An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes and 3-Azetidinones

Article abstract of DOI:10.1021/acs.joc.5b01458

An efficient and convenient procedure that generates the active Ni(0) catalyst in situ from cheap, air stable Ni(II) precursors is developed for the [4 + 2]-cycloaddition of alkynes and 3-azetidinones. The reaction affords useful 3-dehydropiperidinones in

Full text of DOI:10.1021/acs.joc.5b01458

Article
pubs.acs.org/joc
An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes
and 3‑Azetidinones
Ashish Thakur,‡ Judah L. Evangelista, Puneet Kumar,§ and Janis Louie*
Department of Chemistry, University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112-0850, United States
S
* Supporting Information
ABSTRACT: An efficient and convenient procedure that generates the
active Ni(0) catalyst in situ from cheap, air stable Ni(II) precursors is
developed for the [4 + 2]-cycloaddition of alkynes and 3-azetidinones. The
reaction affords useful 3-dehydropiperidinones in comparable yields to the
reported Ni(0) procedure. Additionally, the cycloaddition with 3-oxetanone
afforded the 3-dehydropyranone product. Chiral 2-substituted azetidinones
were also tolerated to form substituted dehydropiperidinones in high yield
and enantiomeric excess.
2a as model substrates (Table 1, eq 2). Gratifyingly, the use of
Ni(acac)2 (acac = acetylacetonate) as Ni(II) source with PPh3
ligand and n-BuLi as reductant led to excellent conversion of 3-
azetidinone to afford the desired cycloadduct 3aa in 92%
isolated yield (entry 1, Table 1).7a−c Substitution of n-BuLi by a
milder reductant such as Zn, however, gave poor conversions of
3-azetidinone (entry 2, Table 1). We also evaluated the
commercially available bis(triphenylphosphine)Ni(II) salts7c−h
in conjunction with Zn, to promote this cycloaddition.
However, poor GC conversions were obtained when these
salts were used in toluene presumably due to the insolubility of
the Ni(II) salts in toluene (entries 3−5, Table 1). Interestingly,
the replacement of toluene with a polar solvent such as
acetonitrile afforded excellent conversions and isolated yields of
cycloadduct 3aa (entries 6−7, Table 1). Further optimizations
led to these final conditions: 5 mol % Ni(PPh3)2Cl2, 20 mol %
Zn, acetonitrile, 60−80 °C, 16−24 h.
INTRODUCTION
■
A major focus of our research laboratory is to develop Ni-
catalyzed cycloaddition reactions for the synthesis of carbo-
cycles and heterocycles. For over a decade, we have developed a
variety of Ni(0)-catalysts to activate C = X π-bonds (X = C, O,
N) in cycloaddition with unsaturated hydrocarbons to afford
pyrones,1 pyridones,1 pyrimidine-dione,1 pyridines,1 amino-
pyridines,1 cyclopentenes,2 pyrans,1b,3 cyclohexadienone,s1,4a
and cycloheptadienones.1,4b Recently, we and others independ-
ently extended this concept to activate challenging C−C σ-
bond in 3-azetidinones via a Ni(COD)2/PPh3-catalyzed
cycloaddition of alkynes and 3-azetidinones (eq 1).5
These optimized reactions were applied to the cycloaddition
of 3-azetidinone with a variety of alkynes (Scheme 1). Several
yields obtained from our previously reported Ni(COD)2/PPh3
catalytic system are also shown in parentheses for compar-
ison.5a The cycloaddition of 4-octyne with 3-azetidinone
afforded the heterocyclic product 3aa in 95% yield. The
sterically biased terminal alkyne 1b was regioselectively coupled
to form cycloadduct 3ba in which the bulky t-butyl group was
placed at the β-position. The reaction also tolerates diaryl
alkyne such as diphenylacetylene to form the substituted 3-
dehydropiperidinone 3ca in good yield. Although the cyclo-
adducts 3ba and 3ca were obtained in slightly lower yields
(60% and 72%, respectively) when compared to our reported
Ni(0) procedure5a (71% and 79%, respectively), the in situ
procedure only requires half the equivalents of alkyne (i.e., 1.5
This interesting reaction provides a unique and single step
access to synthetically important 3-dehydropiperidinone cores
that are challenging to synthesize via conventional methods.6
Despite the use of relatively mild conditions in this method-
ology, one major drawback is the use of air and temperature-
sensitive Ni(COD)2 which necessitates the use of a glovebox or
complicated Schlenk techniques. Furthermore, Ni(COD)2 is an
expensive Ni(0) source and therefore limits its use for large-
scale reactions. In order to make this chemistry synthetically
more convenient and applicable, we developed the use of air-
stable, less expensive, and readily available precursors that
generate the active Ni/PPh3 catalyst in situ. Herein, we report
our results.
RESULTS AND DISCUSSION
The nickel-catalyzed cycloaddition was investigated using
commercially available 4-octyne 1a and 1-Boc-3-azetidinone
■
Received: June 26, 2015
© XXXX American Chemical Society
A
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a
Table 1. In Situ Ni-Catalyzed Cycloaddition of 4-Octyne with 1-Boc-3-azetidinone
b
c
entry
Ni(II)
ligand
reductant
solvent
toluene
conv. (%)
yield (%)
1
2
3
4
5
6
7
8
Ni(acac)2
PPh3
PPh3
−
−
−
−
−
−
n-BuLi
Zn
>99
37
92
−
Ni(acac)2
acetonitrile
toluene
Ni(PPh3)2Cl2
Ni(PPh3)2Br2
Zn
6
trace
d
Zn
toluene
62
n.d.
Ni(PPh3)2 2
I
Zn
toluene
16
trace
95
Ni(PPh3)2Cl2
Ni(PPh3)2Br2
Ni(PPh3)2I2
Zn
acetonitrile
acetonitrile
acetonitrile
>99
>99
15
Zn
95
Zn
trace
a
Reaction Conditions: 4-octyne 1a (1.5 equiv), 1-Boc-3-azetidinone 2a (1 equiv, 0.2 M), 10 mol % Ni(II), 20 mol % ligand, 40 mol % reductant, 60
b
c
d
°C, 16 h. Determined by GC using naphathalene as an internal standard. Isolated yield of the product. n.d. = not determined.
equiv as compared to 3 equiv in Ni(0) procedure) without the
slow addition of alkyne for 2 h and lower reaction temperature
(80 °C vs 100 °C). Interestingly, the use of mixed aryl-alkyl
alkynes led to the regioselective formation of the cycloadducts
(3da−3la) in which the alkyl group remains next to the
carbonyl group. Importantly, the cycloadducts 3da and 3ea
were formed in better yields (86% and 87%, respectively) than
our reported Ni(0) protocol (81% and 74%, respectively). This
methodology also tolerates a stannyl-substituted alkyne to
regioselectively form the heterocycle 3fa, suggesting that the
aryl group, rather than the sterically bulky stannyl group,
governs the regioselectivity. Aryl-silyl alkynes were also coupled
to form 3-dehydropiperidinone products (1ga−1ia) in
excellent regioselectivity and high yields. Interestingly, the
aryl-silyl alkyne bearing electron-withdrawing group (−CF3) on
the phenyl ring afforded lower yield than the alkyne-containing
phenyl with an electron-donating group (−OMe) (3ha vs 3ia).
The challenging heteroaryl-silyl alkynes were also successfully
coupled to form furanyl- and thiophenyl-substituted dehy-
dropiperidinones 3ja and 3ka, in good yields. Importantly, in all
of the above cycloaddition reactions involving the use of mixed
aryl-alkyl alkynes, stannyl-aryl alkynes and aryl/heteroaryl-silyl
alkynes with 3-azetidinone, the in situ procedure only requires
1.5 equiv of alkyne without the need of slow addition of alkyne
and lower reaction temperature than the conditions used in our
previously reported Ni(0) procedure.5a The growing interest in
macrocyclic heterocycles8 prompted us to investigate the
macrocyclic alkyne 1l in this cycloaddition. Gratifyingly, the
cycloaddition underwent smoothly to regioselectively afford the
desired macrocyclic 3-dehydropiperidone 3la in good yield.
Importantly, this methodology is scalable and was success-
fully applied to gram-scale quantities of 3-azetdinone and
diphenylacetylene to afford cycloadduct 3ca in 72% yield (eq
3).
conditions. Alkynes bearing boron-functional groups (Figure 1)
also failed to participate in this cycloaddition and were either
completely decomposed or recovered with partial decom-
position under the reaction conditions.
Figure 1. Attempted substrates in Ni-catalyzed cycloaddition.
The cycloaddition of 3-oxetanaone with diphenylacetylene
afforded the substituted 3-dehydropyranone product 3cb, albeit
in lower yield than the reported Ni(0)-protocol (eq 4).5b
We next investigated the Ni-catalyzed cycloaddition of 2-
substituted-3-azetdinones with alkynes (Table 2). The chiral 2-
substituted azetidinones (2c−2f) were synthesized from the
corresponding amino acids using Seebach’s procedure.9 The
potential challenges associated with the use of chiral
azetidinones in this reaction involve the possibility of
racemization of both the chiral azetidinone and chiral 3-
dehydropiperidinone product due to the presence of Lewis
acidic Ni(II)-precatalyst and ZnCl2 that is formed within the
reaction. Despite these challenges, the cycloaddition works
effectively to afford enantio-enriched cycloadducts in high
yields (Table 2). The yields and enantiomeric excess (ee)
obtained by previously reported Ni(COD)2/PPh3 catalytic
system are also shown in parentheses for comparison.5a,c The
cycloaddition of alanine-derived azetidinone 2c with 4-octyne
led to the regioselective formation of the cycloadduct 3ac,
which suggests the selective insertion of alkyne into the
unsubstituted C(sp2)−C(sp3) σ-bond of 3-azetidinone. The
dehydropiperidinone product 3ac retained 98% ee, which was
slightly less than the reported Ni(0) method. Similarly, the Boc-
protected azetidinone 2d and Cbz-protected azetidinone 2e
afforded regioselective dehydropiperidinones 3ad and 3ae in
Unfortunately, terminal alkynes (e.g., phenylacetylene, 1-
hexyne, and 1-octyne) did not afford dehydropiperidinone
product due to their rapid oligomerization under the reaction
B
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Scheme 1. In Situ Ni-Catalyzed Cycloaddition of Alkynes and 3-Azetidinone
a
Reaction conditions: 1-Boc-3-azetdidinone (1.0 equiv, 0.2 M) alkyne (1.5 equiv), 5 mol % Ni(PPh3)2Cl2, 20 mol % Zn, 60−80 °C, 16−24 h.
b
c
1
Isolated yield (in parentheses) obtained using reported Ni(0) procedure. Regioselectivty (in red) was calculated by H NMR of crude reaction
mixture.
high yields with 93% and 97% ee, respectively. Diaryl alkyne
1m was also coupled with azetidinones 2e and 2f to form
regioselective cycloadducts 3me and 3mf in high yields and
high enantioretention.
methodology toward the synthesis of alkaloid natural products
are underway in our laboratory.
EXPERIMENTAL SECTION
■
General. All reactions were conducted under an atmosphere of N2.
Toluene and acetonitrile were dried over neutral alumina under N2
using a Grubbs type solvent purification system. The alkynes 1l,10a
1m,10b tert-butyl (S)-2-methyl-3-oxoazetidine-1-carboxylate 2c,5c and
tert-butyl (S)-2-benzyl-3-oxoazetidine-1-carboxylate 2d5a were pre-
pared according to literature procedure. All other reagents were
purchased from commercial suppliers and used without further
purification unless otherwise noted.
CONCLUSION
■
In summary, we have developed an efficient and convenient
procedure that can generate the active Ni(0) catalyst in situ to
catalyze the cycloaddition of alkynes and 3-azetidinones. The
reaction affords useful six-membered heterocycles in compara-
ble yields to the reported Ni(0) procedures using fewer
equivalents of alkyne and without the need of slow addition of
alkyne. Additionally, enantiopure 2-substituted azetidinones
were also coupled to form substituted dehydropiperidinones in
high yields and high enantioretention. Efforts to utilize this
1H and 13C nuclear magnetic resonance (NMR) spectra of pure
compounds were acquired at 400 and 100 MHz or 500 and 125 MHz,
respectively, unless otherwise noted. All spectra are referenced to a
1
singlet at 7.27 ppm for H and to the central line of a triplet at 77.23
C
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rt. The mixture was stirred for an additional 5 h. The reaction was
quenched by the addition of water, extracted three times with EtOAc,
washed with brine, and dried over MgSO4. Purification by flash
chromatography on silica gel using 35−45% EtOAc/hexanes, afforded
the pure diazo ketone (2.14 g, 6.7 mmol, 73%). Under N2 atmosphere,
the diazo ketone was dissolved in CH2Cl2 (33 mL), and dry NEt3 (10
μL, 0.07 mmol) was added. After cooling to 0 °C, Rh2(OAc)4 (14.8
mg, 0.03 mmol, 0.5 mol %) was added, and the mixture was stirred for
14 h. After that, water was added, extracted with CH2Cl2, washed with
water, and brine dried over MgSO4. The remaining residue was
purified by silica gel flash column chromatography using 40−50%
ether in hexanes (Rf = 0.29 in 50% ether/hexanes) to afford the title
compound 2e (1.13 g, 3.88 mmol, 58%). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.37 (m, 5H), 5.17 (s, 2H), 5.06 (m, 1H), 4.79 (d, J
= 16.4 Hz, 1H), 4.61 (dd, J = 4.4, 16.4 Hz, 1H), 3.65 (s, 3H), 2.44−
2.59 (m, 2H), 2.19 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm)
199.0, 172.9, 157.0, 136.1, 128.8, 128.6, 128.4, 82.4, 69.7, 67.9, 51.9,
29.5, 25.6. IR (CH2Cl2, cm−1): 2953, 1822, 1733, 1711, 1437, 1403,
1344, 1253, 1119, 1123, 1059, 1026, 745, 699. HRMS (ESI-TOF)
calcd for C15H17NO5Na [M + Na]+ 314.1004, found 314.1006.
Table 2. In Situ Ni-Catalyzed Cycloaddition of Alkynes with
2-Substituted-3-Azetidinones
a
tert-Butyl (S)-2-(3-Methoxy-3-oxopropyl)-3-oxoazetidine-1-car-
boxylate (2f). Azetidinone 2d was prepared according to Seebach’s
procedue.9 To a solution of Boc-Glu(OMe)-OH11b (2.10 g, 8.04
mmol) in THF (40 mL) under N2 atmosphere, dry NEt3 (1.2 mL,
8.44 mmol) and ClCO2Et (0.92 g, 8.44 mmol) were added at −15 °C.
The suspension was allowed to warm to 0 °C. CH2N2 (21.10 mmol)
in Et2O was slowly added in portions over a period of 2 h and allowed
to warm to rt. The mixture was stirred for an additional 5 h. The
reaction was quenched by the addition of water, extracted three times
with EtOAc, washed with brine, and dried over MgSO4. Purification by
flash chromatography on silica gel using 30−35% EtOAc/hexanes,
afforded the pure diazo ketone (2.03 g, 7.1 mmol, 88%). Under N2
atmosphere, the diazo ketone was dissolved in CH2Cl2 (35 mL) and
dry NEt3 (10 μL, 0.07 mmol) was added. After cooling to 0 °C,
Rh2(OAc)4 (15.5 mg, 0.04 mmol, 0.5 mol %) was added, and the
mixture was stirred for 14 h. After that, water was added, extracted
with CH2Cl2, washed with water and brine dried over MgSO4. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 30−40% ether in hexanes (Rf = 0.32 in 40% ether/
hexanes) to afford the title compound 2f (0.96 g, 3.73 mmol, 53%). 1H
NMR (400 MHz, CDCl3): δ (ppm) 4.95 (td, J = 4.8, 6.8 Hz, 1H), 4.71
(d, J = 16.8 Hz, 1H), 4.52 (dd, J = 4.4, 16.8 Hz, 1H), 3.68 (s, 3H), 2.51
(qd, J = 8.0, 16.4, 2H), 2.15 (m, 2H), 1.48 (s, 9H). 13C NMR (100
MHz, CDCl3): δ (ppm) 200.0, 173.1, 156.6, 82.0, 81.3, 69.4, 51.9,
29.6, 28.4, 25.8. IR (CH2Cl2, cm−1): 2978, 2932, 1822, 1738, 1704,
1437, 1367, 1176, 1132, 1060, 1021, 862, 776. HRMS (ESI-TOF)
calcd for C12H19NO5Na [M + Na]+ 280.1161, found 280.1167.
General Procedure “G1” for Cycloaddition. To an oven-dried
Schlenk tube containing a stirring bar was added 5 mol %
Ni(PPh3)2Cl2, 20 mol % activated Zn powder, 3-azetdinone (1
equiv), and alkyne [(1.5 equiv), if solid at room temperature]. This
Schlenk tube containing all the solid compounds was then evacuated
followed by refilling with N2 at room temperature (this process was
repeated two times). Dry acetonitrile (0.2 M, based on 3-azetidinone)
and alkyne [(1.5 equiv), if oil at room temperature] were added via
syringe through the rubber septum, under a flow of nitrogen. The
Schlenk tube was sealed, stirred at 60−80 °C for indicated period of
time, and then opened to air. The remaining residue was filtered
through a short pad of Celite, concentrated in vacuo, and purified by
silica gel flash column chromatography.
a
Reaction conditions: Azetdidinone (1.0 equiv, 0.1 M), alkyne (1.5
equiv), 5 mol % Ni(PPh3)2Cl2, 20 mol % Zn, 60−80 °C, 16−24 h.
b
Isolated yield.
ppm for 13C. The abbreviations s, d, dd, dt, dq, t, td, tq, q, qt, quint,
sext, sept, septd, septt, m, brm, brd, brt, and brs stand for singlet,
doublet, doublet of doublets, doublet of triplets, doublet of quartets,
triplet, triplet of doublets, triplet of quartets, quartet, quartet of triplets,
quintet, sextet, septet, septet of doublets, septet of triplets, multiplet,
broad multiplet, broad doublet, broad triplet, and broad singlet, in that
order. All 13C NMR spectra were proton decoupled.
Synthesis of Chiral 2-Substituted-3-Azetidinones. Benzyl (S)-
2-(3-Methoxy-3-oxopropyl)-3-oxoazetidine-1-carboxylate (2e). Aze-
tidinone 2e was also prepared according to Seebach’s procedure.9 To a
solution of Cbz-Glu(OMe)-OH11a (2.73 g, 9.24 mmol) in THF (45
mL) under N2 atmosphere, dry NEt3 (1.35 mL, 9.71 mmol) and
ClCO2Et (1.05 g, 9.71 mmol) were added at −15 °C. The suspension
was allowed to warm to 0 °C. CH2N2 (23.10 mmol) in Et2O was
slowly added in portions over a period of 2h and allowed to warm to
General Procedure “G2” for Cycloaddition. To an oven-dried
Schlenk tube containing a stirring bar was added 5 mol %
Ni(PPh3)2Cl2, 20 mol % activated Zn powder, and alkyne [(1.5
equiv), if solid at room temperature]. This Schlenk tube containing all
the solid compounds was then evacuated followed by refilling with N2
at room temperature (this process was repeated two times). Dry
D
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acetonitrile (0.2 M, based on 3-azetidinone) and alkyne [(1.5 equiv), if
oil at room temperature] were added via syringe through the rubber
septum, under a flow of nitrogen. The reaction mixture was stirred
under nitrogen for 20 min followed by the addition of 3-azetidinone (1
equiv, 0.2 M) or 3-oxetanone (1 equiv, 0.2 M) in dry acetonitrile. The
Schlenk tube was sealed, stirred at 60−80 °C for indicated period of
time, and then opened to air. The remaining residue was filtered
through a short pad of Celite, concentrated in vacuo, and purified by
silica gel flash column chromatography.
mixture was heated at 80 °C for 20 h. The remaining residue was
purified by silica gel flash column chromatography using 25% ether in
hexanes (Rf = 0.20) to afford the title compound 3da (147.0 mg, 0.51
1
mmol, 86%) as colorless oil. H NMR and 13C NMR were consistent
with reported data.5a
tert-Butyl 3-(4-Methoxyphenyl)-4-methyl-5-oxo-5,6-dihydropyri-
dine-1(2H)-carboxylate (3ea). The general procedure G1 was used
with 105.0 mg (0.61 mmol, 0.2 M) of 3-azetidinone 2a, 134.5 mg
(0.92 mmol) of p-methoxyphenyl-methyl alkyne 1e, 20.1 mg (0.03
mmol) of Ni(PPh3)2Cl2, and 8.0 mg (0.12 mmol) of Zn powder in
acetonitrile. The reaction mixture was heated at 80 °C for 20 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 30% ether in hexanes (Rf = 0.20) to afford the title
compound 3ea (170.0 mg, 0.54 mmol, 87%) as colorless oil. 1H NMR
and 13C NMR were consistent with reported data.5a
tert-Butyl 3-oxo-4,5-Dipropyl-3,6-dihydropyridine-1(2H)-carbox-
ylate (3aa). The general procedure G1 was used with 118.7 mg (0.69
mmol, 0.2 M) of 3-azetidinone 2a, 114.6 mg (1.04 mmol) of 4-octyne
1a, 22.7 mg (0.04 mmol) of Ni(PPh3)2Cl2, and 9.1 mg (0.14 mmol) of
Zn powder in acetonitrile. The reaction mixture was heated at 60 °C
for 16 h. The remaining residue was purified by silica gel flash column
chromatography using 25% ether in hexanes (Rf = 0.24) to afford the
1
title compound 3aa (186.1 mg, 0.66 mmol, 95%) as colorless oil. H
NMR and 13C NMR were consistent with reported data.5a
tert-Butyl 5-oxo-4-Phenyl-3-(tributylstannyl)-5,6-dihydropyri-
dine-1(2H)-carboxylate (3fa). The general procedure G1 was used
with 79.5 mg (0.46 mmol, 0.2 M) of 3-azetidinone 2a, 272.5 mg (0.70
mmol) of tributyltin-phenyl alkyne 1f, 15.3 mg (0.02 mmol) of
Ni(PPh3)2Cl2, and 6.1 mg (0.09 mmol) of Zn powder in acetonitrile.
The reaction mixture was heated at 80 °C for 20 h. The remaining
residue was purified by silica gel flash column chromatography using
15% ether in hexanes (Rf = 0.29) to afford the title compound 3fa
tert-Butyl 5-(tert-Butyl)-3-oxo-3,6-dihydropyridine-1(2H)-carbox-
ylate (3ba). The general procedure G1 was used with 117.5 mg (0.69
mmol, 0.2 M) of 3-azetidinone 2a, 84.6 mg (1.03 mmol) of t-
butylacteylene 1b, 22.6 mg (0.03 mmol) of Ni(PPh3)2Cl2, and 9.0 mg
(0.14 mmol) of Zn powder in acetonitrile. The reaction mixture was
heated at 80 °C for 16 h. The remaining residue was purified by silica
gel flash column chromatography using 15−25% ether in hexanes (Rf
= 0.27 in 25% ether/hexanes) to afford the title compound 3ba (104.5
1
mg, 0.41 mmol, 60%) as colorless oil. H NMR and 13C NMR were
1
(190.0 mg, 0.34 mmol, 73%) as yellow oil. H NMR and 13C NMR
consistent with reported data.5a
were consistent with reported data.5a
tert-Butyl 5-oxo-3,4-Diphenyl-5,6-dihydropyridine-1(2H)-carbox-
ylate (3ca). The general procedure G1 was used with 130.3 mg (0.76
mmol, 0.2 M) of 3-azetidinone 2a, 203.4 mg (1.14 mmol) of
diphenylacetylene 1c, 24.9 mg (0.04 mmol) of Ni(PPh3)2Cl2, and 7.5
mg (0.12 mmol) of Zn powder in acetonitrile. The reaction mixture
was heated at 80 °C for 20 h. The remaining residue was purified by
silica gel flash column chromatography using 15−20% ethyl acetate in
hexanes (Rf = 0.3 in 20% EtOAc/hexanes) to afford the title
compound 3ca (191.0 mg, 0.55 mmol, 72%) as pale oil. 1H NMR and
13C NMR were consistent with reported data.5a
tert-Butyl 5-oxo-3-Phenyl-4-(trimethylsilyl)-5,6-dihydropyridine-
1(2H)-carboxylate (3ga). The general procedure G1 was used with
121.6 mg (0.71 mmol, 0.2 M) of 3-azetidinone 2a, 185.7 mg (1.07
mmol) of phenyl-trimethylsilyl alkyne 1g, 23.2 mg (0.04 mmol) of
Ni(PPh3)2Cl2, and 9.3 mg (0.14 mmol) of Zn powder in acetonitrile.
The reaction mixture was heated at 80 °C for 20 h. The remaining
residue was purified by silica gel flash column chromatography using
15−20% ether in hexanes (Rf = 0.26 in 20% ether/hexanes) to afford
1
the title compound 3ga (184.8 mg, 0.53 mmol, 75%) as pale oil. H
NMR and 13C NMR were consistent with reported data.5a
Gram Scale Reaction. The general procedure G1 was used with
1.43 g (8.35 mmol, 0.2 M) of 3-azetidinone 2a, 2.23 g (12.5 mmol) of
diphenylacetylene 1c, 273.1 mg (0.42 mmol) of Ni(PPh3)2Cl2, and
109.2 mg (1.67 mmol) of Zn powder in acetonitrile. The reaction
mixture was heated at 80 °C for 20 h. The remaining residue was
purified by silica gel flash column chromatography using 15−20% ethyl
acetate in hexanes (Rf = 0.3 in 20% EtOAc/hexanes) to afford the title
compound 3ca (2.11 g, 6.0 mmol, 72%) as pale oil. 1H NMR and 13
C
tert-Butyl 5-(4-Methoxyphenyl)-3-oxo-4-(trimethylsilyl)-3,6-dihy-
dropyridine-1(2H)-carboxylate (3ha). The general procedure G1 was
used with 99.0 mg (0.58 mmol, 0.2 M) of 3-azetidinone 2a, 177.3 mg
(0.87 mmol) of (p-methoxy)phenyl-trimethylsilyl alkyne 1h, 19.0 mg
(0.03 mmol) of Ni(PPh3)2Cl2, and 7.6 mg (0.12 mmol) of Zn powder
in acetonitrile. The reaction mixture was heated at 80 °C for 20 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 25−30% ether in hexanes (Rf = 0.30 in 30% ether/
hexanes) to afford the title compound 3ha (161.1 mg, 0.43 mmol,
74%) as yellow oil.
NMR were consistent with reported data.5a
tert-Butyl 4-Methyl-5-oxo-3-phenyl-5,6-dihydropyridine-1(2H)-
carboxylate (3da). The general procedure G1 was used with 100.5
mg (0.59 mmol, 0.2 M) of 3-azetidinone 2a, 102.2 mg (0.88 mmol) of
phenyl-methyl alkyne 1d, 19.3 mg (0.03 mmol) of Ni(PPh3)2Cl2, and
7.7 mg (0.12 mmol) of Zn powder in acetonitrile. The reaction
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Article
1H NMR (400 MHz, CDCl3): δ (ppm) 7.20 (d, J = 8.0 Hz, 2H),
6.90 (d, J = 8.8 Hz, 2H), 4.29 (s, 2H), 4.05 (s, 2H), 3.82 (s, 3H), 1.48
(s, 9H), 0.11 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 198.4,
161.0, 154.5, 131.74, 131.66, 129.8, 114.0, 113.9, 81.0, 55.5, 51.8, 49.0,
28.6, 0.7. IR (CH2Cl2, cm−1): 2977, 1699, 1665, 1607, 1509, 1458,
1413, 1248, 1160, 1110, 1031, 843, 766, 736. HRMS (ESI-TOF) m/z
calcd for C20H29NO4SiNa [M + Na]+ 398.1764, found 398.1760.
Key g-HMBC correlations: The following cross-peaks were
observed: H(2) and C(1); H(2) and C(6); H(3) and C(6); H(3)
and C(4); H(3) and C(5); H(3) and C(7); H(8) and C(7); H(8) and
C(4).
tert-Butyl-5-oxo-3-(Thiophen-3-yl)-4-(trimethylsilyl)-5,6-dihydro-
pyridine-1(2H)-carboxylate (3ka). The general procedure G1 was
used with 101.0 mg (0.59 mmol, 0.2 M) of 3-azetidinone 2a, 158.7 mg
(0.88 mmol) of thiophenyl-trimethylsilyl alkyne 1k, 19.3 mg (0.03
mmol) of Ni(PPh3)2Cl2, and 7.7 mg (0.12 mmol) of Zn powder in
acetonitrile. The reaction mixture was heated at 80 °C for 24 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 10−20% ether in hexanes (Rf = 0.27 in 20% ether/
hexanes) to afford the title compound 3ka (150.8 mg, 0.43 mmol,
73%) as pale oil. 1H NMR and 13C NMR were consistent with
reported data.5a
tert-Butyl 4,10-dioxo-4,5,6,7,8,10-Hexahydro-1H-benzo[3,4]-
oxecino[5,6-c]pyridine-2(3H)-carboxylate (3la). The general proce-
dure G1 was used with 55.0 mg (0.32 mmol, 0.2 M) of 3-azetidinone
2a, 96.5 mg (0.48 mmol) of macrocyclic alkyne 1l, 10.5 mg (0.02
mmol) of Ni(PPh3)2Cl2, and 4.2 mg (0.06 mmol) of Zn powder in
acetonitrile. The reaction mixture was heated at 80 °C for 20 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 30−40% ether in hexanes (Rf = 0.28 in 40% ether/
hexanes) to afford the title compound 3la (65.5 mg, 0.18 mmol, 55%)
as colorless oil.
tert-Butyl 3-oxo-5-(4-(Trifluoromethyl)phenyl)-4-(trimethylsilyl)-
3,6-dihydropyridine-1(2H)-carboxylate (3ia). The general procedure
G1 was used with 122.0 mg (0.71 mmol, 0.2 M) of 3-azetidinone 2a,
259.0 mg (1.07 mmol) of (p-trifluoromethyl)phenyl-trimethylsilyl
alkyne 1i, 23.3 mg (0.04 mmol) of Ni(PPh3)2Cl2, and 9.3 mg (0.14
mmol) of Zn powder in acetonitrile. The reaction mixture was heated
at 80 °C for 20 h. The remaining residue was purified by silica gel flash
column chromatography using 20% ether in hexanes (Rf = 0.29) to
afford the title compound 3ia (151.0 mg, 0.36 mmol, 51%) as colorless
oil.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.96 (d, J = 7.6 Hz, 1H),
7.55 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.21 (brs, 1H), 4.68
(m, 1H), 4.36−4.50 (m, 3H), 4.19 (m, 1H), 4.00 (brm, 1H), 2.54 (m,
1H), 1.92−2.26 (m, 2H), 1.53−1.77 (m, 3H), 1.47 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 193.8, 167.9, 154.4, 136.9, 135.1, 132.0,
130.2, 129.8, 128.8, 128.2, 125.7, 81.2, 67.3, 52.3, 48.8, 31.8, 28.5, 25.8,
25.2. IR (CH2Cl2, cm−1): 2973, 2917, 2849, 1700.96, 1676, 1626,
1597, 1439, 1417, 1368, 1290, 1246, 1165, 1129, 1089, 1047, 905, 764,
736. HRMS (ESI-TOF) m/z calcd for C21H25NO5Na [M + Na]+
394.1630, found 394.1633.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.67 (d, J = 7.6 Hz, 2H),
7.39 (d, J = 8.0 Hz, 2H), 4.28 (s, 2H), 4.09 (s, 2H), 1.48 (s, 9H), 0.14
(s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 197.7, 154.4, 143.1,
138.8, 131.6 (q, J = 33.0 Hz), 128.5, 125.7 (q, J = 4.0 Hz), 124.0 (q, J
= 270 Hz), 81.3, 51.7, 49.0, 28.5, 0.5. IR (CH2Cl2, cm−1): 2979, 1701
1670, 1588, 1405, 1368, 1324, 1248, 1164, 1128, 1109, 1069, 1016,
938, 843, 766. HRMS (ESI-TOF) m/z calcd for C20H26F3NO3SiNa
[M + Na]+ 436.1532, found 436.1540.
Key g-HMBC correlations: The following cross-peaks were
observed: H(2) and C(1); H(2) and C(6); H(3) and C(6); H(3)
and C(4); H(3) and C(5); H(3) and C(7); H(8) and C(7); H(8) and
C(4).
Key g-HMBC correlations: The following cross-peaks were
observed: H(2) and C(1); H(2) and C(6); H(3) and C(6); H(3)
and C(4); H(3) and C(5); H(3) and C(7); H(7) and C(5); H(7) and
C(1); H(8) and C(5); H(10) and C(11); H(12) and C(4)
4,5-Diphenyl-2H-pyran-3(6H)-one (3cb). The general procedure
G1 was used with 63.4 mg (0.88 mmol, 0.1 M) of 3-oxetanone 2b,
235.3 mg (1.32 mmol) of diphenylacetylene 1c, 29.0 mg (0.04 mmol)
of Ni(PPh3)2Cl2, and 11.6 mg (0.18 mmol) of Zn powder in
acetonitrile. The reaction mixture was heated at 80 °C for 16 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 30% ether in hexanes (Rf = 0.23) to afford the title
compound 3cb (132.2 mg, 0.53 mmol, 60%) as colorless gel. 1H NMR
and 13C NMR were consistent with reported data.5b
tert-Butyl 3-(Furan-3-yl)-5-oxo-4-(trimethylsilyl)-5,6-dihydropyri-
dine-1(2H)-carboxylate (3ja). The general procedure G1 was used
with 86.5 mg (0.51 mmol, 0.2 M) of 3-azetidinone 2a, 124.5 mg (0.76
mmol) of furanyl-trimethylsilyl alkyne 1j, 16.7 mg (0.03 mmol) of
Ni(PPh3)2Cl2, and 6.7 mg (0.10 mmol) of Zn powder in acetonitrile.
The reaction mixture was heated at 80 °C for 24 h. The remaining
residue was purified by silica gel flash column chromatography using
10−20% ether in hexanes (Rf = 0.27 in 20% ether/hexanes) to afford
the title compound 3ja (126.8 mg, 0.38 mmol, 75%) as yellow oil. 1H
NMR and 13C NMR were consistent with reported data.5a
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DOI: 10.1021/acs.joc.5b01458
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The Journal of Organic Chemistry
Article
tert-Butyl (S)-2-Methyl-3-oxo-4,5-dipropyl-3,6-dihydropyridine-
1(2H)-carboxylate (3ac). The general procedure G1 was used with
63.2 mg (0.34 mmol, 0.2 M) of enantiopure 2-methyl-3-azetidinone
2c, 56.4 mg (0.51 mmol) of 4-octyne 1a, 11.2 mg (0.02 mmol) of
Ni(PPh3)2Cl2, and 4.5 mg (0.07 mmol) of Zn powder in acetonitrile.
The reaction mixture was heated at 60 °C for 20 h. The remaining
residue was purified by silica gel flash column chromatography using
15−20% ether in hexanes (Rf = 0.28 in 20% ether/hexanes) to afford
the title compound 3ac (100.8 mg, 0.30 mmol, 87%) as colorless oil.
[α]D 20 = 25.2 (c = 1.0, CHCl3); (Daicel Chiralpak OZ-H Column, 3%
i-PrOH, 25 °C, flow rate = 2 mL/min, 160 bar), Retention time:
powder in acetonitrile. The reaction mixture was heated at 80 °C for
20 h. The remaining residue was purified by silica gel flash column
chromatography using 45−55% EtOAc in hexanes (Rf = 0.25 in 55%
EtOAc/hexanes) to afford the title compound 3me (89.1 mg, 0.15
mmol, 83%) as yellow oil. [α]D 20 = −106.6 (c = 1.0, CHCl3); (Daicel
Chiralpak OZ-H Column, 5−15−50% i-PrOH, 40 °C, flow rate = 30
mL/min, 200 bar), Retention time: major = 16.82 min, minor = 17.6
min, ee = 97%].
1H NMR (400 MHz, CDCl3): δ (ppm) 7.33−7.40 (m, 5H), 6.89
(brd, J = 7.6 Hz, 1H), 6.72−6.75 (m, 2H), 6.57 (brd, J = 8.0 Hz, 1H),
6.49−6.51 (m, 2H), 5.31 (brd, J = 20.4 Hz, 1H), 5.21 (s, 2H), 4.81−
4.91 (m, 1H), 4.11−4.16 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.67 (s,
3H), 3.64 (s, 3H), 3.52 (brs, 3H), 2.40−2.55 (m, 2H), 2.20−2.27 (m,
2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 194.1, 173.2, 155.4,
153.4, 149.9, 148.7, 148.5, 135.9, 133.3, 128.8, 128.6, 128.4, 126.9,
123.7, 121.7, 114.4, 112.7, 111.0, 110.7, 88.2, 68.2, 59.8, 56.0, 55.8,
52.0, 44.2, 30.8, 25.4. IR (CH2Cl2, cm−1): 2916, 2849, 1734, 1700,
1684, 1653, 1559, 1539, 1463, 1456, 1251, 1171, 1144, 1027, 764, 681.
HRMS (ESI-TOF) m/z calcd for C33H35NO9Na [M + Na]+ 612.2210,
found 612.2206.
1
minor = 4.00 min, major = 5.47 min, ee = 98%]. H NMR and 13C
NMR were consistent with reported data.5c
tert-Butyl (S)-2-Benzyl-3-oxo-4,5-dipropyl-3,6-dihydropyridine-
1(2H)-carboxylate (3ad). The general procedure G1 was used with
42.3 mg (0.16 mmol, 0.2 M) of enantiopure 2-benzyl-3-azetidinone
2d, 26.8 mg (0.24 mmol) of 4-octyne 1a, 5.3 mg (0.01 mmol) of
Ni(PPh3)2Cl2, and 2.1 mg (0.03 mmol) of Zn powder in acetonitrile.
The reaction mixture was heated at 60 °C for 20 h. The remaining
residue was purified by silica gel flash column chromatography using
10−20% ether in hexanes (Rf = 0.41 in 20% ether/hexanes) to afford
the title compound 3ad (51.2 mg, 0.14 mmol, 85%) as colorless oil.
20
[α]D = −20.7 (c = 1.0, CHCl3); (Daicel Chiralpak OZ-H Column,
3% i-PrOH, 40 °C, flow rate = 2 mL/min, 160 bar), Retention time:
1
minor = 9.99 min, major = 15.02 min, ee = 93%]. H NMR and 13C
NMR were consistent with reported data.5a,c
tert-Butyl-(S)-4,5-bis(3,4-dimethoxyphenyl)-2-(3-methoxy-3-oxo-
propyl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (3mf). The
general procedure G1 was used with 55.2 mg (0.22 mmol, 0.2 M)
of enantiopure 3-azetidinone 2f, 96.0 mg (0.32 mmol) of alkyne 1m,
7.0 mg (0.01 mmol) of Ni(PPh3)2Cl2, and 2.8 mg (0.04 mmol) of Zn
powder in acetonitrile. The reaction mixture was heated at 80 °C for
20 h. The remaining residue was purified by silica gel flash column
chromatography using 40−50% ethyl acetate in hexanes (Rf = 0.25 in
50% EtOAc/hexanes) to afford the title compound 3mf (105.0 mg,
Benzyl-(S)-2-(3-methoxy-3-oxopropyl)-3-oxo-4,5-dipropyl-3,6-di-
hydropyridine-1(2H)-carboxylate (3ae). The general procedure G1
was used with 53.3 mg (0.18 mmol, 0.2 M) of enantiopure 3-
azetidinone 2e, 30.2 mg (0.27 mmol) of 4-octyne 1a, 6.0 mg (0.01
mmol) of Ni(PPh3)2Cl2, and 2.4 mg (0.04 mmol) of Zn powder in
acetonitrile. The reaction mixture was heated at 60 °C for 20 h. The
remaining residue was purified by silica gel flash column chromatog-
raphy using 10−20% EtOAc in hexanes (Rf = 0.25 in 20% EtOAc/
hexanes) to afford the title compound 3ac (63.4 mg, 0.16 mmol, 86%)
as colorless oil. [α]D 20 = 13.2 (c = 1.0, CHCl3); (Daicel Chiralpak AY-
H Column, 5−15% i-PrOH, 25 °C, flow rate = 2 mL/min, 160 bar),
Retention time: major = 12.76 min, minor = 14.68 min, ee = 97%].
1H NMR (400 MHz, CDCl3): δ (ppm) 7.36 (brs, 5H), 5.13 (brs,
2H), 4.48−4.67 (m, 2H), 3.78−3.91 (m, 1H), 3.61 (s, 3H), 2.17−2.42
(m, 6H), 1.94 (m, 2H), 1.56 (m, 2H), 1.33 (sext, J = 7.6 Hz, 2H), 1.00
(m, 3H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 194.7, 173.2, 155.1, 153.8, 136.1, 133.0, 128.8, 128.5, 128.4,
68.0, 59.5, 51.9, 43.4, 34.2, 30.8, 26.9, 25.7, 22.7, 21.8, 14.5, 14.4. IR
(CH2Cl2, cm−1): 2959, 2872, 1734, 1700, 1668, 1635, 1559, 1498,
1424, 1384, 1230, 1176, 1157, 1108, 1015, 736, 697, 668. HRMS (ESI-
TOF) m/z calcd for C23H31NO5Na [M + Na]+ 424.2100, found
424.2095.
20
0.19 mmol, 88%) as yellow gel. [α]D = −113.9 (c = 1.0, CHCl3);
(Daicel Chiralpak OZ-H Column, 5−15−50% i-PrOH, 40 °C, flow
rate = 30 mL/min, 200 bar), Retention time: major = 13.71 min,
minor = 15.17 min, ee = 95%].
1H NMR (400 MHz, CDCl3): δ (ppm) 6.87 (brm, 1H), 6.74 (d, J =
8.0 Hz, 2H), 6.59 (d, J = 8.0 Hz, 1H), 6.50 (s, 2H), 5.28 (brd, J = 20.4
Hz, 1H), 4.74 (brs, 1H), 4.05 (brd, J = 20.0 Hz, 1H), 3.84 (s, 3H),
3.83 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.53 (s, 3H), 2.50 (m, 2H),
2.18 (m, 2H), 1.52 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm)
194.7, 173.3, 154.5, 153.7, 149.9, 148.7, 148.5, 133.3, 129.0, 127.1,
123.8, 121.7, 114.5, 112.8, 111.0, 110.9, 110.7, 81.6, 59.9, 56.01, 56.00,
55.8, 52.0, 43.7, 39.1, 30.9, 28.6, 25.5. IR (CH2Cl2, cm−1): 2917, 2848,
1736, 1695, 1600, 1594, 1463, 1411, 1366, 1320, 1254, 1205, 1161,
764. HRMS (ESI-TOF) m/z calcd for C30H37NO9Na [M + Na]+
578.2366, found 578.2365.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01458.
Chromatograms of racemic and chiral dehydropiper-
idinones. 1H NMR and 13C NMR spectra of compounds
(PDF)
Benzyl-(S)-4,5-bis(3,4-dimethoxyphenyl)-2-(3-methoxy-3-oxo-
propyl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (3me). The
general procedure G1 was used with 52.7 mg (0.18 mmol, 0.2 M)
of enantiopure 3-azetidinone 2e, 81.0 mg (0.27 mmol) of alkyne 1m,
5.9 mg (0.01 mmol) of Ni(PPh3)2Cl2, and 2.4 mg (0.04 mmol) of Zn
AUTHOR INFORMATION
■
Corresponding Author
*louie@chem.utah.edu
G
DOI: 10.1021/acs.joc.5b01458
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Present Addresses
‡National Center for Advancing Translational Sciences, Na-
tional Institutes of Health, Rockville, Maryland 20850, United
States.
§Discovery Chemistry, Merck & Co. Inc., Rahway, New Jersey
07065, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NIH (GM076125) for financial
support. We thank Dr. J. Muller of the University of Utah for
providing HRMS. We thank Harsh Patel (Sigman Group) at
the University of Utah for the help with the use of SFC
instrument for determination of enantiomeric excess. We also
thank Nabajit Lahiri from the Louie group for the synthesis of
compound 3ba.
REFERENCES
■
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DOI: 10.1021/acs.joc.5b01458
J. Org. Chem. XXXX, XXX, XXX−XXX