Iridium-catalyzed [2+2+2] cycloaddition of α,ω-diynes with isocyanates

Article abstract of DOI:10.1021/jo202083z

[Ir(cod)Cl]₂/BINAP was found to be an efficient catalyst for the [2+2+2] cycloaddition of α,ω-diynes with isocyanates to give 2-pyridones. A wide range of isocyanates can be used for this reaction. Both aliphatic and aromatic isocyanates smooth

Full text of DOI:10.1021/jo202083z

Article
pubs.acs.org/joc
Iridium-Catalyzed [2+2+2] Cycloaddition of α,ω-Diynes with
Isocyanates
Gen Onodera,† Mari Suto, and Ryo Takeuchi*
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo, Sagamihara, Kanagawa
252-5258, Japan
S
* Supporting Information
ABSTRACT: [Ir(cod)Cl]2/BINAP was found to be an efficient catalyst for the [2+2+2] cycloaddition of α,ω-diynes with
isocyanates to give 2-pyridones. A wide range of isocyanates can be used for this reaction. Both aliphatic and aromatic isocyanates
smoothly reacted with α,ω-diynes to give 2-pyridones in high yields. Aliphatic isocyanates were more reactive than aromatic
isocyanates. For aromatic isocyanates, the electronic properties of the substituents affected the reactivity: electron-donating
substituents enhanced the reaction. The reaction of unsymmetrical α,ω-diynes possessing two different internal alkyne moieties
with isocyanates was regiospecific and gave a single product. This regioselectivity could be explained by the reaction of
iridacyclopentadiene with a nitrogen−carbon double bond. The regioselectivity of the reaction of malonate-derived diyne was
controlled by a steric effect, while that of the reaction of ester-tethered diyne was controlled by an electronic effect. [Ir(cod)Cl]2/
chiral diphosphine catalyst could be used for the enantioselective synthesis of C−N axially chiral 2-pyridone. The reaction of
diyne 1a with o-methoxyphenyl isocyanate (7a) gave C−N axially chiral 2-pyridone (R)-8aa in 78% yield with 94% ee.
pyridone. Vollhardt also reported Co-catalyzed reaction.7
INTRODUCTION
The transition metal-catalyzed reaction of heterocumulenes
that would be either difficult or impossible with a Lewis acid
■
Recently, Ru,8 Rh,9,19 and Ni-NHC10 complexes have been
reported to be new catalysts for the cycloaddition of α,ω-diynes
with isocyanates to give 2-pyridones. However, each catalyst
catalyst or under thermal conditions represents a new approach
to heterocyclic compounds.1 Due to its ready availability and
stability, isocyanate is especially important among hetero-
cumulenes. Recently, Rovis developed a [2+2+2] cycloaddition
of alkenylisocyanates with alkyne to give lactam and vinylogous
amide.2 This reaction has been applied to the enantioselective
total synthesis of (+)-Lasubine II.2f On the basis of this success,
isocyanates are becoming an increasingly important substrate.
The cumulative structure of the carbon−nitrogen double bond
and the carbon−oxygen double bond is attractive as a starting
material.3 The transition metal-catalyzed [2+2+2] cycloaddition
of two molecules of alkyne with one molecule of isocyanate is
an atom-economical and environmentally benign reaction for
the synthesis of 2-pyridone, which is a valuable heterocycle for
the production of pharmaceuticals and agrochemicals4 because
the reaction proceeds under mild and neutral conditions
without giving a metal salt as waste. Since the pioneering work
by Yamazaki5 and Hoberg,6 there have been several studies on
the [2+2+2] cycloaddition of alkyne with isocyanate to give 2-
has drawbacks. With Cp*Ru(cod)Cl, it can be difficult to
change the selectivity of the reaction by tuning the steric and
electronic effects of the Cp ligand, since the introduction of
substituents to the Cp ligand requires considerable synthetic
operations. These Rh9a,19a,b and Ni10 catalysts require
preactivation before diynes can be reacted with isocyanates.
[Rh(ethylene)2Cl]2 is a relatively unstable complex.2,9b,c
A
more convenient and stable catalyst that does not require
preactivation is needed to expand the scope of the reaction and
improve the selectivity.
We have been studying iridium-catalyzed carbon−carbon and
carbon−heteroatom bond formation11 since we first found that
an iridium complex was an efficient catalyst for highly
branched-product selective allylic alkylation in 1997.11a We
have also found that [Ir(cod)Cl]2/diphosphine was an efficient
Received: October 7, 2011
Published: December 5, 2011
© 2011 American Chemical Society
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a
Table 1. Reaction of 1,6-Diyne (1a) with Phenyl Isocyanate (2a)
b
entry
ligand
DPPE
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
ClCH2CH2Cl
24
24
24
24
24
24
24
18
24
24
24
24
24
18
24
1
0
16
32
51
54
67
63
96
41
4
DPPP
DPPB
DPPPentane
DPPF
BIPHEP
(R)-H8−BINAP
(R)-BINAP
PPh3
c
9
c
10
P(OPh)3
11
12
13
14
15
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
rac-BINAP
44
28
40
75
80
97
96
THF
benzene
toluene
CH3CH2COCH2CH3
ClCH2CH(Cl)CH3
ClCH2CH(Cl)CH3
d
16
d
17
1
a
Reaction condition: 1a (1 mmol) and 2a (3 mmol) in the presence of [Ir(cod)Cl]2 (0.02 mmol) and a ligand (0.04 mmol) in solvent (5 mL).
Isolated yield. 8 mol % of ligand was used. 1.2 mmol of 2a was used.
b
c
d
catalyst for the cycloaddition of unsaturated compounds to give
cyclic compounds.12 We have extended this iridium chemistry
to cycloaddition with isocyanates. The iridium-catalyzed
cycloaddition of alkynes with isocyanates has not yet been
reported. In this paper, we report the full details of the
[Ir(cod)Cl]2/diphosphine-catalyzed [2+2+2] cycloaddition of
α,ω-diynes with isocyanates to give 2-pyridones. In addition, we
report the construction of C−N axial chirality catalyzed by
[Ir(cod)Cl]2/chiral diphosphine. An Ir catalyst is more
convenient than Rh and Ni catalysts because the catalyst
does not require preactivation. We can use various phosphines
as a ligand for [Ir(cod)Cl]2. It is easy to alter the catalytic
activity by choosing an appropriate phosphine, which can lead
to changes in product-, chemo-, regio-, and enantioselectivity.
BINAP under refluxing 1,2-dichloropropane. A reduction in the
amount of 2a to 1.2 mmol accelerated the reaction rate (entry
16). rac-BINAP gave essentially the same result as that with
(R)-BINAP (entry 17).
Reaction of 1a with Various Isocyanates 2b−u. We
examined the reaction of 1a with various isocyanates under the
optimized reaction conditions described above. The results are
summarized in Table 2. The substituent at the para position on
the aromatic ring affected the reaction. An electron-donating
substituent such as a methoxy or methyl group gave a good
result (entries 1 and 2). These reactions went to completion in
1 h. A weak electron-donating group such as halogen also gave
a good result (entries 4 and 5). Although various trans-
formations of an aromatic carbon−halogen bond catalyzed by
transition metal are possible,13 the aromatic carbon−halogen
bond was compatible under the reaction conditions. The
presence of an electron-withdrawing group at the para position
decreased the yield. The reaction with p-trifluoromethylphenyl
isocyanate (2g) and p-acetylphenyl isocyanate (2h) gave 3ag
and 3ah in respective yields of 72% and 71% (entries 6 and 7).
Strong electron-withdrawing groups such as a cyano or nitro
group gave the corresponding products in low yields (entries 8
and 9). Aromatic isocyanates required heating to give the
product, and aliphatic isocyanate was more reactive than
aromatic isocyanate. The reaction with n-butyl isocyanate (2k)
at room temperature went to completion in 20 min to give 3ak
in 98% yield (entry 10). A longer alkyl isocyanate similarly
underwent cycloaddition at room temperature (entry 11).
Benzyl isocyanate was a good substrate as an aliphatic
isocyanate (entry 12). The reaction with phenethyl isocyanate
(2n) gave the product in somewhat lower yield than that with
benzyl isocyanate (2m) (entry 13). An isocyanate bearing a
heteroaromatic ring could be used for the reaction. In contrast
to the reaction with benzyl isocyanate, which proceeded at
room temperature, the reaction with furfuryl isocyanate (2o)
RESULTS AND DISCUSSION
■
Screening of the Catalyst. Diyne 1a reacted with phenyl
isocyanate (2a) in the presence of 2 mol % of [Ir(cod)Cl]2 and
ligand to give 2-pyridone 3aa. Phosphine ligand had a profound
effect on the reaction. The effect of phosphine ligand was
screened under refluxing 1,2-dichloropropane, and the results
are summarized in Table 1. Although DPPE has been reported
to be an efficient ligand for the Ir-catalyzed cycloaddition of
alkynes to give benzene,12b,d,e DPPE was totally ineffective for
the reaction of 1a with 2a (entry 1). As the number of
methylene groups between the two diphenylphosphino groups
increased from two to five, the yield of 3aa increased from 0%
to 51% (entries 1−4). Biaryl diphosphines were more efficient
than 1,n-bis(diphenylphosphino)alkane (entries 6−8). (R)-
BINAP was the most efficient ligand for this reaction. The
reaction of 1a with 2a using (R)-BINAP for 18 h gave 3aa in
96% yield (entry 8). PPh3 and P(OPh)3 were less efficient than
(R)-BINAP (entries 9 and 10). We examined the effect of
solvent on the reaction by using (R)-BINAP (entries 11−15).
The optimal conditions were determined to be the use of (R)-
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a
Table 2. Reaction of 1,6-Diyne (1a) with Various Isocyanates 2
a
Reaction condition: 1a (1 mmol) and 2 (1.2 mmol) in the presence of [Ir(cod)Cl]2 (0.02 mmol) and (R)-BINAP (0.04 mmol) in 1,2-
b
c
dichloropropane (5 mL). Isolated yield. Reaction condition: 1a (1.5 mmol) and 2g (1 mmol) in the presence of [Ir(cod)Cl]2 (0.02 mmol) and
(R)-BINAP (0.04 mmol) in 1,2-dichloropropane (5 mL). 3-Pentanone was used as a solvent.
d
required heating to give 2-pyridone 3ao. Furfuryl isocyanate
(2o) reacted with diyne 1a under refluxing 1,2-dichloropropane
for 1 h to give 3ao in 92% yield (entry 14). The reaction of allyl
isocyanate (2p) required heating to give N-allyl-2-pyridone 3ap
in 80% yield (entry 15). The introduction of an allyl group on
nitrogen is valuable for further functionalization of the 2-
pyridone ring because the carbon−carbon double bond can be
transformed to another functional group. A functionalized
isocyanate such as ethyl isocyanatoacetate (2q) smoothly
reacted with diyne 1a at room temperature to give 3aq in 99%
yield (entry 16). An ester group was compatible under the
reaction conditions. On the other hand, 2-chloroethyl
isocyanate (2r) did not give 2-pyridone at all (entry 17), and
the starting material was recovered in quantitative yield. Both
acyclic and cyclic secondary isocyanates gave results as good as
primary isocyanates (entries 18 and 19). In contrast to these
successful results with primary and secondary aliphatic
isocyanates, tertiary aliphatic isocyanate 2u failed to react
even under refluxing 1,2-dichloropropane (entry 20). This lack
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of reactivity is considered to be due to steric hindrance by the
tertiary butyl group.
and 3dk in nearly quantitative yields (entries 1 and 3). The
reaction of monoester diyne (1c) gave 3ck in 96% yield, which
was comparable to the yield of 1,3-diester 1a (entry 2). The
reaction of diyne 1e bearing Meldrum’s acid at the 5-position
required heating to give 3ek in 89% yield (entry 4). As shown
above, 2-pyridones fused with a five-membered ring were
obtained in high yields from 2,7-nonadiynes. The reaction was
successfully applied to the synthesis of 2-pyridones fused with a
six-membered ring. The reaction of 2,8-decadiyne 1f under
refluxing 1,2-dichloropropane gave 3fk in 94% yield (entry 5).
However, the reaction of 2,8-decadiyne 1g did not give 2-
pyridone at all (entry 6). These results clearly showed that a
Thorpe−Ingold effect14 was indispensable for cyclization.
Pyrrolidine is an important N-heterocycle as a biologically
active compound because various substituted pyrrolidines are
used as pharmaceuticals. 2-Pyridone fused with pyrrolidine was
obtained with this reaction. N,N-Dipropargyl sulfonamide, 1h,
smoothly underwent cycloaddition with 2k to give 2-pyridone
fused with pyrrolidine 3hk in 96% yield (entry 7). The reaction
of 1,6-heptadiyne, 1i, gave 3ik in 56% yield (entry 8). Monoyne
could not be used for the reaction in place of diyne. The
reaction of monoyne with isocyanate gave no product.
We examined the reaction of diisocyanate 4, and expected
the formation of two 2-pyridone rings in the same molecule
when an excess amount of diyne 1a was used. Both isocyanate
groups participated in cycloaddition to give 5 in 99% yield
under refluxing 1,2-dichloropropane when 2 equiv of 1a was
used (Scheme 1).
Scheme 1. Reaction of 1,6-Diyne 1a with Diisocyanate 4
Regioselective Cycloaddition of Unsymmetrical Diyne
with n-Butyl Isocyanate 2k. Regioselective cycloaddition is
important for the synthesis of substituted 2-pyridones. There
have been few studies on the regioselective cycloaddition of
unsymmetrical α,ω-diynes with isocyanates, and only Ru8a and
Rh9a complexes have been examined as catalysts. In most of the
cases examined so far, the substrates were unsymmetrical
diynes with an internal alkyne moiety and a terminal alkyne
moiety. We examined the regioselectivity of the reactions of
unsymmetrical diynes with isocyanates. The results are
Reactions of Various Diynes with n-Butyl Isocyanate
2k. We examined the reactions of various diynes with n-butyl
isocyanate (2k) because primary alkyl isocyanate was the most
reactive isocyanate among the isocyanates surveyed. The results
are summarized in Table 3. The substituent at the 5-position in
2,7-nonadiyne affected the reaction conditions to give 2-
pyridone 3 in high yield. The reaction was compatible with
various functional groups. Similar to 1,3-diester (1a), cyclic 1,3-
diketone (1d) and acyclic 1,3-diketone (1b) gave good results.
These reactions proceeded at room temperature to give 3bk
a
Table 3. Reaction of Various 1,6-Diynes (1) with Isocyanate 2k
a
Reaction condition: 1a (1 mmol) and 2k (1.2 mmol) in the presence of [Ir(cod)Cl]2 (0.02 mmol) and (R)-BINAP (0.04 mmol) in 1,2-
b
dichloropropane (5 mL). Isolated yield.
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a
Table 4. Reaction of Unsymmetrical 1,6-Diynes (1) with Isocyanates 2
a
Reaction condition: 1 (1 mmol) and 2 (1.2 mmol) in the presence of [Ir(cod)Cl]2 (0.02 mmol) and (R)-BINAP (0.04 mmol) in 1,2-
b
c
d
e
f
dichloropropane (5 mL). E = CO2Me. Isolated yield. 3equiv of 2 was used. Structure of 3 was determined by 2D NMR. Structures of 3mk and
3nk were unambiguously confirmed by X-ray analysis (Figures 1 and 2).
summarized in Table 4. All of the reactions were regiospecific to
give the corresponding 2-pyridones as a single product. We first
Figure 2. ORTEP drawing of 3nk. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
reaction was opposite that of the Ru-catalyzed reaction. The
CpRu(cod)Cl-catalyzed reaction of 1j with n-propyl isocyanate
has been reported to give 2-pyridone in which a methyl group
was substituted at the α-position relative to a nitrogen atom.8a
An unsymmetrical diyne possessing two different internal
alkyne moieties is a more challenging substrate for
regioselective cycloaddition. We next examined the reactions
of such diynes. Ph-substituted diyne 1k underwent cyclo-
addition to give 2-pyridone 3kk in which a phenyl group was
substituted at the α-position relative to a carbonyl group in 97%
yield as a single product (entry 2). Similarly, trimethylsilyl-
substituted diyne 1l smoothly reacted with 2k to give 2-
pyridone 3lk in 86% yield as a single product (entry 3). These
Figure 1. ORTEP drawing of 3mk. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
examined the reaction of malonate-derived diyne possessing a
terminal alkyne moiety and a Me-substituted internal alkyne
moiety (1j) with n-butyl isocyanate (2k). 2-Pyridone 3jk, in
which a methyl group was substituted at the α-position of the
carbonyl group, was obtained in 80% yield as a single product
(entry 1). Notably, the regioselectivity of the Ir-catalyzed
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two reactions showed the same regioselectivity. A trimethylsilyl
group is useful for introducing a functionality into the 2-
pyridone ring. These diynes, 1j, 1k, 1l, possessed sterically
different alkyne moieties. We next examined the reactions of
diynes possessing electronically different alkyne moieties. With
diyne 1m, the terminal ester group connected directly to an
alkyne moiety. The reaction of 1m with n-butyl isocyanate (2k)
gave 2-pyridone 3mk in 69% yield (entry 4). The α-carbon
relative to the carbonyl group in 3mk was substituted with an
ester group. We examined the reaction of ester-tethered diyne
1n. The reaction of 1n with 2k gave 3nk in 91% yield (entry 5).
The regioselective cycloaddition of an unsymmetrical diyne
possessing two different internal alkyne moieties with
isocyanates has been difficult. The CpRu(cod)Cl-catalyzed
reaction of a similar amide-tethered diyne with n-propyl
isocyanate has been reported to give a 83:17 mixture of
regioisomeric 2-pyridones. Our Ir catalyst was able to overcome
the regioselectivity problem. Ester-tethered diynes possessing
Ph- and Me-substituted internal alkyne moieties 1o and 1p
were examined. The reactions of 1o and 1p gave 3ok and 3pk
in respective yields of 75% and 33% (entries 6 and 7). The
regioselectivity of the reactions of 1o and 1p was the same as
that of 1n.
Scheme 3. Plausible Reaction Pathway
pyridones 3jk−lk were obtained. In the reaction of diyne 1m,
the α-substituents on iridacyclopentadiene 6m are an EtO2C
group and a methyl group. Since steric congestion by the ester
group is not much greater than that by a methyl group, it seems
that the steric effect is not decisive in determining the
regioselectivity. The regioselectivity of the reaction of 1m was
believed to be due to the fact that the more stable 1,3-
dicarbonyl compound 3mk was preferentially formed. Ester-
tethered diyne 1n is a good substrate for evaluating the
electronic effect of a carbonyl group on regioselectivity, since,
with regard to steric considerations, diyne 1n possesses the
same alkyne terminus, but an electronically different alkyne
terminus. The steric hindrance at each α-carbon in
iridacyclopentadiene 6n is the same in this case. Consequently,
the electronic effect plays a decisive role in determining the
regioselectivity. With iridacyclopentadiene 6n, an α-carbon
conjugated with an internal carbonyl group is more electron-
deficient than an α-carbon that is not conjugated with a
carbonyl group. Isocyanate nitrogen reacts at the more
electron-deficient α-carbon to give 3nk. Ester-tethered diynes
1o and 1p possess sterically and electronically different alkyne
termini. The electron-withdrawing property of the tethered-
ester group plays a decisive role in determining the
regioselectivity in both cases. The more electron-deficient α-
carbon in iridacyclopentadienes 6o and 6p reacts with the
isocyanate nitrogen to give 3ok and 3pk. Although the steric
effect works in an opposite direction than the electronic effect
in ester-tethered diyne 1o, the regiochemical outcome shows
that the electronic effect of the internal ester group is
predominant over the steric effect of the terminal phenyl
group. With ester-tethered diyne 1p, the steric effect and
electronic effect work in the same direction. Thus, we can
conclude that the regioselectivity of the reaction of malonate-
derived diyne 1j−l is controlled by a steric effect, while that of
ester-tethered diyne 1n−p is controlled by an electronic effect.
The results presented in Table 2 clearly show that the
electronic-properties of the substituent on isocyanate strongly
affect the reaction. The reaction with an aliphatic isocyanate
such as n-butyl isocyanate (2k) proceeded at room temper-
ature, while that with an aromatic isocyanate such as phenyl
isocyanate (2a) or p-methoxyphenyl isocyanate (2b) required
heating to give the corresponding 2-pyridone in high yields.
Moreover, the reaction with an electron-deficient aromatic
Regiochemical and Mechanistic Considerations. The
regioselectivity observed here should be explained on the basis
of mechanistic considerations. A plausible mechanism is as
follows (Scheme 2). Diyne oxidatively adds to an iridium active
Scheme 2. Catalytic Cycle
species to give iridacyclopentadiene.15 Isocyanate reacts with
iridacyclopentadiene to give 2-pyridone. The regioselectivity is
determined when iridacyclopentadiene reacts with isocyanate.
The regioselectivity observed here can be explained by
considering the different reactivities of the α-carbon in
iridacyclopentadiene formed by the oxidative cyclization of
diyne. When the steric effect is predominant, the less-hindered
α-carbon preferentially reacts with an isocyanate nitrogen atom.
When the electronic effect is predominant, the more electron-
deficient α-carbon in iridacyclopentadiene preferentially reacts
with the more electron-rich isocyanate nitrogen atom (Scheme
3). We examined the reaction of malonate-derived diyne and
ester-tethered diyne. When diynes 1j−l possessing a sterically
different alkyne terminus (Me vs H, Me vs Ph, and Me vs
Me3Si) were used, the less-hindered α-carbon of iridacyclo-
pentadienes 6j−l reacted with isocyanate nitrogen to decrease
the steric repulsion with an alkyl group on nitrogen. Thus, 2-
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a
Table 5. Reaction of 1,6-Diynes (1a) with Isocyanate 7a
b
c
entry
ligand
(R)-BINAP
solvent
equiv of 7a
temperature
time (h)
yield (%)
ee (%)
1
ClCH2CH(Cl)CH3
ClCH2CH2Cl
acetone
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60 °C
40 °C
rt
1
24
24
1
58
60
30
54
64
49
57
63
60
60
63
20
84
79
45
20
79
68
12
39
59
0
70
71
77
88
74
75
79
86
86
86
86
88
86
85
85
72
91
77
46
69
72
−
2
(R)-BINAP
3
(R)-BINAP
4
(R)-BINAP
THF
5
(R)-BINAP
1,4-dioxane
MeOCH2CH2OMe
toluene
1
6
(R)-BINAP
1
7
(R)-BINAP
1
8
(R)-BINAP
benzene
1
9
(R)-BINAP
benzene
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
(R)-BINAP
benzene
1
(R)-BINAP
benzene
1
(R)-BINAP
benzene
0 °C
rt
24
1
(R)-BINAP
benzene
(R)-BINAP
benzene
5
rt
24
24
24
24
4
(R)-tol-BINAP
(R)-SEGPHOS
(R)-H8−BINAP
(R)-P-PHOS
(R)-C3-TUNEPHOS
(R)-SYNPHOS
(R)-MeO-BIPHEP
(R,S)-JOSIPHOS
(S,S)-DIPAMP
(R)-H8-BINAP
benzene
3
rt
benzene
3
rt
benzene
3
rt
benzene
3
rt
benzene
3
rt
24
24
24
24
24
1
benzene
3
rt
benzene
3
rt
benzene
3
rt
benzene
3
rt
0
−
94
d
24
benzene
3
reflux
78
a
b
Reaction condition: 1a (1 mmol) and 7a in the presence of [Ir(cod)Cl]2 (0.02 mmol) and ligand (0.04 mmol) in solvent (5 mL). Isolated yield.
c
d
Determined by HPLC. Reaction condition: 1a (0.5 mmol) and 7a (1.5 mmol) in the presence of [Ir(cod)Cl]2 (0.01 mmol) and ligand (0.02
mmol) in solvent (2.5 mL).
isocyanate such as p-nitrophenyl isocyanate (2j) gave the
product in low yield. These results show that the electron-
density of isocyanate nitrogen has a profound effect on the
reaction temperature and the yield. Although it is clear that the
reaction of iridacyclopentadiene 6 with isocyanate 2 proceeds
via a concerted mechanism, bond formation between the
isocyanate nitrogen and the α-carbon in the transition state may
be more advanced than that between the isocyanate carbon and
another α-carbon. Consequently, the electron-density of the
isocyanate nitrogen affects the reactivity. An electron-rich
isocyanate is more reactive than an electron-deficient
isocyanate.
Enantioselective Cycloaddition of Diyne 1a with
Ortho Substituted Isocyanates 7a−g. C−N axially chiral
compounds such as N-o-tert-butyl anilide have received much
attention since the pioneering work by Curran.16 A transition
metal-catalyzed construction of C−N axial chirality has been
developed. Kitagawa and Taguchi reported the Pd-catalyzed
enantioselective N-arylation of N-o-tert-butyl anilides to give
C−N axially chiral anilides in up to 95% ee.17 The Rh-catalyzed
enantioselective 1,4-addition of aryl boronic acid was
successfully applied to the synthesis of axially chiral N-
arylsuccinimides by Hayashi and Shintani.18 In 2008, Tanaka
reported a new approach to C−N axial chirality.19 Malonate-
derived 2,7-nonadiyne reacted with ortho-substituted aryl
isocyanate to give axially chiral N-aryl-2-pyridone in the
presence of cationic rhodium BINAP catalyst. However, the
yield and enantioselectivity needed to be improved. For
example, the reaction of 1a with o-methyl phenyl isocyanate
(7b) has been reported to give a product in 83% yield with 30%
ee. The reaction of 1a with o-bromophenyl isocyanate (7f) has
been reported to give a product in 27% yield with 87% ee.
None of the examples showed both high yield and high
enantioselectivity. We tried to improve both the yield and
enantioselectivity. The reaction conditions and chiral ligand
were optimized in the reaction of 1a with o-methoxyphenyl
isocyanate (7a). The results are summarized in Table 5. The
effect of the solvent on the reaction was examined (entries 1−
8). Benzene gave a good yield (63%) with high enantiose-
lectivity (86% ee) (entry 8). Thus, we next examined the effect
of temperature using benzene as solvent. The reaction
temperature did not appear to influence the enantioselectivity
(entries 8−11). The reaction at 0 °C gave a slightly increased
enantioselectivity (88% ee) with a considerable decrease in
yield (20%) (entry 12). An increase in the amount of
isocyanate 7a from 1.2 equiv to 3 equiv increased the yield
from 63% to 84% (entries 11 and 13), but a further increase in
the amount of 7a to 5 equiv resulted in a slight decrease in yield
(entry 14). We examined the effect of a chiral ligand using the
reaction at room temperature in benzene with 3 equiv of
isocyanate 7a. (R)-Tol-BINAP gave almost the same
enantioselectivity as (R)-BINAP, but the yield was lower than
that with (R)-BINAP (entry 15). (R)-SEGPHOS gave a lower
yield and enantioselectivity than (R)-BINAP (entry 16). (R)-
914
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The Journal of Organic Chemistry
Article
H8-BINAP gave 91% enantioselectivity with 79% yield (entry
17). Other chiral diphosphines were less efficient than (R)-
BINAP (entries 18−23). The reaction using (R)-H8−BINAP
under refluxing conditions increased the enantioselectivity to
94% (entry 24). The reaction of 1a with 7a in the presence of
[Rh(cod)2]BF4/(R)-BINAP has been reported to give 8aa in
92% yield with 58% ee. Our Ir catalyst improved the
enantioselectivity to 94% ee. The absolute configuration of
8aa was determined to be R by the anomalous dispersion
method (Figure 3).
results are summarized in Table 6. The reaction of o-tolyl
isocyanate (7b) gave 8ab in 61% yield with 78% ee (entry 2). A
change in the substituent at the ortho position from a methyl
group to an ethyl group or isopropyl group decreased the yield
(entries 3−6), but the enantioselectivity of the reaction with 7d
reached 90% ee (entry 6). o-Halophenyl isocyanates underwent
cycloaddition to give 8ae and 8af in high yields with good
enantioselectivities. The reaction was tolerant of the aromatic
carbon-halogen bond. The reaction with o-chlorophenyl
isocyanate (7e) gave 8ae in 83% yield with 87% ee (entry 8).
The reaction with o-bromophenyl isocyanate (7f) gave a
slightly lower yield and enantioselectivity than those with o-
chlorophenyl isocyanate (7e) (entries 9 and 10). 1-Naphthyl
isocyanate (7g) underwent cycloaddition to give 8ag in 64%
yield with 73% ee (entry 11). The enantioselectivities of the
reaction with 7a−e and the yield of 8af were improved
compared to the results with Rh.19 These results suggest that an
Ir catalyst was more enantioselective for constructing C−N
axial chirality than a Rh catalyst.
CONCLUSION
■
Figure 3. ORTEP drawing of (R)-8aa. Hydrogen atoms are omitted
for clarity. Thermal ellipsoids are drawn at 50% probability.
In summary, we have developed a new catalyst for the [2+2+2]
cycloaddition of α,ω-diynes with isocyanates. The [Ir(cod)-
Cl]2/BINAP catalyst has a wide range of both diyne and
isocyanate substrates. The reaction proceeded under mild
conditions to give the corresponding 2-pyridones in high yields.
We subjected o-substituted isocyanates to the reaction under
the optimized conditions described above. (R)-BINAP and (R)-
H8-BINAP were examined as ligands for each isocyanate. The
a
Table 6. Reaction of 1,6-Diynes (1a) with Isocyanates 7
a
Reaction condition: 1a (0.5 mmol) and 7 (1.5 mmol) in the presence of [Ir(cod)Cl]2 (0.01 mmol) and ligand (0.02 mmol) in solvent (2.5 mL).
Isolated yield. Determined by HPLC. lit. Ref 19a.
b
c
d
915
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The Journal of Organic Chemistry
Article
Dimethyl 2-(4-chlorophenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
The results described here should lead to new opportunities for
the application of organoiridium chemistry in cycloaddition.
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ae): white
1
solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.06 (s, 3H),
3.39 (s, 2H), 3.47 (s, 2H), 3.79 (s, 6H), 7.10 (d, J = 8.3 Hz, 2H), 7.46
(d, J = 8.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.1, 18.2, 37.5,
39.3, 53.2, 59.2, 116.7, 120.8, 129.5, 129.8, 134.3, 135.7, 137.9, 150.3,
163.8, 171.4. HRMS (FAB): calcd for C20H2135ClNO5 ([M + H]+),
390.1108. Found: m/z 390.1117. IR (KBr): 1745, 1670 cm−1.
Dimethyl 2-(4-bromophenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3af): brown
EXPERIMENTAL SECTION
■
General. 1H and 13C NMR spectra were measured at 500 and 125
MHz using TMS as an internal standard. Samples were dissolved in
CDCl3. GC analyses were performed using 3.2 mm × 2 m glass
columns packed with 5% OV-17 on 60/80 mesh Chromosorb WAW-
DMCS. High-resolution mass spectra were obtained by FAB.
Materials. All reagents and solvents were dried and purified before
use by the usual procedures. [Ir(cod)Cl]2 was prepared as described
previously.20 Diynes 1a,12b 1b,21 1c,22 1e,23 1f,22 1h,21 1j,12b 1l,24 and
1n25 were prepared as described in the literature. Diyne 1d was
prepared by reaction of the sodium salt of dimedone with 1-bromo-2-
butyne. Diyne 1g was purchased. Diyne 1i was prepared by reaction of
the sodium salt of dimethyl malonate with propargyl bromide. Diyne
1k was prepared by Sonogashira reaction of 1j with iodobenzene.
Diyne 1m was prepared by reaction of 1j with methyl chloroformate.
Diynes 1o and 1p were prepared by condensation reaction similar to
that for the preparation of 1n. Isocyanates 2 and 7 were purchased.
Representative Procedure for the Cycloaddition of Diyne (1)
with Isocyanate (2). A flask was charged with [Ir(cod)Cl]2 (14.0 mg,
0.02 mmol) and (R)-BINAP (24.9 mg, 0.04 mmol). The flask was
evacuated and filled with argon. To the flask were added 1,2-
dichloropropane (5 mL) and phenyl isocyanate (2a) (164 mg, 1.4
mmol). Diyne 1a (236 mg, 1.0 mmol) was added to the reaction
mixture. The mixture was stirred under reflux for 1 h. The progress of
the reaction was monitored by GLC. After the reaction was complete,
the solvent was evaporated in vacuo. Column chromatography of the
residue gave 3aa (n-hexane/AcOEt = 30/70, 344 mg, 0.97 mmol, 97%
yield).
1
solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.06 (s, 3H),
3.39 (s, 2H), 3.47 (s, 2H), 3.79 (s, 6H), 7.04 (d, J = 8.7 Hz, 2H), 7.62
(d, J = 8.7 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.1, 18.2, 37.5,
39.3, 53.2, 59.2, 116.8, 120.8, 122.4, 129.9, 132.8, 135.7, 138.5, 150.3,
163.8, 171.4. HRMS (FAB): calcd for C20H2179BrNO5 ([M + H]+),
434.0603. Found: m/z 434.0610. IR (KBr): 1742, 1670 cm−1.
Dimethyl 1,4-dimethyl-3-oxo-2-(4-trifluoromethylphenyl)-5H-
2,3,6,7-tetrahydrocyclopenta[c]-pyridine-6,6-dicarboxylate (3ag):
1
brown solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.07 (s,
3H), 3.40 (s, 2H), 3.48 (s, 2H), 3.80 (s, 6H), 7.31 (d, J = 8.3 Hz, 2H),
7.77 (d, J = 8.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 12.9, 18.0,
37.4, 39.2, 53.0, 59.1, 116.9, 120.8, 123.6 (q, JCF = 272.5 Hz), 126.6 (q,
JCF = 3.8 Hz), 128.8, 130.5 (q, JCF = 32.6 Hz), 135.2, 142.6 (q, JCF
=
1.4 Hz), 150.5, 163.6, 171.3. HRMS (FAB): calcd for C21H21F3NO5
([M + H]+), 424.1372. Found: m/z 424.1361. IR (KBr): 1740, 1671
cm−1.
Dimethyl 2-(4-acetylphenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ah): white
1
solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.07 (s, 3H),
2.64 (s, 3H), 3.40 (s, 2H), 3.48 (s, 2H), 3.80 (s, 6H), 7.28 (d, J = 8.5
Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ
13.1, 18.1, 26.7, 37.5, 39.3, 53.2, 59.2, 116.9, 120.9, 128.6, 129.6, 135.3,
136.9, 143.7, 150.4, 163.7, 171.4, 197.1. HRMS (FAB): calcd for
C22H23NO6 ([M]+), 397.1525. Found: m/z 397.1532. IR (KBr): 1735,
1664 cm−1.
Representative Procedure for the Enantioselective Cyclo-
addition of Diyne (1a) with Isocyanate (7). A flask was charged
with [Ir(cod)Cl]2 (14.0 mg, 0.02 mmol) and (R)-H8-BINAP (24.9 mg,
0.04 mmol). The flask was evacuated and filled with argon. To the
flask were added benzene (2.5 mL) and 2-methoxyphenyl isocyanate
(7a) (164 mg, 1.4 mmol). Diyne 1a (236 mg, 1.0 mmol) was added to
the reaction mixture. The mixture was stirred under reflux for 1 h. The
progress of the reaction was monitored by GLC. After the reaction was
complete, the solvent was evaporated in vacuo. Column chromatog-
raphy of the residue gave 8aa (n-hexane/AcOEt = 30/70, 344 mg, 0.97
mmol, 97% yield).
Dimethyl 2-(4-cyanophenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ai): brown
1
solid. H NMR (500 MHz, CDCl3) δ 1.85 (s, 3H), 2.06 (s, 3H),
3.40 (s, 2H), 3.48 (s, 2H), 3.80 (s, 6H), 7.32 (d, J = 8.5 Hz, 2H), 7.81
(d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.1, 18.2, 37.4,
39.3, 53.2, 59.1, 112.6, 117.3, 118.0, 121.1, 129.5, 133.5, 134.9, 143.6,
150.8, 163.5, 171.3. HRMS (FAB): calcd for C21H21N2O5 ([M + H]+),
381.1450. Found: m/z 381.1451. IR (KBr): 1733, 1668 cm−1.
Dimethyl 1,4-dimethyl-2-(4-nitrophenyl)-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3aj): yellow
Spectroscopic data of 3, 5, and 8 are as follows.
Dimethyl 1,4-dimethyl-3-oxo-2-phenyl-5H-2,3,6,7-
1
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3aa): brown
solid. H NMR (500 MHz, CDCl3) δ 1.87 (s, 3H), 2.07 (s, 3H),
1
solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.07 (s, 3H),
3.40 (s, 2H), 3.49 (s, 2H), 3.81 (s, 6H), 7.38 (d, J = 9.0 Hz, 2H), 8.37
(d, J = 9.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.1, 18.2, 37.5,
39.3, 53.2, 59.2, 117.4, 121.2, 124.9, 129.7, 134.8, 145.2, 147.6, 150.9,
163.5, 171.3. HRMS (FAB): calcd for C20H20N2O7 ([M]+), 400.1271.
Found: m/z 400.1271. IR (KBr): 1740, 1668 cm−1.
3.40 (s, 2H), 3.48 (s, 2H), 3.80 (s, 6H), 7.15 (d, J = 7.3 Hz, 2H), 7.42
(t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H). 13C NMR (125 MHz,
CDCl3) δ 13.2, 18.2, 37.6, 39.3, 53.2, 59.2, 116.4, 120.7, 128.0, 128.3,
129.5, 136.1, 139.5, 150.0, 164.0, 171.5. HRMS (FAB): calcd for
C20H22NO5 ([M + H]+), 356.1498. Found: m/z 356.1500. IR (KBr):
1736, 1666 cm−1.
Dimethyl 2-(n-butyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ak): brown
1
oil. H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.8 Hz, 3H), 1.42
Dimethyl 2-(4-methoxyphenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]-pyridine-6,6-dicarboxylate (3ab): brown
(sextet, J = 7.8 Hz, 2H), 1.63 (quintet, J = 7.8 Hz, 2H), 2.05 (s, 3H),
2.28 (s, 3H), 3.37 (s, 2H), 3.41 (s, 2H), 3.77 (s, 6H), 3.97 (t, J = 7.8
Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.3, 13.7, 16.9, 20.3, 30.6,
37.9, 39.2, 44.7, 53.1, 59.1, 116.6, 120.0, 135.7, 148.8, 163.3, 171.5.
HRMS (FAB): calcd for C18H26NO5 ([M + H]+), 336.1811. Found:
m/z 336.1817. IR (NaCl, neat): 1735, 1661 cm−1.
Dimethyl 2-(n-heptyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3al): white
solid. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H),
1.25−1.41 (m, 8H), 1.64 (quintet, J = 7.8 Hz, 2H), 2.05 (s, 3H), 2.28
(s, 3H), 3.37 (s, 2H), 3.41 (s, 2H), 3.77 (s, 6H), 3.96 (t, J = 7.8 Hz,
2H). 13C NMR (125 MHz, CDCl3) δ 13.3, 14.0, 16.9, 22.5, 27.0, 28.6,
28.9, 31.7, 37.9, 39.2, 44.9, 53.1, 59.1, 116.6, 120.0, 135.7, 148.8, 163.3,
171.5. HRMS (FAB): calcd for C21H32NO5 ([M + H]+), 378.2280.
Found: m/z 378.2276. IR (KBr): 1735, 1663 cm−1.
1
solid. H NMR (500 MHz, CDCl3) δ 1.87 (s, 3H), 2.06 (s, 3H),
3.39 (s, 2H), 3.47 (s, 2H), 3.79 (s, 6H), 3.84 (s, 3H), 6.99 (d, J = 8.7
Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ
13.2, 18.2, 37.6, 39.3, 53.1, 55.4, 59.2, 114.8, 116.3, 120.6, 128.9, 132.1,
136.6, 149.9, 159.2, 164.2, 171.5. HRMS (FAB): calcd for C21H24NO6
([M + H]+), 386.1604. Found: m/z 386.1605. IR (KBr): 1729, 1664
cm−1.
Dimethyl 1,4-dimethyl-2-(4-methylphenyl)-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ac): white
1
solid. H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 2.06 (s, 3H),
2.40 (s, 3H), 3.39 (s, 2H), 3.47 (s, 2H), 3.79 (s, 6H), 7.02 (d, J = 8.3
Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ
13.1, 18.2, 21.1, 37.6, 39.3, 53.1, 59.2, 116.3, 120.6, 127.7, 130.2, 136.3,
136.8, 138.2, 149.9, 164.1, 171.5. HRMS (FAB): calcd for C21H24NO5
([M + H]+), 370.1654. Found: m/z 370.1664. IR (KBr): 1748, 1667
cm−1.
Dimethyl 1,4-dimethyl-3-oxo-2-phenylmethyl-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3am): white
916
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The Journal of Organic Chemistry
Article
solid. 1H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H), 2.18 (s, 3H), 3.36
(s, 2H), 3.45 (s, 2H), 3.77 (s, 6H), 5.32 (s, 2H), 7.14 (d, J = 7.3 Hz,
2H), 7.22 (t, J = 7.3 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H). 13C NMR (125
MHz, CDCl3) δ 13.5, 17.2, 37.8, 39.3, 47.6, 53.1, 59.1, 116.9, 120.1,
126.5, 127.1, 128.6, 136.4, 137.0, 149.5, 163.8, 171.5. HRMS (FAB):
calcd for C21H24NO5 ([M + H]+), 370.1654. Found: m/z 370.1660. IR
(KBr): 1735, 1663 cm−1.
Methyl 2-(n-butyl)-1,4-dimethyl-3-oxo-6-phenyl-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6- carboxylate (3ck): white solid.
1H NMR (500 MHz, CDCl3) δ 0.97 (t, J = 7.8 Hz, 3H), 1.42 (sextet, J
= 7.8 Hz, 2H), 1.64 (quintet, J = 7.8 Hz, 2H), 2.11 (s, 3H), 2.32 (s,
3H), 3.08 (d, J = 14.9 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H), 3.63 (s, 3H),
3.79 (d, J = 14.9 Hz, 1H), 3.80 (d, J = 16.8 Hz, 1H), 3.98 (t, J = 7.8
Hz, 2H), 7.28 (t, J = 6.9 Hz, 1H), 7.32−7.37 (m, 4H). 13C NMR (125
MHz, CDCl3) δ 13.3, 13.7, 16.8, 20.3, 30.7, 40.3, 41.1, 44.7, 52.8, 58.0,
117.6, 120.0, 126.4, 127.3, 128.6, 135.6, 142.0, 149.8, 163.4, 175.3.
HRMS (FAB): calcd for C22H28NO3 ([M + H]+), 354.2069. Found:
m/z 354.2063.
2-(n-Butyl)-1,4,5′,5′-tetramethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6-spiro-2′- cyclohexan-1′,3′-dione
(3dk): white solid. 1H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz,
3H), 1.02 (s, 3H), 1.06 (s, 3H), 1.41 (sextet, J = 7.3 Hz, 2H), 1.61
(quintet, J = 7.3 Hz, 2H), 2.04 (s, 3H), 2.26 (s, 3H), 2.69 (d, J = 14.2
Hz, 2H), 2.73 (d, J = 14.2 Hz, 2H), 3.21 (s, 2H), 3.26 (s, 2H), 3.96 (t,
J = 7.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.3, 13.7, 16.9, 20.3,
28.0, 28.5, 30.57, 30.61, 36.6, 36.8, 44.6, 51.3, 69.8, 116.3, 119.7, 135.6,
149.0, 163.3, 206.2. HRMS (FAB): calcd for C21H30NO3 ([M + H]+),
344.2226. Found: m/z 344.2224.
2-(n-Butyl)-1,2′,2′,4-tetramethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6-spiro-5′-(1′,3′-dioxan-4′,6′-
dione) (3ek): yellow solid. 1H NMR (500 MHz, CDCl3) δ 0.97 (t, J =
7.3 Hz, 3H), 1.43 (sextet, J = 7.3 Hz, 2H), 1.64 (quintet, J = 7.3 Hz,
2H), 1.82 (s, 6H), 2.04 (s, 3H), 2.27 (s, 3H), 3.47 (s, 2H), 3.50 (s,
2H), 3.99 (t, J = 7.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.4,
13.7, 17.1, 20.3, 28.9, 29.0, 30.6, 43.1, 43.6, 44.8, 51.7, 105.3, 115.8,
119.9, 135.7, 148.1, 163.3, 170.2. HRMS (FAB): calcd for C19H26NO5
([M + H]+), 348.1811. Found: m/z 348.1813.
Dimethyl 1,4-dimethyl-3-oxo-2-(2-phenylethyl)-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3an): white
1
solid. H NMR (500 MHz, CDCl3) δ 2.09 (s, 3H), 2.15 (s, 3H),
2.96 (t, J = 7.8 Hz, 2H), 3.34 (s, 2H), 3.43 (s, 2H), 3.77 (s, 6H), 4.17
(t, J = 7.8 Hz, 2H), 7.21−7.25 (m, 3H), 7.28−7.31 (m, 2H). 13C NMR
(125 MHz, CDCl3) δ 13.3, 16.8, 34.6, 37.9, 39.2, 46.7, 53.1, 59.1,
116.7, 120.1, 126.5, 128.5, 128.8, 135.8, 138.6, 149.1, 163.3, 171.5.
HRMS (FAB): calcd for C22H26NO5 ([M + H]+), 384.1811. Found:
m/z 384.1815. IR (KBr): 1735, 1663 cm−1.
Dimethyl 2-(2-furyl)methyl-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ao): white
1
solid. H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.41 (s, 3H),
3.38 (s, 2H), 3.41 (s, 2H), 3.76 (s, 6H), 5.20 (s, 2H), 6.30 (dd, J = 1.8
and 3.2 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H).
13C NMR (125 MHz, CDCl3) δ 13.3, 17.2, 37.8, 39.2, 40.9, 53.1, 59.1,
109.0, 110.5, 116.8, 120.1, 136.1, 141.8, 149.5, 150.2, 163.3, 171.5.
HRMS (FAB): calcd for C19H21NO6 ([M]+), 359.1369. Found: m/z
359.1365. IR (KBr): 1738, 1662 cm−1.
Dimethyl 1,4-dimethyl-3-oxo-2-(2-propenyl)-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3ap): white
1
solid. H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.26 (s, 3H),
3.37 (s, 2H), 3.43 (s, 2H), 3.77 (s, 6H), 4.68 (brd, J = 5.0 Hz, 2H),
5.00 (dd, J = 1.4 and 17.4 Hz, 1H), 5.16 (dd, J = 1.4 and 10.5 Hz, 1H),
5.92 (ddt, J = 10.5, 17.4, and 5.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 13.3, 16.7, 37.8, 39.2, 46.6, 53.1, 59.1, 116.3, 116.7, 120.0,
132.6, 136.1, 149.2, 163.2, 171.5. HRMS (FAB): calcd for C17H22NO5
([M + H]+), 320.1498. Found: m/z 320.1504. IR (KBr): 1742, 1661
cm−1.
Tetraethyl 2-(n-butyl)-1,4-dimethyl-3-oxo-5,6,7,8-tetrahydroiso-
1
quinoline-6,6,7,7-tetracarboxylate (3fk): yellow oil. H NMR (500
MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.43 (sextet, J = 7.3 Hz, 2H),
1.65 (quintet, J = 7.3 Hz, 2H), 2.10 (s, 3H), 2.31 (s, 3H), 3.21 (s, 2H),
3.30 (s, 2H), 4.07 (brt, J = 7.3 Hz, 2H), 4.18−4.26 (m, 8H). 13C NMR
(125 MHz, CDCl3) δ 12.2, 13.66, 13.68, 14.1, 15.5, 20.3, 30.5, 31.7,
33.0, 45.1, 56.8, 57.0, 60.3, 61.90, 61.94, 109.6, 121.9, 138.3, 141.6,
161.9, 169.5, 169.6. HRMS (FAB): calcd for C27H40NO9 ([M + H]+),
522.2703. Found: m/z 522.2697.
Dimethyl 2-ethoxycarbonylmethyl-1,4-dimethyl-3-oxo-5H-
2,3,6,7-tetrahydrocyclopenta[c]- pyridine-6,6-dicarboxylate (3aq):
1
white solid. H NMR (500 MHz, CDCl3) δ 1.29 (t, J = 6.9 Hz, 3H),
5-(n-Butyl)-4,7-dimethyl-6-oxo-2-tosyl-1,3,5,6-tetrahydropyrrolo-
[3,4-c]pyridine (3hk): white solid. 1H NMR (500 MHz, CDCl3) δ 0.95
(t, J = 7.8 Hz, 3H), 1.39 (sextet, J = 7.8 Hz, 2H), 1.58 (quintet, J = 7.8
Hz, 2H), 1.97 (s, 3H), 2.22 (s, 3H), 2.43 (s, 3H), 3.95 (t, J = 7.8 Hz,
2H), 4.37 (s, 4H), 7.35 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H).
13C NMR (125 MHz, CDCl3) δ 13.2, 13.6, 17.0, 20.2, 21.5, 30.5, 44.6,
51.4, 52.2, 113.3, 119.0, 127.5, 129.9, 133.2, 135.6, 143.9, 144.8, 163.0.
HRMS (FAB): calcd for C20H27N2O3S ([M + H]+), 375.1742. Found:
m/z 375.1733.
2.06 (s, 3H), 2.20 (s, 3H), 3.39 (s, 2H), 3.43 (s, 2H), 3.77 (s, 6H),
4.23 (q, J = 6.9 Hz, 2H), 4.76 (s, 2H). 13C NMR (125 MHz, CDCl3) δ
13.2, 14.1, 17.1, 37.7, 39.3, 45.8, 53.1, 59.1, 61.6, 117.0, 120.0, 135.6,
150.0, 163.4, 168.4, 171.4. HRMS (FAB): calcd for C18H23NO7
([M]+), 365.1475. Found: m/z 365.1469. IR (KBr): 1757, 1735,
1663 cm−1.
Dimethyl 2-isopropyl-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6- dicarboxylate (3as): white
1
solid. H NMR (500 MHz, CDCl3) δ 1.59 (br, 6H), 2.01 (s, 3H),
Dimethyl 2-(n-butyl)-3-oxo-5H-2,3,6,7-tetrahydrocyclopenta[c]-
2.28 (br, 3H), 3.36 (s, 2H), 3.39 (s, 2H), 3.77 (s, 6H), 4.40 (br, 1H).
1
pyridine-6,6-dicarboxylate (3ik): brown solid. H NMR (500 MHz,
13C NMR (125 MHz, CDCl3) δ 12.7 (br), 17.4, 19.1 (br), 37.9, 38.8,
CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H), 1.36 (sextet, J = 7.3 Hz, 2H), 1.70
(quintet, J = 7.3 Hz, 2H), 3.34 (s, 2H), 3.42 (s, 2H), 3.76 (s, 6H), 3.86
(t, J = 7.3 Hz, 2H), 6.40 (s, 1H), 7.11 (s, 1H). 13C NMR (125 MHz,
CDCl3) δ 13.6, 19.8, 31.4, 36.5, 39.7, 49.6, 53.1, 60.6, 114.6, 118.8,
131.2, 154.7, 162.3, 171.0. HRMS (FAB): calcd for C16H22NO5 ([M +
H]+), 308.1498. Found: m/z 308.1504.
50.8 (br), 52.7, 58.7, 116.6 (br), 120.9 (br), 135.5 (br), 148.1, 163.8,
171.2. HRMS (FAB): calcd for C17H24NO5 ([M + H]+), 322.1654.
Found: m/z 322.1648. IR (KBr): 1740, 1663 cm−1.
Dimethyl 2-cyclohexyl-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6- dicarboxylate (3at): white
solid. 1H NMR (500 MHz, CDCl3) δ 1.22−1.32 (m, 3H), 1.57−
1.66 (m, 3H), 1.85−1.87 (m, 2H), 2.00 (s, 3H), 2.26 (br, 3H), 2.85−
2.92 (m, 2H), 3.36 (s, 2H), 3.39 (s, 2H), 3.77 (s, 6H), 3.90 (br, 1H).
13C NMR (125 MHz, CDCl3) δ 12.9, 17.6, 25.0, 26.3, 27.9, 38.1, 39.0,
Dimethyl 2-(n-butyl)-4-methyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3jk): white
1
solid. H NMR (500 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H), 1.36
(sextet, J = 7.3 Hz, 2H), 1.70 (quintet, J = 7.3 Hz, 2H), 2.07 (s, 3H),
3.36 (s, 2H), 3.40 (s, 2H), 3.77 (s, 6H), 3.87 (t, J = 7.3 Hz, 2H), 7.00
(s, 1H). 13C NMR (125 MHz, CDCl3) δ 13.3, 13.7, 19.9, 31.4, 37.0,
39.0, 50.1, 53.1, 60.3, 118.1, 123.3, 128.1, 150.0, 162.4, 171.3. HRMS
(FAB): calcd for C17H24NO5 ([M + H]+), 322.1654. Found: m/z
322.1657.
52.9, 58.9, 60.1, 116.8, 121.3, 135.5, 148.2, 164.0, 171.3. HRMS
(FAB): calcd for C20H28NO5 ([M + H]+), 362.1967. Found: m/z
362.1975. IR (KBr): 1738, 1666 cm−1.
6,6-Diacetyl-2-(n-butyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
1
tetrahydrocyclopenta[c]pyridine (3bk): brown solid. H NMR (500
MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.41 (sextet, J = 7.3 Hz, 2H),
1.62 (quintet, J = 7.3 Hz, 2H), 2.06 (s, 3H), 2.18 (s, 6H), 2.30 (s, 3H),
3.28 (s, 2H), 3.32 (s, 2H), 3.97 (t, J = 7.3 Hz, 2H). 13C NMR (125
MHz, CDCl3) δ 13.3, 13.7, 16.9, 20.3, 26.4, 30.6, 34.9, 36.2, 44.7, 73.7,
116.3, 120.1, 136.0, 148.6, 163.2, 203.9. HRMS (FAB): calcd for
C18H26NO3 ([M + H]+), 304.1913. Found: m/z 304.1918.
Dimethyl 2-(n-butyl)-1-methyl-3-oxo-4-phenyl-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3kk): brown
1
solid. H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.8 Hz, 3H), 1.42
(sextet, J = 7.8 Hz, 2H), 1.68 (quintet, J = 7.8 Hz, 2H), 2.35 (s, 3H),
3.41 (s, 2H), 3.42 (s, 2H), 3.73 (s, 6H), 4.01 (t, J = 7.8 Hz, 2H), 7.27−
7.30 (m, 1H), 7.37−7.42 (m, 4H). 13C NMR (125 MHz, CDCl3) δ
917
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The Journal of Organic Chemistry
Article
1H NMR (500 MHz, CDCl3) δ 1.80 (s, 3H), 2.03 (s, 3H), 2.08 (s,
3H), 3.41 (s, 2H), 3.47 (d, J = 17.7 Hz, 1H), 3.52 (d, J = 17.7 Hz, 1H),
3.795 (s, 3H), 3.797 (s, 3H), 7.03−7.05 (m, 1H), 7.27−7.34 (m, 3H).
13C NMR (125 MHz, CDCl3) δ 13.1, 17.3, 17.6, 37.6, 39.3, 53.1, 53.2,
59.2, 116.6, 120.7, 127.2, 127.8, 128.6, 131.1, 135.2, 135.9, 138.6,
150.2, 163.3, 171.5, 171.6. HRMS (FAB): calcd for C21H24NO5 ([M +
H]+), 370.1654. Found: m/z 370.1648.
13.7, 17.2, 20.3, 30.5, 37.8, 40.2, 45.0, 53.1, 59.3, 116.9, 124.0, 127.1,
127.9, 129.6, 135.6, 138.2, 149.6, 162.1, 171.3. HRMS (FAB): calcd for
C23H27NO5 ([M]+), 397.1889. Found: m/z 397.1885.
Dimethyl 2-(n-butyl)-1-methyl-3-oxo-4-trimethylsilyl-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (3lk): white
1
solid. H NMR (500 MHz, CDCl3) δ 0.30 (s, 9H), 0.95 (t, J = 7.8
Hz, 3H), 1.40 (sextet, J = 7.8 Hz, 2H), 1.61 (quintet, J = 7.8 Hz, 2H),
2.28 (s, 3H), 3.29 (s, 2H), 3.46 (s, 2H), 3.76 (s, 6H), 3.91 (t, J = 7.8
Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 0.4, 13.8, 17.1, 20.3, 30.7,
37.0, 41.5, 44.3, 53.1, 59.1, 117.2, 120.9, 140.0, 159.0, 165.8, 171.6.
HRMS (FAB): calcd for C20H32NO5Si ([M + H]+), 394.2050. Found:
m/z 394.2051.
Dimethyl 2-(2-Ethylphenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (8ac). A yellow
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 5.37 min
(minor) and 7.28 (major)). [α]29 −62.2 (c 0.75, CHCl3) (75% ee).
Trimethyl 2-(n-butyl)-1-methyl-3-oxo-5H-2,3,6,7-
D
1H NMR (500 MHz, CDCl3) δ 1.14 (t, J = 7.8 Hz, 3H), 1.80 (s, 3H),
tetrahydrocyclopenta[c]pyridine-4,6,6-tricarboxylate (3mk): white
1
solid. H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.8 Hz, 3H), 1.42
2.08 (s, 3H), 2.29 (dq, J = 15.1 and 7.8 Hz, 1H), 2.38 (dq, J = 15.1 and
7.8 Hz, 1H), 3.41 (s, 2H), 3.48 (d, J = 17.4 Hz, 1H), 3.52 (d, J = 17.4
Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 7.02 (d, J = 7.3 Hz, 1H), 7.27−
7.32 (m, 1H), 7.36−7.42 (m, 2H). 13C NMR (125 MHz, CDCl3) δ
13.2, 13.3, 17.8, 23.4, 37.6, 39.4, 53.1, 53.2, 59.2, 116.6, 120.7, 127.0,
127.9, 128.8, 128.9, 136.1, 138.0, 140.6, 150.1, 163.5, 171.5, 171.6.
HRMS (FAB): calcd for C22H26NO5 ([M + H]+), 384.1811. Found:
m/z 384.1820.
(sextet, J = 7.8 Hz, 2H), 1.65 (quintet, J = 7.8 Hz, 2H), 2.37 (s, 3H),
3.37 (s, 2H), 3.77 (s, 6H), 3.79 (s, 2H), 3.89 (s, 3H), 3.99 (t, J = 7.8
Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 13.6, 17.8, 20.3, 30.2, 37.4,
41.8, 45.1, 51.9, 53.2, 58.7, 113.3, 117.2, 144.2, 157.7, 160.2, 166.4,
171.3. HRMS (FAB): calcd for C19H26NO7 ([M+H]+), 380.1709.
Found: m/z 380.1708.
5-(n-Butyl)-4,7-dimethyl-6-oxo-5,6-dihydrofuro[3,4-c]pyridin-
3(1H)-one (3nk): white solid. 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J
= 7.8 Hz, 3H), 1.46 (sextet, J = 7.8 Hz, 2H), 1.66 (quintet, J = 7.8 Hz,
2H), 2.04 (s, 3H), 2.81 (s, 3H), 4.10 (t, J = 7.8 Hz, 2H), 5.07 (s, 2H).
13C NMR (125 MHz, CDCl3) δ 12.1, 13.6, 14.2, 20.2, 30.2, 44.7, 66.7,
Dimethyl 2-(2-Isopropylphenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]- pyridine-6,6-dicarboxylate (8ad). A yellow
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 4.80 min
102.8, 116.9, 149.1, 150.1, 162.8, 169.6. HRMS (FAB): calcd for
C13H18NO3 ([M + H]+), 236.1287. Found: m/z 236.1294.
(minor) and 6.97 (major)). [α]28 −71.6 (c 0.75, CHCl3) (90% ee).
D
1H NMR (500 MHz, CDCl3) δ 1.15 (d, J = 6.9 Hz, 3H), 1.17 (d, J =
5-(n-Butyl)-7-methyl-6-oxo-4-phenyl-5,6-dihydrofuro[3,4-c]-
pyridin-3(1H)-one (3ok): white solid. 1H NMR (500 MHz, CDCl3) δ
0.75 (t, J = 7.8 Hz, 3H), 1.15 (sextet, J = 7.8 Hz, 2H), 1.54 (quintet, J
= 7.8 Hz, 2H), 2.12 (s, 3H), 3.86 (t, J = 7.8 Hz, 2H), 5.11 (s, 2H),
7.29−7.31 (m, 2H), 7.51−7.57 (m, 3H). 13C NMR (125 MHz,
CDCl3) δ 12.3, 13.3, 19.9, 30.7, 46.2, 66.6, 103.5, 119.1, 128.2, 128.6,
130.09, 130.11, 149.1, 151.1, 162.7, 167.7. HRMS (FAB): calcd for
C18H20NO3 ([M + H]+), 298.1443. Found: m/z 298.1440.
5-Butyl-4-methyl-6-oxo-7-phenyl-5,6-dihydrofuro[3,4-c]pyridin-
3(1H)-one (3pk): brown solid. 1H NMR (500 MHz, CDCl3) δ 0.99 (t,
J = 7.8 Hz, 3H), 1.47 (sextet, J = 7.8 Hz, 2H), 1.72 (quintet, J = 7.8
Hz, 2H), 2.89 (s, 3H), 4.15 (t, J = 7.8 Hz, 2H), 5.11 (s, 2H), 7.33−
7.37 (m, 1H), 7.39−7.44 (m, 4H). 13C NMR (125 MHz, CDCl3) δ
13.6, 14.6, 20.3, 30.2, 45.2, 67.2, 103.3, 120.7, 128.2, 128.5, 128.7,
133.0, 150.1, 151.9, 161.5, 169.3. HRMS (FAB): calcd for C18H20NO3
([M + H]+), 298.1443. Found: m/z 298.1440.
6.9 Hz, 3H), 1.80 (s, 3H), 2.07 (s, 3H), 2.56 (septet, J = 6.9 Hz, 1H),
3.41 (s, 2H), 3.47 (d, J = 17.9 Hz, 1H), 3.52 (d, J = 17.9 Hz, 1H), 3.79
(s, 3H), 3.80 (s, 3H), 6.99 (d, J = 7.3 Hz, 1H), 7.28 (ddd, J = 7.8, 7.3,
and 1.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.44 (dd, J = 7.8 and 1.4 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 13.3, 18.0, 23.1, 24.0, 27.9, 37.7,
39.4, 53.1, 53.2, 59.2, 116.4, 120.6, 126.8, 126.9, 127.9, 129.0, 136.3,
137.1, 145.6, 150.0, 163.7, 171.58, 171.63. HRMS (FAB): calcd for
C23H28NO5 ([M + H]+), 398.1967. Found: m/z 398.1967.
Dimethyl 2-(2-Chlorophenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (8ae). A white
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 6.60 min
(minor) and 8.28 (major)). [α]29 −45.5 (c 0.90, CHCl3) (87% ee).
D
1H NMR (500 MHz, CDCl3) δ 1.85 (s, 3H), 2.08 (s, 3H), 3.42 (s,
Tetramethyl 1,1′,4,4′-tetramethyl-3,3′-dioxo-2,2′-
2H), 3.49 (s, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 7.20−7.25 (m, 1H),
7.37−7.42 (m, 2H), 7.52−7.57. (m, 1H). 13C NMR (125 MHz,
CDCl3) δ 13.1, 17.4, 37.5, 39.3, 53.15, 53.18, 59.2, 116.7, 120.8, 128.0,
129.888, 129.892, 130.4, 132.5, 135.7, 137.2, 150.6, 163.2, 171.3,
171.6. HRMS (FAB): calcd for C20H2135ClNO5 ([M + H]+), 390.1108.
Found: m/z 390.1114.
hexamethylenebis(5H-2,3,6,7- tetrahydrocyclopenta[c]pyridine-
1
6,6-dicarboxylate) (5): brown solid. H NMR (500 MHz, CDCl3) δ
1.42−1.48 (m, 4H), 1.62−1.68 (m, 4H), 2.04 (s, 6H), 2.27 (s, 6H),
3.37 (s, 4H), 3.40 (s, 4H), 3.77 (s, 12H), 3.96 (t, J = 7.8 Hz, 4H). 13C
NMR (125 MHz, CDCl3) δ 13.3, 16.9, 26.6, 28.4, 37.9, 39.2, 44.7,
53.1, 59.1, 116.7, 120.0, 135.7, 148.9, 163.3, 171.5. HRMS (FAB):
calcd for C34H45N2O10 ([M + H]+), 641.3074. Found: m/z 641.3062.
Dimethyl 2-(2-Methoxyphenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]- pyridine-6,6-dicarboxylate (8aa). A white
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
Dimethyl 2-(2-Bromophenyl)-1,4-dimethyl-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (8af). A white
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 6.76 min
(minor) and 8.85 (major)). [α]28 −48.0 (c 0.75, CHCl3) (77% ee).
mL/min, column temperature: 35 °C, retention time: 6.44 min (S)
D
1H NMR (500 MHz, CDCl3) δ 1.84 (s, 3H), 2.08 (s, 3H), 3.42 (s,
1
and 12.01 (R)). [α]30 −19.7 (c 0.50, CHCl3) (94% ee (R)). H
D
2H), 3.50 (s, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 7.23 (dd, J = 1.4 and 7.8
Hz, 1H), 7.31 (dt, J = 1.4 and 7.8 Hz, 1H), 7.45 (dt, J = 1.4 and 7.8
Hz, 1H), 7.72 (dd, J = 1.4 and 7.8 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 13.1, 17.5, 37.5, 39.4, 53.15, 53.18, 59.2, 116.7, 120.9, 122.8,
128.7, 129.9, 130.0, 133.6, 135.6, 138.9, 150.6, 163.1, 171.4, 171.6.
HRMS (FAB): calcd for C20H2079BrNO5 ([M]+), 433.0525. Found:
m/z 433.0520.
NMR (500 MHz, CDCl3) δ 1.83 (s, 3H), 2.07 (s, 3H), 3.41 (s, 2H),
3.46 (d, J = 17.7 Hz, 1H), 3.51 (d, J = 17.7 Hz, 1H), 3.78 (s, 3H), 3.79
(s, 3H), 3.80 (s, 3H), 7.02−7.10 (m, 3H), 7.37−7.41 (m, 1H). 13C
NMR (125 MHz, CDCl3) δ 13.2, 17.4, 37.6, 39.4, 53.10, 53.13, 55.7,
59.2, 112.0, 116.1, 120.3, 121.1, 128.0, 129.4, 129.9, 136.7, 150.1,
154.6, 163.6, 171.5, 171.7. HRMS (FAB): calcd for C21H24NO6 ([M +
H]+), 386.1604. Found: m/z 386.1605.
Dimethyl 1,4-Dimethyl-2-(2-methylphenyl)-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (8ab). A white
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 6.28 min
Dimethyl 1,4-Dimethyl-2-(1-naphthyl)-3-oxo-5H-2,3,6,7-
tetrahydrocyclopenta[c]pyridine-6,6-dicarboxylate (8ag). A white
solid. The ee value was determined by HPLC analysis with a Chiralpak
AY-H column (eluent: n-hexane/2-propanol = 50/50, flow rate: 1.0
mL/min, column temperature: 35 °C, retention time: 7.62 min
(minor) and 10.79 (major)). [α]29D −108.4 (c 0.34, CHCl3) (73% ee).
(minor) and 7.26 (major)). [α]28 −52.0 (c 1.12, CHCl3) (79% ee).
D
918
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The Journal of Organic Chemistry
Article
1H NMR (500 MHz, CDCl3) δ 1.76 (s, 3H), 2.11 (s, 3H), 3.45 (s,
2H), 3.56 (s, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 7.32−7.36 (m, 2H),
7.44−7.51 (m, 2H), 7.55−7.58 (m, 1H), 7.90−7.93 (m, 2H). 13C
NMR (125 MHz, CDCl3) δ 13.2, 17.5, 37.6, 39.4, 53.185, 53.192, 59.2,
116.7, 120.8, 122.0, 125.6, 125.9, 126.4, 127.4, 128.4, 129.0, 129.9,
134.4, 136.2, 136.8, 150.4, 164.0, 171.55, 171.60. HRMS (FAB): calcd
for C24H24NO5 ([M + H]+), 406.1654. Found: m/z 406.1654.
X-ray Crystallographic Studies of 3lk. Colorless crystals of 3lk
suitable for X-ray analysis were obtained by recrystallization from
CH2Cl2/n-hexane. A single crystal was mounted using liquid paraffin
on a 0.4−0.5 mm CryoLoop (Hampton Research) and used for data
collection. All measurements were made on a Bruker APEX II CCD
area detector with graphite monochromated Mo Kα radiation. The
structure was solved by direct methods with SHELXS-97 and refined
by full-matrix least-squares against F2 using SHELXL-97 software.26 An
ORTEP drawing is shown in Figure 1. The details of crystal and data
collection parameters are summarized in Supporting Information. The
analysis was carried out using Yadokari-XG.27 The program
ORTEP328 was used to generate the X-ray structural diagrams.
X-ray Crystallographic Studies of 3mk. Yellow crystals of 3mk
suitable for X-ray analysis were obtained by recrystallization from
CH2Cl2/n-hexane. A single crystal was mounted using liquid paraffin
on a 0.4−0.5 mm CryoLoop (Hampton Research) and used for data
collection. All measurements were made on a Bruker APEX II CCD
area detector with graphite monochromated Mo-Ka radiation. The
structure was solved by direct methods with SHELXS-97 and refined
by full-matrix least-squares against F2 using SHELXL-97 software.26 An
ORTEP drawing is shown in Figure 2. The details of crystal and data
collection parameters are summarized in Supporting Information. The
analysis was carried out using Yadokari-XG.27 The program
ORTEP328 was used to generate the X-ray structural diagrams.
X-ray Crystallographic Studies of 8aa. Colorless crystals of 8aa
suitable for X-ray analysis were obtained by recrystallization from
CH2Cl2/n-hexane. A single crystal was mounted using Paratone-N
(Hampton Research) on a 200 μm MicroMount (MiTeGen) and used
for data collection. All measurements were made on a Rigaku R-AXIS
RAPID II with a VariMax Cu diffractometer using graphite
monochromated Cu Kα radiation. The structure was solved by direct
methods with SIR200829 and refined by full-matrix least-squares
against F2 using SHELXL-9726 software. The absolute structure was
deduced on the basis of the Flack parameter.30 An ORTEP drawing is
shown in Figure 3. The details of crystal and data collection
parameters are summarized in Supporting Information. All calculations
were performed using the CrystalStructure31 crystallographic software
package except for refinement, which was performed using SHELXL-
97.26 The program ORTEP328 was used to generate the X-ray
structural diagrams.
Sports, Science and Technology of Japan. We thank Rigaku
Corporation for the single-crystal X-ray analysis of 8aa. We
thank Prof. Nishibayashi for measuring IR spectra.
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ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra of 3aa−at, 3bk−ek, 3fk−ik, 3jk−pk, 5, 8aa−ag
and single-crystal X-ray diffraction data of compounds 3mk,
3nk and 8aa. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*takeuchi@chem.aoyama.ac.jp
■
Present Address
†Division of Chemistry and Materials Science, Graduate School
of Engineering, Nagasaki University, 1-14 Bunkyo, Nagasaki
852-8521, Japan
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ACKNOWLEDGMENTS
■
This research was supported by Grants-in-Aid for Scientific
Research (C) (21550107) from the Japan Society for the
Promotion of Science and the Ministry of Education, Culture,
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