Conjugate addition reactions of N -carbamoyl-4-pyridones and 2,3-dihydropyridones with grignard reagents in the absence of Cu(I) Salts

Article abstract of DOI:10.1021/jo400936z

N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF₃·Et ₂O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures.

Full text of DOI:10.1021/jo400936z

Article
pubs.acs.org/joc
Conjugate Addition Reactions of N‑Carbamoyl-4-pyridones and 2,3-
Dihydropyridones with Grignard Reagents in the Absence of Cu(I)
Salts
Fenghai Guo,†,‡ Ramesh C. Dhakal,† and R. Karl Dieter*
Howard L. Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, South Carolina 29634-0973, United States
S
* Supporting Information
ABSTRACT: N-Boc- and N-ethoxycarbonyl-4-pyridones and
the resulting 2,3-dihydropyridones undergo 1,4-addition
reactions with Grignard reagents in the presence of
chlorotrimethylsilane (TMSCl) or BF3·Et2O in excellent
yields. Copper catalysis is not required, and mechanistic
considerations suggest that the reaction is proceeding by a
conjugate addition pathway rather than by a pathway involving
1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-
dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or
cis diastereomers or mixtures.
INTRODUCTION
■
Piperidines and their annulated derivatives are an extremely
important class of medicinal compounds1,2 reflected in the
examination of over 12 000 discrete piperidine entities in
clinical or preclinical studies over a 10-year period.1b Numerous
synthetic strategies for the synthesis of piperidine derivatives
have been developed.3,4 Although most of these strategies rely
extensively on manipulation of the chiral pool for appropriate
starting materials3b or use of chiral auxiliaries,3d these protocols
have been developed into effective methods that can be done
on large scales and provide considerable versatility for the
synthesis of a wide variety of N-heterocycles. Asymmetric
synthetic routes to piperidines3 generally revolve around four
strategic approaches:3a (A) ring formation via alkylation of a
nitrogen center with an acyclic precursor containing pre-
established stereogenic centers; (B) asymmetric generation of
stereocenters and substitution patterns on an existing six-
membered nitrogen heterocycle; (C) ring expansion of
pyrrolidine or furan derivatives; and more recently, (D) ring
closing-metathesis on dialkyl substituted nitrogen derivatives
where each alkyl group contains an appropriately positioned
alkene functional group. Recent reports involving 2,3-dihydro-
4-pyridones4 are particularly attractive for piperidine syntheses
via conjugate addition reactions.5−7 Much of this work involves
the use of dialkylzinc reagents in conjunction with copper
catalysts, and these reagents remain limited in reactivity and
Figure 1. Synthesis of substituted-2,3-dihydropyridones.
general applicability.5,7a,c Recent developments in copper-
catalyzed asymmetric Grignard conjugate additions promise
greater reactivity and versatility6,7b as do the rhodium-catalyzed
substituted piperidines or piperidinones, we reported the
1,4-additions of arylboroxines.4b
Regioselective 1,2-addition of Grignard reagents to pyridi-
conjugate addition reactions of organocuprates, and of
organozincate and organolithium reagents to N-carbamoyl-4-
nium salts is also a well established synthetic strategy for the
preparation of N-heterocycles containing the piperidine motif
Received: May 30, 2013
(Figure 1A).8,9 In pursuit of a catalytic asymmetric approach to
© XXXX American Chemical Society
A
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Article
pyridones in the presence of catalytic or substoichiometric
amounts of copper(I) salts (Figure 1A).10 Subsequently, we
examined the use of Grignard reagents with copper catalysis in
pursuit of catalytic asymmetric conjugate additions to 4-
pyridones. Chlorotrimethylsilane (TMSCl) accelerates copper
mediated conjugate addition reactions in THF,11 and after our
initial report, we discovered that Grignard reagents in the
presence of TMSCl undergo a formal 1,4-addition reaction to
N-carbamoyl-4-pyridones in the absence of Cu(I) salts. The
conjugate addition of a dithianyllithium12a reagent to a N-
carbamoyl-4-quinolone and an N-carbamoylallyllithium re-
agent12b to a 4-pyridone represent two very limited examples
of copper-free conjugate additions to these systems and do not
demonstrate a generality of the reaction. Since the pioneering
observation by Barbier13a and later detailed studies by Victor
Grignard,13b the Grignard reagent has become ubiquitious in
carbon−carbon bond forming reactions and offers advantages
over the more basic and nucleophilic organolithium reagents.
The use of highly functionalized Grignard reagents readily
available from the corresponding halocompounds via halogen
metal exhange reactions allows for an expansive application of
this chemistry.14
(TMSCl). No 1,2-addition product was observed. Surprisingly,
an even higher chemical yield of the 1,4-adduct was obtained
when the CuCN catalyst was eliminated from the reaction
mixture (entry 3). In a control experiment, elimination of both
the CuCN catalyst and the TMSCl additive afforded a low yield
of the 1,4-adduct (entry 4). Alkyl Grignard reagents also added
to the ethyl carbamate 2 in the presence (entry 5) and absence
of CuCN (entry 6), although the yields were slightly lower than
those obtained with the tert-butylcarbamate 1. Although aryl
Grignard reagents gave excellent yields of 1,4-addition products
in the presence of CuCN (entries 7 and 9) and reduced yields
in its absence (entry 8) with ethylcarbamate 2, the heteroaryl
cuprates gave good yields of conjugate addition products
without the use of CuCN (entries 10 and 11).
Given the sometimes lower yields obtained with ethyl
carbamate 2, the scope of the addition of Grignard reagents to
4-pyridones in the absence of CuCN was explored with N-tert-
butoxycarbonyl-4-pyridone 1 (Table 2).
Table 2. Reaction of Grignard Reagents with N-tert-
Butoxycarbonyl-4-pyridone 1 in the Absence of CuCN
RESULTS
■
Initially, we started our investigation with n-BuMgCl and tert-
butyl carbamate 1 sequentially reducing the amount of added
CuCN catalyst. The reaction afforded the 1,4-adduct in good
chemical yields (Table 1, entries 1−2) with either 10.0 or 1.0
mol % of CuCN in the presence of trimethylsilyl chloride
a
b
entry
R (RMgX)
Me
RMgX (equiv)
3
%
yield
40
1
1.2
1.2
1.2
1.1
2.0
1.1
1.2
1.2
2.0
1.0
2.0
2.0
2.0
2.0
1.0
1.2
1.2
3g
3h
3h
3b
3i
2
Et
89
83
86
81
85
86
95
96
86
79
83
85
70
86
75
82
Table 1. Reactions of R1 MgCl with N-Carbamoyl-4-
Pyridones with or without Catalytic Amounts of CuCN
c
3
Et
iPr
4
5
PhCH2
Ph
6
3j
7
2-MeOC6H4
2-MeC6H4
4-Me2NC6H4
3c
3d
3k
3l
8
9
10
11
12
13
14
15
16
17
2-ClCH2C6H4
1-naphthyl
2-thienyl
3m
3e
3f
2-furyl
2-(1-Me)pyrrolyl
5-(1-Me)indolyl
vinyl
3n
3o
3p
3q
ab
,
c
entry
R1
CuCN (mol %)
product
% yield
1
1
1
1
1
2
2
2
2
2
2
2
10
1
3a
3a
3a
3a
4a
4b
4c
4c
4d
4e
4f
79
85
90
2
(E) 1-hexenyl
a
3
0
Reactions were run without the addition of CuCN. All the reactions
d
4
0
<5
were performed in the presence of 3.0 equiv of TMSCl. After the
addition of starting 4-pyridone 1 and TMSCl (3.0 equiv) in THF at
−78 °C, the reaction was allowed to warmed to room temperature and
stirred overnight. All the reactions were quenched at room
5
10
0
76
60
71
46
72
78
75
6
7
10
0
b
temperature. Yields are based on isolated products purified by
8
c
column chromatography. The reaction was run in a 1:1 mixture of
9
10
0
THF and t-BuOMe.
10
11
0
Alkyl Grignard reagents such as methyl, ethyl, isopropyl, and
benzyl all readily added to N-tert-butoxycarbonyl (N-Boc)-4-
pyridone (1) to afford the 1,4-conjugate adduct in modest to
excellent chemical yields (Table 2, entries 1−5, 40−89%). With
the employment of a 1:1 mixture of THF and t-BuOMe,
ethylmagnesium chloride gave a slightly lower chemical yield
than in pure THF (Table 2, entry 3 vs 2, 83 vs 89%). Aryl and
heteroaryl Grignard reagents also added to N-Boc-4-pyridone
a
All the reactions were run in THF using 1.1−2.0 equiv of R1 MgX (X
= Cl, Br). TMSCl (3.0 equiv) was added as an additive. After the
addition of starting 4-pyridone (1 or 2) at −78 °C, the reaction was
stirred overnight and allowed to warm up to room temperature.
b
CuCN was added to a flask charged with argon as a solid, and dry
c
THF was added followed by addition of R1 MgCl at −78 °C. Yields
are based on isolated product purified by column chromatography.
d
No TMSCl was added.
B
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(1) affording 3c,d,j−m (79−96%) and 3e,f,n,o (70−86%),
respectively, with good to excellent yields (Table 2, entries 6−
11 and 12−15, respectively) illustrating a compatibility with
additional heteroatom functionality in the Grignard reagent.
The utilization of vinyl Grignard reagents also proved
successful (entries 16 and 17), affording the 1,4-adducts in
comparable yields.
The procedure failed with alkynyl Grignard reagents and
with Grignard reagents derived from N-methylimidazole, 2-
bromonitrobenzene, and 1,3-dimethyl-5-iodouracil. The
Grignard reagent derived from N-methylimidazole was
successfully added to benzaldehyde (71%). Ketone and ester
enolates also failed to undergo conjugate addition reactions.
Attempts to extend the protocol to α,β-unsaturated amides was
also unsuccessful.
TMSCl, 1 equiv of BF3·Et2O proved effective (entry 12), albeit
in lower yields than when 2 equiv were employed.
Silanes other than TMSCl gave either cleavage of the
carbamate functionality (e.g., TMSOTf) or recovered starting
t
material (e.g., BuMe2SiCl) (Table 4). The cleavage pathway
Table 4. NMR Investigations of 4-Pyridone−Lewis Acid
Mixtures
bc
,
entry
R1, R, X
LA (equiv)
t (h)
NMR ratio 1:5(6):7:8
A brief examination of Lewis Acids revealed that
trimethylsilyl triflate (TMSOTf), tert-butyldimethylsilyl chlor-
ide (TBDMSCl), TiCl4 and Ti(OiPr)4 failed to promote the
addition reaction, while both TMSCl (Tables 2 and 3) and BF3·
a
1
Me , Cl
2.0
2.0
2.0
2.0
2.0
2.0
4.0
4.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
1.0
0.08
0.33
0.66
1.0
no rxn
a
2
Me , Cl
94.5:5.5:3.7:1.8
91:9:6:3
a
3
Me , Cl
a
4
Me , Cl
87.3:20.5:13.7:6.8
74.1:24.9:16.6:8.3
76:24:14:19
56.3:43.7:29.1:14.6
0:100:66:33
no rxn
a
n
5
Me , Cl
2.0
Table 3. Reaction of 4-Pyridone 1 with BuMgCl and Lewis
a
6
Me , Cl
3.0
Acids
a
7
Me , Cl
0.08
18
a
8
Me , Cl
9
tBu, Me, Cl
tBu, Me, Cl
tBu, Me, Cl
tBu, Me, Cl
tBu, Me, Cl
tBu, Me, Cl
tBu, Me, Cl
Me, OTf
0.08
0.33
0.66
0.08
0.66
15
10
11
12
13
14
15
16
no rxn
no rxn
no rxn
no rxn
c
LA
entry Lewis Acid (equiv)
T (°C), t
(h)
3a, %
b
1:3a or
b
a
73:(27):14:13
53:(47):22:25
yield
(% 5)
92
1
2
3
4
5
6
7
8
9
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
BF3.Et2O
BF3.Et2O
BF3.Et2O
2.0
2.0
2.0
1.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
1.0
−23, 1
−23, 2
−23, 3
48
55:45
45:55
30:70
−
0.08
0:100:78:22
53
a
b
c
R1 = R. The 7:8 ratios are determined relative to 5 or 6. The ratios
61
1
d
were calculated from H NMR absorption peaks. Reactions were run
at room temperature.
A
trace
57
25, 2
25, 3
25, 3
25, 3
25, 3
68
e
47
(41)
(37)
(13)
was slow with 2.0 equiv of TMSCl (entries 1−6), moderate
with 4.0 equiv of TMSCl (entries 7−8), very slow with
tBuMe2SiCl (entries 9−15), and rapid with TMSOTf (entry
16). In NMR control experiments, the time-dependent
observation of the carbamate cleavage product at 25 °C was
a function of TMSCl concentration (entries 1−8). Cleavage
products were confirmed by the presence of isobutylene (i.e., 7:
13C NMR15a,b δ 142.4, 110.5, 24.1; 1H NMR15c) and tBuCl (8a:
f
f
g
55
h
73
d
10
11
12
A
82
70
57
f
d
A
d
A
a
n
The reaction was run using 2 equiv of BuMgCl unless otherwise
b
noted. Yields are based upon isolated products purified by column
chromatography. Determined by NMR integration ratios of the olefin
c
15d
t
13C NMR δ 33.9, 66.7). The corresponding BuOTf 8b was
d
e
absorptions. A = −78 to 25 °C, 12 h. The reaction was conducted in
f
g
PhCH3. nBuMgCl (1.0−1.2 equiv). The reaction was done in
not observed.
h
n
CHCl3. The reaction was done in CH2Cl2.
When the reaction of 1 with BuMgCl and TMSCl (3.0
equiv) was monitored by NMR spectroscopy (25 °C,
CDCl3:THF, 4:1) species A was observed, which was slowly
converted into B. The solution became cloudy after 45 min and
displayed a suspension after 2 h, although the Grignard reagent
absorption signal [i.e., δ −0.45 (t, 2H), −CH2−MgCl]
disappeared after 5 min. Addition of nBuN4F (1.0 equiv)
converted the suspension into a clear solution. NMR analysis
and comparison with known compounds revealed that B was 4-
silyloxypyridine 5 resulting from carbamate cleavage, and
product isolation from the mixture revealed the presence of
3a (7%) and 1 (7%) as minor components along with
carbamate cleavage products. When the CDCl3 was filtered
through basic aluminia to remove adventitious DCl before
sample preparation, starting material and a new species
consistent with the expected silyl enol ether 9 [13C NMR δ
Et2O were effective (Table 3). The reaction was slow at −23 °C
(entries 1−3), gave lower yields of 3a when conducted at room
temperature (Table 3, entries 5−6 vs Table 1, entry 3) with
2.0−3.0 equiv of TMSCl, and failed with 1 equiv of TMSCl
(entry 4). When the reaction was carried out at room
temperature, 3a was formed in lower yields in toluene (entry
7) and chloroform (entry 8) than in THF (entries 6) but gave
slightly higher yields in CH2Cl2 (entry 9). A significant amount
of N-Boc cleavage product 5 was isolated from reactions run at
room temperature confirming the competitive rate of the
carbamate cleavage pathway at higher temperatures. BF3·Et2O
was as effective as TMSCl under the standard conditions (i.e.,
THF, −78 to 25 °C, 12 h, entries 10−12). In contrast to
C
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(calcd. value16): 162.5 (155.4), 151.0 (153.1) 122.5 (121.5)
114.3 (111.0), 98.4 (109.2), 43.7 (49.1)] were observed
(Scheme 1). Control samples of 1 with and without added
Scheme 2. Preparation of 2,6-Disubstituted-4-Piperidinones
via Conjugate Addition of Organometallic Reagents to
Dihydropyridones
Scheme 1. Attempted Trapping of Enol Ether 9
TMSCl showed no discernible difference in the chemical shifts
of the absorption peaks, and the chemical yields of product in
these NMR experiments mirrored those obtained in control
experiments with untreated CHCl3 (7%) and CHCl3 treated
with neutral alumina to remove HCl (50%).
Efforts to effect reaction of the putative silyl enol ether
n
proved unsuccessful. Reaction of 1 with BuMgCl and TMSCl
n
followed by sequential addition of Bu4NF and allyl bromide
gave only the addition product 3a (64%). Treatment of the
n
n
reaction mixture of 1, TMSCl, and BuMgCl with Bu4NF and
NBS gave N-Boc-5-bromo-2-butyl-2,3-dihydro-4-pyridone (i.e.,
10, 73% yield) involving bromination of the encarbamate
moiety and not the putative silyl enol ether. The 5-bromo-4-
pyridone derivative could also be prepared by treatment of 3a
with NBS in 77% yield (Scheme 1) as previously reported.18a
All attempts to convert 3a into the silyl enol ether [e.g., Et3N,
TMSCl, DMF, 80 °C, or (i) NaH (THF or CH2Cl2), (ii)
TMSCl] yielded only starting material upon careful workup
designed to avoid silyl enol ether hydrolysis.17
acid converted 3d into a 60:40 mixture of diastereomers (i.e.,
11c + 12c, Scheme 2) with the major diastereomer identical to
the single diastereomer obtained from the RMgCl/TMSCl
procedure. However, reaction of 3a with nBu2CuLi gave a single
diastereomer that was different than that obtained upon
n
reaction of 3a with BuMgCl/TMSCl, and on the basis of
literature precedent, the former was assigned as the cis-
diastereomer 14a.20 Reaction of 3d with Bu2CuLi in THF
n
resulted in 1,4-conjugate reduction to afford the 2-aryl
tetrahydropyridone in 76% yield.
This new protocol affords 1,4-adducts of 4-pyridones8a,b,18,20
that can be utilized in further synthetic applications. Previous
studies have reported that Grignard reagents undergo conjugate
addition to 2,3-dihydropyridinones in very low yields in the
absence of Cu(I) salts.19 In five experiments, we observed
TMSCl-promoted conjugate addition of Grignard reagents to
N-Boc-2,3-dihydropyridones in yields comparable to those
observed for the N-Boc-4-pyridones (Scheme 2). For example,
In an attempt to obtain crystals for X-ray analysis, 11c was
converted into a series of derivatives. The 3,5-dinitrophenyl
hydrazone gave crystals too small for X-ray analysis, while the
oxime gave an inseparable mixture of syn and anti
diastereomers. N-Boc deprotection of 11c and conversion of
the free amine to piperidinium salts with CF3COOH, HCl, or
picric acid failed to yield crystals as did conversion of the amine
to the n-benzyl amine, methane sulfonamide, or N-chloro
amine derivatives. Crystals suitable for X-ray analysis were
obtained for tetrahydropyridone 11a and the trans stereo-
chemistry was thus confirmed.
i
n
the facile addition of PhCH2MgBr, PrMgBr or BuMgCl to 2-
substituted-2,3-dihydro-N-Boc-4-pyridone 3d afforded the 1,4-
adducts 11a−c as single diastereomers, while addition of
n
iPrMgBr or BuMgCl to dihydropyridone 3a also gave 2,6-
disubstituted tetrahydro-4-pyridones 13a,b, respectively, as
single diastereomers in good yields (Scheme 2, 85−89%).
The stereochemistry in these bis-conjugate addition products
could not be unambiguously assigned by literature prece-
dent19,20 or by simple analysis of NMR coupling constants.
NOESY experiments on 11 and 12 did show NOE effects for
the two methine protons adjacent to the N-atom and the
methylene protons adjacent to the ketone but did not allow
unambiguous stereochemical assignments. Alkylcuprate addi-
tions to 2-aryl-2,3-dihydro-4-pyridones were reported to afford
the cis-2,6-disubstitution products,18h,20a while utilization of
arylcuprates on similar substrates gave trans-2,6-disubstituted
products.19 In our hands, utilization of a literature protocol [i.e.,
nBuMgCl (2.0 equiv), CuI (2.0 equiv), BF3·Et2O (1.0
equiv)]20a employing an alkyl copper reagent and a Lewis
Since attempted NOESY experiments on 11a−c were
ambiguous, dihydropyridones 11c, 13a,b, 12c, and 14a were
reduced to the corresponding alcohols 15−19, respectively,
while 11b was reduced to piperidinol 23.18h Although
dihydropyridones 13a (δ 4.09) and 14a (δ 4.95) displayed a
single broad singlet for the two methine protons adjacent to the
n
N-Boc group and one set of 13C-signals for both Bu groups
due to potential symmetry (e.g., 14a with rotation about the
amide bond)19 or conformational equilibration (e.g., 13a),
alcohol 16 displayed two methine proton absorptions (δ 4.01,
4.10) adjacent to the N-Boc group, while 19 displayed only one
(δ 4.14), confirming the trans stereochemistry in 16 and the cis
arrangement of substituents in 19 (Scheme 3). These chemical
shift arguments were confirmed by NOESY experiments, which
showed a single correlation for the carbinol and N-Boc methine
D
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coordinate. An alternative mechanistic scenario (Scheme 4)
involves formation of a TMSCl-pyridone complex 16 that
Scheme 3. Determination of Stereochemistry in 2,6-
Disubstituted-4-Piperidinones
Scheme 4. Mechanistic Implications for TMSCl-Promoted
Addition of Grignard Reagents to N-Boc-4-pyridones
activates the 4-pyridone toward Grignard addition but does not
fully form a pyridinium ion (i.e., 15) intermediate. Once
formed, this complex can undergo rapid addition of the
Grignard reagent and a slow noncompetitive cleavage of the
carbamate moiety. This behavior is reminiscent of a phenol-
TMSCl complex that cleaves carbamates and does not generate
HCl in situ24 and of the use of TMSCl to accelerate cuprate
conjugate addition reactions.11c,25 Data from several studies on
TMSCl, TMSI, and HMPA-TMSCl promoted acceleration of
cuprate conjugate addition reactions in THF, support argu-
ments involving stabilization of the transition state for reductive
elimination from a Cu(III) intermediate with weak silylating
agents (i.e., TMSCl)25a and direct silylation of an enone-Cu
complex with strong silylating reagents [e.g, HMPA-TMSCl
protons in the trans isomers 15 and 16 and two correlations for
the cis isomer 18. Reduction of 11b afforded the alcohol syn to
the aryl group as the major diastereomer (86%, 85:15 dr),
which showed a NOESY correlation between the carbinol
proton and the benzylic methine proton confirming the trans-
2,6-stereochemistry. Reduction of 13b gave a 55:45 mixture of
diastereomers (87%) implicating the trans-2,6-stereochemistry,
which could not be confirmed by NOESY experiments on the
mixture of alcohols.
Refluxing of 3j with NaOMe in MeOH furnished the tricyclic
compound 20 in 77% yield illustrating the synthetic versatility
available in these conversions of N-Boc-4-pyridone 1 to 2-
substituted-2,3-dihydro-4-pyridinones (eq 1).
(i.e., Me3SiOPN[(Me)2]3 Cl−), TMSOTf, and TMSI] rather
+
than cuprate attack on an enone-TMSCl complex.25 Although
pyridones 1 and 2 are vinylogous amides that could be more
prone to form a complex with TMSCl than simple enones, we
were unable to unambiguously observe such a complex (i.e.,
16) by NMR spectroscopy, which could be due to low
concentration of 16 or rapid equilibrium between the
complexed and uncomplexed species. Alternatively, invoking a
concerted but nonsimultanous push−pull mechanism accom-
modates the relative rates of carbamate cleavage with reagent
silylating ability but involves a significantly less likely ter-
molecular activated complex.
The issue of 1,4- vs 1,2-addition is then largely a matter of
semantics since formation of a TMSCl-pyridone complex
before or during the Grignard addition enhances the electro-
philic character of the enone β-carbon atom, which will also
have a resonance contributor involving the carbamate N-lone
pair. Although we were unable to definitively identify this
complex in the NMR studies, the need for 2−3 equiv of TMSCl
in order to obtain good yields of conjugate adducts is suggestive
of formation of such a complex in a bimolecular or termolecular
process. Partitioning between carbamate cleavage and Grignard
addition can be subtlely influenced by reaction conditions (e.g.,
solvent and temperature).
DISCUSSION
■
The addition of Grignard reagents to 4-pyridones 1 and 2 in
the presence of TMSCl could in principle be viewed as either a
1,4-conjugate addition reaction to the enone π-system or as a
1,2-nucleophilic addition to a pyridinium intermediate.
Although organocopper reagents are ubiquitious in organo-
metal mediated conjugate addition reactions, Grignard21 and
organolithium22 reagents do play a limited role in conjugate
additions23 to nitroalkenes,21a cyclopentadienones,21b N-
enoylsultams,21c,d α-silylenones,21e enamides,21f,22a enoic
acids,21f ennitriles,21g,h ynnitriles,21i indolylidenmalonates,21j
and enamidomalonates.21k
The failure of TBDMSCl and TMSOTf to promote the
addition of Grignard reagents to 4-pyridones 1 and 2 and their
differential ability to promote carbamate cleavage suggests that
a pyridinium ion is not an intermediate along the reaction
The assignment of stereochemistry in N-Boc-2,6-disubsti-
tuted-4-piperidinones is fraught with difficulty revolving around
conformational dynamics in the six-membered ring, which is
E
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illustrated by literature assignments involving NOESY experi-
ments. For piperidinone 21, an NOE was reported for the two
methine protons, and a chair conformation (i.e., 21C) with the
two alkyl substituents in an equatorial orientation was
invoked,18c while piperidinone 22 displayed NOE between
the methyl and the 1′-CH2-group of the n-propyl substitutent
and a chair conformation (i.e., 22C) with the two alkyl groups
in an axial orientation was invoked.18g There is ample literature
precedent suggesting that both N-acyl cis26- and trans19-2,6-
disubstituted piperidinones preferentially adopt a boat or twist
boat conformation rather than chair conformations involving
either 1,3-diaxial interactions or A1,3-strain between the
equatorial substituents and the amide functionality. For the
NOE correlations reported (Scheme 5), it seems far more likely
Chart 1. Relative Conformational Energies (i.e., ΔE Internal
a
Energy) in kcal/mol
Scheme 5. Reported NOEs in N-Boc-2,6-Disubstituted
Piperidinones18c,g
that these interactions are arising from similar boat or twist
boat conformations (e.g., 21B and 22B) or are resulting from
conformational dynamic averaging of NOE accessible con-
formations.27,28
A computational sampling of a small region of conforma-
tional space for several N-Boc-2,6-disubstituted-4-piperidinones
and a 4-piperidinol was examined. Although the semiempirical
calculations AM1 and PM3 gave inconsistent ordering of
conformational stability, both ab initio calculations [(i.e.,
Hartree−Fock (HF, 6-31G*) and Density Functional Theory
(DFT, B3LYP, 6-31G*)] generally gave consistent relative
stability ordering for various chair and twist boat conformations
(Chart 1). The trans-2-tolyl derivative 11c was calculated to be
most stable in the chair conformation with an axial aryl
substituent, while the twist boat and chair conformations in the
cis isomer 12c with an axial aryl substitutent were each
predicted to be more stable by HF and DFT calculations,
respectively, although the energy differences in the HF
calculation are insignificant. Hartree−Fock calculations pre-
dicted the twist boat conformation of the trans-2-isopropyl
derivative to be more stable than the chair, and both ab initio
calculations predicted the twist boat comformation of the trans-
2-arylpiperidinol to be more stable than the axial 2-aryl chair
conformer. The 1,4-twist conformations shown in Chart 1 are
also in equilibrium with 2,5-twist and 3,6-twist boat
conformations.27a These conformational transformations via
pseudorotation about the ring atoms lead to a large number of
conformational minima, some of which will be capable of
displaying NOE (i.e., generally internuculear distances ≤3.5 Å)
effects.29
a
C = chair, TB = twist boat, ax = axial, diax = diaxial.
The reaction of 2-substituted-2,3-dihydropyridones with
Grignard reagents in the presence of TMSCl always leads to
the trans-2,6-disubstituted piperidinones, while the conjugate
addition of cuprate reagents leads to mixtures of cis and trans
diastereomers where either isomer may predominate (Table 5).
Formation of the trans-piperidinones in the Grignard conjugate
addition reactions plausibly arise from an enone-TMSCl
complex where the Lewis acid is not associated with the
Grignard reagent, which attacks from the least sterically
hindered enone π-face opposite the axial substituent (i.e., R1).
By contrast, cuprate conjugate addition generally requires
coordination of the metal cation (e.g., Li+) to the enone
carbonyl30 and given the dihedral angles for these half chair
conformations31 would favor attack of the cuprate reagent upon
the π-face of the carbonyl shielded by the axial substituent R1.
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argued by Comins20a the more stable axial conformer generally
prefers to undergo axial attack by the organometallic reagent
leading to the cis-diastereomer, but as our work and that of
Hamblett and co-workers19 shows, this stereoelectronic
preference can be circumvented by the cumulative steric
hindrance of the 2-substitutent on the 2,3-dihydropyridone and
the organometallic ligand to afford the trans-diastereomer. This
perspective also accounts for the range of cis/trans-diaster-
eomers observed as a function of the cuprate reagent20a and
presumably solvent reflecting the reacting cuprate structure and
composition.30
Table 5. Stereoselectivity in Conjugate Additions to 2,3-
Dihydropyridones 3a, 3d, 3j, 24, and 25
Reduction of the 2,6-disubstituted piperidinones is also
intriguing, giving a 4:1 diastereomeric ratio for 11c and a 1:1
ratio for 13b. The higher diastereoselectivity obtained for
reduction of 11c can be rationalized by the larger A-value for
the phenyl substitutent in either the boat or chair conformation
while the lack of stereoselectivity in the reduction of 13b
reflects the comparable A-values for the nBu and iPr-
substituents. These diastereomeric ratios are also consistent
with calculations indicating a preference for the chair
conformation for 11c and a twist boat conformation for 13b
(Chart 1).
cis:trans
R1, R: Cu reagent and reaction cond
R1 = 3,4-(MeO)2C6H4; R = Cl(CH2)4: R2CuMgCl (?),
THF
(R1, R)
3:1
[ref]
20a
RCu or RCuBrMgBr/BF3·Et2O, THF
R1 = Ph; R = Me: MeCu or MeCuBrMgBr/BF3·Et2O,
4.7:1
5:1
20a
18h
THF
a
n
n
n
R1 = 2-MeC6H4; R = Bu: BuCu or BuCuIMgX/BF3·
1:1.5
Et2O, THF
a
nBu2CuLi, Me2S, Et2O
1:99
R1 = R = Ph: R2CuMgX, THF
1:20
20:1
19
SUMMARY
R1 = CH2CHCH2; R = CH2CH2: MeCuRM [M = Li
20b
■
or MgX], THF:Et2O (3:1)
In summary, we have successfully developed conjugate addition
reactions of Grignard reagents with N-carbamoyl-4-pyridones
in the presence of TMSCl without using Cu(I) salts. This
reaction was shown to be compatible with alkyl, aryl, benzyl,
vinyl 1-naphthyl and highly functionalized heterocycle contain-
ing Grignard reagents. The synthetic utilities of the 1,4-adducts
provided by this new Grignard reagent conjugate addition
protocol was demonstrated. This methodology provides a
direct route to the highly functionalized and synthetically
important 2-substituted-2,3-dihydropyridones,4b,8a,b,18−20 which
can be utilized for the synthesis of piperidones, piperidines,
indolizidines, and quinolizidines and provides opportunities for
development of catalytic enantioselective 1,4-additions to 4-
pyridones using Grignard reagents.
R1 = CH2CHCH2; R = CH2CH(CH3): MeCuRM
9:1
20b
[M = Li or MgX], THF:Et2O (3:1)
a
n
n
R1 = R = Bu: Bu2CuLi, Me2S, Et2O
99:1
a
This work.
No simple pattern emerges from the data presented in Table 5
suggesting that multiple factors determine the stereochemical
outcome. These multiple factors may include the steric
hindrance of R1 (i.e., A-values), the steric hindrance of the
cuprate reagent (e.g., homodimer in Et2O, heterodimer in
THF, mixed cuprate reagents such as RCuMeLi or
RCuBrMgBr)30 including the transferable ligand, the cuprate
counterion (e.g., Li+, MgX+), the C5−C4−C3−C2 dihedral
angle in the substrate influencing the orientation of the
carbonyl functional group, and the conformation preference of
the specifically substituted 2,3-dihydropyridone.
The formation of cis-substituted derivatives has been
rationalized by the more stable 2-substituted-2,3-dihydropyr-
idone axial conformer undergoing axial attack by the cuprate
reagent,20a while the trans-substituted derivatives are rational-
ized by cuprate axial attack on a half-boat confomer postulated
to occur for 2,3-dihydropyridones containing a bulky 2-
substitutent19 (e.g., aryl). Since 2-aryl-2,3-dihydropyridones
are reported to undergo cuprate-mediated conjugate addition
to form both cis-18h,20 and trans-substituted19 2,6-tetrahydro-
pyridones, the stereochemical outcome of the conjugate
addition most likely results from a complex interplay of
multiple factors. AM1 semiempirical calculations employing
MacSpartan confirm that the axial conformer for both 3a and 3j
is more stable than the equatorial conformer by 2.0−2.6 kcal/
mol.20a Additionally, both have roughly the same conformation
of the pyridone ring, which is closer to a chair conformation
than to a half-boat. The supposition of a half-boat conformation
was predicated on an X-ray structure,19 which need not mirror
solution conformations. The cis/trans-stereochemical outcome
of the conjugate addition reactions seems to reflect the steric
hindrance of both the 2-substitutent on the 2,3-dihydropyr-
idone and the ligand on the organometallic reagent. Thus, as
EXPERIMENTAL SECTION
General Methods. NMR spectra were recorded as CDCl3 or C6D6
solutions on a 500 MHz NMR instrument. The H NMR chemical
■
1
shifts are reported as δ values in parts per million (ppm) relative to
tetramethylsilane (TMS, δ = 0.00)/CHCl3 (δ = 7.28) or C6H6 (δ =
7.16) as internal standard. The 13C NMR chemical shifts are reported
as δ values in parts per million (ppm) downfield from TMS and
referenced with respect to the CDCl3 signal (triplet, centerline δ =
77.0 ppm) or C6D6 signal (multiplet, centerline δ = 128.4 ppm).
Infrared (IR) spectra were recorded as neat samples (liquid films on
NaCl plates). Gas chromatography−mass spectrometry measurements
were performed on a GC coupled to a quadrupole detector at 70 eV.
Analytical thin layer chromatography (TLC) was performed on silica
gel plates, 200 μ mesh with F254 indicator. Visualization was
accomplished by UV light (254 nm), and/or a 10% ethanol solution
of phosphomolybdic acid. Flash column chromatography was
performed with 200−400 μ silica. The yields are of materials isolated
by column chromatography.
Anhydrous tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl. TMSCl was distilled from CaH2 under a positive
N2 atmosphere. n-BuLi (2.5 M in hexane) was commercially available
and titrated using sec-butyl alcohol and 1,10-phenanthroline
monohydrate in THF. n-BuMgCl (1.6 M in THF), EtMgCl (1. 0 M
in THF), MeMgCl (3.0 M in diethyl ether), i-PrMgBr (2.0 M in
diethyl ether), and PhMgCl (2.80 M in diethyl ether) were
commercially available and titrated using menthol and 1,10-
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phenanthroline monohydrate in THF.32 All glassware was flame-dried
under a high vacuum and purged with argon and then cooled under a
dry nitrogen atmosphere. Low temperature baths (as low as −78 °C)
were prepared using thermoflasks with dry ice-isopropyl alcohol slush
bath mixtures. All reactions were conducted under a positive, dry
argon atmosphere in anhydrous solvents in flasks fitted with a rubber
septum.
HRMS data on compounds 3e, 3f, 3k−n, 3q, 4d, 11b, 12c, 13a, 16,
19, and 20 were analyzed by Q-TOF detector (hybrid quadrupole
time-of-flight MS), while compounds 4b−c, 4e, 4f, 10, 11c, 13b, 14a,
15, 17−18 and 23 were analyzed by TOF MS. Compounds 1, 2, 3a,
3b, 3d, 3g−j, 3p, and 4a have been fully characterized and
reported.1b,10,38,39
reaction mixture was warmed to room temperature overnight with
continuous stirring. Then the reaction mixture was diluted with
dichloromethane (5.0 mL), quenched with saturated aqueous NH4Cl
(5.0 mL) and extracted with dichloromethane (3 × 10.0 mL). The
combined organic phase was washed with water (10.0 mL), brine
(10.0 mL), dried over anhydrous MgSO4, filtered, concentrated in
vacuo, and purified by flash column chromatography (silica, 1−3%
MeOH in CH2Cl2, v/v) to give pure compounds.
General Procedure C: Preparation of N-Carbamoyl-4-
pyridones (1−2). N-Carbamoyl-4-pyridones (1 and 2) used for the
reactions were prepared using a modified literature procedure.36 To
the solution of 4-hydroxypyridine (1.90 g, 20.0 mmol) in tBuOH (20.0
mL) was added sodium hydride (624 mg, 26.0 mmol) under argon,
and the reaction mixture was heated in hot water bath (∼50 °C) until
the mixture turned to a slurry. Then the appropriate chloroformate
Method A: Synthesis of Grignard Reagents from Heteroaryl
Compounds. The heteroaryl Grignard reagents were prepared from a
slight modification of a literature procedure.33 To the heteroaryl
compound (2.0 mmol) in THF (3.0 mL) at 0 °C under argon was
added n-BuLi (0.80 mL, 2.50 M in hexane, 2.00 mmol) dropwise.
Then the reaction mixture was warmed to room temperature and
stirred for 2 h at this temperature. The reaction mixture was
transferred to flame-dried MgBr2 (368 mg, 2.0 mmol) in THF (5.0
mL) at 0 °C via cannula under argon, stirred for 30 min at this
temperature and used for further reactions using General Procedure A.
Method B: Synthesis of Grignard Reagents from Aryl
Halides. Aryl Grignard reagents that were not available commercially
were synthesized in situ by using a modified literature procedure34
from the corresponding aryl halides as described below. To
magnesium (192 mg) in THF (5.0 mL) under argon was added a
catalytic amount of iodide (15 mg). Then a solution of aryl halide
(2.00 mmol in 5.0 mL THF) was added dropwise. During addition,
the reaction mixture was heated at 50 °C for 10 min. After the addition
was complete, the reaction mixture was stirred for an additional 30 min
at room temperature and used for the conjugate addition reactions
using General Procedure A.
Method C: Synthesis of Grignard Reagent via Halogen
Metal Exchange. The halogen metal exchange reaction of the vinyl
iodide was performed by using the literature procedure.35 To i-
PrMgCl (1.20 mL, 2.0 M in diethyl ether, 2.4 mmol) in THF (3.0 mL)
at 0 °C was added n-BuLi (1.92 mL, 2.5 M in hexane, 4.8 mmol)
under argon, and the mixture was stirred for 10 min. Iodo compound
(2.0 mmol) was added, and the mixture was stirred for 1 h at 0 °C and
then used for further reactions following General Procedure A.
General Procedure A: Reaction of Grignard Reagents with
N-Carbamoyl-4-pyridones in the Presence of TMSCl. To the
cooled −78 °C solution of Grignard reagent (1−2 equiv) was added
the starting N-carbamoyl-4-pyridone (1 or 2) [1.0 mmol mixed with
TMSCl (3.0 equiv) in THF (3.0 mL)] dropwise. The reaction mixture
was allowed to warm to room temperature overnight with stirring.
Then the reaction mixture was diluted with dichloromethane (5.0
mL), quenched with saturated aqueous NH4Cl (5.0 mL) and extracted
with dichloromethane (3 × 10.0 mL). The combined organic phase
was washed with water (10.0 mL), brine (10.0 mL), dried over
anhydrous MgSO4, filtered, concentrated in vacuo, and purified by
flash column chromatography (silica, 1−3% MeOH in CH2Cl2, v/v) to
give pure compounds.
t
(26.0 mmol) in BuOH (7.0 mL) was added dropwise. The reaction
mixture was cooled to room temperature and stirred for 12 h at that
temperature. The reaction mixture was quenched with water (20.0
mL) with caution, acidified to pH = 7 with 10% HCl, and the aqueous
portion was extracted with ether (3 × 15.0 mL). The ether layers were
combined, dried over anhydrous MgSO4, filtered and concentrated by
a vacuum to give crude product. Purification by flash chromatography
(1−3% MeOH in CH2Cl2, v/v) afforded N-carbamoyl-4-pyridones 1−
2.
Preparation of N-tert-Butoxycarbonyl-4-pyridone (1). Em-
ploying General Procedure C and using, tert-butoxycarbonyl anhydride
(5.67 g, 26.0 mmol), 4-hydroxypyridine (1.90 g, 20.0 mmol) gave 1
after purification by flash column chromatography (silica gel, 1−3%
1
MeOH:CH2Cl2, v/v) as a white solid in good yields (73%). H NMR
and 13C NMR data are identical to a literature report.12b
Preparation of N-Ethoxycarbonyl-4-pyridone (2). Employing
General Procedure C and using ethyl chloroformate (2.82 g, 26.0
mmol) 4-hydroxypyridine (1.90g, 20.0 mmol) gave 2 after purification
by flash column chromatography (silica gel, 1−3% MeOH:CH2Cl2, v/
1
v) as white solid in good yields (79%). H NMR and 13C NMR data
were identical to a literature report.37
N-Boc-2-(2-methoxyphenyl)-2,3-dihydro-4-pyridone (3c).
Employing Method B, General Procedure A and using 2-bromoanisole
(374 mg, 2.00 mmol), magnesium (192 mg, 8.0 mmol), N-(tert-
butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0 mmol) and TMSCl (326
mg, 3.0 mmol) after purification by flash column chromatography
(silica, 1−3% MeOH:CH2Cl2, v/v) gave white crystalline solid 3c (260
mg, 86%): mp 112.8−114.9 °C; IR (neat) 2975 (w), 2838 (w), 1721
(s), 1667 (s), 1602 (s), 1489 (m), 1457 (m), 1421 (m), 1316 (s),
1
1243 (m), 1150 (s), 1027 (m), 853 (m), 752 (m) cm−1; H NMR
(500 MHz, CDCl3) δ 1.40 (br s, 9H), 2.79 (d, J = 16.9 Hz, 1H), 3.06
(dd, J = 8.2, 16.5 Hz, 1H), 3.85 (s, 3H), 5.36 (d, J = 8.2 Hz, 1H), 5.94
(d, J = 7.8 Hz, 1H), 6.81−6.90 (m, 2H), 6.98 (d, J = 7.3 Hz, 1H),
7.20−7.26 (m, 1H), 8.11 (d, J = 7.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 27.9, 40.6, 51.5, 55.3, 83.4, 106.5, 110.8, 120.5, 125.1, 126.5,
128.9, 143.7, 151.4, 156.1, 191.9; mass spectrum m/z (relative
intensity) EI 303 (M+, 0.01), 223 (0.04), 203 (100), 187 (6), 172
(16), 160 (16), 134 (38), 119 (97), 105 (9), 91 (85), 77 (19), 65 (21),
51 (11). Elemental analysis, found: C, 67.22; H, 7.18; N, 4.52%.
Calculated for C17H21NO4: C, 67.31; H, 6.98; N, 4.62%.
N-Boc-2-(2-methylphenyl)-2,3-dihydro-4-pyridone (3d).38
Employing Method B, General Procedure A and using 2-
bromotoluene (342 mg, 2.0 mmol), magnesium (192 mg, 8.0
mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0 mmol)
and TMSCl (326 mg, 3.0 mmol) after purification by flash column
chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave white
amorphous solid 3d (273 mg, 95%): mp 117.1−119.5 °C; IR (neat)
3077 (w), 2974 (m), 2929 (w), 1724 (s), 1667 (s), 1605 (s), 1458
(w), 1417 (m), 1368 (m), 1319 (s), 1258 (m), 1213 (m), 1148 (s),
General Procedure B: Reaction of Organocuprate Reagents
with N-Boc-2-alkyl-2,3-dihydropyridone. The organocuprate
reagents used for the reaction were prepared by the reaction of either
RLi (2.0 equiv), CuCN (1.0 equiv) and LiCl (2.0 equiv) or the
reaction of RMgX (1.0 equiv) with CuI (1.0 equiv). In the first
method, to the mixture of LiCl (2.0 equiv), CuCN (1.0 equiv) and
Me2S (2.0 equiv) under argon in diethyl ether was added n-BuLi (2.0
equiv) at −78 °C, and the reaction mixture warmed up to −30 °C over
30 min. In the second method, CuI (1.0 equiv) was mixed with RMgX
(1.0 equiv) in THF under argon at −60 °C, and the resulting mixture
was warmed to −30 °C over 30 min following slight modification of
Comin’s procedure.20a The reaction mixture was cooled to −78 °C,
boron trifluoride etherate (0.5 equiv) was added, and the resulting
mixture was stirred for 10 min before N-carbamoyl-4-pyridone (1.0
equiv in 2.0 mL diethyl ether) was added over 10 min at −78 °C. The
1
1009 (w), 976 (w), 923 (w), 853 (w), 756 (m) cm−1; H NMR (500
MHz, CDCl3) δ 1.28 (s, 9 H), 2.28 (s, 3 H), 2.48 (d, J = 16.5 Hz, 1H),
3.07 (dd, J = 8.7, 16.4 Hz, 1H), 5.33 (d, J = 8.7 Hz, 1 H), 5.67 (d, J =
8.7 Hz, 1H), 6.96−7.12 (m, 4H), 8.08 (d, J = 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 19.0, 27.9, 40.8, 53.3, 83.7, 106.3, 123.9, 126.6,
127.8, 131.2, 133.8, 137.7, 144.3, 151.4, 191.8; mass spectrum m/z
H
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+
(relative intensity) EI 287 (M+, 0.02), 239 (0.10), 207 (0.42), 187
(56), 172 (6), 158 (7), 144 (29), 130 (100), 117 (100), 96 (51), 70
(36), 51 (13).
151.2, 191.5; mass spectrum m/z (relative intensity) EI 322 (M ,
2.11), 308 (2), 294 (2), 192 (11), 190 (27), 165 (21), 164 (83), 149
(100), 134 (6), 121 (14), 104 (8), 91 (9), 77 (9), 65 (8), 51 (8);
HRMS (ESI) calculated for [C17H21NO3Cl]+ 322.1210, found
322.1205.
N-Boc-2-(2-thienyl)-2,3-dihydro-4-pyridone (3e). Employing
Method A, General Procedure A and using thiophene (168 mg, 2.0
mmol), n-BuLi (0.80 mL, 2.50 M in hexane, 2.0 mmol), MgBr2 (368
mg, 2.0 mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless oil 3e (232 mg, 83%): IR (neat) 2977 (m), 2925 (w), 1723
(s), 1663 (s), 1599 (s), 1418 (m), 1366 (m), 1328 (s), 1260 (m),
N-Boc-2-(1-napthanyl)-2,3-dihydro-4-pyridone (3m). Em-
ploying Method B, General Procedure A and using 1-napthanyl
bromide (414 mg, 2.0 mmol), magnesium (192 mg, 8.0 mmol), N-
(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0 mmol) and TMSCl
(326 mg, 3.0 mmol) after purification by flash column chromatog-
raphy (silica, 1−3% MeOH:CH2Cl2, v/v) gave white amorphous solid
3m (256 mg, 79%): mp 126.5−128.3 °C; IR (neat) 2977 (w), 1727
1
1215 (m), 1151 (s), 1004 (m), 850 (m), 763 (m) cm−1; H NMR
1
(500 MHz, CDCl3) δ 1.53 (br s, 9 H), 2.84 (d, J = 16.9 Hz, 1 H), 3.07
(dd, J = 6.8, 16.4 Hz, 1H), 5.32 (d, J = 8.2 Hz, 1H), 5.84 (br s, 1H),
6.86 (dd, J = 3.6, 5.0 Hz, 1H), 6.92 (dd, J = 0.9, 3.6 Hz, 1H), 7.18 (d, J
= 5.0 Hz, 1H), 7.70 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 28.1,
41.5, 51.7, 84.2, 106.9, 125.5, 126.0, 126.5, 141.3, 141.8, 151.1, 192.4;
mass spectrum m/z (relative intensity) EI 279 (M+, 0.05), 239 (0.06),
195 (0.5), 179 (36), 162 (18), 151 (20), 136 (4), 110 (100), 84 (10),
66 (17), 51 (50); HRMS (ESI) calculated for [C14H17NO3S]+
279.09292, found 279.09328.
(s), 1670 (s), 1312 (b), 1149 (b), 857 (b), 773 (s) cm−1; H NMR
(500 MHz, CDCl3) δ 1.31 (br s, 9H), 2.87 (d, J = 16.5 Hz, 1H), 3.30
(dd, J = 8.7, 16.5 Hz, 1H), 5.43 (d, J = 8.7 Hz, 1H), 6.44 (d, J = 8.2
Hz, 1H), 7.27−7.92 (m, 7H), 8.25 (d, J = 8.7 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 27.7, 41.3, 53.0, 83.7, 106.1, 121.6, 121.9, 125.1,
125.7, 126.6, 128.5, 129.4, 133.9, 134.4, 143.9, 151.3, 191.6; mass
spectrum m/z, (relative intensity) EI 323 (0.01, M+), 289 (9), 288
(39), 230 (14), 229 (70), 198 (58), 197 (32), 181 (47), 170 (34), 157
(97), 165 (27), 159 (15), 158 (15), 157(97), 155 (39), 154 (32), 141
(19), 132 (17), 129 (97), 128 (63), 127 (38), 117 (19), 91 (60), 90
(24), 75 (100), 73 (68), 58 (7); HRMS (ESI) calculated for
[C20H22NO3]+ 324.1600, found 324.1606.
N-Boc-2-(2-(1-methyl)-pyrrolyl)-2,3-dihydro-4-pyridone
(3n). Employing Method A, General Procedure A and using N-
methylpyrrole (162 mg, 2.0 mmol), n-BuLi (0.80 mL, 2.0 mmol, 2.50
M in hexane,), MgBr2 (368 mg, 2.0 mmol), N-(tert-butoxycarbonyl)-4-
pyridone 1 (195 mg, 1.0 mmol) and TMSCl (326 mg, 3.0 mmol) after
purification by flash column chromatography (silica, 1−3%
MeOH:CH2Cl2, v/v) gave yellow viscous oil 3n (193 mg, 70%): IR
(neat) 2973 (m), 2925 (m), 1720 (s), 1667 (s), 1599 (s), 1366 (m),
1321 (s), 1215 (m), 1151 (s), 1008 (m), 853 (w), 714 (m) cm−1; 1H
NMR (500 MHz, CDCl3) δ 1.50 (s, 9 H), 2.68 (dd, J = 1.3, 17.8 Hz, 1
H), 3.08 (dd, J = 7.3, 16.5 Hz, 1 H), 3.66 (s, 3 H), 5.41 (dd, J = 0.9,
7.3 Hz, 1 H), 5.73 (d, J = 6.8 Hz, 1 H), 5.99 (dd, J = 2.7, 3.2 Hz, 1 H),
6.05 (d, J = 2.3 Hz, 1 H), 6.54 (s, 1 H), 7.77 (d, J = 8.2 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 28.1, 34.3, 41.7, 48.7, 83.7, 107.1, 107.2,
107.9, 123.0, 129.7, 142.5, 151.1, 192.6; mass spectrum m/z (relative
intensity) EI 276 (M+, 1), 261 (0.15), 246 (1), 232 (3), 219 (1), 203
(5), 185 (1), 176 (22), 159 (65), 148 (12), 131 (8), 118 (4), 107
(100), 94 (16), 81 (15), 56 (21); HRMS (ESI) calculated for
[C15H20N2O3]+ 276.14740, found 276.14772.
N-Boc-2-(2-furyl)-2,3-dihydro-4-pyridone (3f). Employing
Method A, General Procedure A and using furan (136 mg, 2.0
mmol), n-BuLi (0.80 mL, 2.50 M in hexane, 2.0 mmol), MgBr2 (368
mg, 2.0 mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless oil 3f (224 mg, 85%): IR (neat) 2977 (w), 2925 (w), 1723
(s), 1667 (s), 1595 (s), 1430 (w), 1370 (m), 1317 (s), 1260 (m), 1219
1
(m), 1151 (s), 1008 (m), 853 (w), 760 (m) cm−1; H NMR (500
MHz, CDCl3) δ 1.54 (s, 9H), 2.80 (d, J = 16.5 Hz, 1 H), 2.99 (dd, J =
6.9, 16.9 Hz, 1H), 5.29 (d, J = 9.6 Hz, 1H), 5.70 (br s, 1H), 6.17 (d, J
= 2.7 Hz, 1H), 6.27 (d, J = 1.4 Hz, 1H), 7.31 (s, 1H), 7.72 (br s, 1H);
13C NMR (125 MHz, CDCl3) δ 28.1, 39.0, 50.1, 83.9, 106.7, 108.0,
110.3, 141.9, 142.6, 151.2, 151.3, 192.3; mass spectrum m/z (relative
intensity) EI 263 (M+, 0.88), 239 (0.05), 231 (0.05), 218 (0.08), 207
(25), 190 (2), 163 (28), 135 (17), 106 (10), 94 (76), 81 (5), 57
(100); HRMS (ESI) calculated for [C14H18NO4]+ 264.1236, found
264.1233.
N-Boc-2-(4-N,N-dimethylaminophenyl)-2,3-dihydro-4-pyri-
done (3k). Employing Method B, General Procedure A and using
N,N-dimethyl-4-bromoaniline (400 mg, 2.0 mmol), magnesium (192
mg, 8.0 mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
white amorphous powder 3k (302 mg, 96%): mp 115.9−117.3 °C; IR
(neat) 2976 (w), 2360 (b), 1722 (s), 1656 (s), 1603 (s), 1330 (b),
1221 (s), 1151(s) cm−1; 1H NMR (500 MHz, CDCl3) δ 1.50 (s, 9H),
2.78 (d, J = 16.4 Hz, 1H), 2.94 (s, 6H), 3.09 (dd, J = 7.3, 16.5 Hz, 1H),
5.34 (d, J = 8.2 Hz, 1H), 5.61(d, J = 6.9 Hz, 1H), 6.68 (d, J = 8.5 Hz,
1H), 7.13 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 27.9, 40.5, 41.6, 54.9, 83.4, 106.7, 112.6, 126.9,
127.1, 142.7, 149.8, 151.5, 192.9; mass spectrum m/z (relative
N-Boc-2-(5-(1-methyl)-indole)-2,3-dihydro-4-pyridone (3o).
Employing Method C, General Procedure A and using i-PrMgBr
(0.6 mL, 1.2 mmol, 2.0 M in diethyl ether), n-BuLi (0.96 mL, 2.50 M
in hexane, 2.4 mmol), 5-iodo-N-methyl indole (257 mg, 1.0 mmol), N-
(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0 mmol) and TMSCl
(326 mg, 3.0 mmol) after purification by flash column chromatog-
raphy (silica, 1−3% MeOH:CH2Cl2, v/v) gave white amorphous solid
3o (286 mg, 88%): mp 127.4−129.1 °C; IR (neat) 2977 (w), 1722
(s), 1668 (s), 1604 (s), 1332 (m), 1153 (s), 762 (s) cm−1; H NMR
1
(500 MHz, CDCl3) δ 1.52 (s, 9H), 2.87 (d, J = 16.9 Hz, 1H), 3.20
(dd, J = 7.3, 16.5 Hz, 1H), 3.78 (s, 3H), 5.38 (d, J = 8.7 Hz, 1H), 5.79
(d, J = 7.3 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 3.2 Hz, 1H)
7.13 (dd, J = 1.3, 8.7 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H),
7.98 (d, J = 7.8 Hz, 1H) ; 13C NMR (125 MHz, CDCl3) δ 28.1, 32.9,
42.4, 56.1, 83.5, 101.3, 107, 109.6, 118.3, 120.0, 128.5, 129.5, 130.1,
136.3, 143.1, 151.7, 192.9; mass spectrum m/z (relative intensity) EI
327 (0.01, M+), 227 (12), 226 (75), 225 (24), 209 (32), 198 (10), 197
(13), 183 (10), 181 (15), 157 (100), 156 (26), 144 (8), 131(16), 115
(18), 103 (5), 96 (10), 77 (9), 63 (4). Elemental analysis, found: C,
69.87; H, 6.90; N, 8.38%. Calculated for C19H22N2O3: C, 69.92; H,
6.79; N, 8.58%.
+
+
intensity) EI 317 (M +1, 3.6), 316 (M , 18), 260 (30), 216 (41),
147 (100), 146 (37), 134 (20), 91 (5), 77 (11), 57 (32); HRMS (ESI)
calculated for [C18H24N2O3]+ 316.17870, found, 316.17786.
N-Boc-2-(2-chloromethylphenyl)-2,3-dihydro-4-pyridone
(3l). Employing Method C, General Procedure A and using i-PrMgBr
(0.6 mL, 1.2 mmol, 2.0 M in diethyl ether), n-BuLi (0.96 mL, 2.4
mmol, 2.50 M in hexane), 2-iodo-(1-chloromethyl) benzene (253 mg,
1.0 mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0 mmol)
and TMSCl (326 mg, 3.0 mmol) after purification by flash column
chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave yellow
viscous oil 3l (278 mg, 86%): IR (neat) 2976 (w), 1725 (s), 1668 (s),
1609 (s), 1370 (s), 1319 (b), 1217 (s), 1150 (s); 1H NMR (500 MHz,
CDCl3) δ 1.34 (br s, 9H), 2.71 (d, J = 16.5 Hz, 1H), 3.31 (dd, J = 8.7,
16.5 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.83 (d, J = 11.9, 1H), 5.40
(d, J = 8.7 Hz, 1H), 5.84 (d, J = 8.75 Hz, 1H), 7.22−7.32 (m, 4H),
8.09 (d, J = 8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 27.9, 41.9,
43.6, 52.3, 84.0, 106.1, 125.2, 128.4, 129.7, 131.2, 133.5, 139.5, 144.2,
N-Boc-2-ethenyl-2,3-dihydro-4-pyridone (3p).39 Using Gen-
eral Procedure A and vinyl magnesium bromide (1.2 mL, 1.0 M in
THF, 1.20 mmol), N-(tert-butoxycarbonyl)-4-pyridone 1 (195 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
yellow oil 3p (166 mg, 75%): IR (neat) 2980 (w), 2354 (b), 1723 (s),
I
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1670 (s), 1420 (w), 1335 (w), 1156 (s), 766 (s) cm−1; 1H NMR (500
MHz, CDCl3) δ 1.53 (s, 9H), 2.52 (d, J = 16.5 Hz, 1H), 2.91 (dd, J =
7.3, 16.5 Hz, 1H), 4.05 (br s, 1H), 5.13 (dd, J = 1.3, 16.9 Hz), 5.21
(dd, J = 0.9, 10.5 Hz, 1H), 5.28 (d, J = 8.2 Hz, 1H), 5.79 (ddd, J = 1.4,
6.4,11.9 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 27.9, 39.8, 54.4, 83.5, 106.4, 117.0, 133.0, 142.1, 151.1,
192.4; mass spectrum m/z (relative intensity), EI 223 (3.2, M+), 167
(10), 123 (15), 106 (3), 96 (23), 95 (15), 80 (9), 68 (9), 57 (100), 54
(16).
N-Boc-2-(1-hexenyl)-2,3-dihydro-4-pyridone (3q). Employing
Method C, General Procedure A and using i-PrMgBr (1.20 mL, 2.4
mmol, 2.0 M in diethyl ether), n-BuLi (1.92 mL, 4.8 mmol, 2.50 M in
hexane), 1-iodohexene (420 mg, 2.0 mmol), N-(tert-butoxycarbonyl)-
4-pyridone 1 (195 mg, 1.0 mmol) and TMSCl (326 mg, 3.0 mmol)
after purification by flash column chromatography (silica, 1−3%
MeOH:CH2Cl2, v/v) gave yellow viscous oil 3q (226 mg, 82%): IR
(neat) 2979 (w), 2354 (b), 1722 (s), 1672 (s), 1335 (b), 1155 (b),
861 (s), 766 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.3
Hz, 3H), 1.22−1.34 (m, 4H), 1.53 (s, 9H), 1.99 (q, J = 6.8 Hz, 2H),
2.47 (d, J = 16.0 Hz, 1H), 2.88 (dd, J = 6.8, 16.5 Hz, 1H), 4.98 (br s,
1H), 5.27 (d, J = 8.2 Hz, 1H), 5.45 (dd, J = 5.9, 15.1 Hz, 1H), 5.55−
5.61 (m, 1H), 7.76 (d, J = 7.7 Hz,1H); 13C NMR (125 MHz, CDCl3)
δ 13.9, 22.0, 27.9, 31.0, 31.7, 40.5, 54.3, 83.2, 106.2, 124.5, 134.0,
142.1, 151.2, 192.9; mass spectrum m/z (relative intensity) EI 279
(0.2, M+), 224 (2), 223 (3), 206 (2), 179 (10), 178 (5), 136 (23), 122
(16), 108 (7), 96 (26), 95 (8), 94 (19), 83 (8), 81 (15), 80 (18), 70
(11), 57 (100), 54 (25); HRMS (ESI) calculated for [C16H25NO3]+
279.18345, found 279.18300.
mg, 3.0 mmol) after purification by flash column chromatography
(silica, 1−3% MeOH:CH2Cl2, v/v) gave yellow viscous oil 4d (186
mg, 72%): IR (neat) 3081 (w), 2974 (m), 2929 (w), 1728 (s), 1671
(s), 1605 (s), 1462 (w), 1422 (m), 1368 (m), 1303 (s), 1254 (m),
1209 (m), 1168 (m), 1107 (m), 1021 (m), 976 (w), 919 (w), 764 (m)
cm−1; 1H NMR (500 MHz, CDCl3) δ 1.13 (t, J = 6.9 Hz, 3H), 2.29 (s,
3H), 2.49 (d, J = 16.0 Hz, 1H), 3.08 (dd, J = 8.7, 16.5 Hz, 1 H), 4.12
(q, J = 6.8 Hz, 2 H), 5.36 (d, J = 8.7 Hz, 1 H), 5.75 (d, J = 8.2 Hz,
1H), 6.98−7.05 (m, 1H), 7.05−7.12 (m, 3H), 8.09 (d, J = 8.2 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 14.2, 19.1, 40.9, 53.2, 63.7,
107.0, 124.1, 126.6, 128.0, 131.3, 134.0, 137.4, 143.8, 152.7, 191.7;
mass spectrum m/z (relative, intensity) EI 259 (M+, 22), 244 (3), 230
(1), 216 (5), 202 (100), 186 (19), 168 (30), 158 (17), 144 (16), 130
(27), 117 (96), 105 (18), 96 (47), 91 (29), 77 (8), 65 (10), 51 (5);
HRMS (ESI) calculated for [C15H18NO3]+ 260.1287, found 260.1276.
N-Ethoxycarbonyl-2-(2-thienyl)-2,3-dihydro-4-pyridone
(4e). Employing Method A, General Procedure A and using thiophene
(168 mg, 2.0 mmol), n-BuLi (0.80 mL, 2.50 M in hexane, 2.0 mmol),
MgBr2 (368 mg, 2.0 mmol), N-ethoxycarbonyl-4-pyridone 2 (167 mg,
1.0 mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless oil 4e (195 mg, 78%): IR (neat) 3082 (w), 2970 (w), 2917
(w), 2846 (w), 1723 (s), 1659 (s), 1595 (s), 1422 (w), 1366 (m),
1
1290 (m), 1260 (m), 1087 (w), 1012 (w), 756 (w) cm−1; H NMR
(500 MHz, CDCl3) δ 1.35 (t, J = 6.9 Hz, 3 H), 2.87 (d, J = 16.5 Hz,
1H), 3.10 (dd, J = 6.8, 16.9 Hz, 1H), 4.27−4.40 (m, 2H), 5.39 (d, J =
8.2 Hz, 1H), 5.92 (d, J = 4.1 Hz, 1H), 6.89 (dd, J = 3.6, 5.0 Hz, 1H),
6.95 (s, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 4.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 14.4, 41.7, 52.0, 64.0, 107.7, 125.6, 126.2,
126.6, 141.0, 141.4, 152.5, 192.1; mass spectrum m/z (relative
intensity) EI 252 (M++1, 9), 251 (M+, 59), 234 (2), 223 (13), 208 (5),
195 (2), 178 (28), 162 (11), 150 (8), 134 (9), 110 (100), 97 (31), 84
(11), 66 (16), 51 (31); HRMS (ESI) calculated for [C12H14NO3S]+
252.0694, found 252.0689.
N-Ethoxycarbonyl-2-(2-furyl)-2,3-dihydro-4-pyridone (4f).
Employing Method A, General Procedure A and using furan (136
mg, 2.0 mmol), n-BuLi (0.80 mL, 2.50 M in hexane, 2.0 mmol), MgBr2
(368 mg, 2.0 mmol) N-ethoxycarbonyl-4-pyridone 2 (167 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
yellow viscous oil 4f (176 mg, 75%): IR (neat) 3117 (w), 2981 (w),
2928 (w), 1727 (s), 1667 (s), 1603 (s), 1426 (m), 1373 (m), 1313 (s),
1264 (m), 1219 (s), 1173 (m), 1106 (w), 1012 (m), 763 (m) cm−1;
1H NMR (500 MHz, CDCl3) δ 1.34 (t, J = 7.3 Hz, 3H), 2.82 (d, J =
N-Ethoxycarbonyl-2-(1-methylethyl)-2,3-dihydro-4-pyri-
done (4b). Employing General Procedure A and using i-PrMgBr
(0.55 mL, 2.0 M in Et2O, 1.1 mmol), N-ethoxycarbonyl-4-pyridone 2
(167 mg, 1.0 mmol) and TMSCl (326 mg, 3.0 mmol) after
purification by flash column chromatography (silica, 1−3%
MeOH:CH2Cl2, v/v) gave colorless oil 4b (127 mg, 60%): IR
(neat) 2962 (m), 2923 (m), 2871 (w), 2851 (w), 1723 (s), 1664 (s),
1601 (s), 1466 (m), 1421 (m), 1369 (m), 1324 (s), 1258 (s), 1223
1
(m), 1192 (s), 1164 (m), 1084 (m), 993 (m), 765 (m) cm−1; H
NMR δ 0.83 (d, J = 6.90 Hz, 3H), 0.87 (d, J = 6.85 Hz, 3 H), 1.28 (t, J
= 7.35 Hz, 3H), 2.00−2.11 (m, 1 H), 2.54 (d, J = 16.95 Hz, 1H), 2.70
(dd, J = 6.90, 16.45 Hz, 1H), 4.19−4.29 (m, 2H), 5.24 (d, J = 6.40 Hz,
1H), 7.76 (d, J = 6.40 Hz, 1H); 13C NMR δ 14.4, 19.0, 19.6, 29.0, 29.8,
38.3, 58.7, 63.4, 107.6, 142.2, 153.2, 193.6; mass spectrum m/z
(relative intensity) EI 211 (M+, 25), 196 (0.06), 183 (0.83), 168 (69),
140 (16), 124 (1), 96 (100), 78 (12), 68 (20), 56 (10); HRMS (ESI)
calculated for [C11H18NO3]+ 212.1287, found 212.1295.
16.5 Hz, 1H), 3.00 (dd, J = 6.9, 16.5 Hz, 1H), 4.27−4.39 (m, 2H),
5.33 (d, J = 8.2 Hz, 1H), 5.75 (s, 1H), 6.19 (d, J = 3.2 Hz, 1H), 6.27
(dd, J = 1.8, 3.2 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.74 (br s, 1H); 13C
NMR (125 MHz, CDCl3) δ 14.4, 39.0, 50.2, 63.8, 107.4, 108.3, 110.3,
141.3, 142.7, 151.0, 152.7, 192.1; mass spectrum m/z (relative
intensity) EI 235 (M+, 48), 218 (5), 207 (9), 193 (49), 162 (25), 146
(17), 134 (27), 120 (9), 106 (16), 94 (100), 81 (20), 66 (31), 53 (7);
HRMS (ESI) calculated for [C12H14NO4]+ 236.0923, found 236.0913.
Synthesis of N-Boc-2-butyl 2,3-dihydro-5-bromo-4-pyri-
done (10). To the mixture of N-tert-butyl-carbamoyl-4-pyridone (1,
195 mg, 1.0 mmol) and TMSCl (326 mg, 3.0 mmol) in THF under
argon was added n-butyl magnesium chloride (0.75 mL, 1.6 M in
THF, 1.2 mmol) dropwise at room temperature, and the resulting
mixture was stirred for 3 h. After that tetra-n-butyl ammonium fluoride
(n-Bu4NF, 1.0 M solution in THF, 1.0 mmol) was added, and the
reaction mixture was stirred for 10 min. Next, N-bromosuccinimide
(356 mg, 2.0 mmol) was added, and the reaction mixture was stirred
overnight. Then the reaction mixture was diluted with dichloro-
methane (5.0 mL), quenched with saturated aqueous NH4Cl (5.0 mL)
and extracted with dichloromethane (3 × 10.0 mL). The combined
organic phase was washed with water (10.0 mL), brine (10.0 mL),
dried over anhydrous MgSO4, filtered, concentrated in vacuo, and
purified by flash column chromatography (silica, 1−3%
MeOH:CH2Cl2, v/v) to give a colorless oil (10, 243 mg, 73%). The
use of a literature method18a (3a with NBS in CH2Cl2) gave 256 mg,
77% yield: IR (neat) 3105 (w), 2977 (w), 1733 (s), 1677 (s), 1401
N-Ethoxycarbonyl-2-(2-methoxyphenyl)-2,3-dihydro-4-pyri-
done (4c). Employing Method B, General Procedure A and using 2-
bromoanisole (374 mg, 2.0 mmol), magnesium (192 mg, 8.0 mmol),
N-ethoxycarbonyl-4-pyridone 2 (167 mg, 1.0 mmol) and TMSCl (326
mg, 3.0 mmol) after purification by flash column chromatography
(silica, 1−3% MeOH:CH2Cl2, v/v) gave yellow viscous oil 4c (195
mg, 71%). Without addition of CuCN, lower chemical yield was
observed (46 vs 71%): IR (neat) 2979 (w), 2925 (w), 2841 (w), 1725
(s), 1670 (s), 1605 (s), 1489 (m), 1461 (m), 1410 (m), 1367 (m),
1302 (s), 1243 (m), 1200 (s), 1106 (m), 1027 (m), 752 (m) cm−1; 1H
NMR (500 MHz, CDCl3) δ 1.21 (br s, 3H), 2.81 (d, J = 16.5 Hz, 1H),
3.03 (dd, J = 8.2, 16.5 Hz, 1H), 3.83 (s, 3H), 4.21 (q, J = 6.8 Hz, 2H),
5.36 (d, J = 8.7 Hz, 1H), 5.95 (d, J = 7.3 Hz, 1H), 6.78−6.90 (m, 2H),
6.95 (d, J = 7.3 Hz, 1H), 7.17−7.24 (m, 1H), 8.11 (d, J = 7.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 14.3, 40.6, 51.8, 55.3, 63.6, 107.4,
110.9, 120.5, 125.3, 125.9, 129.0, 135.3, 143.3, 156.1, 192.8; mass
spectrum m/z (relative, intensity) EI 276 (11, M++1), 275 (59, M+),
274 (M-1, 29), 258 (0.57), 244 (12), 232 (5), 216 (6), 202 (100), 187
(14), 168 (17), 160 (8), 144 (6), 134 (42), 119 (93), 108 (11), 91
(60), 77 (15), 65 (13), 51 (6); HRMS (ESI) calculated for
[C15H18NO4]+ 276.1236, found 276.1225.
N-Ethoxycarbonyl-2-(2-methylphenyl)-2,3-dihydro-4-pyri-
done (4d). Employing Method B, General Procedure A and using 2-
bromotoluene (342 mg, 2.0 mmol), magnesium (192 mg, 8.0 mmol),
N-ethoxycarbonyl-4-pyridone 2 (167 mg, 1.0 mmol) and TMSCl (326
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1
(m), 1363 (m), 1259 (m), 1210 (s), 1116 (w), 776 (m) cm−1; H
NMR (500 MHz, CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 1.16−1.29 (m,
4H), 1.53 (s, 3H), 1.55−1.65 (m, 2H), 2.66 (d, J = 16.5 Hz, 1H), 2.86
(dd, J = 6.7, 16.5 Hz, 1H), 4.52 (br s, 1H), 8.08 (br s, 1H); 13C NMR
(125 MHz, CDCl3) δ 13.7, 22.2, 27.7, 27.8, 30.0, 39.4, 53.4, 84, 99.2,
142.5, 150.1, 185.8; mass spectrum m/z (relative intensity) EI 333
(M+, 0.1), 331 (M+ 0.1), 233 (28), 231 (29), 176 (98), 174 (100), 152
(32), 148 (12), 122 (8), 120 (8), 110 (14), 96 (70), 95 (69), 67 (68),
55 (12); HRMS (ESI) calculated for [C14H23NO3Br]+ 332.0861,
found 332.0860.
43.0, 51.3, 52.5, 80.1, 124.2, 126.1, 127.1, 131.1, 134.1, 141.3, 154.7,
206.9; mass spectrum m/z (relative intensity) EI, 345 (M+, 0.1), 245
(13), 213 (10), 202 (30), 188 (88), 145 (100), 118 (13), 117 (76), 91
(51), 65 (15); HRMS (ESI) calculated for [C21H31NO3Na]+
368.2202, found 368.2207. cis-N-Boc-2-(2-methylphenyl)-6-butyl-4-
piperidinone 12c: IR (neat) 2972 (s), 29333 (s), 1664 (s), 1359 (s),
1172 (s), 1052 (s) 772 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.92
(t, J = 6.9 Hz, 3H), 1.17 (br s, 9H), 1.26−1.54 (m, 5H), 1.89 (br s,
1H), 2.34 (s, 3H), 2.58−2.75 (m, 4H), 4.61−4.67 (m, 1H), 5.31 (br s,
1H), 7.12−7.23 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.0, 19.1,
22.4, 27.9, 29.1, 37.0, 43.5, 44.6, 51.7, 52.3, 80.4, 124.1, 126.6, 126.8,
130.5, 134.2, 142.9, 155.5, 208.1; mass spectrum m/z (relative
intensity) EI 345 (M+, 0.1), 274 (4), 245 (4), 213 (11), 210 (10), 188
(49), 146 (44), 145 (100), 117 (38), 115 (34), 91 (25), 65 (81);
HRMS (ESI) calculated for [C21H32NO3]+ 346.2382, found 346.2377.
trans-N-Boc-2,6-butyl-4-piperidinone (13a). Using General
Procedure A and n-BuMgCl (0.63 mL, 1.6 M in THF, 1.0 mmol),
N-Boc-2- butyl-2,3-dihydro-4-pyridone 3a (127 mg, 0.50 mmol) and
TMSCl (163 mg, 1.5 mmol) after purification by flash column
chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave colorless oil
13a (138 mg, 89%): IR (neat) 2961 (m), 2927 (s), 1723 (m), 1693
trans-N-Boc-2-(2-methylphenyl)-6-phenylmethyl-4-piperidi-
none (11a). Employing Method B, General Procedure A and using
benzylbromide (342 mg, 2.0 mmol), magnesium (192 mg, 8.0 mmol),
N-Boc-2-(2-methylphenyl)-2,3-dihydro-4-pyridone 3d (287 mg, 1.0
mmol) and TMSCl (326 mg, 3.0 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless crystals (337 mg, 89%). The stereochemistry of this molecule
was determined by X-ray crystallography: m.p. 109.3−111.4 °C; IR
(neat) 3449 (br, s), 2975 (s), 2854 (s), 1668 (s), 1366 (s), 1167 (s),
702 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 1.30 (br s, 9H), 2.31 (s,
3H), 2.54 (d, J = 17.5 Hz, 1H), 2.66−2.78 (m, 3H), 3.00 (dd, J = 8.2,
18.0 Hz, 1H), 3.38 (dd, J = 3.2, 13.0 Hz, 1H), 4.77 (br s, 1H), 5.61 (br
s, 1H), 7.15−7.35 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 19.2,
28.2, 41.2, 43.0, 43.1, 52.8, 53.5, 80.5, 124.2, 126.1, 126.8, 127.2, 128.7,
129.5, 131.2, 137.7, 154.7, 206.5; mass spectrum m/z (relative
intensity) EI 379 (M+, 0.1), 279 (2.0), 207 (3.0), 188 (60), 145 (100),
117 (23), 91 (25), 70 (15), 65 (8).
1
(s), 1464 (w), 1359 (s), 1249 (s), 1113 (s), 977 (w) cm−1; H NMR
(500 MHz, CDCl3) δ 0.87 (t, J = 6.9 Hz, 6H), 1.22−1.35 (m, 10H),
1.48 (s, 9H), 1.78 (br s, 2H), 2.52 (d, J = 17.9 Hz, 2H), 2.68 (dd, J =
6.0, 17.9 Hz, 2H), 4.10 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ
13.9, 22.4, 28.4, 28.9, 36.7, 41.5, 51.0, 79.8, 154.6, 208.4; mass
spectrum m/z (relative intensity) EI 311 (M+, 0.74), 270 (3), 254
(75), 238 (18), 199 (40), 198 (99), 156 (34), 155 (28), 154 (100),
112 (93), 96 (13), 83 (15), 69 (33), 57 (99); HRMS (ESI) calculated
for [C18H34NO3]+ 312.2539, found 312.2550.
trans-N-Boc-2-(1-methylethyl)-6-butyl-4-piperidinone (13b).
Using General Procedure A and i-PrMgBr (0.50 mL, 2.0 M in diethyl
ether, 1.0 mmol), N-Boc-2- butyl-2,3-dihydro-4-pyridone 3a (127 mg,
0.50 mmol) and TMSCl (163 mg, 1.5 mmol) after purification by flash
column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless oil 13b (130 mg, 88%): IR (neat) 2961 (m), 2925 (m), 2867
(w), 1723 (m), 1691 (s), 1468 (w), 1367 (m), 1338 (m), 1252 (w),
1169 (m), 1101 (w), 1007 (w), 978 (w), 863 (w), 773 (w); 1H NMR
(500 MHz, CDCl3) δ 0.86 (t, J = 7.3 Hz, 3H), 0.90 (d, J = 6.4 Hz,
3H), 0.95 (d, J = 6.9 Hz, 3H), 1.18−1.32 (m, 6H), 1.46 (s, 9H), 1.64−
1.72 (m, 1H), 2.47 (dd, J = 2.7, 17.8 Hz, 1H), 2.56−2.60 (m, 2H),
2.62 (dd, J = 1.8, 6.4 Hz, 1H), 3.95 (br s, 1H), 4.00 (br s, 1H); 13C
NMR (125 Hz, CDCl3) δ 14.1, 19.3, 20.3, 22.6, 28.5, 29.1, 34.8, 36.6,
41.8, 41.9, 51.8, 56.3, 80.0, 155.5, 209.0; mass spectrum m/z (relative
intensity) EI 297 (M+, 1), 296 (M+ − 1, 6), 282 (1), 266 (3), 240
(53), 226 (13), 196 (39), 182 (14), 170 (2), 156 (6), 140 (29), 112
(28), 98 (6), 86 (7), 69 (20), 57 (100); HRMS (ESI) calculated for
[C17H31NO3Na]+ 320.2202, found 320.2203.
cis-N-Boc-2,6-dibutyl-4-piperidinone (14a). Employing Gen-
eral Procedure B and n-BuLi (0.80 mL, 2.5 M in THF, 2.0 mmol),
CuCN (89 mg, 1.0 mmol), LiCl (85 mg, 2.0 mmol), N-Boc-2-butyl-
2,3-dihydro-4-pyridone 3a (127 mg, 1.0 mmol) after purification by
flash column chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave
colorless oil 14a (135 mg, 86%): IR (neat) 2964 (m), 2923 (s), 1718
(m), 1689 (s), 1467 (w), 1361 (s), 1254 (s), 1110 (s), 976 (w) cm−1;
1H NMR (500 MHz, CDCl3) δ 0.91 (t, J = 6.9 Hz, 3H), 1.26−1.37
(m, 4H), 1.43−1.48 (m, 1H), 1.49 (s, 9H), 1.61−1.67 (m, 1H), 2.35
(d, J = 14.7 Hz, 1H), 2.68 (dd, J = 7.8, 14.7 Hz, 1H), 4.57 (br s, 1H);
13C NMR (125 MHz, CDCl3) δ 14.0, 22.4, 28.4, 29.1, 36.5, 43.7, 52.7,
trans-N-Boc-2-(2-methylphenyl)-6-(1-methylethyl)-4-piperi-
dinone (11b). Employing Method B, General Procedure A and using
i-PrMgBr (0.50 mL, 2.0 M in diethyl ether, 1.0 mmol), N-Boc-2-(2-
methylphenyl)-2,3-dihydro-4-pyridone 3d (143 mg, 0.50 mmol) and
TMSCl (163 mg, 1.5 mmol) after purification by flash column
chromatography (silica, 1−3% MeOH:CH2Cl2, v/v) gave pure 11b
(141 mg, 85%): IR (neat) 2966 (m), 2925 (m), 2872 (w), 1723 (m),
1690 (s), 1460 (w), 1362 (s), 1339 (m), 1249 (m), 1170 (s), 1110
1
(m), 1019 (w), 974 (w), 861 (w), 767 (w), 748 (w); H NMR (500
MHz, CDCl3) δ 0.91 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H),
1.15 (br s, 9H), 1.79−1.89 (m, 1H), 2.24 (s, 3H), 2.53 (d, J = 17.4 Hz,
1H), 2.62 (dd, J = 2.3, 17.8 Hz, 1H), 2.78 (dd, J = 5.9, 18.3 Hz, 1H),
2.99 (dd, J = 7.8, 17.4 Hz, 1H), 4.20 (br s, 1H), 5.45 (d, J = 7.3 Hz,
1H), 7.02−7.09 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.2, 19.4,
20.5, 28.1, 35.0, 42.1, 43.2, 52.9, 56.6, 80.2, 124.0, 126.2, 127.1, 131.1,
134.1, 142.0, 155.5, 207.4; mass spectrum m/z (relative intensity) EI
331 (M+, 0.09), 288 (26), 258 (2), 232 (30), 214 (1), 188 (81), 174
(4), 145 (93), 117 (17), 91 (12), 70 (6), 57 (100); HRMS (ESI)
calculated for [C20H29NO3]+ 331.21475, found 331.21528.
trans-N-Boc-2-(2-methylphenyl)-6-butyl-4-piperidinone
(11c). Using General Procedure A and n-BuMgCl (0.63 mL, 1.6 M in
THF, 1.0 mmol), N-Boc-2-(2-methylphenyl)-2,3-dihydro-4-pyridone
3d (143 mg, 0.50 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 1−3% meth-
anol:dichloromethane, v/v) gave colorless oil 11c (154 mg, 89%). On
the other hand, using General Procedure B and n-BuLi (0.80 mL, 2.5
M in THF, 2.0 mmol), CuCN (89 mg, 1.0 mmol), LiCl (85 mg, 2.0
mmol), N-Boc-2-(2-methylphenyl)-2,3-dihydro-4-pyridone 3d (143
mg, 0.50 mmol) after purification by flash column chromatography
(silica, 1−3% MeOH:CH2Cl2, v/v) gave colorless oil 11c (152 mg,
88%), while the application of n-BuMgCl (0.63 mL, 1.6 M in THF, 1.0
mmol), CuI (191 g, 1.0 mmol), BF3·OEt2 (0.5 mmol), N-Boc-2-(2-
methylphenyl)-2,3-dihydro-4-pyridone 3d (143 mg, 0.50 mmol) after
purification by flash column chromatography (silica, 1−3% meth-
anol:dichloromethane, v/v) gave colorless oil 11c (85 mg, 49% and
12c (56 mg, 32.5%). trans-N-Boc-2-(2-methylphenyl)-6-butyl-4-
piperidinone 11c: IR (neat) 2960 (s), 2931 (s), 2861 (s), 1668 (s),
1367 (s), 1171 (s), 754 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.92
(t, J = 6.4 Hz, 3H), 1.28 (br s, 9H), 1.33−1.41 (m, 3H), 1.45−1.52 (m,
1H), 1.62 (br s, 1H), 1.90−1.99 (m, 1H), 2.31 (s, 3H), 2.65 (dd, J =
17.4, 33.9 Hz, 2H), 2.87 (dd, J = 6.0, 17.9 Hz, 1H), 3.07 (dd, J = 7.8,
17.4 Hz, 1H), 4.51 (br s, 1H), 5.55 (d, J = 6.9 Hz, 1H), 7.14 (s, 4H);
13C NMR (125 MHz, CDCl3) δ 14.0, 19.1, 22.5, 28.1, 28.9, 37.0, 42.4,
80.1, 154.9, 209.0; mass spectrum m/z (relative intensity) EI 311 (M+,
0.9), 270 (13), 254 (68), 238 (38), 199 (41), 198 (100), 156 (31), 155
(22), 154 (99), 112 (91), 96 (24), 83 (36), 69 (31), 57 (89); HRMS
(ESI) calculated for [C18H33NO3Na]+ 334.2358, found 334.2355.
General Procedure D: Reduction of 2,6-Disubstituted 4-
Piperidinones.40 To the solution of 2,6-disubstituted 4-piperidinone
(1.0 equiv) was added NaBH4 (2.0 equiv) in methanol, and the
resulting mixture was stirred for 30 min at room temperature. The
reaction mixture was quenched with saturated ammonium chloride
(5.0 mL) and extracted with diethyl ether (3 × 10.0 mL). The
combined organic phase was washed with water (10.0 mL), brine
K
dx.doi.org/10.1021/jo400936z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(10.0 mL), dried over anhydrous magnesium sulfate, and filtered. The
mixture was concentrated in vacuo and purified by flash column
chromatography (silica, 20−25% ethyl acetate:petroleum ether, v/v).
trans-N-Boc-2-(2-methylphenyl)-6-butyl-4-piperidinol (15).
Employing General Procedure D and using trans-N-Boc-2-(2-
methylphenyl)-6-butyl-4-piperidinone (70 mg, 0.2 mmol, 11c) and
NaBH4 (15 mg, 0.4 mmol) after purification by flash column
chromatography (silica, 20−25% ethyl acetate:petroleum ether, v/v)
gave colorless oil 15 along with other minor isomer (63 mg, 91%,
75:25 dr at CHOH): IR (neat) 3402 (br s), 2961 (s), 2926 (s), 2857
(s), 1655 (s), 1543 (s), 1366 (s), 1172 (s), 1066 (s), 792 (s); Major,
1H NMR (500 MHz, CDCl3) δ 0.85 (t, J = 6.0 Hz, 3H), 1.02 (s, 9H),
1.16−1.33 (m, 5H), 1.50−1.69 (m, 4H), 2.14−2.23 (m, 2H), 2.26 (s,
3H), 3.94−3.99 (m, 1H), 4.35 (br s, 1H), 4.64 (dd, J = 4.2, 9.2 Hz,
1H), 7.01−7.21 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.1, 19.4,
22.6, 27.8, 28.1, 29.3, 32.3, 35.6, 40.8, 51.8, 53.6, 64.2, 79.6, 125.1,
126.1, 130.4, 133.8, 143.3, 156.1; mass spectrum m/z (relative
intensity) EI 347 (M+, 0.1), 220 (27) 205 (100), 189 (4), 177 (11),
4.22−4.28 (m, 1H), 4.89 (dd, J = 5.1, 12.5 Hz, 1H), 7.12−7.34 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 14.2, 19.0, 22.7, 28.0, 29.3, 37.0,
38.3, 39.6, 51.7, 53.8, 65.6, 79.5, 124.4, 126.1, 126.3, 130.2, 133.6,
144.4, 155.8; mass spectrum m/z (relative intensity) EI 347 (M+, 0.7),
220 (33) 205 (100), 189 (14), 177 (17), 145 (9), 105 (12), 57 (34);
HRMS (ESI) calculated for [C21H34NO3]+ 348.2539, found 348.2531.
cis-N-Boc-2,6-dibutyl-4-piperidinol (19). Employing General
Procedure D and using cis-N-Boc-2,6-dibutyl-4-piperidinone (78 mg,
0.25 mmol, 14a) and NaBH4 (19 mg, 0.5 mmol) after purification by
flash column chromatography (silica, 20−25% ethyl acetate:petroleum
ether, v/v) gave colorless oil 19 (68 mg, 87%): IR (neat) 3433 (br, s),
2931 (s), 2869 (s), 1687 (s), 1662 (s), 1409 (s), 1365 (s), 1175 (s),
1
1095 (s) cm−1; H NMR (500 MHz, CDCl3) δ 0.91 (t, J = 6.9 Hz,
6H), 1.26−1.34 (m, 8H), 1.46 (s, 9H), 1.49−1.60 (m, 4H), 1.71−1.79
(m, 3H), 2.14 (m, 2H), 3.89−3.93 (m, 1H), 4.11−4.18 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 14.1, 22.6, 28.5, 29.0, 36.1, 38.1, 50.3,
65.8, 79.2, 155.4; mass spectrum m/z (relative intensity) EI 313 (M+,
0.08), 256 (25), 240 (5), 200 (100), 156 (99), 138 (26), 112 (54), 95
(8), 69 (25), 57 (98); HRMS (ESI) calculated for [C18H36NO3]+
314.2695, found 314.2703.
1
145 (12), 105 (8), 57 (26); Minor, H NMR (500 MHz, CDCl3) δ
0.82 (t, J = 7.3 Hz, 3H), 1.00 (s, 9H), 1.78−1.85 (m, 1H), 1.98−2.03
(m, 1H), 2.24 (s, 3H), 3.81 (s, 1H), 3.94−3.99 (m, 1H), 5.23 (s, 1H),
7.01−7.21 (m, 4H), other hydrogens were imbedded underneath
major isomer hydrogens; 13C NMR (125 MHz, CDCl3) δ 14.1, 19.2,
22.5, 28.1, 29.1, 29.7, 35.4, 35.9, 36.5, 52.8, 63.4, 79.4, 125.2, 125.5,
126.5, 130.8, 135.1, 143.5, 155.4; HRMS (ESI) calculated for
[C21H33NO3Na]+ 370.2358, found 370.2360.
1,10b-Dihydropyrido[2,1,α]isoindole-2-one (20). The cycliza-
tion of compound 3l to tricyclic compound 20 was carried out using
literature procedure.41 To the solution of N-Boc-2-(2′chloromethyl-
phenyl)-2,3-dihydro-4-pyridone 3l (161 mg, 0.5 mmol) in methanol
(5.0 mL) was added sodium metal (48 mg, 2.0 mmol), and the
mixture was heated to reflux for 1 h. The mixture was concentrated in
vacuo and purified by flash column chromatography (silica, 1−3%
MeOH:CH2Cl2, v/v) to give white pure solid 20 (71 mg, 77%): mp
134.7−136.1 °C; IR (neat) 2961 (m), 2944 (s), 1715 (m), 1464 (w),
trans-N-Boc-2,6-dibutyl-4-piperidinol (16). Employing General
Procedure D and using trans-N-Boc-2,6-dibutyl-4-piperidinone (78
mg, 0.25 mmol, 13a) and NaBH4 (19 mg, 0.5 mmol) after purification
by flash column chromatography (silica, 20−25% ethyl acetate:petro-
leum ether, v/v) gave colorless oil 16 (75 mg, 96%): IR (neat) 3447
(br, s), 2941 (s), 2909 (s), 2830 (s), 1681 (s), 1666 (s), 1423 (s),
1
1363 (s), 1241 (s), 1170 (s), 1010 (m), 934 (w), 737 (w); H NMR
(500 MHz, CDCl3) δ 2.66 (t, J = 16.5 Hz, 1H), 2.81 (dd, J = 5.0, 17.0
Hz, 1H), 4. 85 (dd, J = 14.0, 34.5 Hz, 2H), 5.11 (d, J = 7.0 Hz, 1H),
5.22 (dd, J = 4.5, 16.0 Hz, 1H), 7.25−7.38 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 40.8, 54.5, 62.7, 98.7, 122.1, 122.9, 128.3 (2-carbons),
136.6, 139.6, 149.6, 191.3; mass spectrum m/z (relative intensity) EI
186 (M++1, 14.34), 185 (M+, 100), 168 (17), 157 (15), 156 (52), 142
(8), 130 (17), 129 (20), 115 (34), 91 (9), 77 (11), 65 (6), 51 (8);
HRMS (ESI) calculated for [C12H11NO]+ 185.08407, found
185.08450.
1
1233 (s), 1069 (s) cm−1; H NMR (500 MHz, CDCl3) δ 0.90 (t, J =
6.4 Hz, 3H), 0.92 (t, J = 6.9 Hz, 3H), 1.25−1.36 (m, 9H), 1.46 (s,
9H), 1.60−1.71 (m, 4H), 1.89−1.95 (m, 1H), 1.99−2.06 (m, 3H),
3.41−3.51 (m, 1H), 4.09 (br s, 1H), 4.07−4.12 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.0 (2-carbons), 22.5, 22.6, 28.5, 29.0, 29.4,
32.6, 34.9, 35.3, 36.4, 51.5, 51.7, 64.7, 79.2, 155.4; mass spectrum m/z
(relative intensity) EI 313 (M+, 0.07), 256 (35), 240 (38), 213 (7),
200 (98), 156 (100), 138 (57), 112 (31), 95 (18), 69 (33), 57 (93);
HRMS (ESI) calculated for [C18H36NO3]+ 314.2695, found 314.2686.
trans-N-Boc-2-(1-methylethyl)-6-butyl-4-piperidinol (17).
Employing General Procedure D and using trans-N-Boc-2-(1-
methylethyl)-6-butyl-4-piperidinone (70 mg, 0.2 mmol, 13b) and
NaBH4 (15 mg, 0.4 mmol) after purification by flash column
chromatography (silica, 20−25% ethyl acetate:petroleum ether, v/v)
gave colorless oil 17 (52 mg, 87%, 1:1 dr at CHOH): IR (neat) 3412
(br s), 2975 (s), 2931 (s), 1664 (s), 1539 (s), 1359 (s), 1163 (s), 1075
trans-N-Boc-2-(2-methylphenyl)-6-(1-methylethyl)-4-piperi-
dinol (23). Employing General Procedure D and using trans-N-Boc-2-
(2-methylphenyl)-6-(1-methylethyl)-4-piperidinone (70 mg, 0.2
mmol, 11b) and NaBH4 (15 mg, 0.4 mmol) after purification by
flash column chromatography (silica, 20−25% ethyl acetate:petroleum
ether, v/v) gave colorless oil 23 along with other minor isomer (62
mg, 93%): IR (neat) 3431 (br s), 2955 (s), 2933 (s), 2872 (s), 1643
(s), 1371(s), 1273 (s), 1166 (s), 752 (s); Major, 1H NMR (500 MHz,
CDCl3) δ 1.02 (dd, J = 6.4, 8.3 Hz, 6H), 1.10 (s, 9H), 1.23 (br s, 1H),
1.74−2.07 (m, 3H), 2.29−2.35 (m, 1H), 2.35 (s, 3H), 2.39−2.42 (m,
1H), 4.02−4.11 (m, 1H), 4.14−4.18 (m, 1H), 4.81 (dd, J = 5.1, 11.9
Hz, 1H), 7.11−7.30 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.5,
20.0, 20.9, 27.8, 31.4, 35.2, 39.2, 52.0, 58.2, 64.3, 79.3, 125.4, 126.0,
126.3, 130.6, 134.2, 142.9, 156.3. Minor, 1H NMR (500 MHz, CDCl3)
δ 0.93 (dd, J = 6.9, 21.5 Hz, 6H), 1.12 (s, 9H), 1.26 (s, 1H), 1.42−1.48
(m, 2H), 2.34 (s, 3H), 3.48−3.52 (m, 1H), 4.02−4.11 (m, 1H), 5.32
(br s, 1H), 7.11−7.30 (m, 4H); other hydrogens were imbedded
underneath the major isomer hydrogens); 13C NMR (125 MHz,
CDCl3) δ 19.2 (2-carbons), 20.4, 28.1, 29.6, 33.0, 34.8, 53.6, 57.6,
63.6, 79.8, 125.2, 125.5, 126.5, 130.8, 134.1, 142.8, 155.7; mass
spectrum m/z (relative intensity) EI 333 (M+, 0.02), 207 (3), 190
(100), 172 (10), 147 (57), 129 (21), 117 (16), 105 (8), 91 (16);
HRMS (ESI) calculated for [C20H31NO3Na]+ 356.2202, found
356.2202.
1
(s), H NMR (500 MHz, CDCl3) δ 0.88−0.96 (m, 18H), 1.21−1.39
(m, 8H), 1.46 (s, 18H), 1.47−1.59 (m, 6H), 1.75−1.83 (m, 3H),
1.90−1.96 (m, 3H), 1.99−2.06 (m, 3H), 2.28−2.35 (m, 1H), 2.98−
3.07 (m, 1H), 3.17−3.23 (m, 1H), 3.62−3.68 (m, 1H), 3.91−4.02 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 15.4 (2-carbons), 19.8, 20.1,
20.5, 20.8, 22.5, 22.6, 22.7, 28.5 (2-carbons), 28.9 (2-carbons), 29.5,
30.9, 34.2, 35.1, 35.6, 36.6, 38.3, 52.2, 52.3, 58.5, 59.2, 66.0 (2-
carbons), 79.3 (2-carbons), 156.3, 156.4; mass spectrum m/z (relative
intensity), major EI 299 (M+, 0.01), 256 (21), 226 (6), 201 (22), 200
(100), 186 (11), 157 (11), 156 (90), 142 (12), 138 (29), 112 (32),
111 (12), 98 (11), 57 (99), 41 (36); HRMS (ESI) calculated for
[C17H33NO3Na]+ 322.2358, found 322.2367.
cis-N-Boc-2-(2-methylphenyl)-6-butyl-4-piperidinol (18).
Employing General Procedure D and using cis-N-Boc-2-(2-methyl-
phenyl)-6-butyl-4-piperidinone (35 mg, 0.1 mmol, 12c) and NaBH4 (8
mg, 0.2 mmol) after purification by flash column chromatography
(silica, 20−25% ethyl acetate:petroleum ether, v/v) gave colorless oil
18 (29 mg, 84%): IR (neat) 3448 (br s), 2961 (s), 2930 (s), 2859 (s),
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1687 (s), 1366 (s), 1171 (s), 1071 (s), 782 (s) cm−1; H NMR (500
1H and 13C NMR spectra for 3c−f, 3k−q, 4b−f, 10, 11a−c,
12c, 13a,b, 14a, 15−20, 23, ab initio minimized geometries for
twist-boat conformations 11c-TBdiax, 12c-TBArax, 12c-TBRax,
MHz, CDCl3) δ 0.96 (t, J = 7.1 Hz, 3H), 1.12 (s, 9H), 1.26 (br s, 1H),
1.40−1.47 (m, 4H), 1.65−1.78 (m, 3H), 2.02−2.08 (m, 1H), 2.16−
2.25 (m, 1H), 2.36 (s, 3H), 2.37−2.44 (m, 1H), 4.07−4.13 (m, 1H),
L
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and 15-TBdiax and coordinates of all stationary points are
included. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dieterr@clemson.edu.
■
Present Address
‡Winston-Salem State University, 601 South Martin Luther
King Jr. Drive, Winston-Salem, North Carolina 27110, United
States.
Author Contributions
†F. Guo and R. C. Dhakal contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by the ACS-Petroleum
Research Fund (ACS-PRF 42853-AC). Support of the NSF
Chemical Instrumentation Program for purchase of a JEOL 500
MHz NMR instrument is gratefully acknowledged (CHE-
9700278). We thank Mrs. Tugba Kucukkal for performing the
ab initio calculations, Professor Stephen J. Stuart for helpful
discussions, Professor Colin McMillan for X-ray crystallo-
graphic determinations, and Professor Nicolas Gouault for
copies of NMR spectra for compound 22c.
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