Enantioselective Desymmetrization of Glutarimides Catalyzed by Oxazaborolidines Derived from cis-1-Amino-indan-2-ol

Article abstract of DOI:10.1021/acs.joc.5b02177

Enantioselective reductive desymmetrization of glutarimides has been achieved employing an oxazaborolidine catalyst derived from cis-1-amino-indan-2-ol. The reaction was found to proceed through a stereoablative process that upgraded the enantioselectivity of an intermediate hydroxy-lactam. The reaction was generally tolerant of a number of substituents in the 4-position, giving enantiomeric excesses of greater than 82%.

Full text of DOI:10.1021/acs.joc.5b02177

Article
pubs.acs.org/joc
Enantioselective Desymmetrization of Glutarimides Catalyzed by
Oxazaborolidines Derived from cis-1-Amino-indan-2-ol
Ibrahim U. Kutama and Simon Jones*
Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield, S3 7HF, U.K.
S
* Supporting Information
ABSTRACT: Enantioselective reductive desymmetrization of glutarimides has
been achieved employing an oxazaborolidine catalyst derived from cis-1-amino-
indan-2-ol. The reaction was found to proceed through a stereoablative process
that upgraded the enantioselectivity of an intermediate hydroxy-lactam. The
reaction was generally tolerant of a number of substituents in the 4-position,
giving enantiomeric excesses of greater than 82%.
the first by Simpkins and co-workers using a chiral bis-lithium
INTRODUCTION
■
amide base to give chiral 3,4-disubstituted piperidin-2,5-
diones,15 and the second by Ikariya and co-workers using
chiral Cp*Ru(PN) catalysts to affect the enantioselective
hydrogenative desymmetrization to give the corresponding
hydroxyamides in excellent ee’s (88−98%).16,17 Here, we
present the enantioselective desymmetrization of 3-substituted
glutarimides using oxazaborolidine catalysts derived from cis-1-
amino-indan-2-ol.
Desymmetrization to access chiral molecules is a popular
strategy in organic synthesis, providing compounds with
multiple stereogenic centers in one operation. The synthetic
chemistry used in these strategies can be wide-ranging, for
example, the addition of chiral alcohols to cyclic meso-
anhydrides to yield diastereomerically enriched mono esters,1
or the use of chiral C3-symmetric zirconium(IV) and C2-
symmetric chromium(III) complexes to catalyze the addition of
azide nucleophiles to meso-epoxides.2 Desymmetrization of five-
membered ring meso-imides is an important approach, as
enantioselective reduction of one of the carbonyl groups leads
to the chiral 5-hydroxy-2-pyrrolidinones, important intermedi-
ates in the synthesis of many natural products and other
important heterocyclics.3−5 Strategies within this area of
chemistry include the use of chiral auxiliaries,6 BINAL-H
complexes,7 and thiazazincolidine complexes8 for enantiose-
lective reduction to affect such transformations. Oxazabor-
olidine mediated borane reduction, using catalysts derived from
α,α-diphenylprolinol, has also been reported, but requires as
much as 50 mol % catalyst to obtain high yield and
selectivity.9,10 Several reports from this research group have
shown that alternative oxazaborolidine catalysts derived from
cis-1-amino-indan-2-ol are very effective for this desymmetriza-
tion process, proceeding with good enantiomeric excess at
significantly lower catalyst loadings compared to reactions using
the prolinol-derived catalyst,11 with further studies demonstrat-
ing the crucial role of the nitrogen substituent in obtaining high
selectivities.12 The use of these catalysts for the kinetic
resolution of racemic C-3 substituted imides has also been
reported.13 More recently, in attempting to accessing the target
molecule pyrrolam A, we have disclosed a hitherto unreported
stereoablative process that serves to upgrade the enantiose-
lectivity of this process.14
RESULTS AND DISCUSSION
■
The 3-aryl-substituted glutaric acids 1b−1f required for
preparing the glutarimides were synthesized from the
corresponding aldehydes by adapting literature procedures.
The aldehydes were first converted to the 2-substituted
tetraethylpropane tetracarboxylates through Knoevenagel con-
densation, followed by Michael addition.18 In the case of p-
substituted aromatic aldehydes, these solvent-free conditions do
not give the required tetracarboxylates but instead yield the
corresponding benzoic acid. However, dropwise addition of a
solution of the aldehyde in toluene to a mixture of
diethylmalonate and AlCl3 in toluene in the Knoevenagel
condensation step led to the required product. For the 3-alkyl
glutaric acids 1h and 1i, the method of Theisen et al. gave
better yields, which uses ethyl cyanoacetate in the Knoevenagel
step and dimethyl sodiomalonate for the Michael addition
(Scheme 1).19 The resultant dimalonates then underwent acid
hydrolysis and decarboxylation, giving the corresponding
glutaric acids in moderate yields (Scheme 1). 3-Phenylglutaric
acid 1a and 3-methylglutaric acid 1g are commercially available
and were used as purchased. The glutarimides 3, 4a−i, 5, and 6
were accessed in a procedure developed by Ikariya et al. by
transforming the glutaric acids 1a−i to the corresponding
anhydrides 2a−i, which were subsequently converted to the
imides (Scheme 1, Table 1).16
Although there has been much work on the desymmetriza-
tion of five-membered ring meso-imides, the six-membered ring
glutarimides have received little attention. There appear to be
only two strategies developed to desymmetrize glutarimides,
Received: September 16, 2015
© XXXX American Chemical Society
A
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Scheme 1. Route to Glutarimide Substrates
Table 1. Synthesis of 3-Substituted Glutaric Acids, Anhydrides, and Glutarimides
yield
a
entry
R1
R2
glutaric acid
anhydride
imide
b
1
2
Ph
Ph
Ph
Ph
4-MeOC6H4
CH2C6H5
1a
2a 82%
2a 82%
2a 82%
2a 82%
2b 75%
2c 93%
2d 73%
3e 85%
3f 80%
3g 79%
3h 79%
3i 70%
3 80%
b
1a
4a 85%
5 71%
b
3
CH2(2-MeC6H4)
CH2(2-MeOC6H4)
CH2C6H5
1a
b
4
1a
6 60%
5
2-FC6H4
4-FC6H4
2-MeC6H4
4-MeC6H4
1-naphthyl
Me
1b 52%
1c 57%
1d 51%
1e 50%
1f 60%
4b 87%
4c 71%
4d 60%
4e 67%
4f 52%
4g 68%
4h 70%
4i 89%
6
CH2C6H5
7
CH2C6H5
8
CH2C6H5
9
CH2C6H5
b
10
11
12
CH2C6H5
1g
iPr
CH2C6H5
1h 35%
1i 58%
t-Bu
CH2C6H5
a
b
Refers to yield of isolated product after 3-step sequence. Commercially available material, so no yield reported.
The initial screening for the best desymmetrization
Scheme 2. Reduction of meso-Glutarimides 3, 4a, 5, and 6
conditions was first carried out on N-PMP protected 3-
phenylglutarimide 3 using both B-OMe catalyst 7 and B-Me
catalyst 8 employing BH3·THF as borane source. Two methods
of preparing the catalysts were evaluated; the first involved
preparing the stock solution of the catalyst in situ at room
temperature and using it immediately, while the second
involved repeated azeotropic distillations before the final
stock solution of the catalyst was made. In all cases, monitoring
of the reaction by TLC indicated an optimum conversion to
product after 3 h, and therefore, the reactions were stopped at
this point and the crude mixture reduced with triethylsilane to
convert the intermediate hydroxyl-lactam to the more stable 2-
piperidinone 10a to aid analysis (Scheme 2, Table 2). In all
cases, the presence of the piperidine 11a was observed, formed
by over-reduction of the intermediate hydroxy-lactam. This
relatively rapid formation of the doubly reduced product was
observed in earlier work on related N-PMP five-membered
imides.14
(Table 2, entry 1), while method B gave 43% yield of the
desired product 10a and 15% of the undesired product 11b
(Table 2, entry 2). For the B-Me catalyst, a significant
difference in both yield and enantioselectivity was observed for
the two methods of preparing the catalyst (Table 2, entries 3
and 4). Only 18% yield and 53% ee of the desired product were
When using the N-PMP substrate 3 with the B-OMe catalyst,
both methods of preparation gave excellent ee’s of piperidinone
10a; however, method A produced the 2-piperidinone 10a in a
48% yield and the undesired piperidine 11a in a 21% yield
B
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a
Table 2. Screening Catalysts for Desymmetrization of Glutarimides 3, 4a, 5, and 6
b
c
entry
substrate
catalyst
method
product/yield (%)
10a−d ee (%)
d
1
2
3
7
7
8
8
7
7
8
8
9
8
8
A
3a (20)
3a (37)
3a (66)
3a (28)
4a (60)
4a (59)
4a (62)
4a (20)
10a (48)
10a (43)
10a (18)
10a (33)
10b (34)
10b (30)
10b (20)
10b (60)
10b (13)
10c (25)
10d (21)
11a (21)
11a (15)
11a (10)
11a (30)
11b (5)
11b (5)
11b (9)
11b (12)
99
99
53
95
85
92
80
90
14
88
90
e
3
B
d
3
3
A
e
4
3
B
d
5
4a
4a
4a
4a
4a
5
A
e
6
B
d
7
A
e
8
B
e
f
f
10
11
12
B
ND
ND
e
f
f
B
ND
ND
e
f
f
6
B
ND
ND
a
Reactions conducted by treating a solution of the glutarimide 3 in dry CH2Cl2 with 10 mol % of the catalyst solution and 1 equiv of BH3·THF at rt
b
for 3 h, followed workup, dissolution into CH2Cl2 and treatment with Et3SiH/TFA for 1 h. Refers to isolated components after column
chromatography. Determined by chiral phase HPLC. Catalyst prepared by mixing (1R,2S)-cis-1-aminoindan-2-ol (1.00 mmol) and either
c
d
trimethylborate (0.10 mL, 1.00 mmol) or trimethylboroxine (0.05 mL, 0.33 mmol) in THF (3 mL) and allowing to stir for 45 min, before dilution to
e
5 mL with THF. Catalyst prepared by reaction of (1R,2S)-cis-amino-2-indanol (1.00 mmol) in dry toluene (3 mL) with either trimethylboroxine
(0.33 mmol) or trimethylborate (1.00 mmol) and allowed to stir for 30 min before azeotropic distillation with dry toluene. Dry dichloromethane (5
f
mL) was added to give a stock solution of the catalyst. ND: not determined.
obtained when the catalyst was prepared in situ at room
temperature, while the method involving azeotropic distillation
gave 33% yield of the desired product in 95% ee. The undesired
over-reduced product was also increased from 10% to 30%.
The desymmetrization of 3-phenyl N-benzyl glutarimide
analogue 4a was also explored using both B-Me and B-OMe
catalysts (Table 2, entries 5−8). The formation of the
piperidine product 11b was significantly slower compared to
N-PMP glutarimide 3, which allowed the reaction time to be
extended to as long as 24 h. As expected, a slight decrease in
selectivity was observed with both catalysts showing consis-
tency with observations from earlier work on five-membered
meso-imides.12 As with the PMP substrates, the B-OMe catalyst
gave rather disappointing results, but again, use of the repetitive
azeotropic distillation protocol for the preparation of B-Me
catalyst led to a significant increase in the yield of the
desymmetrised product, from 33% (Table 2, entry 4) to 60%
(Table 2, entry 8), with only a slight decrease in
enantioselectivity. Thus, this was adopted as the optimum
catalyst and procedure. For comparison purposes, desymmet-
rization of N-benzyl-4-phenylpiperidin-2,5-dione 4a using these
optimized conditions with a catalyst prepared in situ from (S)-
(−)-α,α-diphenyl-2-pyrrolidinemethanol 9 gave only 13% yield
and 14% ee of the lactam product 10b (Table 2, entry 10). This
showed a remarkable superiority of oxazaborolidines derived
from cis-1-amino-indan-2-ol over those derived from α,α-
diphenyl prolinol with these substrates.
B-Me catalyst 8, employing the repeated distillation procedure
since the highest yield of the over-reduced compound with a
significant change in selectivity was observed (Scheme 3). The
Scheme 3. Stereoablation Experiment with N-PMP
Glutarimide 3
N-PMP glutarimide substrate 3 was first reduced using both
enantiomers of the B-Me catalyst 8 separately under standard
conditions but purifying the intermediate hydroxy-lactams by
flash column chromatography. This led to isolation of the two
enantiomers of the hydroxy-lactam 12, both as a 2:1
diastereomeric ratio, in 20% yield for (1R,2S) catalyst and
27% yield for (1S,2R) catalyst, respectively. A scalemic mixture
of the two enantiomers of the hydroxy-lactam 12 was then
prepared by mixing these in a 2:1 ratio (1R,2S:1S,2R), and a
portion of this quantitatively converted to the lactam to
determine the ee. A sample of the scalemic hydroxyl-lactam
mixture was then subjected to reduction with the (1R,2S)
version of the B-Me catalyst, followed by further reduction to
the corresponding lactam. The same procedure was repeated
with the (1S,2R) version of the catalyst for comparison.
When a representative sample from the scalemic hydroxy-
lactam 12 (31% ee) was subjected to reduction with the
(1R,2S) enantiomer of the B-Me catalyst 8, followed by
subsequent reduction with Et3SiH, the lactam was obtained in
73% yield and 60% ee. As observed in previous work with the
anthracene-maleimide, there was an upgrade in the ee of the
scalemic hydroxy-lactam 12 from 31% to 60%, showing a
stereoablative reduction of one enantiomer of the hydroxy-
lactam by the (1R,2S) catalyst (presumably the minor
enantiomer) to the piperidine 11. On the other hand, when
Since the change in nitrogen protecting group afforded a
significant increase in yield, use of modified benzyl protecting
groups (2-methylbenzyl and 2-methoxybenzyl) was probed, but
this led to a significant fall in yield (25% and 21%, respectively)
but kept the ee at excellent levels (Table 2, entries 11 and 12).
This further reinforces the delicate nature of the N-protecting
groups in influencing the yield and/or selectivity of the
oxazaborolidine mediated desymmetrization. Hence, N-benzyl
was chosen as the optimum protecting group for further
exemplification.
Recently, we have reported the discovery of an in situ
stereoablative process, partly responsible for the excellent ee
observed for N-PMP anthracene-maleimide cyloadduct desym-
metrization.14 This was also investigated in this series, with the
C
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the reaction was repeated with the (1S,2R) version of the
catalyst, a near identical yield of 75% of the lactam was
obtained. However, unlike in the anthracene-maleimide case
where the ee of the scalemic hydroxy-lactam remained the same
with this version of the catalyst, the ee of the scalemic hydroxy-
lactam in this case eroded to 14%. This shows that the (1S,2R)
catalyst selectively reduces the opposite enantiomer of the
hydroxy-lactam, the major enantiomer in this case, thereby
diminishing the ee of the scalemic hydroxy-lactam 12. Thus, a
double stereo-differentiation process is operative, whereby
matched and mismatched catalyst/substrate combinations are
observed with the two versions of the B-Me catalyst. The near
identical yields of the lactam products obtained (73% and 75%)
under the same experimental conditions suggests similar
reaction rates of the two catalyst in this stereoablation reaction.
Further experiments probing the effect of the nitrogen
protecting group on the stereoablative process are underway.
The optimum catalyst system (Table 2, entry 8) was then
applied to the remainder of the N-benzyl glutarimides 4b−i
over a 24 h period in an attempt to maximize yield and
selectivity. All 4-aryl substrates 4a−e furnished the chiral 2-
piperidinones 13b−i in moderate yields (51−61%) and
excellent enantioselectivities of 82−92% ee (Scheme 4 and
reduced piperidine products were observed in variable
quantities in the H NMR spectrum of all unpurified reaction
mixtures, but in these examples, only the 2-piperidinone was
isolated and characterized.
1
The absolute configuration was assigned as (4R) by
comparison of the specific rotation with that of known
compounds for the N-benzyl-4-phenyl lactam 10b (Table 3,
entry 1) and N-benzyl-4-(4-fluorophenyl) lactam 13e (Table 3,
entry 5). The remainder of the N-benzyl products have
comparable values to these, with the exception of the 1-
naphthyl system (Table 3, entry 6), which has an outlying
negative value. For the N-PMP-phenyl lactam 3, the specific
rotation [+6.0 (c 1.3, CHCl3)] closely matched that of a related
known compound, N-PMP-4-(4-fluorophenyl)piperidin-2-one
[+8.0 (c 1.3, CHCl3)21].
To explain the stereochemical outcome, two possible pre-
transition state intermediates involving the imide and the
borane-activated oxazaborolidine catalyst can be imagined
(Figure 1). The models are based on the assumption that the
Scheme 4. Desymmetrization of N-Bn Glutarimides Using B-
Me Catalyst
Figure 1. Pre-transition state models for imide reduction.
catalyst is coordinated to the least hindered carbonyl lone pair
anti to the amide C−N bond. When placing the borane B−H
bond in the correct orientation to affect reduction of the
carbonyl group, interactions of the B−Me bond occur with the
group at the 4-position of the glutarimide.
In conclusion, an efficient strategy for the highly
enantioselective desymmetrization of glutarimides using
oxazaborolidines has been developed, providing an efficient
method to access important piperidine building blocks. This
strategy appears to be heavily reliant on catalysts derived from
cis-1-amino-indan-2-ol. Further evidence has also been accrued
for a stereoablative upgrade of enantioselectivity through a
double stereo-differentiation process with the N-PMP-3-phenyl
Table 3, entries 1−4). However, a notable decrease in both
yield and ee was observed when the aryl group was changed to
1-naphthyl (Table 3, entry 6). A change from 4-substituted
aryls to 4-substituted alkyls 3g−i was well tolerated, but a slight
drop in the yield of the products was noticeable (Table 3,
entries 6−8). As expected, residual starting material and over-
a
Table 3. Desymmetrization of N-Benzyl-3-Substituted Glutarimides 4a−i Using B-Me Catalyst 8
b
c
entry
imide
product/yield (%)
ee (%)
measured [α]2D0
literature [α]2D0
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
10b (60)
13b (61)
13c (51)
13d (51)
13e (54)
13f (20)
13g (46)
13h (41)
13i (46)
90
86
88
82
92
54
90
86
87
+33.0 (c 1.1, CHCl3)
+39.4 (c 0.3, CHCl3)
+ 33.6 (c 1.1, CHCl3)
+ 20.1 (c 2.1, CHCl3)
+30.0 (c 1.1, CHCl3)
−13.3 (c 0.5, CHCl3)
+ 46.6 (c 3.3, CHCl3)
+ 44.3 (c 1.9, CHCl3)
+ 36.8 (c 1.4, CHCl3)
+35.0 (c 1.1, CHCl3)20
unknown
unknown
unknown
+33.0 (c 1.1, CHCl3)20
unknown
4g
4h
4i
unknown
unknown
unknown
a
Reactions conducted by treating a solution of the glutarimide 4a−i in dry CH2Cl2 with 10 mol % of the catalyst solution [prepared by reaction of
(1R,2S)-cis-amino-indan-2-ol (1.00 mmol) in dry toluene (3 mL) with trimethylboroxine (0.33 mmol) and allowing to stir for 30 min before
azeotropic distillation with dry toluene. Dry dichloromethane (5 mL) was added to give a stock solution of the catalyst] and 1 equiv of BH3·THF at
rt for 24 h, followed workup, dissolution into CH2Cl2 and treatment with Et3SiH/TFA for 1 h. Refers to isolated material after column
b
c
chromatography. Determined by chiral phase HPLC.
D
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The combined organic extracts were dried over MgSO4 and filtered.
The solvent was removed in vacuo and excess diethylmalonate was
removed by vacuum distillation (130 °C, 9.5 × 10−1 mbar) to leave the
crude tetraethyl 2-(ortho or para substituted phenyl)propane-1,1,3,3-
tetracarboxylate as an oily residue, which was taken to the next
synthetic step without further purification. This material was dissolved
in conc. HCl (10 mL) and was heated at reflux for 24 h. The conc.
HCl was evaporated to about 4 mL, and fresh conc. HCl (10 mL) was
added and further heated at reflux for additional 24 h. The mixture was
allowed to cool to room temperature, and the solid was filtered and
recrystallized from EtOAc/petroleum ether (40−60).
General Procedure C for the Synthesis of 3-Isopropyl and 3-
tert-Butyl Glutaric Acids. A mixture of isobutyraldehyde or
trimethylacetaldehyde (1.0 equiv), ethylcyanoacetate (1.0 equiv), and
piperidine (0.01 equiv) in toluene (40 mL) was heated at reflux for 4 h
and allowed to cool to room temperature. The solvent was removed in
vacuo, and the residue was dissolved in CH2Cl2 (30 mL), dried over
MgSO4, and filtered. The solvent was evaporated in vacuo to give an
orange oily residue, which was added to a solution of dimethylsodio-
malonate [made from dimethylmalonate (1.0 equiv) and sodium (0.1
equiv) in dry MeOH (20 mL)]. The mixture was heated at reflux for
17 h, allowed to cool to room temperature, and acidified with 1 M HCl
(15 mL). The mixture was then extracted with ether (5 × 60 mL), and
the combined ethereal fractions were washed with water (60 mL),
dried over MgSO4, and filtered. The ether was evaporated under
reduced pressure to give the crude cyanotricarboxylate as an orange
oil. The crude cyanotricarboxylate in conc. HCl (10 mL) was heated at
reflux for 24 h. The conc. HCl was evaporated to about 4 mL, and
fresh conc. HCl (10 mL) was added. The reaction mixture was again
heated at reflux for an additional 24 h. The mixture was allowed to
cool to room temperature, poured into an ice/water mixture (50 mL),
and extracted with ether (5 × 30 mL). The combined ethereal
portions were washed with water (20 mL), dried over MgSO4, and
filtered, and solvent was evaporated in vacuo to obtain a dark brown
liquid, which, upon standing in a fridge, turned to a brown solid, which
was purified by recrystallization from EtOAc/hexane.
glutarimide substrate, and more experiments probing this
process are underway.
EXPERIMENTAL SECTION
■
General Experimental Methods. All solvents were obtained dry
from a dry solvent system, and glassware was flame-dried and cooled
under vacuum before use. All dry reactions were carried out under a
nitrogen atmosphere. TLC was carried out using aluminum TLC
sheets (silica gel 60 F254) and was performed using a UV lamp or by
dipping in KMnO4 solution, then exposure to heat. Flash column
chromatography was carried out with silica gel 40−63 μ, 60 Å. 1H and
13C NMR spectra were measured using CDCl3 as solvent unless
otherwise stated. 13C NMR spectra were recorded using the JMOD
method. Specific rotations were measured using the 589 nm (Na D-
Line) at 20 °C unless otherwise stated, and are given in 10−1 deg cm2
g−1. HPLC was carried out using a 4.6 mm × 250 mm chiral column
with conditions as described in individual experiments. The flow rate
was 1.00 mL/min, and the detector was set at 220 or 254 nm. All
chemicals were used as received without further purification except
(1R,2S)-cis-1-amino-2-indanol and (1S,2R)-cis-1-amino-2-indanol,
which were recrystallized from hot toluene prior to use. Borane−
THF was used as a 1 M solution in THF.
General Procedure A for the Synthesis of 3-(o-Substituted
Phenyl) Glutaric Acids.18 AlCl3 (0.1 equiv) was slowly added to a
mixture of 2-substituted benzaldehyde (1 equiv) and diethylmalonate
(2 equiv), and the mixture was stirred at room temperature for 24 h.
The mixture was poured into an ice−water/conc. HCl solution
mixture (25:5 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried over MgSO4 and filtered. The
solvent was removed in vacuo and excess diethylmalonate was removed
by vacuum distillation (130 °C, 9.5 × 10−1 mbar) to give the crude
diethyl o-substituted benzylidenemalonate, which was taken to the
next step without further purification. AlCl3 (0.05 equiv) was slowly
added to a mixture of the crude benzylidene malonate (1 equiv) and
diethylmalonate (1 equiv), and the mixture was stirred at 60 °C for 24
h. Another portion of AlCl3 (0.05 equiv) was slowly added to the
mixture, the reaction temperature was raised to 70 °C, and the mixture
was further stirred for an additional 24 h. The mixture was allowed to
cool to room temperature, poured into an ice/conc. HCl solution
mixture (25:5 mL), and extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were dried over MgSO4 and filtered. The
solvent was removed in vacuo and excess diethylmalonate was removed
by vacuum distillation (130 °C, 9.5 × 10−1 mbar) to give the crude
material as an oily residue, which was taken to the next synthetic step
without further purification. This material was dissolved in conc. HCl
(10 mL) and was heated at reflux for 24 h. The conc. HCl was
evaporated to about 4 mL, and fresh conc. HCl (10 mL) was added
and further heated at reflux for additional 24 h. The mixture was
allowed to cool to room temperature, and the solid was filtered and
recrystallized from EtOAc/petroleum ether (40−60).
3-(2-Fluorophenyl)pentan-1,5-dioic Acid 1b. Using general
procedure A starting with (8.250 g, 66.47 mmol) of 2-fluorobenzalde-
hyde and diethylmalonate (20.20 mL, 132.9 mmol), the crude diethyl
2-fluorobenzylidene malonate (17.00 g) was obtained as a yellow
liquid, which was not purified [selected data: δH (400 MHz, CDCl3)
1.26 (t, J = 6.6 Hz, 6H), 4.23 (qd, J = 7.1, 1.2 Hz, 4H), 7.00−7.07 (m,
2H), 7.28−7.34 (m, 1H), 7.36−7.40 (m, 1H), 7.83 (s, 1H)]. This was
taken onto the next step, and the tetraethyl 2-(2-fluorophenyl)-
propane-1,1,3,3-tetracarboxylate (23.29 g) was obtained as a yellow
liquid. [selected data: δH (400 MHz, CDCl3) 0.90 (t, J = 7.1 Hz, 6H),
1.11 (t, J = 7.1 Hz, 6H), 3.82 (q, J = 7.1 Hz, 4H), 3.98−4.06 (m, 6H),
4.36 (t, J = 9.4 Hz, 1H), 6.83−6.88 (m, 1H), 6.90−6.94 (m, 1H),
7.07−7.12 (m, 1H), 7.28−7.32 (m, 1H); δC (100 MHz, CDCl3) 13.7
(2 × CH3), 13.9 (2 × CH3), 38.3 (CH), 54.4 (2 × CH), 61.4 (2 ×
CH2), 61.7 (2 × CH2), 115.4 (d, JC‑F = 22.9 Hz, CH), 123.8 (d, JC‑F
=
3.3 Hz, CH), 124.8 (d, JC‑F = 14.6 Hz, C), 129.5 (d, JC‑F = 8.6 Hz, CH),
131.6 (CH), 161.2 (d, JC‑F = 248.0 Hz, C), 167.4 (2 × C), 167.8 (2 ×
C). Final decarboxylation gave a brown solid that was purified by
recrystallization from EtOAc/petroleum ether (40−60) to give the
title compound 1b as white crystals (7.66 g, 52% over 3 steps); mp =
140−142 °C; Anal. Calcd for C11H11FO4: C, 58.41; H, 4.90. Found: C,
58.23; H, 4.96; νmax/cm−1 (ATR) 2890 (brd, O-H), 1693 (s, CO),
1489 (w, Ar CC); δH (400 MHz, DMSO) 2.58 (dd, J = 15.9, 8.5 Hz,
2H), 2.66 (dd, J = 15.9, 6.6 Hz, 2H), 3.73 (quintet, J = 7.0 Hz, 1H),
7.09−7.15 (m, 2H), 7.21−7.27 (m, 1H), 7.37 (td, J = 7.7, 1.5 Hz, 1H),
12.16 (s, 2H); δC (100 MHz, DMSO) 31.8 (CH), 39.4 (2 × CH2),
115.8 (d, JC‑F = 22.5 Hz, CH), 124.7 (d, JC‑F = 2.9 Hz, CH), 128.7 (d,
JC‑F = 8.4 Hz, CH), 129.5 (d, JC‑F = 4.5 Hz, CH), 130.4 (d, JC‑F = 14.2
Hz, C), 160.7 (d, JC‑F = 244.0 Hz, C), 173.1 (2 × C); δF (235 MHz,
DMSO) −117.9; MS (ESI+ TOF) m/z: 227 ([MH]+, 70%), 209 ([M
− OH]+, 100%).
General Procedure B for the Synthesis of 3-(p-Substituted
Phenyl) Glutaric Acids.18 A solution of p-substituted benzaldehyde
(1 equiv) in toluene (10 mL) was added dropwise to a mixture of
AlCl3 (0.1 equiv) and diethylmalonate (2 equiv) in toluene (10 mL),
and the mixture was stirred at room temperature for 24 h. The mixture
was poured into an ice−water/conc. HCl solution mixture (25:5 mL)
and extracted with CH2Cl2 (3 × 25 mL). The combined organic
extracts were dried over MgSO4 and filtered. The solvent was removed
in vacuo and excess diethylmalonate was removed by vacuum
distillation (130 °C, 9.5 × 10−1 mbar) to give the crude diethyl p-
substituted benzylidene malonate as an oily residue, which was taken
to the next step without further purification. AlCl3 (0.05 equiv) was
slowly added to a mixture of the crude benzylidene malonate (1 equiv)
and diethylmalonate (1 equiv), and the mixture was stirred at 60 °C
for 24 h. Another portion of AlCl3 (0.05 equiv) was slowly added to
the mixture, the reaction temperature was raised to 70 °C, and the
mixture was further stirred for an additional 24 h. The mixture was
allowed to cool to room temperature, poured into an ice/conc. HCl
solution mixture (25:5 mL), and extracted with CH2Cl2 (3 × 25 mL).
3-(4-Fluorophenyl)pentan-1,5-dioic Acid 1c.17 Using general
procedure B starting with (10.00 g, 80.57 mmol) of 4-fluorobenzalde-
hyde and diethylmalonate (24.50 mL, 161.1 mmol), the crude diethyl
E
DOI: 10.1021/acs.joc.5b02177
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Article
4-fluorobenzylidenemalonate (18.22 g) was obtained as a yellow
liquid, which was not purified {selected data; δH (400 MHz, CDCl3)
0.90 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H), 4.16 (q, J = 7.1 Hz,
2H), 4.21 (q, J = 7.1 Hz, 2H), 6.82 [(AX)2, 2H], 7.35 [(AX)2, 2H],
7.56 (s, 1H)}. This was taken onto the next step, and the tetraethyl 2-
(4-fluorophenyl)propane-1,1,3,3-tetracarboxylate (23.29 g) was ob-
tained as a yellow liquid {selected data: δH (400 MHz, CDCl3) 0.89 (t,
J = 7.1 Hz, 6H), 1.08 (t, J = 7.1 Hz, 6H), 3.82 (q, J = 7.1 Hz, 4H),
3.94−4.02 (m, 7H), 6.80 (app t, J = 8.7 Hz, 2H), 7.24 [(AX)2, 2H]}.
Final decarboxylation gave a brown solid that was purified by
recrystallization from EtOAc/petroleum ether (40−60) to give the
title compound 1c as white crystals (9.881 g, 55% over 3 steps); mp =
145−147 °C (lit.22 146−147 °C); Anal. Calcd for C11H11FO4: C,
58.41; H, 4.90. Found: C, 58.36; H, 4.65; υmax/cm−1 (ATR) 2914 (brd,
O-H), 1708 (s, CO), 1604 (w, Ar CC), 1509 (w, Ar CC); δH
(400 MHz, DMSO) 2.51 (dd, J = 15.8, 8.8 Hz, 2H), 2.65 (dd, J = 15.8,
6.2 Hz, 2H), 3.37−3.45 (m, 1H), 7.10 [(AX)2, 2H], 7.31 [(AX)2, 2H],
12.11 (2brd s, 2H); δC (100 MHz, DMSO) 37.7 (CH), 40.6 (2 ×
CH2), 115.3 (d, JC‑F = 21.0 Hz, 2 × CH), 129.8 (d, JC‑F = 7.8 Hz, 2 ×
CH), 140.0 (d, JC‑F = 2.6 Hz, C), 161.3 (d, JC‑F = 242.0 Hz, C), 173.2
(2 × C); δF (235 MHz, DMSO) −116.8; MS (ESI+ TOF) m/z: 250
([MH + Na]+, 20%), 227 ([M + H]+, 30%), 209 ([M − OH]+, 100%).
All data are in accordance with the literature.
3-(2-Methylphenyl)pentan-1,5-dioic Acid 1d. Using general
procedure A starting with 2-methylbenzaldehyde (9.350 g, 77.82
mmol) and diethylmalonate (23.60 mL, 155.6 mmol), the crude
diethyl 2-methylbenzylidene malonate (17.00 g) was obtained as a
yellow liquid, which was not purified [selected data; δH (400 MHz,
CDCl3) 1.05 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 2.24 (s, 3H),
4.10 (q, J = 7.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 7.02−7.09 (m, 2H),
7.15 (app td, J = 7.5, 1.2 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.87 (s,
1H)]. This was taken onto the next step, and the crude tetraethyl 2-(2-
methylphenyl)propane-1,1,3,3-tetracarboxylate (15.90 g) was obtained
as a yellow liquid [selected data; δH (400 MHz, CDCl3) 0.89 (t, J = 7.1
Hz, 6H), 1.17 (t, J = 7.1 Hz, 6H), 2.42 (s, 3H), 3.80 (q, J = 7.1 Hz,
4H), 3.96 (d, J = 9.5 Hz, 2H), 4.03−4.11 (m, 4H), 4.51 (t, J = 9.5 Hz,
1H), 7.00−7.06 (m, 3H), 7.18 (d, J = 6.8 Hz, 1H)]. Final
decarboxylation gave a brown solid that was purified by recrystalliza-
tion from EtOAc/petroleum ether (40−60), giving the title compound
1d as white crystals (8.942 g, 52% over 3 steps); mp = 154−156 °C;
Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.71; H, 6.46;
υmax/cm−1 (ATR) 2971 (brd, O-H), 1708 (,s CO) 1514 (w, Ar C
C); δH (400 MHz, DMSO) 2.37 (s, 3H), 2.49−2.63 (m, 4H), 3.69−
3.76 (m, 1H), 7.04−7.16 (m, 3H), 7.27 (d, J = 7.6 Hz, 1H), 12.60 (s,
2H); δC (100 MHz, DMSO) 19.7 (CH3), 33.2 (CH), 40.5 (2 × CH2),
126.2 (CH), 126.4 (CH), 126.5 (CH), 130.5 (CH), 136.2 (C), 142.3
(C), 173.4 (2 × C); MS (ESI− TOF) m/z: 221 ([M − H]−, 100%).
3-(4-Methylphenyl)pentan-1,5-dioic Acid 1e.23 Using general
procedure B starting with 4-methylbenzaldehyde (10.00 g, 83.23
mmol) and diethylmalonate (25.30 mL, 166.5 mmol), the crude
diethyl 4-methylbenzylidenemalonate (17.23 g) was obtained as a
yellow liquid, which was not purified [selected data; δH (400 MHz,
CDCl3) 1.20 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 2.24 (s, 3H),
4.18 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 7.07 (d, J = 8.1 Hz,
1H), 7.25 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H)]. This was taken onto the
next step, and the crude tetraethyl 2-(4-methylphenyl)propane-1,1,3,3-
tetracarboxylate (25.20 g) was obtained as a yellow liquid [selected
data; δH (400 MHz, CDCl3) 0.98 (t, J = 7.1 Hz, 6H), 1.18 (t, J = 7.1
Hz, 6H), 2.22 (s, 3H), 3.90 (q, J = 7.1 Hz, 4H), 4.02−4.15 (m, 7H),
7.00 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H)]. Final
decarboxylation gave a brown solid that was purified by recrystalliza-
tion from EtOAc/petroleum ether (40−60) to give the title compound
1e as white crystals (10.55 g, 57% over 3 steps); mp = 122−124 °C
(lit.23 118−121 °C); Anal. Calcd for C12H14O4: C, 64.85; H, 6.35.
Found: C, 64.85; H, 6.13; υmax/cm−1 (ATR) 2925 (brd, O-H), 1704
(s, CO), 1515 (w, Ar CC); δH (400 MHz, DMSO) 2.25 (s, 3H),
2.48 (dd, J = 15.7, 8.7 Hz, 2H), 2.62 (dd, J = 15.7, 6.3 Hz, 2H), 3.34−
3.41 (m, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 12.06
(s, 2H); δC (100 MHz, DMSO) 21.1 (CH3), 38.0 (CH), 40.7 (2 ×
CH2), 127.8 (2 × CH), 129.2 (2 × CH), 135.8 (C), 140.8 (C), 173.3
(2 × C); MS (ESI+ TOF) m/z: 223 ([MH]+, 10%), 205 ([M − OH]+,
100%). Literature 13C NMR data are missing a signal at 40.7;
otherwise, all data are in accordance with the literature.
3-(1-Naphthyl)pentan-1,5-dioic Acid 1f.24 Using general proce-
dure A starting with 1-naphthaldehyde (10.35 g, 66.27 mmol) and
diethylmalonate (20.12 mL, 132.5 mmol), the crude diethyl 1-
naphthylidenemalonate (19.25 g) was obtained as a pale yellow liquid,
which was not purified [selected data; δH (400 MHz, CDCl3) 1.06 (t, J
= 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 4.38
(q, J = 7.1 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.49−7.56 (m, 2H), 7.61
(d, J = 7.8 Hz, 1H), 7.83−7.87 (m, 2H), 8.00 (d, J = 7.8 Hz, 1H), 8.50
(s, 1H)]. This was taken onto the next step, and the crude tetraethyl 2-
(1-naphthyl)propane-1,1,3,3-tetracarboxylate (32.56 g) was obtained
as a dark brown liquid [selected data; δH (400 MHz, CDCl3) 0.73 (t, J
= 7.1 Hz, 6H), 1.17 (t, J = 7.1 Hz, 6H), 3.67−3.76 (m, 4H), 4.06−4.14
(m, 4H), 4.24 (d, J = 9.0 Hz, 2H), 5.25 (t, J = 9.0 Hz, 1H), 7.37 (t, J =
7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.51−7.56 (m, 2H), 7.70 (d, J =
8.1 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H)]. Final
decarboxylation gave a brown solid that was purified by recrystalliza-
tion from EtOAc/petroleum ether (40−60), giving the title compound
1f as white crystals (10.20 g, 60% over 3 steps); mp = 185−187 °C
(lit.24 181.5 °C); Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found:
C, 69.64; H, 5.39; υmax/cm−1 (ATR) 2904 (brd, O-H), 1707 (s, C
O), 1599 (w, CC), 1511 (w, CC); δH (400 MHz, DMSO) 2.76
(d, J = 7.2 Hz, 4H), 3.39 (quintet, J = 7.2 Hz, 1H), 7.46−7.62 (m,
4H), 7.80 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.6
Hz, 1H), 12.17 (s, 2H); δC (100 MHz, DMSO) 38.0 (CH), 40.3 (2 ×
CH2), 123.5 (CH), 123.7 (CH), 125.9 (CH), 126.0 (CH), 126.6
(CH), 127.3 (CH), 129.2 (CH), 131.5 (C), 134.0 (C), 140.0 (C),
173.4 (2 × C); MS (ESI− TOF) m/z: 257 ([M − H]−, 100%). Only a
melting point is reported in the literature.
3-Isopropylpentan-1,5-dioic Acid 1h.25 Using general procedure C
starting with isobutyraldehyde (10.00 g, 138.7 mmol), the title
compound 1h was obtained as white crystals by recrystallization from
EtOAc/petroleum ether (40−60) (8.211 g, 34% over 3 steps); mp =
94−96 °C (lit.25 87.5−88.5 °C); Anal. Calcd for C8H14O4: C, 55.16;
H, 8.10. Found: C, 55.14; H, 8.16; υmax/cm−1 (ATR) 2966 (brd, O-
H), 1692 (s, CO); δH (400 MHz, DMSO) 0.82 (d, J = 6.9 Hz, 6H),
1.70 (pent d, J = 6.9, 3.4 Hz, 1H), 2.10−2.15 (m, 3H), 2.19−2.26 (m,
2H), 12.10 (brd s, 2H); δC (100 MHz, DMSO) 19.2 (2 × CH3), 29.9
(CH), 35.9 (2 × CH2), 37.5 (CH), 174.5 (2 × C); MS (ESI+ TOF) m/
z: 198 ([M + Na]+, 40%), 175 ([MH]+, 30%), 157 ([M − OH]+,
100%). Only a melting point is given in the literature.
3-tert-Butylpentan-1,5-dioic Acid 1i.26 Using general procedure C
starting with trimethylacetaldehyde (10.00 g, 116.3 mmol), the title
compound 1i was obtained as white crystals by recrystallization from
EtOAc/petroleum ether (40−60) (12.76 g, 58% over 3 steps); mp =
146−148 °C (lit.26 153−154 °C); υmax (ATR)/cm−1 2966 (brd, O-H),
1704 (s, CO); δH (400 MHz, CDCl3) 0.96 (s, 9H), 2.15−2.22 (m,
2H), 2.32 (tt, J = 9.7, 1.8 Hz, 1H), 2.66 (dd, J = 14.2, 1.8 Hz, 2H),
12.36 (brd s, 2H); δC (100 MHz, CDCl3) 27.3 (3 × CH3), 33.1 (C),
36.1 (2 × CH2), 42.4 (CH), 180.9 (2 × C); MS (ESI+ TOF) m/z: 230
([MH + Na]+, 30%), 212 ([MH]+, 55%), 189 ([M − OH]+, 100%),
171 (70%); HRMS (ESI+ TOF): calcd for C9H117O4 ([MH]+),
1891127; found, 189.1130. Only a melting point and H NMR were
reported in the literature.
General Procedure D for the Synthesis of Glutaric
Anhydrides.16 A mixture of glutaric acid in acetyl chloride (30
mL) was heated at reflux for 48 h. The mixture was cooled to room
temperature and the acetyl chloride was removed in vacuo to give a
brown liquid, which was purified by recrystallization.
4-Phenyldihydropyran-2,6-dione 2a.19 Using general procedure D
starting with commercially available 3-phenylglutaric acid (4.10 g, 0.02
mol), the title compound 2a was obtained as white crystals by
recrystallization from EtOAc/hexane (3.22 g, 84%); mp = 104−106
°C (lit.19 104−105 °C); υmax/cm−1 (ATR) 1812 (s, CO), 1752 (s,
CO); δH (400 MHz, CDCl3) 2.90 (dd, J = 17.5, 11.5 Hz, 2H), 3.11
(dd, J = 17.5, 4.3 Hz, 2H), 3.42 (tt, J = 11.5, 4.3 Hz, 1H), 7.21−7.24
(m, 2H), 7.34−7.45 (m, 3H); δC (100 MHz, CDCl3) 34.1 (CH), 37.2
(2 × CH2), 126.2 (2 × CH), 128.2 (CH), 129.4 (2 × CH), 139.1 (C),
F
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165.8 (C); MS (ESI+ TOF) m/z: 191 ([MH]+, 100%). All data are in
accordance with the literature.
4-Methyldihydropyran-2,6-dione 2g.30 Using general procedure D
starting with commercially available 3-methylglutaric acid (10.0 g, 63.5
mmol), the title compound 2g was obtained as white crystals by
recrystallization from EtOAc/petroleum ether (40−60) (6.89 g, 79%);
mp = 44−46 °C (lit.30 45−46 °C); Anal. Calcd for C6H8O3: C, 56.24;
H, 6.29. Found: C, 56.27; H, 6.31; υmax/cm−1 (ATR) 2977 (w, C-H),
1806 (s, CO), 1757 (s, CO), 1744 (s, CO); δH (400 MHz,
CDCl3) 1.16 (d, J = 6.4 Hz, 3H), 2.29−2.37 (m, 1H), 2.39−2.46 (m,
2H), 2.88 (dd, J = 17.1, 4.2 Hz, 2H); δC (100 MHz, CDCl3) 20.0
(CH3), 24.0 (CH), 37.7 (2 × CH2), 166.4 (2 × C); MS (TOF MS
ES+) m/z: 129 ([MH]+, 100%). Only a melting point and a copy of
4-(2-Fluorophenyl)dihydropyran-2,6-dione 2b. Using general
procedure D starting with glutaric acid 1b (3.00 g, 13.3 mmol), the
title compound 2b was obtained as white crystals by recrystallization
from EtOAc/petroleum ether (40−60) (2.00 g, 73%); mp 84−86 °C;
υmax/cm−1 (ATR) 1812 (w), 1754 (s, CO), 1710 (s, CO), 1586
(w, CC); δH (400 MHz, CDCl3) 2.99 (dd, J = 17.2, 11.2 Hz, 2H),
3.13 (dd, J = 17.2, 4.2 Hz, 2H), 3.66−3.73 (m, 1H), 7.11−7.21 (m,
3H), 7.33−7.38 (m, 1H); δC (100 MHz, CDCl3) 28.9 (CH), 35.5 (2 ×
CH2), 116.3 (d, JC‑F = 21.8 Hz, CH), 125.0 (d, JC‑F = 3.4 Hz, CH),
126.0 (d, JC‑F = 13.3 Hz, C), 127.2 (d, JC‑F = 3.8 Hz, CH), 129.9 (d,
JC‑F = 8.5 Hz, CH), 160.7 (d, JC‑F = 246.6 Hz, C), 165.7 (2 × C); δF
(235 MHz, CDCl3) −117.0; MS (EI+) m/z: 208 ([M]+, 30%), 122
(100%), 96 (20%); HRMS (EI+): calcd for C11H9FO3 ([M]+),
208.0536; found, 208.0544.
1
the H NMR spectrum are recorded in the literature.
4-Isopropyldihydropyran-2,6-dione 2h.19 Using general procedure
D starting with glutaric acid 1h (5.74 g, 33.0 mmol), a brown liquid
was obtained. This was vacuum distilled (bp = 110 °C, 85 × 10−2
mbar, lit.19 138 °C, 0.5 Torr) to give a colorless liquid, which solidified
upon standing. This was recrystallized from hexane to give the title
compound 2h as white crystals (3.93 g, 76%); mp = 25−26 °C (lit.19
25.5−26.5 °C); υmax/cm−1 (ATR) 2967 (m, C-H), 2878 (m, C-H),
1798 (s, CO), 1757 (s, CO), 1702 (s, CO); δH (400 MHz,
CDCl3) 0.97 (d, J = 6.8 Hz, 6H), 1.62 (octet, J = 6.8 Hz, 1H), 1.94
(dtt, J = 6.8, 11.5, 4.4 Hz, 1H), 2.43 (dd, J = 17.3, 11.5 Hz, 2H), 2.88
(dd, J = 17.3, 4.4 Hz, 2H); δC (100 MHz, CDCl3) 18.9 (2 × CH3),
31.3 (CH), 34.0 (2 × CH2), 35.0 (CH), 166.9 (2 × C); HRMS (ESI+
TOF): calcd for C8H13O3 ([MH]+), 157.0865; found, 157.0870. All
data are in accordance with the literature.
4-(4-Fluorophenyl)dihydropyran-2,6-dione 2c.27 Using general
procedure D starting with glutaric acid 1c (2.50 g, 11.1 mmol), the
title compound 2c was obtained as white crystals by recrystallization
from EtOAc/petroleum ether (40−60) (1.96 g, 85%); mp = 84−86
°C (lit.27 98 °C); Anal. Calcd for C11H9FO3: C, 63.46; H, 4.36. Found:
C, 63.22; H, 4.08; υmax/cm−1 (ATR) 1806 (s, CO), 1755 (s, C
O), 1717 (m, CO), 1606 (w, CC), 1512 (s, CC); δH (400
MHz, CDCl3) 2.86 (dd, J = 17.4, 11.4 Hz, 2H), 3.13 (dd, J = 17.4, 4.4
Hz, 2H), 3.45 (tt, J = 11.4, 4.4 Hz, 1H), 7.09−7.14 (m, 2H), 7.18−
7.23 (m, 2H); δC (100 MHz, CDCl3) 33.5 (CH), 37.3 (2 × CH2),
116.4 (d, JC‑F = 21.6 Hz, 2 × CH), 127.9 (d, JC‑F = 8.1 Hz, 2 × CH),
134.8 (d, JC‑F = 3.2 Hz, C), 162.3 (d, JC‑F = 248.5 Hz, C), 165.6 (2 ×
C); MS (EI+) m/z: 208 ([M]+, 40%), 123 (30%), 122 (100%). All data
are in accordance with the literature.
4-tert-Butyldihydropyran-2,6-dione 2i.19 Using general procedure
D starting with glutaric acid 1i (5.00 g, 26.6 mmol), a brown liquid was
obtained that was vacuum distilled (bp = 120 °C, 16 × 10−2 mbar,
lit.19 146−148 °C, 0.5 Torr) to give a colorless liquid, which solidified
upon standing to give the title compound 2i as a white solid (3.15 g,
70%); mp = 62−64 °C (lit.19 63.5−64.5 °C); υmax/cm−1 (ATR) 2967
(m, C-H), 1808 (s, CO), 1748 (s, CO); δH (400 MHz, CDCl3)
0.96 (s, 9H), 1.94 (tt, J = 12.9, 4.1 Hz, 1H), 2.35−2.43 (m, 2H), 2.90
(dd, J = 17.2, 4.1 Hz, 2H); δC (100 MHz, CDCl3) 26.4 (3 × CH3),
32.0 (C), 32.3 (2 × CH2), 38.7 (CH), 167.2 (C); HRMS (ESI+ TOF):
calcd for C9H15O3 ([MH]+), 171.1021; found, 171.1024. All data are
in accordance with the literature.
4-(2-Methylphenyl)dihydropyran-2,6-dione 2d.28 Using general
procedure D starting with glutaric acid 1d (3.00 g, 13.5 mmol), the
title compound 2d was obtained as white crystals by recrystallization
from EtOAc/hexane (2.07 g, 75%); mp = 103−105 °C (lit.28 106−109
°C); υmax (ATR)/cm−1 1808 (s, CO), 1749 (s, CO), 1712 (s,
CO); δH (400 MHz, CDCl3) 2.39 (s, 3H), 2.86 (dd, J = 17.4, 11.6
Hz, 2H), 3.08 (dd, J = 17.4, 4.4 Hz, 2H), 3.65 (tt, J = 11.6, 4.4 Hz,
1H), 7.13 (d, J = 6.9 Hz, 1H), 7.24−7.31 (m, 3H); δC (100 MHz,
CDCl3) 19.3 (CH3), 30.1 (CH), 36.6 (2 × CH2), 124.1 (CH), 127.1
(CH), 127.9 (CH), 131.4 (CH), 135.6 (C), 137.2 (C), 166.1 (2 × C);
MS (EI+) m/z: 204 ([MH]+, 40%), 144 (60%), 118 (100%), 91
(45%); HRMS (EI+): calcd for C12H12O3 ([MH]+), 204.0786; found,
204.0792. All data are in accordance with the literature.
General Procedure E for the Synthesis of Glutarimides.16
The corresponding amine (1.0 equiv) was slowly added to a solution
of the glutaric anhydride (1.0 equiv) and triethylamine (1.0 equiv) in
dry THF (30 mL). The mixture was heated at reflux for 48 h, cooled
to room temperature, and concentrated under reduced pressure.
Dichloromethane (15 mL) was added, and the resulting solution was
washed with 1 M HCl (5 mL) and brine (5 mL), dried over MgSO4,
and filtered. The solvent was removed in vacuo, and the residue was
dissolved in acetyl chloride (30 mL), heated at 60 °C for 48 h, and
cooled to room temperature. The solvent was removed in vacuo to give
a brown solid, which was purified by recrystallization.
N-(4-Methoxyphenyl)-4-phenylpiperidin-2,6-dione 3. Using gen-
eral procedure E starting with 3-phenylglutaric anhydride 2a (1.00 g,
5.26 mmol), p-anisidine (0.65 g, 5.26 mmol), and triethylamine (0.70
mL, 5.26 mmol), the title compound 3 was obtained as white crystals
by recrystallization from EtOAc (1.23 g, 80%); mp = 248−250 °C;
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
73.00; H, 5.52; N, 4.66; υmax/cm−1 (ATR) 1731 (m, CO), 1672 (s,
CO), 1610 (s), 1511 (s); δH (400 MHz, CDCl3) 3.02 (dd, J = 17.2,
11.4 Hz, 2H), 3.18 (dd, J = 17.2, 4.4 Hz, 2H), 3.58 (tt, J = 11.4, 4.4 Hz,
1H), 3.85 (s, 3H), 6.99−7.06 (m, 4H), 7.28−7.45 (m, 5H); δC (100
MHz, CDCl3) 34.7 (CH), 40.1 (2 × CH2), 55.4 (CH3), 114.7 (2 ×
CH), 126.4 (2 × CH), 127.3 (C), 127.7 (CH), 129.2 (2 × CH), 129.3
(2 × CH), 140.5 (C) 159.5 (C), 172.0 (2 × C); MS (TOF MS ES+)
m/z: 296 ([MH]+, 100%), 270 (10%), 249 (40%), 241 (8%).
1-(Phenylmethyl)-4-phenylpiperidin-2,6-dione 4a. Using general
procedure E starting with 3-phenylglutaric anhydride 2a (1.50 g, 7.89
mmol), benzylamine (0.85 g, 7.89 mmol), and triethylamine (1.10 mL,
7.89 mmol), the title compound 4a was obtained as white crystals by
recrystallization from EtOAc/petroleum ether (40−60) (1.87 g, 85%);
mp = 100−102 °C (lit.31 94−96 °C); υmax/cm−1 (ATR) 3031 (w, C-
H), 1726 (m, CO), 1668 (s, CO); δH (400 MHz, CDCl3) 2.85
4-(4-Methylphenyl)dihydropyran-2,6-dione 2e.29 Using general
procedure D starting with glutaric acid 1e (7.00 g, 31.5 mmol), the
title compound 2e was obtained as white crystals by recrystallization
from EtOAc/petroleum ether (40−60) (6.00 g, 93%); mp = 136−138
°C; υmax/cm−1 (ATR) 1806 (s, CO), 1753 (s, CO), 1518 (w,
CC); δH (400 MHz, CDCl3) 2.37 (s, 3H), 2.87 (dd, J = 17.4, 11.4
Hz, 2H), 3.12 (dd, J = 17.4, 4.5 Hz, 2H), 3.41 (tt, J = 11.4, 4.5 Hz,
1H), 7.11 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H); δC (100 MHz,
CDCl3) 21.0 (CH3), 33.7 (CH), 37.3 (2 × CH2), 126.1 (2 × CH),
130.0 (2 × CH), 136.1 (C), 138.0 (C), 165.9 (2 × C); MS (EI+) m/z:
204 ([M]+, 40%), 118 (100%), 91 (20%); HRMS (EI+): calcd for
C12H12O3 ([M]+), 204.0786; found, 204.0796. No analytical data were
given for the compound in the literature.
4-(1-Naphthyl)dihydropyran-2,6-dione 2f. Using general proce-
dure D starting with glutaric acid 1f (3.00 g, 0.01 mol), the title
compound 2f was obtained as white crystals by recrystallization from
EtOAc/petroleum ether (40−60) (2.24 g, 80%); mp = 148−150 °C;
Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.64; H, 4.68;
υmax/cm−1 (ATR) 1808 (s, CO), 1753 (s, CO), 1599 (w, CC);
δH (400 MHz, CDCl3) 3.05 (dd, J = 17.3, 10.5 Hz, 2H), 3.31 (dd, J =
17.3, 4.5 Hz, 2H), 4.28 (tt, J = 10.5, 4.5 Hz, 1H), 7.31 (d, J = 7.2 Hz,
1H), 7.49−7.53 (m, 1H), 7.57−7.66 (m, 2H), 7.87 (d, J = 8.2 Hz,
1H), 7.94−7.98 (m, 2H); δC (100 MHz, CDCl3) 29.5 (CH), 36.8 (2 ×
CH2), 121.8 (CH), 122.0 (CH), 125.5 (CH), 126.3 (CH), 127.1
(CH), 128.9 (CH), 129.5 (CH), 130.6 (C), 134.1 (C), 134.8 (C),
166.0 (2 × C); MS (TOF MS ES+) m/z: 241 ([MH]+, 100%).
G
DOI: 10.1021/acs.joc.5b02177
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The Journal of Organic Chemistry
Article
(dd, J = 17.2, 11.8 Hz, 2H), 3.05 (dd, J = 17.2, 4.3 Hz, 2H), 3.38 (tt, J
= 11.8, 4.3 Hz, 1H), 5.02 (s, 2H), 7.18−7.22 (m, 2H), 7.28−7.42 (m,
8H); δC (100 MHz, CDCl3) 34.6 (CH), 39.9 (2 × CH2), 42.9 (CH2),
126.3 (2 × CH), 127.5 (CH), 127.6 (CH), 128.4 (2 × CH), 128.9 (2
× CH), 129.1 (2 × CH), 137.1 (C) 140.6 (C), 171.6 (2 × C); MS
(TOF MS ES+) m/z: 280 ([MH]+, 100%). Only a melting point and
1H NMR were cited in the literature.17,31
1-(Phenylmethyl)-4-(2-fluorophenyl)piperidin-2,6-dione 4b.
Using general procedure E starting with glutaric anhydride 2b (2.00
g, 9.62 mmol), benzylamine (1.10 mL, 9.62 mmol), and triethylamine
(1.34 mL, 9.62 mmol), the title compound 4b was obtained as a white
powder by recrystallization from EtOAc/petroleum ether (40−60)
(1.7 g, 60%); mp = 76−78 °C; Anal. Calcd for C18H16FNO2: C, 72.71;
H, 5.42; N, 4.71. Found: C, 72.38; H, 5.26; N, 4.57; υmax/cm−1 (ATR)
3068 (w, C-H), 1728 (m, CO), 1672 (s, CO); δH (400 MHz,
CDCl3) 2.91 (dd, J = 16.9, 11.4 Hz, 2H), 3.04 (dd, J = 16.9, 4.0 Hz,
2H), 3.61−3.68 (m, 1H), 5.02 (s, 2H), 7.07−7.13 (m, 3H), 7.27−7.34
(m, 4H), 7.42 (d, J = 7.0 Hz, 2H); δC (100 MHz, CDCl3) 29.1 (CH),
38.3 (2 × CH2), 43.0 (CH2), 116.1 (d, JC‑F = 22.1 Hz, CH), 124.7 (d, J
C‑F = 3.3 Hz, CH), 127.2 (d, J C‑F = 4.0 Hz, CH), 127.4 (d, JC‑F = 14.4
Hz, C), 127.6 (CH), 128.5 (2 × CH), 129.0 (2 × CH), 129.3 (d, J C‑F
HRMS (ESI+ TOF): calcd for C19H20NO2 ([MH]+), 294.1494; found,
294.1504.
1-(Phenylmethyl)-4-(1-naphthyl)piperidin-2,6-dione 4f. Using
general procedure E starting with glutaric anhydride 2f (2.00 g, 8.33
mmol), benzylamine (0.90 mL, 8.33 mmol), and triethylamine (1.16
mL, 8.33 mmol), the title compound 4f was obtained as a white
powder by recrystallization from EtOAc/petroluem ether (40−60)
(1.42 g, 52%); mp = 116−118 °C; υmax/cm−1 (ATR) 3052 (w, C-H),
2964 (w, C-H), 1723 (m, CO), 1672 (s, CO), 1598 (m); δH (400
MHz, CDCl3) 2.98 (dd, J = 16.9, 10.8 Hz, 2H), 3.21 (dd, J = 16.9, 3.8
Hz, 2H), 4.15−4.22 (m, 1H), 5.08 (s, 2H), 7.23−7.38 (m, 4H), 7.40−
7.48 (m, 3H), 7.53−7.61 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.92 (d, J
= 7.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H); δC (100 MHz, CDCl3) 30.0
(CH), 39.5 (2 × CH2), 43.1 (CH2), 122.2 (CH), 122.3 (CH), 125.5
(CH), 126.1 (CH), 126.8 (CH), 127.6 (CH), 128.3 (CH), 128.5 (2 ×
CH), 129.1 (2 × CH), 129.3 (CH), 130.8 (C), 134.1 (C), 136.3 (C),
137.1 (C), 171.8 (2 × C); HRMS (ESI+ TOF): calcd for C22H20NO2
([MH]+), 330.1494; found, 330.1504.
1-(Phenylmethyl)-4-methylpiperidin-2,6-dione 4g.17 Using gen-
eral procedure E starting with glutaric anhydride 2g (3.50 g, 27.3
mmol), benzylamine (2.93 g, 27.3 mmol), and triethylamine (3.82 mL,
27.3 mmol), the title compound 4g was obtained as a white powder by
recrystallization from 50% EtOAc/hexane (4.13 g, 70%); mp = 68−70
°C; Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.74; H, 6.87; N, 6.46; υmax/cm−1 (ATR) 2961 (w, C-H), 1721 (m,
CO), 1665 (s, CO); δH (400 MHz, CDCl3) 1.08 (d, J = 6.4 Hz,
3H), 2.17−2.29 (m, 1H), 2.31−2.37 (m, 2H), 2.80 (dd, J = 16.7, 3.8
Hz, 2H), 4.97 (s, 2H), 7.24−7.32 (m, 3H), 7.37−7.39 (m, 2H); δC
(100 MHz, CDCl3) 20.3 (CH3), 24.5 (CH), 40.7 (2 × CH2), 42.7
(CH2), 127.4 (CH), 128.4 (2 × CH), 128.8 (2 × CH), 137.3 (C),
172.1 (2 × C); MS (TOF MS ES+) m/z: 218 ([MH]+, 100%). Only
1H NMR was cited in the literature.17
1-(Phenylmethyl)-4-isopropylpiperidin-2,6-dione 4h. Using gen-
eral procedure E starting with glutaric anhydride 2h (2.00 g, 12.8
mmol), benzylamine (1.37 g, 12.8 mmol), and triethylamine (1.80 mL,
12.8 mmol), a yellowish liquid was obtained that turned to a yellowish
solid upon standing. The solid was purified via flash column
chromatography eluting with EtOAc/petroleum ether (40−60) (3:7)
to afford the title compound 4h as a colorless liquid, which turned to a
white solid upon standing (2.10 g, 67%); mp = 45−46 °C; Anal. Calcd
for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.24; H, 7.75;
N, 5.53; υmax/cm−1 (ATR) 2960 (w), 2874 (w), 1724 (m, CO),
1668 (s, CO); δH (400 MHz, CDCl3) 0.95 (d, J = 6.7 Hz, 6H), 1.57
(octet, J = 6.7 Hz, 1H), 1.81−1.91 (m, 1H), 2.35 (dd, J = 17.1, 12.3
Hz, 2H), 2.82 (dd, J = 17.1, 4.0 Hz, 2H), 4.96 (s, 2H), 7.23−7.32 (m,
3H), 7.39 [(AX)2, 2H]; δC (100 MHz, CDCl3) 19.2 (2 × CH3), 31.4
(CH), 35.5 (CH), 36.9 (2 × CH2), 42.8 (CH2), 127.4 (CH), 128.4 (2
× CH), 128.8 (2 × CH), 137.2 (C), 172.6 (2 × C); HRMS (ESI+
TOF): calcd for C15H20NO2 ([MH]+), 246.1494; found, 246.1504.
1-(Phenylmethyl)-4-tert-butylpiperidin-2,6-dione 4i. Using gen-
eral procedure E starting with glutaric anhydride 2i (1.30 g, 7.65
mmol), benzylamine (0.89 g, 7.65 mmol), and triethylamine (1.10 mL,
7.65 mmol), a yellowish solid was obtained. The solid was purified via
flash column chromatography eluting with EtOAc:petroleum ether
(40−60) (3:7) to afford the title compound 4i as a colorless liquid,
which turned to a white solid upon standing (1.12 g, 57%); mp = 44−
46 °C; υmax/cm−1 (ATR) 2951 (w, C-H), 2874 (w, C-H), 1719 (m,
CO), 1666 (s, CO); δH (400 MHz, CDCl3) 0.93 (s, 9H), 1.86
(tt, J = 13.5, 3.8 Hz, 1H), 2.30−2.37 (m, 2H), 2.83 (dd, J = 17.0, 3.8
Hz, 2H), 4.96 (s, 2H), 7.24−7.33 (m, 3H), 7.37−7.40 (m, 2H); δC
(100 MHz, CDCl3) 26.5 (3 × CH3), 31.8 (C), 35.0 (2 × CH2), 39.2
(CH), 42.8 (CH2), 127.5 (CH), 128.4 (2 × CH), 128.8 (2 × CH),
137.2 (C), 172.9 (2 × C); HRMS (ESI+ TOF): calcd for C16H22NO2
([MH]+), 260.1651; found, 260.1650.
= 8.5 Hz, CH), 137.1 (C), 160.8 (d, J
= 246.6 Hz, C), 171.4 (2 ×
C‑F
C); δF (235 MHz, CDCl3) −117.4; MS (TOF MS ES+) m/z: 298
([MH]+, 100%).
1-(Phenylmethyl)-4-(4-fluorophenyl)piperidin-2,6-dione 4c.17
Using general procedure E starting with glutaric anhydride 2c (4.00
g, 19.20 mmol), benzylamine (2.10 mL, 19.2 mmol), and triethylamine
(2.60 mL, 19.20 mmol), the title compound 4c was obtained as a
white powder by recrystallization from EtOAc/petroleum ether (40−
60) (1.20 g, 67%); mp = 120−122 °C; Anal. Calcd for C18H16FNO2:
C, 72.71; H, 5.42; N, 4.71. Found: C, 72.47; H, 5.31; N, 4.67; υmax
/
cm−1 (ATR) 2955 (w, C-H), 1718 (m, CO), 1672 (s, CO), 1604
(m), 1512 (s); δH (400 MHz, CDCl3) 2.81 (dd, J = 17.1, 11.5 Hz,
2H), 3.00 (dd, J = 17.1, 4.3 Hz, 2H), 3.37 (tt, J = 11.5, 4.3 Hz, 1H),
5.01 (s, 2H), 7.02−7.07 (m, 2H), 7.13−7.17 (m, 2H), 7.28−7.32 (m,
3H), 7.38−7.41 (m, 2H); δC (100 MHz, CDCl3) 33.9 (CH), 40.0 (2 ×
CH2), 42.9 (CH2), 115.9 (d, J
= 21.5 Hz, 2 × CH), 127.6 (CH),
C‑F
127.9 (d, J
= 7.0 Hz, 2 × CH), 128.4 (2 × CH), 128.9 (2× CH),
C‑F
136.3 (d, J C‑F = 3.0 Hz, C), 137.0 (C), 162.0 (d, J C‑F = 246.6 Hz, C),
171.3 (2 × C); δF (235 MHz, CDCl3) −114.7; HRMS (ESI+ TOF):
calcd for C18H17FNO2 ([MH]+), 298.1243; found, 298.1233. Only 1H
NMR data were reported in the literature.17
1-(Phenylmethyl)-4-(2-methylphenyl)piperidin-2,6-dione 4d.
Using general procedure E starting with glutaric anhydride 2d (1.50
g, 7.35 mmol), benzylamine (0.81 mL, 7.35 mmol), and triethylamine
(1.02 mL, 7.35 mmol), the title compound 4d was obtained as a white
powder by recrystallization from EtOAc/petroleum ether (40−60)
(1.88 g, 87%); mp = 138−140 °C; υmax/cm−1 (ATR) 3017 (w, C-H),
1728 (m, CO), 1670 (s, CO), 1605 (w); δH (400 MHz, CDCl3)
2.37 (s, 3H), 2.81 (dd, J = 17.2, 11.8 Hz, 2H), 2.98 (dd, J = 17.2, 4.3
Hz, 2H), 3.58 (tt, J = 11.8, 4.3 Hz, 1H), 5.04 (s, 2H), 7.09−7.12 (m,
1H), 7.20−7.23 (m, 3H), 7.27−7.37 (m, 3H), 7.43−7.46 (m, 2H); δC
(100 MHz, CDCl3) 19.3 (CH3), 30.7 (CH), 39.3 (2 × CH2), 43.0
(CH2), 124.5 (CH), 126.8 (CH), 127.4 (CH), 127.6 (CH), 128.5 (2 ×
CH), 129.1 (2 × CH), 131.1 (CH), 135.6 (C), 137.1 (C), 138.7 (C),
171.9 (2 × C); HRMS (ESI+ TOF): calcd for C19H20NO2 ([MH]+),
294.1494; found, 294.1485.
1-(Phenylmethyl)-4-(4-methylphenyl)piperidin-2,6-dione 4e.
Using general procedure E starting with glutaric anhydride 2e (5.00
g, 24.5 mmol), benzylamine (2.67 mL, 24.5 mmol), and triethylamine
(3.40 mL, 24.5 mmol), the title compound 4e was obtained as a white
powder by recrystallization from EtOAc/petroleum ether (40−60)
(5.10 g, 71%); mp = 106−108 °C; υmax/cm−1 (ATR) 2955 (w, C-H),
1727 (m, CO), 1669 (s, CO); δH (400 MHz, CDCl3) 2.36 (s,
3H), 2.82 (dd, J = 17.1, 11.8 Hz, 2H), 3.03 (dd, J = 17.1, 4.2 Hz, 2H),
3.34 (tt, J = 11.8, 4.2 Hz, 1H), 5.02 (s, 2H), 7.09 (d, J = 8.0 Hz, 2H),
7.18 (d, J = 8.0 Hz, 2H), 7.26−7.35 (m, 3H), 7.39−7.52 (m, 2H); δC
(100 MHz, CDCl3) 21.0 (CH3), 34.2 (CH), 40.1 (2 × CH2), 42.9
(CH2), 126.2 (2 × CH), 127.5 (CH), 128.4 (2 × CH), 128.9 (2 ×
CH), 129.7 (2 × CH), 137.1 (C), 137.3 (C), 138.6 (C), 171.7 (2 × C);
1-(2-Methylphenylmethyl)-4-phenylpiperidin-2,6-dione 5. Using
general procedure E starting with 3-phenylglutaric anhydride 2a (1.70
g, 8.95 mmol), 2-methylbenzylamine (1.09 g, 8.95 mmol), and
triethylamine (1.25 mL, 8.95 mmol), the title compound 5 was
obtained as white crystals by recrystallization from EtOAc/petroleum
ether (40−60) (1.87 g, 71%); mp = 123−125 °C; Anal. Calcd for
H
DOI: 10.1021/acs.joc.5b02177
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C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.53; H, 6.51; N,
4.76; υmax/cm−1 (ATR) 2973 (w, C-H), 1727 (m, CO), 1667 (s,
CO); δH (250 MHz, CDCl3) 2.44 (s, 3H), 2.91 (dd, J = 17.0, 11.5
Hz, 2H), 3.10 (dd, J = 17.0, 4.4 Hz, 2H), 3.46 (tt, J = 11.5, 4.4 Hz,
1H), 5.01 (s, 2H), 6.96 [(AX)2, 1H], 7.08−7.18 (m, 3H), 7.23−7.27
(m, 2H), 7.32−7.44 (m, 3H); δC (100 MHz, CDCl3) 19.4 (CH3), 34.6
(CH), 39.9 (2 × CH2), 40.4 (CH2), 126.0 (CH), 126.0 (CH), 126.4 (2
× CH), 127.1 (CH), 127.7 (CH), 129.1 (2 × CH), 130.3 (CH), 134.7
(C), 135.8 (C), 140.5 (C), 171.7 (2 × C); MS (TOF MS ES+) m/z:
294 ([MH]+, 100%).
1-(2-Methoxyphenylmethyl)-4-phenylpiperidin-2,6-dione 6.
Using general procedure E starting with 3-phenylglutaric anhydride
2a (2.00 g, 10.5 mmol), 2-methoxybenzylamine (1.37 mL, 10.5
mmol), and triethylamine (1.47 mL, 10.5 mmol), the title compound 6
was obtained as white crystals by recrystallization from EtOAc/
petroleum ether (40−60) (1.97 g, 60%); mp = 98−100 °C; Anal.
Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.50; H,
6.06; N, 4.44; υmax/cm−1 (ATR) 2960 (w, C-H), 1728 (m, CO),
1671 (s, CO), 1603 (m); δH (400 MHz, CDCl3) 2.91 (dd, J = 17.1,
11.5 Hz, 2H), 3.08 (dd, J = 17.1, 4.3 Hz, 2H), 3.44 (tt, J = 11.5, 4.3 Hz,
1H), 3.86 (s, 3H), 5.08 (s, 2H), 6.88−6.96 (m, 3H), 7.22−7.28 (m,
3H), 7.31−7.35 (m, 1H), 7.38−7.40 (m, 2H); δC (100 MHz, CDCl3)
34.6 (CH), 38.5 (2 × CH2), 39.9 (CH2), 55.4 (CH3), 110.4 (CH),
120.3 (2 × CH), 124.8 (C), 126.5 (2 × CH), 127.0 (CH), 127.6 (CH),
128.2 (CH), 129.1 (CH), 140.7 (C) 157.1 (C), 171.5 (2 × C); HRMS
(ESI+ TOF): calcd for C19H20NO3 ([MH]+), 310.1443; found,
310.1451.
General Procedure F for the Asymmetric Reduction of 4-
Phenylglutarimides Using B-OMe Catalyst 7, Followed by
Conversion to the Corresponding Lactam. A solution of (1R,2S)-
cis-1-amino-indan-2-ol (0.15 g, 1.00 mmol) in THF (3 mL) was
treated with trimethylborate (0.10 mL, 1.00 mmol) and allowed to stir
for 45 min. The solution was then diluted to 5 mL by further addition
of THF, to give the catalyst 7 as a stock solution. The glutarimide
(1.00 mmol) was dissolved in dry DCM (30 mL) under a nitrogen
atmosphere, and this solution was treated with the catalyst stock
solution (0.50 mL, 10 mol %), then a dropwise addition of BH3·THF
(1.00 mL, 1.00 mmol), and allowed to stir at rt for 3 h (for N-PMP
glutarimide) or 24 h (for N-Bn glutarimide). The reaction was
quenched by the addition of MeOH (5 mL) and 1 M HCl (5 mL),
and extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were dried over MgSO4 and filtered. The solvent was removed
in vacuo to give the crude hydroxy-lactam as a white powder, which
was immediately redissolved in CH2Cl2 (25 mL) and treated with TFA
(1 mL) and triethylsilane (1 mL) in CH2Cl2 (5 mL). This mixture was
allowed to stir at rt for 1 h, after which the solution was added to an
ice−water mixture (15 mL), followed by extraction with CH2Cl2 (3 ×
15 mL). The combined organic extracts were washed with saturated
NaHCO3 (15 mL), dried over MgSO4, and filtered. The solvent was
removed in vacuo to give a white solid, which was purified via flash
column chromatography.
General Procedure G for the Asymmetric Reduction of
Glutarimides Using B-Me Catalyst 8, Followed by Conversion
to the Corresponding Lactam. A suspension of (1R,2S)-cis-amino-
2-indanol (0.15 g, 1.00 mmol) in dry toluene (3 mL) was treated with
trimethylboroxine (0.05 mL, 0.33 mmol) and allowed to stir under
nitrogen for 30 min. Dry toluene (5 mL) was added, and the reaction
distilled until approximately 2 mL of solvent remained. This procedure
was repeated twice, after which the final volume of toluene was
removed under pressure to give a yellow solid. Dry dichloromethane
(5 mL) was added to give a stock solution of the B-Me catalyst 8. The
catalyst (0.5 mL, 10 mol %) was added to the solution of the
glutarimide substrate (1.00 mmol) in dry dichloromethane (30 mL),
followed by a dropwise addition of BH3·THF (1 mL, 1.00 mmol). The
solution was then allowed to stir at room temperature for 3 h (for N-
PMP glutarimide) or 24 h (for N-Bn glutarimides). The reaction was
finally quenched by addition of MeOH (2 mL) and 1 M HCl (2 mL),
extracted with CH2Cl2 (3 × 15 mL), dried over MgSO4, and filtered.
The solvent was evaporated in vacuo to give the crude hydroxy-lactam
as a white powder, which was immediately redissolved in CH2Cl2 (30
mL) and treated with TFA (1 mL) and triethylsilane (1 mL) in
CH2Cl2 (5 mL). This mixture was allowed to stir at rt for 1 h, after
which the solution was added to an ice−water mixture (15 mL),
followed by extraction with CH2Cl2 (3 × 15 mL). The combined
organic extracts were washed with saturated NaHCO3 (3 × 15 mL),
dried over MgSO4, and filtered. The solvent was removed in vacuo to
give a crude white solid, which was purified via flash column
chromatography eluting with EtOAc/petroleum ether (40−60) (7:3).
Procedure for the Asymmetric Reduction of N-(Benzyl)-4-
phenylpiperidin-2,6-dione 4a Using Catalyst 9, Followed by
Conversion to the Corresponding Lactam 10b. A suspension of
(S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (0.25 g, 1.00 mmol) in
dry toluene (3 mL) was treated with trimethylboroxine (0.05 mL, 0.33
mmol) and allowed to stir under nitrogen for 30 min. Dry toluene (5
mL) was added, and the reaction distilled until approximately 2 mL of
solvent remained. This procedure was repeated twice, after which the
final volume of toluene was removed under pressure to give a yellow
solid. Dry dichloromethane (5 mL) was added to give a stock solution
of the B-Me CBS catalyst. The catalyst (0.50 mL, 10 mol %) was
added to the solution of the glutarimide substrate 4a (0.28 g, 1.00
mmol) in dry dichloromethane (30 mL), followed by a dropwise
addition of BH3·THF (1 mL, 1.00 mmol). The solution was then
allowed to stir at room temperature for 24 h. The reaction was finally
quenched by addition of MeOH (2 mL) and 1 M HCl (2 mL),
extracted with CH2Cl2 (3 × 15 mL), dried over MgSO4, and filtered.
The solvent was evaporated in vacuo to give the crude hydroxy-lactam
as a white powder, which was immediately redissolved in CH2Cl2 (30
mL) and treated with TFA (1 mL) and triethylsilane (1 mL) in
CH2Cl2 (5 mL). This mixture was allowed to stir at rt for 1 h, after
which the solution was added to an ice−water mixture (15 mL),
followed by extraction with CH2Cl2 (3 × 15 mL). The combined
organic extracts were washed with saturated NaHCO3 (15 mL), dried
over MgSO4, and filtered. The solvent was removed in vacuo to give a
crude white solid, which was purified via flash column chromatography
eluting with EtOAc:petroleum ether (40−60) (7:3) to afford the
corresponding lactam as a white solid (0.03 g, 13% over 2 steps, 14%
ee determined by HPLC on a Lux 3 μ Cellulose-2 column (hexane/2-
propanol = 80/20, flow rate = 1.0 mL/min, tminor = 21.1 min, tmajor
=
23.1 min). All analytical data correspond to those reported for
compound 10b.
(4R)-1-(4-Methoxyphenyl)-4-phenylpiperidin-2-one 10a. Using
glutarimide 3 (0.30 g, 1.00 mmol), the title compound was obtained
as a white solid using general procedure G (0.07 g, 33% over 2 steps,
95% ee determined by HPLC on a Cellulose-1 column (hexane/2-
propanol = 80/20, flow rate = 1.0 mL/min, tminor = 27.3 min, tmajor
=
29.9 min); mp = 204−206 °C; [α]2D0 + 6.0 (c 1.3, CHCl3; 95% ee);
vmax/cm−1 (ATR) 2940 (w, C-H), 1640 (s, CO), 1620 (m, CO),
1605 (m, CO), 1506 (s, CC); δH (400 MHz, CDCl3) 2.11−2.21
(m, 1H), 2.23−2.30 (m, 1H), 2.73 (dd, J = 17.5, 10.8 Hz, 1H), 2.92
(ddd, J = 17.5, 5.3 Hz, 1.9 Hz, 1H), 3.29 (tdd, J = 10.8, 5.3 Hz, 3.4 Hz,
1H), 3.65 (ddd, J = 10.8, 5.3, 3.4 Hz, 1H), 3.74−3.81 (m, 1H), 3.84 (s,
3H), 6.96 [(AX)2, 2H], 7.22 [(AX)2, 2H], 7.28−7.32 (m, 3H), 7.38−
7.42 (m, 2H); δC (100 MHz, CDCl3) 30.7 (CH2), 38.8 (CH), 39.8
(CH2), 51.0 (CH2), 55.5 (CH3), 114.6 (2 × CH), 126.6 (2 × CH),
126.9 (CH), 127.4 (2 × CH), 128.8 (2 × CH), 135.9 (C), 143.4 (C),
158.3 (C), 169.6 (C); HRMS (ESI+ TOF): calcd for C18H20NO2
([MH]+), 282.1494; found, 282.1493.
(4R)-1-(Phenylmethyl)-4-phenylpiperidin-2-one 10b.20 Using glu-
tarimide 4a (0.30 g, 1.00 mmol), the title compound 10b was obtained
as a white solid using general procedure G (0.16 g, 60% over 2 steps,
90% ee determined by HPLC on a Lux 3 μ Cellulose-2 column
(hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tmajor = 23.5
min, tminor = 26.1 min); mp = 80−82 °C (lit.32 88−90 °C); [α]D20
+
33.0 (c 1.1, CHCl3; 90% ee), lit.20 [α]D20 + 35.0 (c 1.1, CHCl3, 92.5%
ee); vmax/cm−1 (ATR) 1619 (s, CO), 1494 (m, CC); δH (400
MHz, CDCl3) 1.97 (dtd, J = 13.2, 10.8, 6.0 Hz, 1H), 2.07−2.14 (m,
1H), 2.63 (dd, J = 17.5, 11.0 Hz, 1H), 2.83 (ddd, J = 17.5, 5.2, 2.0 Hz,
1H), 3.13 (tdd, J = 11.0, 5.2, 3.1 Hz, 1H), 3.26−3.37 (m, 2H), 4.59 (d,
J = 14.5 Hz, 1H), 4.77 (d, J = 14.5 Hz, 1H), 7.21−7.39 (m, 10H); δC
(100 MHz, CDCl3) 30.3 (CH2), 38.7 (CH), 39.5 (CH2), 46.4 (CH2),
I
DOI: 10.1021/acs.joc.5b02177
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
50.0 (CH2), 126.5 (2 × CH), 126.8 (CH), 127.5 (CH), 128.2 (2 ×
CH), 128.6 (2 × CH), 128.8 (2 × CH), 137.1 (C), 143.4 (C), 169.3
(C); MS (EI+) m/z: 265 ([M]+, 100%), 174 (12), 131 (32), 104
(230), 131 (32), 91 (70). All data are in accordance with the
literature.20,32,33
(0.30 g, 1.00 mmol), but halting the reaction and purifying the crude
hydroxy-lactam before conversion to the N-PMP lactam, gave the title
compound 12 as a white powder in a 2:1 diastereomeric ratio (0.06 g,
20%); mp = 156−158 °C; [α]2D0 + 18.2 (c 1.7, CHCl3); vmax/cm−1
(ATR) 3188 (w, O-H), 2935 (w, C-H), 1644 (m, CO), 1620 (s,
CO), 1602 (s, CO), 1507 (s, CC); δH (400 MHz, CDCl3)
major diastereoisomer 2.60−2.74 (m, 2H), 2.86−2.96 (m, 2H), 3.21−
3.31 (m, 2H), 3.84 (s, 3H), 5.30−5.34 (m, 1H), 6.96−6.98 (m, 3H),
7.28−7.30 (m, 6H); δC (100 MHz, CDCl3) major diastereoisomer 30.7
(CH2), 33.1 (CH), 51.0 (CH2), 55.5 (CH3), 81.9 (CH), 114.8 (2 ×
CH), 126.7 (2 × CH), 127.4 (CH), 128.8 (2 × CH), 129.2 (2 × CH),
133.4 (C), 143.1 (C), 158.9 (C), 170.0 (C); HRMS (ESI+ TOF): calcd
for C18H19NO3 ([MH]+), 298.1443; found, 298.1446.
(4R)-1-(2-Methylbenzyl)-4-phenylpiperidin-2-one 10c. Using glu-
tarimide 5 (0.30 g, 1.00 mmol), the title compound 10c was obtained
as a white solid using general procedure G (0.07 g, 25% over 2 steps,
88% ee determined by HPLC on a Lux 3 μ Cellulose-2 column
(hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tmajor = 20.6
min, tminor = 22.3 min); mp = 72−74 °C; [α]2D0 + 26.6 (c 0.8, CHCl3;
88% ee); Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01.
Found: C, 81.81; H, 7.82; N, 4.85; vmax/ cm−1 (ATR) 3024 (w, C-H),
2915 (w, C-H), 1627 (s, CO), 1605 (m, CC); δH (400 MHz,
CDCl3) 1.93−2.03 (m, 1H), 2.09−2.15 (m, 1H), 2.34 (s, 3H), 2.64
(dd, J = 17.5, 11.1 Hz, 1H), 2.88 (ddd, J = 17.5, 5.2, 2.1 Hz, 1H), 3.15
(tdd, J = 11.1, 5.2, 3.1 Hz, 1H), 3.22−3.31 (m, 2H), 4.63 (d, J = 15.1
Hz, 1H), 4.81 (d, J = 15.1 Hz, 1H), 7.17−7.29 (m, 7H), 7.35−7.39
(m, 2H); δC (100 MHz, CDCl3) 19.25 (CH3), 30.3 (CH2), 38.7 (CH),
39.5 (CH2), 46.3 (CH2), 47.7 (CH2), 126.1 (CH), 126.5 (2 × CH),
126.8 (CH), 127.5 (CH), 128.1 (CH), 128.8 (2 × CH), 130.5 (CH),
134.5 (C), 136.6 (C), 143.4 (C), 169.2 (C); HRMS (ESI+ TOF): calcd
for C19H22NO ([MH]+), 280.1701; found, 280.1713.
(4R)-1-(Phenylmethyl)-4-(2-fluorophenyl)piperidin-2-one 13b.
Using glutarimide 4b (0.30 g, 1.00 mmol), the title compound 13b
was obtained as a white solid using general procedure G (0.17 g, 61%
over 2 steps, 86% ee determined by HPLC on a Lux 3 μ Cellulose-2
column (hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tmajor
=
16.4 min, tminor = 18.2 min); mp = 60−62 °C; [α]2D0 + 20.1 (c 2.1,
CHCl3; 86% ee); vmax/cm−1 (ATR) 2925 (w, C-H), 1616 (s, CO),
1580 (m, CC); δH (400 MHz, CDCl3) 1.98−2.10 (m, 2H), 2.64
(dd, J = 17.4, 10.8 Hz, 1H), 2.85 (ddd, J = 17.4, 5.3 Hz, 1.9 Hz, 1H),
3.25−3.38 (m, 2H), 3.45 (td, J = 10.8, 5.3, 3.9 Hz, 1H), 4.58 (d, J =
14.6 Hz, 1H), 4.76 (d, J = 14.6 Hz, 1H), 7.03−7.36 (m, 9H); δC (100
MHz, CDCl3) 28.9 (CH2), 32.2 (d, JC‑F = 1.5 Hz, CH), 38.0 (CH2),
(4R)-1-(2-Methoxybenzyl)-4-phenylpiperidin-2-one 10d. Using
glutarimide 6 (0.30 g, 1.00 mmol), the title compound 10d was
obtained as a white solid using general procedure G (0.06 g, 21% over
2 steps, 90% ee determined by HPLC on a Lux 3 μ Cellulose-2 column
(hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tmajor = 21.3
min, tminor = 23.6 min); mp = 80−82 °C; [α]2D0 + 21.7 (c 1.0, CHCl3;
90% ee); vmax/cm−1 (ATR) 2940 (w, C-H), 1636 (s, CO); δH (400
MHz, CDCl3) 1.95−2.03 (m, 1H), 2.09−2.13 (m, 1H), 2.62 (dd, J =
17.5, 11.1 Hz, 1H), 2.84 (ddd, J = 17.5 Hz, 5.3, 2.0 Hz, 1H), 3.15 (tdd,
J = 11.1, 5.3, 3.2 Hz, 1H), 3.31−3.37 (m, 2H), 3.86 (s, 3H), 4.65 (d, J
= 15.1 Hz, 1H), 4.77 (d, J = 15.1 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H),
6.97 (td, J = 7.5, 0.9 Hz, 1H), 7.23−7.30 (m, 5H), 7.34−7.38 (m, 2H);
δC (100 MHz, CDCl3) 30.4 (CH2), 38.7 (CH), 39.5 (CH2), 44.5
(CH2), 46.8 (CH2), 55.4 (CH3), 110.3 (CH), 120.7 (CH), 125.1 (C),
126.6 (2 × CH), 126.8 (CH), 128.5 (CH), 128.7 (2 × CH), 129.1
(CH), 143.6 (C), 157.6 (C), 169.4 (C); HRMS (EI+): calcd for
C19H21NO2 (M+), 295.1572; found, 295.1563; MS (EI+) m/z: 295
(M+, 100%), 264 (50), 176 (27), 149 (35), 121 (60), 91 (85).
1-(4-Methoxyphenyl)-4-phenylpiperidine 11a. Using general
procedure G and glutarimide 3 (0.30 g, 1.00 mmol), the title
compound 11a was obtained as white crystals (0.08 g, 30% over 2
steps); mp = 150−152 °C; Anal. Calcd for C18H21NO: C, 80.86; H,
7.92; N, 5.24. Found: C, 80.74; H, 7.91; N, 5.12; vmax/cm−1 (ATR)
2953 (w, C-H), 2938 (m, C-H), 2917 (m, C-H), 2810 (m, C-H), 1508
(s, CO); δH (400 MHz, CDCl3) 1.95−1.96 (m, 4H), 2.61−2.69 (m,
1H), 2.75−2.82 (m, 2H), 3.65−3.69 (m, 2H), 3.81 (s, 3H), 6.90
[(AX)2, 2H], 7.00 [(AX)2, 2H], 7.24−7.38 (m, 5H); δC (100 MHz,
CDCl3) 33.6 (2 × CH2), 42.4 (CH), 52.2 (2 × CH2), 55.6 (CH3),
114.4 (2 × CH), 118.9 (2 × CH), 126.3 (CH), 126.9 (2 × CH), 128.5
(2 × CH), 146.2 (C), 146.4 (C), 153.8 (C); HRMS (ESI+ TOF): calcd
46.3 (CH2), 50.1 (CH2), 115.6 (d, JC‑F = 22.4 Hz, CH), 124.4 (d, JC‑F
3.5 Hz, CH), 127.3 (d, JC‑F = 4.6 Hz, CH), 127.5 (CH), 128.2 (2 ×
CH), 128.3 (d, JC‑F = 8.4 Hz, CH), 128.7 (2 × CH), 130.1 (d, JC‑F
=
=
14.2 Hz, C), 137.0 (C), 160.6 (d, J
= 245.8 Hz, C), 169.1 (C); δF
C‑F
(235 MHz, CDCl3) −118.6; HRMS (EI+): calcd for C18H18FNO
(M+), 283.1372; found, 283.1382; MS (EI+) m/z: 283 (M+, 100%),
149 (50), 109 (25), 103 (58) 105 (93), 91 (95), 77 (98).
(4R)-1-(Phenylmethyl)-4-(4-fluorophenyl)piperidin-2-one 13c.
Using glutarimide 4c (0.30 g, 1.00 mmol), the title compound 13c
was obtained as a white solid using general procedure G (0.15 g, 54%
over 2 steps, 88% ee determined by HPLC on a Chiralpak IA column
(hexane/2-propanol = 93/7, flow rate = 1.0 mL/min, tminor = 38.2 min,
tmajor = 40.0 min); mp = 114−116 °C; [α]2D0 + 30.0 (c 1.1, CHCl3; 88%
ee, lit.20 [α]2D0 + 33.0 (c 1.07, CHCl3); vmax/cm−1 (ATR) 3071 (w, C-
H), 1625 (s, CO), 1601 (m, CC); δH (400 MHz, CDCl3) 1.87−
1.97 (m, 1H), 2.07−2.10 (m, 1H), 2.57 (dd, J = 17.4, 11.0 Hz, 1H),
2.83 (dd, J = 17.4, 3.4 Hz, 1H), 3.09−3.14 (m, 1H), 3.25−3.36 (m,
2H), 4.57 (d, J = 14.5 Hz, 1H), 4.77 (d, J = 14.5 Hz, 1H), 7.03 [(AX)2,
2H], 7.18 [(AX)2, 2H], 7.28−7.38 (m, 5H); δC (100 MHz, CDCl3)
30.3 (CH2), 38.0 (CH), 39.6 (CH2), 46.2 (CH2), 50.0 (CH2), 115.5
(d, JC‑F = 21.2 Hz, 2 × CH), 127.5 (CH), 128.0 (d, JC‑F = 7.8 Hz, 2 ×
CH), 128.2 (2 × CH), 128.7 (2× CH), 137.1 (C), 139.1 (d, JC‑F = 3.0
Hz, C), 161.7 (d, JC‑F = 245.0 Hz, C), 169.1 (C); δF (235 MHz,
CDCl3) −116.0; HRMS (ESI+ TOF): calcd for C18H19FNO ([MH+]),
284.1451; found, 284.1437. All data are in accordance with the
literature.20,33,36
(4R)-1-(Phenylmethyl)-4-(2-methylphenyl)piperidin-2-one 13d.
Using glutarimide 4d (0.30 g, 1.00 mmol), the title compound 13d
was obtained as a white solid using general procedure G (0.14 g, 51%
over 2 steps, 82% ee determined by HPLC on a Lux 3 μ Cellulose-2
1
for C18H22NO ([MH+]), 268.1701; found, 268.1693. Only H NMR
and low resolution mass spectrometry data were provided in the
34
1
column (hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tminor
=
literature. The literature H NMR data are mis-assigned.
15.3 min, tmajor = 18.3 min); mp = 68−70 °C; [α]2D0 + 39.4 (c 0.3,
CHCl3; 82% ee); vmax/cm−1 (ATR) 2925 (w, C-H), 1626 (s, CO),
1587 (m, CC); δH (400 MHz, CDCl3) 2.01−2.04 (m, 2H), 2.37 (s,
3H), 2.56 (dd, J = 17.5, 11.0 Hz, 1H), 2.81 (ddd, J = 17.5, 5.2, 1.9 Hz,
1H), 3.28−3.37 (m, 3H), 4.55 (d, J = 14.5 Hz, 1H), 4.85 (d, J = 14.5
Hz, 1H), 7.16−7.22 (m, 4H), 7.33−7.40 (m, 5H); δC (100 MHz,
CDCl3) 19.3 (CH3), 29.3 (CH2), 34.6 (CH), 39.0 (CH2), 46.5 (CH2),
50.1 (CH2), 125.0 (CH), 126.5 (CH), 126.6 (CH), 127.5 (CH), 128.3
(2 × CH), 128.7 (2 × CH), 130.7 (CH), 135.3 (C), 137.2 (C), 141.5
(C) 169.6 (C); HRMS (ESI+ TOF): calcd for C19H22NO ([MH+]),
280.1701; found, 280.1710.
1-(Phenylmethyl)-4-phenylpiperidine 11b. Using general proce-
dure G and glutarimide 3 (0.30 g, 1.00 mmol), the title compound 11b
was obtained as an undesired product as a yellow oil (0.03 g, 12% over
2 steps); vmax/cm−1 (ATR) 3026 (w, C-H), 2933 (m, C-H), 2798 (m,
C-H), 2754 (m, C-H), 1493 (m, CO); δH (250 MHz, CDCl3)
1.75−1.95 (m, 4H), 2.05−2.21 (m, 2H), 2.48−2.60 (m, 1H), 3.03−
3.10 (m, 2H), 3.60 (s, 2H), 7.20−7.40 (m, 10H); δC (75 MHz,
CDCl3) 33.6 (2 × CH2), 42.8 (CH), 54.3 (2 × CH2), 63.5 (CH2),
126.1 (CH), 126.9 (2 × CH), 127.0 (CH), 128.2 (2 × CH), 128.4 (2
× CH), 129.2 (2 × CH), 138.6 (C), 146.6 (C); HRMS (ESI+ TOF):
calcd for C18H22N ([MH+]), 252.1752; found, 252.1764. All data are
in accordance with the literature.35
(4R)-1-(Phenylmethyl)-4-(4-methylphenyl)piperidin-2-one 13e.
Using glutarimide 4e (0.30 g, 1.00 mmol), the title compound 13e
was obtained as a white solid using general procedure G (0.14 g, 54%
(6R)- and (6S)-(4R)-5-Hydroxy-1-(4-methoxyphenyl)-4-phenyl-
piperidin-2-one 12. Using general procedure G with glutarimide 3
J
DOI: 10.1021/acs.joc.5b02177
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
over 2 steps, 92% ee determined by HPLC on a Chiralpak IA column
(hexane/2-propanol = 92/7, flow rate = 1.0 mL/min, tminor = 31.3 min,
tmajor = 32.9 min); mp = 105−106 °C; [α]2D0 + 33.6 (c 1.1, CHCl3; 92%
ee); Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C,
81.58; H, 7.54; N, 4.90; vmax/cm−1 (ATR) 2924 (w, C-H), 1625 (s,
CO); δH (400 MHz, CDCl3) 1.89−1.99 (m, 1H), 2.05−2.12 (m,
1H), 2.36 (s, 3H), 2.60 (dd, J = 17.5, 11.1 Hz, 1H), 2.83 (ddd, J =
17.5, 5.2, 2.0 Hz, 1H), 3.10 (tdd, J = 11.1, 5.2, 3.1 Hz, 1H), 3.25−3.36
(m, 2H), 4.59 (d, J = 14.6 Hz, 1H), 4.76 (d, J = 14.6 Hz, 1H), 7.13
[(AX)2, 2H], 7.17 [(AX)2, 2H], 7.28−7.39 (m, 5H); δC (100 MHz,
CDCl3) 21.0 (CH3), 30.4 (CH2), 38.3 (CH), 39.6 (CH2), 46.4 (CH2),
50.0 (CH2), 126.4 (2 × CH), 127.4 (CH), 128.2 (2 × CH), 128.6 (2 ×
CH), 129.4 (2 × CH), 136.4 (C), 137.2 (C), 140.5 (C) 169.4 (C);
HRMS (ESI+ TOF): calcd for C19H22NO ([MH+]), 280.1701; found,
280.1692.
(4R)-1-(Phenylmethyl)-4-(1-naphthyl)piperidin-2-one 13f. Using
glutarimide 4f (0.33 g, 1.00 mmol), the title compound 13f was
obtained as a white solid using general procedure G (0.06 g, 20% over
2 steps, 54% ee determined by HPLC on a Chiralpak IA column
(hexane/2-propanol = 92/7, flow rate = 1.0 mL/min, tmajor = 41.3 min,
tminor = 44.9 min); mp = 122−124 °C; [α]2D0 −13.3 (c 0.5, CHCl3; 54%
ee); vmax/cm−1 (ATR) 2950 (w, C-H), 1636 (s, CO), 1624 (s, C
O); δH (400 MHz, CDCl3) 2.10−2.20 (m, 1H), 2.25−2.28 (m, 1H),
2.74 (dd, J = 17.5, 10.1 Hz, 1H), 3.05 (dd, J = 17.5, 3.6 Hz, 1H), 3.10
(dt, J = 10.1, 4.7 Hz, 1H), 3.38−3.45 (m, 1H), 3.95−3.99 (m, 1H),
4.61 (d, J = 14.5 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 7.31−7.41 (m,
6H), 7.44−7.57 (m, 3H), 7.78 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 7.7,
1.5 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H); δC (100 MHz, CDCl3) 29.6
(CH2), 33.8 (CH), 39.3 (CH2), 46.2 (CH2), 50.2 (CH2), 122.4 (CH),
122.7 (CH), 125.6 (CH), 125.7 (CH), 126.3 (CH), 127.4 (CH), 127.5
(CH), 128.3 (2 × CH), 128.7 (2 × CH), 129.1 (CH), 131.0 (C), 134.0
(C), 137.1 (C), 138.9 (C), 169.5 (C); HRMS (ESI+ TOF): calcd for
C22H22NO ([MH+]), 316.1701; found, 316.1689.
was obtained, which was purified via flash column chromatography
eluting with EtOAc:CH2Cl2:petroleum ether (40−60) (3:1:6) to
afford the title compound 12i as a yellow oil (0.11 g, 46% over 2 steps,
87% ee determined by HPLC on a Lux 3 μ Cellulose-2 column
(hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, tminor = 11.3 min,
tmajor = 12.4 min); [α]2D0 + 36.8 (c 1.4, CHCl3; 87% ee); vmax/cm−1
(ATR) 2957 (s, C-H), 2867 (s, C-H), 1636 (s, CO); δH (400 MHz,
CDCl3) 0.90 (s, 9H), 1.40 (qd, J = 12.5, 5.5 Hz, 1H), 1.57 (tdd, J =
12.5, 4.8, 2.3 Hz, 1H), 1.86−1.90 (m, 1H), 2.21 (dd, J = 17.3, 12.5 Hz,
1H), 2.59 (ddd, J = 17.3, 4.8, 2.3 Hz, 1H), 3.17 (td, J = 12.6, 4.8 Hz,
1H), 3.26 (ddd, J = 12.6, 5.5, 2.3 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H),
4.71 (d, J = 14.6 Hz, 1H), 7.26−7.36 (m, 5H); δC (100 MHz, CDCl3)
24.6 (CH2), 26.8 (3 × CH3), 32.0 (C), 34.3 (CH2), 43.2 (CH), 47.1
(CH2), 49.9 (CH2), 127.3 (CH), 128.1 (2 × CH), 128.6 (2 × CH),
137.2 (C), 170.5 (C); HRMS (ESI+ TOF): calcd for C16H24NO
([MH+]), 246.1858; found, 246.1861.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02177.
1H and 13C NMR spectra of all compounds, HPLC of
lactam products 10a−d, 13b−13i (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: simon.jones@sheffield.ac.uk.
■
Notes
The authors declare no competing financial interest.
(4R)-1-(Phenylmethyl)-4-methylpiperidin-2-one 13g. Using gen-
eral procedure G and glutarimide 4g (0.22 g, 1.00 mmol), a crude oily
solid was obtained, which was purified via flash column chromatog-
raphy eluting with EtOAc:petroleum ether (40−60):Et3N (2:8:0.05)
to afford the title compound 13g as a pale yellow oil (0.09 g, 46% over
2 steps, 90% ee determined by HPLC on a Lux 3 μ Cellulose-2 column
(hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, tminor = 13.2
min, tmajor = 14.1 min); [α]2D0 + 46.6 (c 3.3, CHCl3; 90% ee); vmax/cm−1
(ATR) 2953 (w, C-H), 1634 (s, CO); δH (400 MHz, CDCl3) 1.01
(d, J = 6.5 Hz, 3H), 1.39−1.47 (m, 1H), 1.78−1.85 (m, 1H), 1.90−
2.00 (m, 1H), 2.07 (dd, J = 17.2, 10.7 Hz, 1H), 2.58 (ddd, J = 17.2,
4.9, 2.1 Hz, 1H), 3.18−3.22 (m, 2H), 4.48 (d, J = 14.7 Hz, 1H), 4.72
(d, J = 14.7 Hz, 1H), 7.24−7.34 (m, 5H); δC (100 MHz, CDCl3) 21.0
(CH3), 28.0 (CH), 30.9 (CH2), 40.5 (CH2), 46.3 (CH2), 50.0 (CH2),
127.3 (CH), 128.0 (2 × CH), 128.6 (2 × CH), 137.3 (C), 169.7 (C);
HRMS (ESI+ TOF): calcd for C13H18NO ([MH+]), 204.1388; found,
204.1394.
ACKNOWLEDGMENTS
■
The authors thank the Tertiary Education Trust Fund
(TETFUND), Federal Government of Nigeria Kano University
of Science and Technology (I.U.K.), for financial support.
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■
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