Synthesis of pyridines from ketoximes and terminal alkynes via C-H bond functionalization

Article abstract of DOI:10.1021/jo202280e

An expedient one-pot rhodium catalyzed C-H bond functionalization/ electrocyclization/dehydration procedure has been developed for the synthesis of highly substituted pyridine derivatives from terminal alkynes and α,β-unsaturated ketoximes. The use of electron-deficient phosphite ligands is important to suppress dimerization of the terminal alkynes to enynes.

Full text of DOI:10.1021/jo202280e

Note
pubs.acs.org/joc
Synthesis of Pyridines from Ketoximes and Terminal Alkynes via C−H
Bond Functionalization
Rhia M. Martin,† Robert G. Bergman,*,‡ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: An expedient one-pot rhodium catalyzed C−H
bond functionalization/electrocyclization/dehydration proce-
dure has been developed for the synthesis of highly substituted
pyridine derivatives from terminal alkynes and α,β-unsaturated
ketoximes. The use of electron-deficient phosphite ligands is
important to suppress dimerization of the terminal alkynes to enynes.
he modular synthesis of highly substituted nitrogen
heterocycles is an important area of research due to
tion. For example, ketoxime 1a and 1-hexyne provided pyridine
products in high yield as a 3:1 mixture of regioisomers 2a and
3a when P(O-i-Pr)3 was used as the ligand (entry 1, Table 1).
Different Rh−ligand stoichiometries were evaluated with 2
equiv of the phosphite providing optimal results (entries 1 and
2).17 At 105 °C, comparable yields and regioselectivities were
observed for THF, toluene, and cyclopentyl methyl ether
(CPME) as solvents (entries 1, 3, and 4). Because we
anticipated that higher temperatures might be required for
the electrocyclization and dehydration steps for more hindered
coupling partners, the reaction was also performed at 135 °C
and resulted in nearly identical yields and regioselectivity (entry
5). Moreover, lower catalyst loading (1 mol % of the Rh
precatalyst) and fewer equivalents of alkyne (1.5 equiv) gave
similar yields and regioselectivity at this higher temperature
(entries 6 and 7). A ligand screen composed of other
phosphites and phosphoramidites such as P(OPh)3, P(O-t-
Bu)3, P(O-i-Pr)2NEt2, and P(O-i-Pr)2N-i-Pr2 with varying steric
and electronic properties was undertaken; however, none
proved to be superior to the simple and inexpensive P(O-i-Pr)3
in terms of yield or regioselectivity (see Supporting
Information).
We next sought to evaluate the substrate scope for the
preparation of differentially substituted pyridine products using
a variety of α,β-unsaturated oximes (Table 2). The ketoxime
starting material lacking either α- or β-substitution provided the
disubstituted pyridine product 2b,c in moderate yield as a
single regioisomer.18 Ketoximes with only α-substitution gave
pyridines in good yields and with good to high regioselectivities
that ranged from 2.3:1 to a single regioisomer depending on the
structure of the α-substituent (2c−f and 3d−f). Ketoximes with
only β-substitution resulted in pyridine products with generally
lower regioselectivities (2g−j and 3g−j). It is noteworthy that
cyclic ketoximes (2k,l and 3k,l) and ketoximes substituted with
T
their prevalence in natural products and drugs. In particular,
pyridines are the most extensively used nitrogen heterocycles in
pharmaceutical research.1−3 We have previously reported an
efficient synthesis of highly substituted pyridines from α,β-
unsaturated imines and alkynes.4 In this sequence, rhodium-
catalyzed C−H alkenylation of the imine is followed by in situ
electrocylization to afford a dihydropyridine, which can be
aromatized to the corresponding pyridine in one pot (Scheme
1). Additionally, the Cheng group reported an analogous
synthesis from α,β-unsaturated ketoximes and alkynes where
dehydration occurs in situ after electrocyclization to provide the
corresponding pyridine directly (Scheme 1).5 However, for
neither method, with the exception of phenylacetylene, were
terminal alkynes competent substrates.
Numerous transition-metal-mediated head-to-head dimeriza-
tions of alkynes have been developed as an atom-economical
and expedient route to enynes, which are present in natural
products and serve as handles for further synthetic elabo-
ration.6−12 Unfortunately, the very facility with which terminal
alkynes dimerize has rendered their application as coupling
partners problematic for a variety of transition-metal-mediated
functionalizations.13−16 In our previous attempts to employ
terminal alkynes as coupling partners for pyridine synthesis
alkyne dimerization proved competitive with the desired
functionalization for both α,β-unsaturated N-benzylimines and
oximes.2 Herein, we report an effective method for the
synthesis of highly substituted pyridines via the C−H bond
functionalization of α,β-unsaturated ketoximes with terminal
alkynes through the use of inexpensive triisopropyl phosphite as
a key ligand for minimizing alkyne homocoupling side
reactions.
In performing a ligand screen, we serendipitously discovered
that phosphites and phosphoramidites provided an active Rh-
catalyst system for the desired C−H alkenylation, while
suppressing the undesired competing terminal alkyne dimeriza-
Received: November 10, 2011
Published: February 14, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Synthesis of Pyridines via Rhodium-Catalyzed C−H Bond Functionalization
a
Table 1. Reaction Optimization
b
entry
[RhCl(coe)2]2 (mol %)
P(OiPr)3 (mol %)
solvent
yield (%)
ratio 2a:3a
1
2
3
4
5
5
5
5
5
1
5
10
20
10
10
20
4
THF
81
92
75
83
92
84
92
2.9:1
3.2:1
2.6:1
3.1:1
2.9:1
2.4:1
2.3:1
THF
toluene
CPME
THF
c
5
c
6
c,d
THF
7
20
THF
a
b
All reactions were performed by employing 0.05 mmol of ketoxime 1a and 0.25 mmol of 1-hexyne. Yields determined by 1H NMR relative to 2,6-
c
d
dimethoxytoluene as an internal standard. 135 °C. 1.5 equiv of 1-hexyne.
both aromatic and branched and unbranched alkyl groups were
all well tolerated. Under our standard conditions, aldoximes
proved to be challenging substrates, consistent with Cheng’s
report on coupling internal alkynes,5 necessitating higher
reaction temperatures and resulting in diminished yield (2m
and 3m).
Terminal alkyne scope was also quite reasonable (Table 3).
Both phenylacetylene and benzylacetylene reacted to give a
single pyridine regioisomer in good yield (4a, 4b). In addition,
α- and β-branched terminal alkynes coupled in high yields and
with reasonable regioselectivities (4c,d and 5c,d, respectively).
Additionally, the use of internal alkynes afforded pyridines 6a
and 6b in high yield (eq 1 and 2).
In summary, we have developed a one-step synthesis of
pyridines by rhodium-catalyzed C−H bond functionalization of
α,β-unsaturated ketoximes with terminal alkynes. This affords
substituted pyridines in moderate to excellent regioselectivities
through the use of triisopropyl phosphite as a simple and
inexpensive ligand that suppresses the undesired competitive
dimerization of terminal alkynes. The use of phosphite ligands
may also prove useful for suppressing competitive terminal
alkyne dimerization for other Rh(I)-catalyzed transformations
of alkynes.
EXPERIMENTAL SECTION
General Procedure for Pyridine Synthesis. The desired alkyne
(2.5 mmol) was placed in a sealable glass vessel in an inert atmosphere
box. To the reaction vessel was added [RhCl(coe)2]2 (21.8 mg,
■
19
0.025 mmol, 5 mol %) dissolved in 1 mL of THF, triisopropyl
phosphite (25.2 mg, 0.050 mmol, 20 mol %) dissolved in 1 mL of
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Note
a
Table 2. Substrate Scope of Oxime
a
All reactions were performed by heating ketoxime 1 (1 equiv), alkyne (5 equiv), [RhCl(coe)2]2 (5 mol %), and P(O-i-Pr)3 (20 mol %) in THF (0.1
M) in a sealed tube for 24 h at 135 °C. Yields represent isolated material. When a mixture of isomers is indicated, yields correspond to the combined
b
c
yield of both isomers. Major isomer isolated; ratio determined by NMR analysis of the crude material. 48 h at 175 °C.
a
from the inert atmosphere box, and heated in a 135 °C oil bath for 24
Table 3. Substrate Scope of Terminal Alkynes
h. The reaction vessel was then allowed to cool to ambient
temperature and opened and the solvent removed in vacuo. The
resulting oil was dissolved in 10 mL of CH2Cl2 and washed with 10
mL of 0.1 M NaOH. The aqueous layer was extracted with CH2Cl2 (2
× 10 mL). The combined organic layers were dried over Na2SO4, and
the solvents were removed in vacuo. The residue was purified by
column chromatography on silica gel.
5-Butyl-2,3,4-trimethylpyridine (2a) and 6-Butyl-2,3,4-trime-
thylpyridine (3a). 3-Methyl-3-pentene-2-one oxime (68.0 mg) and 1-
hexyne (0.29 mL) were subjected to the standard procedure with
purification by chromatography (10:1:0.01 hexanes/tert-butyl methyl
ether/triethylamine). 5-Butyl-2,3,4-trimethylpyridine was obtained in
1
56% yield (49 mg, 0.27 mmol) as a brown oil: H NMR (CDCl3) δ
8.02 (s, 1H), 2.57−2.48 (m, 2H), 2.44 (s, 3H), 2.16 (s, 3H), 2.15 (s,
3H), 1.51−1.40 (m, 2H), 1.34 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C
NMR (CDCl3) δ 154.1, 146.6, 143.5, 134.0, 130.0, 33.0, 31.1, 23.4,
22.8, 15.4, 15.3, 14.1; HRMS (ES+) calcd for C12H19N (M + H)+
178.1590, found 178.1589. 6-Butyl-2,3,4-trimethylpyridine was
obtained in 17% yield (15 mg, 0.09 mmol) as a brown oil: 1H
NMR (CDCl3) δ 6.77 (s, 1H), 2.69−2.62 (m, 2H), 2.48 (s, 3H), 2.22
(s, 3H), 2.14 (s, 3H), 1.64 (m, 2H), 1.37 (m, 2H), 0.92 (m, 3H); 13C
NMR (CDCl3) δ 158.6, 155.9, 145.9, 127.4, 122.1, 38.0, 32.8, 23.3,
23.0, 20.3, 14.7, 14.3; HRMS (ES+) calcd for C12H19N (M + H)+
178.1590, found 178.1589.
5-Butyl-2,3-dimethylpyridine (2b). 3-Methyl-3-buten-2-one
oxime (60.0 mg) and 1-hexyne (0.29 mL) were subjected to the
standard procedure. 5-Butyl-2,3-dimethylpyridine was purified by
chromatography (20:1:0.01 hexanes/ethyl acetate/triethylamine) in
39% yield (29 mg, 0.20 mmol) as a brown oil: H NMR (CDCl3) δ
8.14 (s, 1H), 7.21 (s, 1H), 2.56−2.50 (m, 2H), 2.45 (s, 3H), 2.25 (s,
a
b
c
See footnote a in Table 2. 48 h. Ratio determined by NMR analysis
of the crude material.
THF, the desired oxime (0.500 mmol) dissolved in 1 mL of THF, and
finally 2 mL of THF. The reaction vessel was then sealed, removed
1
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Note
3H), 1.60−1.52 (m, 2H), 1.34 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13
C
HRMS (ES+) calcd for C11H17N (M + H)+ 164.1434, found 164.1429.
6-Butyl-2,4-dimethylpyridine was obtained in 9% yield (7 mg, 0.05
mmol) as a brown oil: 1H NMR (CDCl3) δ 6.77 (d, J = 6.3 Hz, 2H),
2.73−2.66 (m, 2H), 2.48 (s, 3H), 2.26 (s, 3H), 1.66 (m, 2H), 1.38 (m,
3H), 0.93 (t, J = 7.4 Hz, 4H); 13C NMR (CDCl3) δ 162.0, 157.7,
147.7, 121.7, 120.8, 38.5, 32.7, 24.6, 23.0, 21.2, 14.3; HRMS (ES+)
calcd for C11H17N (M + H)+ 164.1434, found 164.1431.
NMR (CDCl3) δ 154.5, 146.6, 137.5, 135.6, 131.0, 33.7, 32.4, 22.5,
22.3, 19.4, 14.1; HRMS (ES+) calcd for C10H15N (M + H)+ 150.1277,
found 150.1274.
5-Butyl-2,3-dimethylpyridine (2c). 3-Buten-2-one oxime (51.4
mg) and 1-hexyne (0.29 mL) were subjected to the standard
procedure. 5-Butyl-2,3-dimethylpyridine was purified by chromatog-
raphy (20:1:0.01 hexanes/ethyl acetate/triethylamine) in 54% yield
(45 mg, 0.27 mmol) as a brown oil: 1H NMR (CDCl3) δ 8.30 (d, J =
2.0 Hz, 1H), 7.37 (dd, J = 7.9, 2.0 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H),
2.58−2.53 (m, 2H), 2.50 (s, 3H), 1.57 (m, 2H), 1.34 (m, 2H), 0.91 (t,
J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ 155.8, 149.4, 136.6, 135.1,
123.1, 33.7, 32.6, 24.2, 22.5, 14.2; HRMS (ES+) calcd for C11H17N (M
+ H)+ 164.1434, found 164.1430.
5-Butyl-2-methyl-4-isopropylpyridine (2h). 5-Methyl-3-hexen-
2-one oxime (77.0 mg) and 1-hexyne (0.29 mL) were subjected to the
standard procedure. 5-Butyl-2-methyl-4-isopropylpyridine was purified
by chromatography (20:1:0.01 hexanes/tert-butyl methyl ether/
1
triethylamine) in 46% yield (45 mg, 0.23 mmol) as a brown oil: H
NMR (CDCl3) δ 8.20 (s, 1H), 6.98 (s, 1H), 3.09 (m, 1H), 2.65−2.53
(m, 2H), 2.49 (s, 3H), 1.57−1.46 (m, 3H), 1.39 (m, 3H), 1.21 (d, J =
6.8 Hz, 7H), 0.94 (t, J = 7.2 Hz, 4H); 13C NMR (CDCl3) δ 156.1,
155.9, 150.1, 132.2, 119.9, 34.1, 29.8, 28.6, 24.4, 23.6, 22.9, 14.2;
HRMS (ES+) calcd for C13H21N (M + H)+ 192.1747, found 192.1744.
5-Butyl-2-methyl-4-phenylpyridine (2i) and 6-Butyl-2-meth-
yl-4-phenylpyridine (3i). 4-Phenyl-3-buten-2-one oxime (97.6 mg)
and 1-hexyne (0.29 mL) were subjected to the standard procedure
with purification by chromatography (10:1:0.01 hexanes/tert-butyl
methyl ether/triethylamine). 5-Butyl-2-methyl-4-phenylpyridine and
6-butyl-2-methyl-4-phenylpyridine were obtained as a 1.6:1 mixture in
53% yield (60 mg, 0.27 mmol) as a brown oil: 1H NMR (MHz,
CDCl3) δ 8.39 (s, 1H), 7.62−7.58 (m, 1.25H), 7.47−7.34 (m, 4.25H),
7.29−7.25 (m, 2.63H), 7.16 (d, J = 4.2 Hz, 1.25H), 6.97 (s, 1H),
2.86−2.78 (m, 2H), 2.61−2.52 (m, 6H), 1.73 (m, 2H), 1.47−1.34 (m,
4H), 1.19 (m, 2H), 0.95 (t, J = 7.4 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H);
13C NMR (CDCl3) δ 162.8, 158.4, 155.7, 150.4, 149.8, 149.2, 139.8,
5-Butyl-3-ethyl-2-methylpyridine (2d). 3-Ethyl-3-pentene-2-
one oxime (68.0 mg) and 1-hexyne (0.29 mL) were subjected to
the standard procedure. 5-Butyl-3-ethyl-2-methylpyridine was purified
by column chromatography (10:1:0.01 hexanes/tert-butyl methyl
ether/triethylamine) in 50% yield (44 mg, 0.25 mmol) as a brown
1
oil: H NMR (CDCl3) δ 8.18 (s, 1H), 6.90 (s, 1H), 2.58−2.51 (m,
2H), 2.45 (s, 3H), 2.24 (s, 2H), 1.55−1.47 (m, 2H), 1.37 (m, 2H),
0.93 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ 155.8, 149.5, 145.5,
133.8, 124.9, 32.7, 30.1, 24.1, 22.9, 18.9, 14.2; HRMS (ES+) calcd for
C12H19N (M + H)+ 178.1590, found 178.1588.
5-Butyl-3-isopropyl-2-methylpyridine (2e) and 6-Butyl-3-
isopropyl-2-methylpyridine (3e). 3-Isopropyl-3-pentene-2-one
oxime (77.0 mg) and 1-hexyne (0.29 mL) were subjected to the
standard procedure with purification by chromatography (10:1:0.01
hexanes/tert-butyl methyl ether/triethylamine). 5-Butyl-3-isopropyl-2-
methylpyridine was obtained in 62% yield (60 mg, 0.31 mmol) as a
brown oil: 1H NMR (CDCl3) δ 8.13 (s, 1H), 7.30 (s, 1H), 3.11−3.01
(m, 1H), 2.58−2.47 (m, 5H), 1.59−1.50 (m, 2H), 1.38−1.15 (m, 8H),
0.90 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ 152.9, 146.0, 141.5,
136.0, 133.2, 33.7, 32.8, 29.3, 23.1, 22.6, 21.6, 14.1; HRMS (ES+)
calcd for C13H21N (M + H)+ 192.1747, found 192.1750. 6-Butyl-3-
isopropyl-2-methylpyridine was obtained in 10% yield (10 mg, 0.05
mmol) as a brown oil: 1H NMR (CDCl3) δ 7.41 (d, J = 7.9 Hz, 1H),
6.94 (d, J = 7.9 Hz, 1H), 3.09 (m, 1H), 2.75−2.68 (m, 2H), 2.54 (s,
3H), 1.71−1.61 (m, 2H), 1.44−1.35 (m, 2H), 1.21 (d, J = 6.9 Hz,
6H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 159.0, 155.2,
138.8, 133.2, 120.5, 38.2, 32.7, 29.2, 23.3, 23.0, 22.4, 14.3; HRMS (ES
+) calcd for C13H21N (M + H)+ 192.1747, found 192.1746.
139.2, 132.6, 129.2, 129.0, 128.7, 128.6, 128.0, 127.3, 124.1, 118.8,
118.0, 38.7, 33.5, 32.7, 29.8, 24.9, 24.1, 22.9, 22.6, 14.3, 14.0; HRMS
(ES+) calcd for C16H19N (M + H)+ 226.1590, found 226.1587.
5-Butyl-2-ethyl-4-methylpyridine (2j) and 6-Butyl-2-ethyl-4-
methylpyridine (3j). 4-Penten-3-one oxime (68.0 mg) and 1-hexyne
(0.29 mL) were subjected to the standard procedure with purification
by chromatography (20:1:0.01 hexanes/ethyl acetate/triethylamine).
5-Butyl-2-ethyl-4-methylpyridine was obtained in 49% yield (44 mg,
0.25 mmol) as a brown oil: 1H NMR (CDCl3) δ 8.17 (s, 1H), 6.86 (s,
1H), 2.69 (m, 2H), 2.55−2.47 (m, 2H), 2.22 (s, 3H), 1.53−1.42 (m,
2H), 1.38−1.29 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.3 Hz,
3H); 13C NMR (CDCl3) δ 161.0, 149.5, 145.6, 133.9, 123.6, 32.6,
31.0, 30.1, 22.9, 19.0, 14.3, 14.2; HRMS (ES+) calcd for C12H19N (M
+ H)+ 178.1590, found 178.1587. 6-Butyl-2-ethyl-4-methylpyridine
5-Butyl-3-ethyl-2-methylpyridine (2f) and 6-Butyl-3-ethyl-2-
methylpyridine (3f). 3-Phenyl-3-pentene-2-one oxime (97.6 mg)
and 1-hexyne (0.29 mL) were subjected to the standard procedure
with purification by chromatography (10:1:0.01 hexanes/tert-butyl
methyl ether/triethylamine). 5-Butyl-3-phenyl-2-methylpyridine was
1
was obtained in 20% yield (18 mg, 0.10 mmol) as a brown oil: H
NMR (CDCl3) δ 6.78 (d, J = 4.7 Hz, 2H), 2.73 (m, 4H), 2.28 (s, 3H),
1.72−1.62 (m, 2H), 1.38 (m, 2H), 1.27 (t, J = 8.5 Hz, 3H), 0.93 (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3) δ 163.1, 162.0, 147.7, 121.0, 120.2,
38.5, 32.7, 31.7, 23.0, 21.3, 14.6, 14.3; HRMS (ES+) calcd for C12H19N
(M + H)+ 178.1590, found 178.1588.
1
obtained in 36% yield (41 mg, 0.18 mmol) as a brown oil: H NMR
(CDCl3) δ 8.35 (s, 1H), 7.44 (m, 2H), 7.38 (d, J = 7.5 Hz, 1H), 7.36−
7.30 (m, 3H), 2.62 (t, J = 7.7 Hz, 2H), 2.49 (s, 3H), 1.67−1.57 (m,
2H), 1.39 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ
153.3, 148.4, 140.6, 137.6, 136.9, 135.6, 129.4, 128.7, 127.7, 33.8, 32.6,
23.3, 22.7, 14.3; HRMS (ES+) calcd for C16H19N (M + H)+ 226.1590,
found 226.1588. 6-Butyl-3-phenyl-2-methylpyridine was obtained in
3-Butyl-2-methyl-5,6,7,8-tetrahydroisoquinoline (2k) and 2-
Butyl-2-methyl-5,6,7,8-tetrahydroisoquinoline (3k). 1-Acetyl-1-
cylohexene oxime (84.2 mg) and 1-hexyne (0.29 mL) were subjected
to the standard procedure with purification by chromatography
(10:1:0.01 hexanes/tert-butyl methyl ether/triethylamine). 3-Butyl-2-
methyl-5,6,7,8-tetrahydroisoquinoline was obtained in 54% yield (55
1
16% yield (18 mg, 0.08 mmol) as a brown oil: H NMR (CDCl3) δ
7.42 (m, 3H), 7.36 (m, 1H), 7.33−7.29 (m, 2H), 7.04 (d, J = 7.7 Hz,
1H), 2.83−2.78 (m, 2H), 2.49 (s, 3H), 1.78−1.69 (m, 2H), 1.43 (m,
2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 161.1, 155.3,
140.6, 137.9, 134.4, 129.5, 128.7, 127.5, 120.1, 38.4, 32.7, 23.7, 23.0,
14.3; HRMS (ES+) calcd for C16H19N (M + H)+ 226.1590, found
226.1588.
1
mg, 0.27 mmol) as a brown oil: H NMR (CDCl3) δ 8.01 (s, 1H),
2.63 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.50−2.45 (m, 2H),
2.37 (s, 3H), 1.76 (m, 4H), 1.49 (m, 2H), 1.35 (m, 2H), 0.91 (t, J =
7.3 Hz, 3H); 13C NMR (CDCl3) δ 154.5, 145.9, 144.0, 133.7, 130.5,
32.5, 29.8, 26.7, 26.3, 23.0, 22.8, 22.5, 22.3, 14.2; HRMS (ES+) calcd
for C14H21N (M + H)+ 204.1747, found 204.1744. 2-Butyl-2-methyl-
5,6,7,8-tetrahydroisoquinoline was obtained in 15% yield (15 mg, 0.08
5-Butyl-2,4-dimethylpyridine (2g) and 6-Butyl-2,4-dimethyl-
pyridine (3g). 3-Penten-2-one oxime (60.0 mg) and 1-hexyne (0.29
mL) were subjected to the standard procedure with purification by
chromatography (10:1:0.01 hexanes/tert-butyl methyl ether/triethyl-
amine). 5-Butyl-2,4-dimethylpyridine was obtained in 43% yield (35
1
mmol) as a brown oil: HRMS (ES+) calcd for H NMR (CDCl3) δ
6.68 (s, 1H), 2.70−2.63 (m, 4H), 2.57 (t, J = 6.4 Hz, 2H), 2.40 (s,
3H), 1.86−1.79 (m, 2H), 1.77−1.70 (m, 2H), 1.64 (m, 2H), 1.42−
1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 158.0,
156.5, 146.3, 128.1, 120.9, 38.0, 32.8, 29.8, 26.1, 23.5, 23.0, 22.6, 22.40
14.3; HRMS (ES+) calcd for C14H21N (M + H)+ 204.1747, found
204.1744.
1
mg, 0.22 mmol) as a brown oil: H NMR (CDCl3) δ 8.16 (s, 1H),
6.88 (s, 1H), 2.58−2.47 (m, 2H), 2.43 (s, 3H), 2.22 (s, 3H), 1.49 (m,
2H), 1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ
155.6, 149.3, 145.4, 133.6, 124.7, 32.5, 30.0, 23.9, 22.7, 18.8, 14.1;
2504
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The Journal of Organic Chemistry
Note
3-Butyl-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine (2l)
and 2-Butyl-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine
(3l). 1-Acetyl-1-cylopentene oxime (75.8 mg) and 1-hexyne (0.29
mL) were subjected to the standard procedure with purification by
chromatography (10:1:0.01 hexanes/tert-butyl methyl ether/triethyl-
amine). 3-Butyl-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine and
2-butyl-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine were obtained
as a 2.1:1 mixture of isomers in 89% yield (84 mg, 0.45 mmol) as a
6H), 1.51−1.39 (m, 1H), 1.27−1.06 (m, 4H), 0.97−0.84 (m, 2H); 13
C
NMR (CDCl3) δ 154.3, 146.9, 138.3, 134.1, 131.0, 40.7, 39.8, 33.2,
26.7, 26.4, 22.1, 19.3; HRMS (ES+) calcd for C14H21N (M + H)+
204.1747, found 204.1744.
2,3-Diethyl-4,5,6-trimethylpyridine (6a). Penten-3-one oxime
(68.0 mg) and 3-hexyne (0.29 mL) were subjected to the standard
procedure. Purification by chromatography (10:1:0.01 hexanes/tert-
butyl methyl ether/triethylamine) provides 6a in 73% yield (66.1 mg,
0.37 mmol). The analytical data for this compound are consistent with
previously reported data.4 1-Methyl-3,4-diphenyl-6,7-dihydro-5H-
cyclopenta[c]pyridine (6b). 1-Acetyl-1-cylohexene oxime (84.2 mg)
and diphenylacetylene (445 mg) were subjected to the standard
procedure. Purification by chromatography on silica gel (10:1:0.01
hexanes/tert-butyl methyl ether/triethylamine) provided 6b in 79%
yield (112 mg, 0.40 mmol). The analytical data for this compound are
consistent with previously reported data.5
1
brown oil: H NMR (CDCl3) δ 8.04 (s, 1H), 6.83 (s, 0.47H), 2.88−
2.75 (m, 5.88H), 2.71−2.65 (m, 1H), 2.54−2.47 (m, 2H), 2.40 (m,
4.41H), 2.04 (m, 3H), 1.63 (m, 1H), 1.55−1.46 (m, 2H), 1.41−1.27
(m, 3H), 0.89 (m, 4.41H); 13C NMR (CDCl3) δ 159.9, 154.0, 153.1,
152.0, 151.4, 147.0, 137.7, 135.3, 131.7, 116.6, 38.4, 33.1, 33.0, 32.5,
31.5, 31.1, 30.7, 30.5, 24.6, 24.3, 22.9, 22.7, 22.3, 22.0, 14.3, 14.1;
HRMS (ES+) calcd for C13H19N (M + H)+ 190.1590, found 190.1585.
3-Butyl-5-methylpyridine (2m) and 2-n-Butyl-5-methylpyr-
idine (3m). 4-Phenyl-3-buten-2-one oxime (51.0 mg) and 1-hexyne
(0.29 mL) were subjected to the standard procedure with purification
by chromatography (10:1:0.01 hexanes/tert-butyl methyl ether/
triethylamine). 3-Butyl-5-methylpyridine and 2-butyl-5-methylpyridine
were obtained as a 2.4:1 mixture in 20% yield (15.4 mg, 0.10 mmol) as
a brown oil: 1H NMR (CDCl3) δ 8.32 (s, 1H), 8.23 (s, 2.4H), 8.22 (s,
2.4H), 7.35 (d, J = 7.9 Hz, 1H), 7.27 (s, 2.4H), 7.00 (d, J = 7.9 Hz,
1H), 2.75−2.68 (m, 2H), 2.57−2.51 (m, 4.8H), 2.28 (s, 7.2H), 2.26 (s,
3H), 1.70−1.61 (m, 2H), 1.56 (m, 4.8H), 1.40−1.28 (m, 6.8H), 0.94−
0.82 (m, 10.2H); 13C NMR (CDCl3) δ 159.8, 149.8, 147.9, 147.4,
137.6, 137.1, 136.7, 132.8, 130.2, 122.4, 37.9, 33.6, 32.8, 32.5, 22.8,
22.5, 18.6, 18.3, 14.2, 14.1.
Oxime Substrate Preparation. The syntheses of oximes 1a,5 1b,5
1c,20 1f,21 1g,5 1i,5 1k,22 1l,5 and 1m23 from commercially available
ketones have been previously reported. Oxime 1h was prepared from
the corresponding ketone, which was synthesized according to
literature methods.24 The remaining oximes 1d and 1e were prepared
from the common Weinreb amide intermediate 2,2-diethoxy-N-
methoxy-N-methylpropanamide prepared from 2,2-diethoxypropionic
acid ethyl ester.25
3-Methylenepentan-2-one Oxime (1d). In a 100 mL round-
bottom flask equipped with a stir bar were added 4.0 g of Weinreb
amide (19.5 mmol, 1.0 equiv) and 24 mL of THF. The flask was
cooled to −20 °C, 29.2 mL of ethylmagnesium chloride (58.5 mmol,
3.0 M., 3.0 equiv) was added slowly, and the mixture was allowed to
warm to room temperature with stirring. After 14 h, the reaction
mixture was cooled to 0 °C, and the reaction was quenched by slow
addition of 1 N HCl (40 mL). The mixture was diluted with water
(120 mL) and extracted with diethyl ether (3 × 120 mL). The
combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The resulting oil was purified by chromatog-
raphy (5:1 hexanes/ethyl acetate) to yield diethoxypentan-3-one as a
5-Phenyl-2,3-dimethylpyridine (4a). 3-Methyl-3-buten-2-one
oxime (60.0 mg) and ethynylbenzene (0.26 mL) were subjected to
the standard procedure. 5-Phenyl-2,3-dimethylpyridine was purified by
chromatography (20:1:0.01 hexanes/ethyl acetate/triethylamine) in
1
63% yield (58 mg, 0.32 mmol) as a brown oil: H NMR (CDCl3) δ
8.55 (s, 1H), 7.60 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.45 (m, 2H), 7.36
(m, 1H), 2.54 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3) δ 156.2,
145.0, 138.2, 135.9, 134.5, 131.6, 129.3, 128.0, 127.3, 22.5, 19.5;
HRMS (ES+) calcd for C13H13N (M + H)+ 184.1121, found 184.1119.
5-Benzyl-2,3-dimethylpyridine (4b). 3-Methyl-3-buten-2-one
oxime (60.0 mg) and 2-propynylbenzene (0.29 mL) were subjected
to the standard procedure. 5-Benzyl-2,3-dimethylpyridine was purified
by column chromatography (20:1:0.01 hexanes/ethyl acetate/triethyl-
1
colorless oil (1.8 g, 40%): H NMR (CDCl3) δ 3.58−3.34 (m, 4H),
2.63 (q, J = 7.3 Hz, 2H), 1.37 (s, 3H), 1.21 (t, J = 7.1 Hz, 6H), 1.04 (t,
J = 7.3 Hz, 3H); 13C NMR (CDCl3) δ 210.7, 102.5, 57.9, 31.5, 21.3,
15.7, 7.8; HRMS (ES+) calcd for C9H18O3 (M + Na)+ 197.1148,
found 197.1179.
1
amine) in 61% yield (61 mg, 0.31 mmol) as a brown oil: H NMR
In a 100 mL round-bottom flask equipped with a stir bar was
combined 3.4 g of 2,2-diethoxypentan-3-one (19.5 mmol, 1.0 equiv),
10.5 g of methyltriphenylphosphonium bromide (30.0 mmol, 1.5
equiv), 3.3 g of potassium tert-butoxide (30.0 mmol, 1.5 equiv), and
110 mL of toluene. The slurry was then heated to 110 °C with stirring
for 14 h. The reaction mixture was cooled, and solvents were removed
in vacuo. The resulting residue was filtered over basic alumina
(hexanes) to yield a colorless oil (2.2 g, 65%) used without further
(CDCl3) δ 8.13 (s, 1H), 7.19 (m, 2H), 7.09 (m, 4H), 3.80 (s, 2H),
2.37 (s, 3H), 2.11 (s, 3H); 13C NMR (CDCl3) δ 155.2, 146.8, 140.7,
137.9, 134.1, 131.4, 129.0, 128.9, 126.6, 38.8, 22.4, 19.4; HRMS (ES+)
calcd for C14H15N (M + H)+ 198.1277, found 198.1274.
5-Cyclohexyl-2,3-dimethylpyridine (4c) and 6-Cyclohexyl-
2,3-dimethylpyridine (5c). 3-Methyl-3-buten-2-one oxime (60.0
mg) and ethynylcyclohexane (0.32 mL) were subjected to the standard
procedure with purification by chromatography (10:1:0.01 hexanes/
tert-butyl methyl ether/triethylamine). 5-Cyclohexyl-2,3-dimethylpyr-
idine was obtained in 53% yield (50 mg, 0.26 mmol) as a brown oil:
1H NMR (CDCl3) δ 8.16 (s, 1H), 7.21 (s, 1H), 2.44 (s, 3H), 2.24 (s,
1
purification: H NMR (CDCl3) δ 5.36 (s, 1H), 4.97 (s, 1H), 3.47−
3.29 (m, 4H), 2.09−2.00 (m, 2H), 1.36 (s, 3H), 1.17 (t, J = 7.1 Hz,
6H), 1.07 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 151.4, 110.6,
101.4, 56.3, 23.5, 23.37, 15.4, 12.4.
3H), 1.87−1.70 (m, 7H), 1.43−1.33 (m, 4H); 13C NMR (CDCl3) δ
154.7, 145.6, 140.7, 135.9, 131.1, 41.9, 34.6, 27.1, 26.3, 22.4, 19.5;
HRMS (ES+) calcd for C13H19N (M + H)+ 190.1590, found 190.1588.
6-Cyclohexyl-2,3-dimethylpyridine was obtained in 18% yield (17 mg,
In a 4 dram vial equipped with a stir bar was combined 1.0 g of 2,2-
diethoxy-3-methylenepentane (5.8 mmol, 1.0 equiv), 605 mg of
hydroxylamine hydrochloride (8.7 mmol, 1.5 equiv), 667 mg of
sodium acetate (8.1 mmol, 1.4 equiv), and 15 mL of methanol. The
resulting slurry was stirred for 14 h at ambient temperature. The
solvents were removed in vacuo. The white residue was dissolved in
DCM (15 mL) and filtered over Celite, and the filtrate was
concentrated in vacuo. The resulting oil was purified by chromatog-
raphy (5:1 hexanes:ethyl acetate) to yield a colorless oil (230 mg,
1
0.09 mmol) as a brown oil: H NMR (CDCl3) δ 7.31 (d, J = 7.8 Hz,
1H), 6.89 (d, J = 7.8 Hz, 1H), 2.64 (m, 1H), 2.47 (s, 3H), 2.22 (s,
3H), 1.94 (m, 2H), 1.85−1.70 (m, 4H), 1.49−1.35 (m, 4H); 13C
NMR (CDCl3) 163.8, 156.3, 137.9, 128.6, 118.0, 46.6, 33.6, 27.0, 26.5,
23.0, 19.1; HRMS (ES+) calcd for C13H19N (M + H)+ 190.1590,
found 190.1588.
1
35%): H NMR (CDCl3) δ 9.63 (s, 1H), 5.40 (s, 1H), 5.26 (s, 1H),
2.36 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H); 13C
NMR (CDCl3) δ 156.5, 147.0, 115.7, 25.3, 13.2, 10.8; HRMS (ES+)
calcd for C6H11NO (M + H)+ 114.0913, found 114.0911.
5-(Cyclohexylmethyl)-2,3-dimethylpyridine (4d). 3-Methyl-3-
buten-2-one oxime (60.0 mg) and 2-propynylcyclohexane (0.36 mL)
were subjected to the standard procedure with purification by
chromatography (10:1:0.01 hexanes/tert-butyl methyl ether/triethyl-
4-Methyl-3-methylenepentan-2-one Oxime (1e). In a 100 mL
round-bottom flask equipped with a stir bar were added 5.0 g of
Weinreb amide (24.3 mmol, 1.0 equiv) and 30 mL of THF. The
round-bottom flask was cooled to −20 °C, and 36.5 mL of
1
amine) in 64% yield (66 mg, 0.32 mmol) as a brown oil: H NMR
(CDCl3) δ 8.08 (s, 1H), 7.15 (s, 1H), 2.45 (d, J = 10.0 Hz, 3H), 2.37
(t, J = 11.4 Hz, 2H), 2.21 (d, J = 15.8 Hz, 3H), 1.65 (t, J = 11.2 Hz,
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The Journal of Organic Chemistry
Note
isopropylmagnesium chloride (73.1 mmol, 2.0 M., 3.0 equiv) was
added slowly and allowed to warm to room temperature with stirring.
After 14 h, the reaction mixture was cooled to 0 °C, and the reaction
was quenched by slow addition of 1 N HCl (40 mL). The mixture was
diluted with water (120 mL) and extracted with diethyl ether (3 × 120
mL). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The resulting oil was purified by chromatog-
raphy (5:1 hexanes/ethyl acetate) to yield a colorless oil (1.8 g, 54%):
1H NMR (CDCl3) δ 3.50 (m, 2H), 3.39 (m, 2H), 3.23 (m, 1H), 1.37
(s, 3H), 1.20 (t, J = 7.1 Hz, 6H), 1.07 (d, J = 6.8 Hz, 6H); 13C NMR
(CDCl3) δ 214.7, 103.1, 57.9, 35.7, 21.5, 19.2, 15.7; HRMS (ES+)
calcd for C10H20O3 (M + Na)+ 211.1305, found 211.1306.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grant No. GM069559 (to
J.A.E.) and by the Director, Office of Energy Research, Office
of Basic Energy Science, Chemical Sciences Division, U.S.
Department of Energy, under contract DE-AC02-05CH11231
(to R.G.B.). R.M.M. is grateful for a National Science
Foundation Fellowship and a University of California, Berkeley
Chancellor’s Fellowship. We are grateful to the Keck Center of
Yale University for collecting the high-resolution mass
spectrometry (HRMS) data.
In a 100 mL round-bottom flask equipped with a stir bar was
combined 1.5 g of 2,2-diethoxy-4-methylpentan-3-one (8.0 mmol, 1.0
equiv), 4.3 g of methyltriphenylphosphonium bromide (12.0 mmol,
1.5 equiv), 1.3 g of potassium tert-butoxide (12.0 mmol, 1.5 equiv),
and 45 mL of toluene. The slurry was then heated to 110 °C with
stirring for 14 h. The reaction mixture was cooled, and solvents were
removed in vacuo. The resulting residue was filtered over basic
alumina (hexanes) to yield a colorless oil (840 mg, 57%) used without
REFERENCES
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further purification: H NMR (CDCl3) δ 5.37 (d, J = 1.3 Hz, 1H),
5.07 (d, J = 1.2 Hz, 1H), 3.49−3.36 (m, 4H), 2.47 (sept, J = 6.8 Hz,
1H), 1.41 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H), 1.09 (d, J = 6.9 Hz, 6H);
13C NMR (CDCl3) δ 110.9, 101.8, 56.6, 23.8, 23.7, 15.6, 12.7.
In a 4 dram vial equipped with a stir bar was combined 500 mg of
2,2-diethoxy-4-methyl-3-methylenepentane (2.7 mmol, 1.0 equiv), 280
mg of hydroxylamine hydrochloride (4.0 mmol, 1.5 equiv), 308 mg of
sodium acetate (3.8 mmol, 1.4 equiv), and 13 mL of methanol. The
slurry was stirred for 14 h at ambient temperature. The solvents were
removed in vacuo. The white residue was dissolved in DCM (7 mL)
and filtered over Celite, and the filtrate was concentrated in vacuo. The
resulting oil was purified by chromatography (5:1 hexanes/ethyl
1
acetate) to yield a colorless oil (160 mg, 47%): H NMR (CDCl3) δ
8.79 (s, 1H), 5.36 (s, 1H), 5.24 (s, 1H), 2.94−2.83 (m, 1H), 2.05 (s,
3H), 1.09 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3) δ 156.8, 152.4,
113.7, 29.0, 22.7, 11.4; HRMS (ES+) calcd for C7H13NO (M + H)+
128.1069, found 128.1057.
5-Methylhex-3-en-2-one Oxime (1h). In a 100 mL round-
bottom flask equipped with a stir bar were combined 1.20 g (10.7
mmol) of 5-methylhex-3-en-2-one, 1.10 g of hydroxylamine hydro-
chloride (16.0 mmol), 1.30 g of sodium acetate (16.0 mmol), and 25
mL of methanol. The resulting slurry was stirred for 14 h at ambient
temperature. The solvents were removed in vacuo. The resulting white
residue was dissolved in DCM (25 mL). The resulting mixture was
filtered over Celite, and the filtrate was concentrated in vacuo. The
oxime was isolated by column chromatography (5:1 hexanes/ethyl
acetate) in a 3.7:1 ratio of isomers as a colorless oil (550 mg, 40%): 1H
NMR (CDCl3) δ 9.13 (s, 1H), 6.83 (dd, J = 16.2, 1.4 Hz, 0.27H), 6.14
(dd, J = 16.2, 6.9 Hz, 1H), 6.11−5.99 (m, 2H), 2.41 (m, 1.27H), 1.99
(s, 3H), 1.98 (s, 0.81H), 1.07 (d, J = 6.8 Hz, 1.62H), 1.04 (d, J = 6.8
Hz, 6H); 13C NMR (CDCl3) δ 156.8, 153.7, 147.4, 143.4, 124.9,
117.1, 32.1, 31.7, 22.4, 22.2, 17.2, 10.0; HRMS (ES+) calcd for for
C7H13NO (M + H)+ 128.1070, found 128.1068.
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ASSOCIATED CONTENT
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■
S
* Supporting Information
Reaction optimization table. Copies of 1H NMR and 13C NMR
sprectroscopic data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
̈
̈
̇
(13) Karabulut, S.; Ozturk, B. O.; Imamoglu, Y. J. Organomet. Chem.
̌
̈
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Chem. 2001, 66, 6339.
AUTHOR INFORMATION
■
(15) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(16) Richard, M. E.; Reese, K. P.; Stone, J. J.; Pickett, P. D.; Tillman,
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(17) When 1-hexyne was heated in the presence of [RhCl(coe)2]2
and P(O-i-Pr)3, in THF for 24 h at 135 °C, no new alkene peaks, e.g.,
Corresponding Author
*E-mail: (R.G.B.) rbergman@berkeley.edu; (J.A.E.) jonathan.
ellman@yale.edu.
Notes
1
The authors declare no competing financial interest.
from alkyne dimerization, were observed by H NMR analysis.
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The Journal of Organic Chemistry
Note
(18) In all cases where a single regioisomer resulted, no other
1
isomers were observed by H NMR or GC/MS analysis of the crude
material.
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2507
dx.doi.org/10.1021/jo202280e | J. Org. Chem. 2012, 77, 2501−2507