1405s, 1270s, 1150m,
ꢃ1
1
1075m, 1045s, 987s, 912s, 845m cm
CDCl ): d 8.36 (d, J = 5.2 Hz, 1H, py-H6), 8.27 (s, 1H, py-
H2), 7.06 (d, J = 5.2 Hz, 1H, py-H5), 5.86 (m, 2H, 3-py-side-
chain; 2ꢂ CH=CH ), 5.68 (m, 2H, 4-py side-chain; 2ꢂ
CH=CH ), 5.38 (s, br, 1H, 3-py side-chain; OH), 5.21 (m, 1H,
; H-NMR (400 MHz,
(
(
allyl=CH
allyl—CH
2
), 115.1 (C4), 78.0 (CH—OMe), 57.4 (OMe), 37.4
—), 20.8 (Me); NMR assignments are based on
3
H
2
HSQC and HMBC experiments.
2
Preparation of 22, 23, and 24. A solution of diester 3 (300
mg, 1.44 mmol) and Me(MeO)NHꢀHCl (330 mg, 3.3 mmol) in
2
3
-py-side-chain; =CHH), 5.19 (m, 1H, 3-py-side-chain; =CHH),
ꢁ
5.18 (m, 1H, 3-py-side-chain; =CHH), 5.16 (m, 1H, 3-py-side-
chain; =CHH), 5.02 (m, 2H, 4-py side-chain; 2ꢂ =CHH), 5.00
dry THF (30 ml) at ꢃ5 C was added allylMgCl (6 mL, 12
mmol, 2M in THF) over 2 h. The reaction mixture was kept
(
m, 1H, 4-py-side-chain; =CHH), 4.98 (m, 1H, 4-py-side-chain;
stirring for 20 h, and then HCl (10 mL, 10%) was added. pH 9
was obtained by addition of a NaHCO solution. The products
=
CHH), 3.26 (s, 2H, 3-py—CH ), 2.77 (s, br, 1H, 4-py side-
2
3
chain; OH), 2.65 (dd, J = 14.0, 7.2 Hz, 2H, 4-py side-chain;
2
2 (94 mg, 26%), 23 (12 mg, 3%), and 24 (108 mg, 24%) were
2
ꢂ CHH), 2.54 (dd, J = 14.0, 7.6 Hz, 2H, 4-py side-chain;
isolated by extraction and flash chromatography [EtOAc/
pentane (1:6)]. Correspondingly, only product 22 (32%) was
2
ꢂ CHH), 2.38 (dd, J = 14.0, 7.2 Hz, 2H, 3-py side-chain;
ꢁ
2ꢂ CHH), 2.23 (dd, J = 14.0, 7.6 Hz, 2H, 3-py side-chain;
isolated from an experiment carried out at ꢃ15 C for only 2 h,
13
2
1
2
ꢂ CHH); C-NMR (100 MHz, CDCl ): d 155.1 (py—C2),
using 3 (200 mg, 0.95 mmol), Me(MeO)NHꢀHCl (220 mg, 2.2
mmol), and allylMgCl (1.1 mL, 2.2 mmol, 2M in THF) in dry
THF (30 mL).
3
C
54.4 (py—C4), 147.5 (py—C6), 133.4 (4-py-side-chain;
ꢂ CH=C), 133.2 (3-py-side-chain; 2ꢂ CH=C), 131.0 (py—
C3), 122.6 (py—C5), 119.9 (3-py-side-chain; 2ꢂ CH
2
=C),
1
-(3-(2-Allylpenta-1,4-dienyl)pyridin-4-yl)but-3-en-1-one (22).
1
1
19.0 (4-py-side-chain; 2ꢂ CH =C), 78.4 (4-py—C—OH), 73.8
H-NMR (400 MHz, CDCl ): d 8.31 (d, J = 5.2 Hz, 1H, py—H6),
2
3
H
(
3-py—CH —C—OH), 48.1 (3-py-side-chain; 2ꢂ CH —
8
.15 (s, 1H, py—H2), 6.81 (d, J = 5.2 Hz, 1H, py—H5), 5.88
), 5.72 (m, 1H, 4-py-side-chain; CH=CH ),
.52 (s, 2H, 3-py-side-chain; 2ꢂ CH=C), 5.20 (m, 1H, 4-py-
2
2
(
m, 1H, CH=CH
2
2
CH=CH
2 2 2
), 43.9 (4-py-side-chain; 2ꢂ CH —CH=CH ), 39.6
5
2
(3-py—CH ); NMR assignments are based on APT, HMBC,
side-chain; =CHH), 5.16 (m, 1H, 4-py-side-chain; =CHH),
.07 (m, 2H, 3-py-side-chain; =CHH), 5.06 (m, 1H, 3-py-
side-chain; =CHH), 5.03 (m, 1H, 3-py-side-chain; =CHH),
2
and HSQC experiments and D O exchange; ms: m/z 313
+
5
(M , 22%), 273 (8), 246 (10), 186 (57), 171 (18), 157 (29), 127
(31), 125 (83), 91 (34), 44 (100).
2
.92 (dd, J = 6.0, 1.2 Hz, 2H, 4-py-side-chain; C—CH2),
.65 (dd, J = 7.2, 1.0 Hz, 4H, 3-py-side-chain; 2ꢂ C—CH );
C-NMR (100 MHz, CDCl ): d 156.2 (C=O), 148.3 (py—
2
2
13
3
C
REFERENCES AND NOTES
C6), 144.9 (py—C2), 140.1 (py—C4), 133.4 (4-py-side-chain;
CH=C), 133.2 (3-py-side-chain; 2ꢂ CH=C), 127.8 (py—C3),
[1] Holt, J.; Tjosås, F.; Bakke, J.; Fiksdahl, A. J Heterocycl Chem
2004, 41, 987.
1
20.1 (py—C5), 119.3 (3-py-side-chain; 2ꢂ CH =C), 118.5
2
2
(
4-py-side-chain; CH
=C), 96.3 (3-py—CH=), 81.8 (3-py—
[2] Tjosås, F.; Fiksdahl, A. Molecules 2006, 11, 130.
[
[
3] Tjosås, F.; Fiksdahl, A. Tetrahedron 2007, 63, 11893.
4] Saniewski, M.; Saniewska, A.; Kanlayanarat, S. Acta Hortic
CH=C), 42.6 (3-py-side-chain; 2ꢂ CH —CH=CH ), 38.8 (4-
2
2
2 2
py-side-chain; CH —CH=CH ); NMR assignments are based
2
007, 755, 133.
[5] Bentley, R. Nat Prod Rep 2008, 25, 118.
6] Kundu, N. G.; Nandi, B.; Chang, J.; Boehme, P. H. J. Indian
Chem Soc 1997, 74, 877.
on APT, HMBC, and HSQC experiments; EI-MS: m/z 253
+
(
M , 4%), 212 (100), 193 (9), 170 (14), 167 (9), 154 (8),
[
1
2
42 (33), 130 (8), 115 (17); EI-HRMS: calcd. for C H NO;
17 19
53.1467; observed 253.1469.
-(2-Allyl-3-(2-allylpenta-1,4-dienyl)pyridin-4-yl)but-3-en-1-
[7] Kundu, N. G.; Wright, J. A.; Perlman, K. L.; Hallett, W.;
1
Heidelberger, C. J Med Chem 1975, 18, 395.
1
one (23).
H, py—H6), 6.72 (d, J = 4.8 Hz, 1H, py—H5), 6.04 (m, 1H,
CH=CH ), 5.90 (m, 1H, CH=CH ), 5.73 (m, 2H, 2ꢂ CH=CH ),
H-NMR (400 MHz, CDCl
3
): d
H
8.27 (d, J = 4.8 Hz,
[8] Pandey, R. C.; Toussaint, M. W.; Stroshane, R. M.; Kalita, C.
C.; Aszalos, A. A.; Garretson, A. L.; Wei, T. T.; Byrne, K. M.;
Geoghegan, R. F., Jr.; White, R. J. J Antibiot 1981, 34, 1389.
1
2
2
2
[
9] Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J
Am Chem Soc 1988, 110, 6471.
10] Yoshizawa, K.; Yahara, K.; Taniguchi, A.; Yamabe, T.;
5
=
.60 (s, 1H, 3-py—CH=C), 5.22 (m, 1H, =CHH), 5.17 (m, 1H,
CHH), 5.13 (m, 1H, =CHH), 5.09 (m, 1H, =CHH), 5.07 (m,
[
2
3
6
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