Convenient synthesis of 4-tert-butyl 2-ethyl 3-amino-1-benzyl-5- dialkylamino-1H-pyrrole-2,4-dicarboxylate derivatives

Article abstract of DOI:10.1016/j.tet.2011.02.071

Optimization details and limitations of a novel synthetic method of 4-tert-butyl 2-ethyl 3-amino-1-benzyl-5-dialkylamino-1H-pyrrole-2,4- dicarboxylate derivatives are herein disclosed. This synthesis consists of four steps that include a highly selective cyclization, and can be carried out from starting materials to target compounds without column chromatography purification. The high selectivity is controlled by lithium coordination and steric hindrance caused by tert-butyl ester.

Full text of DOI:10.1016/j.tet.2011.02.071

Tetrahedron 67 (2011) 3124e3131
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of 4-tert-butyl 2-ethyl 3-amino-1-benzyl-5-dialkylamino-
1H-pyrrole-2,4-dicarboxylate derivatives
,
b
b
a
Yukihiro Nishio a , Katsuya Uchiyama , Makoto Kito , Hiroyuki Nakahira
*
a Drug Research Division, Dainippon Sumitomo Pharma., Ltd., 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan
b Research and Development Division, Dainippon Sumitomo Pharma., Ltd., 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimization details and limitations of a novel synthetic method of 4-tert-butyl 2-ethyl 3-amino-1-
benzyl-5-dialkylamino-1H-pyrrole-2,4-dicarboxylate derivatives are herein disclosed. This synthesis
consists of four steps that include a highly selective cyclization, and can be carried out from starting
materials to target compounds without column chromatography purification. The high selectivity is
controlled by lithium coordination and steric hindrance caused by tert-butyl ester.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 November 2010
Received in revised form 21 February 2011
Accepted 22 February 2011
Available online 1 March 2011
Keywords:
Pyrrole synthesis
Selective cyclization
1. Introduction
Dipeptidyl peptidase IV (DPP-4) inhibitors have recently been
the focus of new treatment for type 2 diabetes.1 DPP-4 is a serine
protease distributed throughout the body, and is known to cleave
a variety of peptides and modulate their biological activity. One of
the peptides cleaved by DPP-4 is Glucagon-like peptide 1, which
plays an important role in maintaining normal blood glucose
level.2,3 Based on this mechanism of action, a number of DPP-4
inhibitors have already been approved for the treatment of di-
abetes, while others are under clinical or preclinical inves-
Fig. 1. Structures of new chemotype DPP-4 inhibitors.
instead of
a
-aminoketones has never been reported. Other reported
methods for the preparation of
difficult to apply to our intermediate 3 due to starting materials and
products limitations.11 Although amination of
-bromo pyrrole has
been reported as an alternative method to prepare -amino pyrrole
derivatives,12 our attempt to use amination of
-bromo pyrrolo[3,2-
a-amino pyrrole derivatives are
tigation.4e7 We have previously reported
a series of new
a
a
chemotype DPP-4 inhibitors, including the pyrolo[3,2-d]pyrimidine
structure 1 and the deazahypoxanthine structure 2 (Fig. 1). These
compounds showed potent in vitro DPP-4 inhibitory activity, good
pharmacokinetic profile, and considerable in vivo efficacy.8 To
a
d]pyrimidine in the synthesis of compound 1 resulted in no re-
action or desorption of the bromo. Under these circumstances, we
tried to look for a new way to make the target pyrrole compound 3,
and could produce it by selective cyclization, as disclosed briefly in
our previous work.8 In that report, compound 3 was synthesized in
moderate yield in a step-by-step reaction, although the scope and
limitations of this reaction have not been investigated. Preparation
of DPP-4 inhibitors from intermediate 3 included elimination of
protecting benzyl and benzylation steps. These steps needed harsh
hydrogenation conditions, gave low yields, and were consequently
considered unnecessary manipulations. As it was imperative to
prepare appropriate pyrrole derivatives for the synthesis of DPP-4
inhibitors, a more convenient method, and its scope and limitations
were required. Here, we report in details our optimizations of
a novel method for preparation of appropriate pyrrole derivatives.
In addition, we show an improved method, which can be carried
prepare structures 1 and 2, we have shown that the
role derivative 3 is an important synthetic intermediate.
Efficient methods to make -amino pyrrole structures have
rarely been reported. Indeed, it is difficult to introduce an amine at
a-amino pyr-
a
the a-position of the pyrrole by traditional methods, such as Knorr
pyrrole synthesis.9 Conventionally, pyrroles are synthesized by
cyclodehydration between primary amines and 1,4-dicarbonyl
compounds or a-aminoketones and b-ketoesters. However, using
amide derivatives instead of 1,4-dicarbonyl compounds requires
a microwave reaction,10 and the use of diaminoketone derivatives
* Corresponding author. Tel.: þ81 6 6466 5223; fax: þ81 6 6466 5287; e-mail
address: yukihiro-nishio@ds-pharma.co.jp (Y. Nishio).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.071

Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
3125
out from starting material to target pyrroles without column
chromatography, and its scope and limitations. Finally, as this novel
synthetic method includes a highly selective cyclization, we con-
sider here the effects of tert-butyl ester and lithium coordination on
this cyclization.
improvement was observed (data not shown). Regarding the sol-
vent, CH3CN was the most suitable (entries 5 and 8). Finally, in-
vestigation of the reaction temperature and time indicated that
80 ꢀC and 5 h are the most suitable conditions (entry 9).
As alkylation of 6 to obtain 7 (C) proceeded smoothly under a set
of 1.2 equiv of K2CO3 and 1.1 equiv of ethyl bromoacetate in DMF at
50 ꢀC, conditions of the selective cyclization from 7 to 3 (D) were
investigated. The most important step of this new method is this
selective cyclization, which occurs between the generated carb-
2. Optimization of reaction conditions
As shown in Scheme 1, the synthetic method for the preparation
of pyrrole derivatives consists of four steps. Our goal was to carry
out the synthesis from starting materials to the target pyrroles
without column chromatography purification. First, details of the
optimization of each step (AeD) are given below.
anion at the a-position of the ethyl ester and the nitril. A similar
selective cyclization to produce pyrimidine structures by reaction
of amidines with an ethyl ester or nitril has already been reported
in the literature.13 Its selectivity was controlled by a combination of
reagents and solvents, i.e., NaOEt/EtOH, p-TSA/benzene or HCl/di-
oxane. However, in the case of our compound strong acids can
cleave the tert-butoxycarbonyl (Boc) protection and tert-butyl ester
at C3-position of the pyrrole. Therefore, we decided to search for
other conditions using any bases to control selectivity in our re-
action (Table 2).
Me
Me
NHBoc
NHBoc
MeS
NC
MeS
NC
HN
B
A
SMe
N
N
NC
CO Bu
CO Bu
CO Bu
4
6
5
Table 2
Me
Me
NHBoc
EtO C
NHBoc
EtO C
H N
N
Reaction conditions for cyclization (7e3) (D)
N
C
D
N
N
NC
Entry
Base
Solvent
Temp ꢀC
Yielda (%)
CO Bu
7
CO Bu
3
1b
2b
3b
4b
5b
6c
7c
8c
K2CO3 (1.2 equiv)
NaH (2.0 equiv)
DMF
DMF
THF
t-BuOH
t-BuOH
t-BuOH
CH3CN
CH3CN
50/120
50/120
50
d
d
Scheme 1. Synthetic route to the intermediate 3.
t-BuOK (1.2 equiv)
t-BuOK (1.2 equiv)
t-BuONa (1.2 equiv)
t-BuOLid (1.2 equiv)
t-BuOLid (1.2 equiv)
t-BuOLid (2.0 equiv)
Trace
14
21
32
64
50
50
50
30
The reaction from 4 to 5 (A) proceeded smoothly at 50 ꢀC in
various solvents without the use of a base and gave a quantitative
yield. To reduce the number of steps involved, we attempted the
reaction between the intermediate 5 and N-benzyl glycine ethyl
ester to make 7 directly. Unfortunately, the reaction did not proceed
even under various conditions, i.e. different bases, solvents, and
temperatures. Therefore, the conditions of the reaction from 5 to 6
(B) were investigated (Table 1).
30
72
a
Isolated yield.
Reaction was conducted at 1.0 mmol scale.
Reaction was conducted at 5.0 mmol scale.
b
c
d
Reagent was generated in situ from LiNH2 and t-BuOH.
The use of K2CO3 and NaH was not effective in DMF at 50 ꢀC and
Table 1
120 ꢀC (entries 1 and 2, respectively). Other bases, such as KHMDS,
gave undesired products or no products (data not shown). On the
other hand, the use of potassium tert-butoxide produced a trace
amount of the target 3 as indicated by LC/MS (entry 3). When the
reaction was conducted in tert-butanol, the target pyrrole 3 was
obtained in low yield (entry 4). To examine the effects of various
alkoxides on the reaction, sodium tert-butoxide and lithium tert-
butoxide, which was generated in situ from lithium amide and tert-
butanol, were used. Both alkoxides gave even better results than
potassium tert-butoxide (entries 5 and 6).The use of other solvents
with tert-butanol improved the yield, and the combination of
CH3CN and tert-butanol afforded the best result (entry 7). In ad-
dition, it was possible to reduce the reaction temperature from
50 ꢀC to 30 ꢀC (entry 7). Finally, investigation into the base equiv-
alent revealed 2.0 equiv of LiNH2 as the most appropriate (entry 8).
As for by-products, the reaction gave a tert-butyl ester instead of
ethyl ester at the 2-position of the pyrrole, which could be sepa-
rated by column chromatography, with a yield less than 5% com-
pared to the target product 3.
Based on the findings above, we tried to examine the continuous
reactions from step A to step D without purification. Unfortunately,
except for the first step, all other steps of the reaction needed to be
modified. In the second step (B), the reaction proceeded slowly, and
finally 10 h was needed to consume 5 completely. As for the al-
kylation step (C), the remaining benzylamine used in the second
step seemed to prevent the reaction from completion probably due
to reaction of the benzylamine with ethyl bromacetate. Finally,
3.0 equiv of K2CO3 and 1.3 equiv of ethyl bromacetate were nec-
essary for the smooth progression of this step. Regarding the cy-
clization step (D), the reaction was stopped under the optimum
Reaction conditions for the second step (5e6) (B)
Entry
Base
Solvent
Temp ꢀC
Yielda (%)
1
2
3
4
5
6
7
8
9
d
EtOH
EtOH
EtOH
DMF
CH3CN
CH3CN
CH3CN
Dioxane
CH3CN
50
80
50
50
50
50
50
50
80c
d
d
d
K2CO3 (1.5 equiv)
K2CO3 (1.5 equiv)
DBU (1.5 equiv)
Et3N (1.5 equiv)
DBU (2.0 equiv)
DBU (1.5 equiv)
DBU (2.0 equiv)
Trace
37
69
Trace
76 (66)b
42
72b
a
LC yield. All reactions were performed for 8 h.
Isolated yield.
Reaction was performed for 5 h.
b
c
In the absence of a base, the second step (B) did not proceed at
50 ꢀC or 80 ꢀC (entries 1 and 2). With potassium carbonate, only
a trace amount of 6 was detected by LC/MS (entry 3). At the same
time, it was revealed that the use of EtOH was not appropriate for
this step due to production of a by-product obtained by reaction
between 5 and the ethoxide, which displaces the methylthiol. Using
DMF instead of EtOH gave the target molecule in low yield (entry
4), but the use of K2CO3 in other solvents, such as toluene, THF and
CH3CN, did not work well (data not shown). These findings suggest
that this step needs a base, however, inorganic bases are usually
inefficient in low polar solvents, such as those described above.
Therefore, we focused our search on organic bases. The use of 1,8-
diazabicyclo[5,4,0]undeca-7-ene (DBU) in CH3CN gave 6 in good
yield, but Et3N afforded only a trace amount of the target product
(entries 5 and 6). As for DBU equivalent, 2.0 equiv gave the best
yield (entries 5 and 7). When more than 2.0 equiv DBU was used, no

3126
Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
conditions, (entry 8, Table 2), probably due to generation of by-
products from the former reactions. Therefore, the appropriate
amount of t-BuOLi was investigated, and 2.5 equiv of LiNH2 was
found to be necessary. Based on these results, we explored the
scope and limitations of this modified synthesis.
1 and 2). When a cyclohexylmethylamine or a cyclohexylamine was
used, the desired intermediate was obtained in the second step (B).
However, the third step (C) did not proceed to completion (entry 3).
A phenetylamine gave the same result (entry 4), and the use of
aniline prevented progression even of the second step (B) (entry 5).
These results suggest that steric hindrance around NH2 and basicity
of the reagents are important in the second step (B) and that
benzylamines are appropriate as primary amines (Z-NH2).
3. Scope and limitations
As shown in Table 3, we first investigated the R1R2 limitation in
the first step (A). A benzylamine was selected as reagent in the
second step (B), and the use of a secondary amine was examined.
Cycloalkylamines were preferable for this step, and N-methyl-
benzylamine was also accepted (entries 1e4). However, other
alkylamines could not be used (entries 5e7). N-Ethylbutylamine
afforded the intermediate in the second step (B), but in the third step
(C) the reaction did not proceed to completion, and gave a complex
mixture (entry 5). What prevented the reaction from completion in
the third step (C) is not clear. However, when a dipropylamine was
used as R1R2NH, even the first step (A) did not proceed (entry 6).
Among a series of N-methylalkylamines, N-methylcyclohexylamine
was also inappropriate (entry 7). These results suggest that R1R2
steric hindrance has an impact on the first step (A) and that cyclo-
alkylamines and N-methylalkylamines are suitable.
The results described above led us to investigate the scope of
substituents of R1R2NH and R3-PhCH2NH2 (Table 5). The modified
synthesis gave almost the same yield as the basic step-by-step re-
action (entry 1). A number of substituents of R1R2NH and R3 were
accepted in this synthetic method. An ester substituent was toler-
ated under basic conditions of cyclization (D). However, there was
a significant difference between R1R2 and R3. An ethyl ester for R1R2
gave a good yield, but a methyl ester for R3 afforded modest yield
(entries 3 and 8). When ethyl isonipecotate was used in the first
step (A), no by-products were obtained in the whole step (entry 3).
However, in the cyclization step (D), the use of methyl (4-amino-
methyl)benzoate for R3-PhCH2NH2 produced by-products, which
were difficult to isolate by SiO2-column chromatography due to the
presence of other close by-products.
LC/MS analysis suggested that one of the by-products was an
ester exchange product, and ester exchange was occurred at the
methyl ester of R3. While a series of carbamates were accepted,
amines afforded complex mixtures in the third step (C) (entries 1, 4,
6, and 9). The reason for this limitation was assumed to be reaction
To explore limitations of the primary amines (Z-NH2) in the
second step (B), a piperidine was chosen as R1R2NH, and the use of
primary amines was investigated (Table 4). A benzylamine was
acceptable, but a-methyl benzylamine was not appropriate (entries
Table 3
Limitations of R1R2 in the first step (A)
B)
A)
C)
D)
R1
HN
EtO2C
R2
EtO2C
H2N
H2N
CO2Et
Br
R1
R1
LiNH2 (2.5 eq)
MeS
N
R1
HN
NC
N
(1.0 eq)
SMe
(1.2 eq)
(1.3 eq)
t-BuOH (20 eq)
N
N
N
CH3CN, 30 oC
2 h
R2
R2
t
CO2 Bu
8a-d
R2
50 oC, 1 h
NC
K2CO3 (3.0 eq)
DMF, 50 oC, 2 h
DBU (2.0 eq)
NC
t
t
80 oC, 10 h
CO2 Bu
t
CO2 Bu
CO2 Bu
CH3CN
4
Entry
R1R2NH
(A)
(B)
(C)
(D)
Yielda (%)
1 (8a)
/
/
/
/
55
HN
2 (8b)
3 (8c)
/
/
/
/
/
/
/
/
48
69
HN
HN
4 (8d)
/
/
/
/
/
63
HN
Me
Et
5
6
/
Not finish
d
d
d
d
HN
HN
Me
Me
Pr
Not proceed
Not proceed
d
d
7
d
d
d
d
HN
Me
a
Isolated yield.

Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
3127
Table 4
Limitations of primary amines in the second step (B)
B)
A)
HN
C)
D)
Z
Z
N
Z
Z
EtO2C
H2N
(1.2 eq)
CO2Et
Br
LiNH2 (2.5 eq)
EtO2C
H2N
MeS
NC
N
HN
(1.0 eq)
50 oC, 1 h
(1.3 eq)
t-BuOH (20 eq)
SMe
N
N
N
CH3CN, 30 oC
2 h
K2CO3 (3.0 eq)
DBU (2.0 eq)
NC
NC
t
t
DMF, 50 oC, 2 h
CO2 Bu
80 oC, 10 h
CO2 Bu
CO2 Bu
8a
t
t
CO2 Bu
CH3CN
4
Entry
Z-NH2
(A)
(B)
(C)
(D)
Yielda (%)
H2N
1 (8a)
/
/
/
/
/
55
H2N
Me
2
Not finish
d
d
d
H2N
3
4
/
/
/
/
Not finish
d
d
d
d
n
Not finish
H2N
H2N
5
/
Not proceed
d
d
d
a
Isolated yield.
of amines with ethyl bromacetate. As for the results of R3, strong
electron withdrawing groups seemed to decrease the yield (entries
5, 7, and 8). This synthetic method afforded compound 8i, an im-
portant intermediate in the preparation of our DPP-4 inhibitor,
DSR-12727, in moderate yield and gave almost the same yield in
a larger preparation (entry 6). DSR-12727 is one of our compounds
in preclinical development and its biological activity data will be
discussed in future reports.
effects caused by unknown by-products from former steps. For that,
once intermediate 9 was isolated, it was subjected to cyclization.
The yield of the target product 10 was half that of the undesired
product 11. This finding indicates that the lithium enolate attack the
carbonyl carbon of the ester group faster than the nitril, however,
steric hindrance of the tert-butyl ester prevents this attack.
Next, to examine the effect of coordination, HMPA, which can
prevent coordination between the lithium enolate and the nitril or
the tert-butyl ester (1.0 equiv or 3.0 equiv to lithium) was added to
the reaction (Scheme 3). The target pyrrole 3 and by-product 11
were obtained in almost the same yield, which means that co-
ordination also influences the selectivity. These results suggest that
both steric hindrance and coordination have effects on the selec-
tivity in the cyclization step (D). However, tert-butyl ester seems to
be more important than lithium tert-butoxide.
4. Effects of lithium coordination and tert-butyl ester on the
cyclization step (D)
As our new synthesis resulted in a highly selective cyclization
(D), we decided to examine factors that affect this selectivity. Based
on the fact that nucleophilic addition produced pyrrole structures,
we assumed that the stereochemistry (E and Z isomers) of the third
intermediate 7 is the most important aspect of the selectivity. Ac-
cordingly, we presumed that the nucleophilic attack was controlled
by the position of the ethyl ester. However, NMR analysis did not
confirm the configuration of intermediate 7. In fact, 1H NMR of 7
measured in both DMSO and CDCl3 with or without heat showed no
clear peak, and 13C NMR gave no detectable peaks. The third
structure 7 seems to be in a fast equilibrium between E and Z iso-
mers. Based on these findings, we thought that the selectivity in our
synthesis is controlled only by conditions of the final step (D).
Therefore, we paid attention to two factors that apparently relate to
control of selectivity. One is the steric hindrance caused by tert-
butyl ester, and the other is coordination between the lithium and
carbonyl group of the tert-butyl ester or nitril. To confirm our hy-
pothesis, two additional experiments were conducted.
5. Conclusion
In conclusion, we herein report details of our optimization and
the modification, as well as the scope and limitations, of a novel
synthetic method of 4-tert-butyl 2-ethyl 3-amino-1-benzyl-5-dia-
lkylamino-1H-pyrrole-2,4-dicarboxylate derivatives. This synthesis
afforded new
a-amino pyrrole derivatives that are difficult to be
synthesized by conventional methods.
6. Experimental section
6.1. General
All reagents and solvents were obtained from commercial sup-
pliers and used without further drying or purification. All reactions
were performed under nitrogen atmosphere. Normal-phase col-
umn chromatography was performed using Yamazen W-prep
To investigate the influence of the tert-butyl ester methyl
2-cyano-3,3-bis(methylthio)acrylate was used as starting material
instead of 4 (Scheme 2). First, we had to eliminate any surplus

3128
Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
Table 5
Applications of the reaction
R3
R3
R3
R3
C)
B)
A)
D)
R1
R2
HN
EtO2C
H2N
CO2Et
Br
R1
R1
LiNH2 (2.5 eq)
EtO2C
H2N
MeS
N
R1
HN
NC
N
(1.0 eq)
(1.2 eq)
(1.3 eq)
t-BuOH (20 eq)
SMe
N
N
N
CH3CN, 30 oC
2 h
R2
R2
t
CO2 Bu
3, 8e-k
R2
50 oC, 1 h
NC
K2CO3 (3.0 eq)
DMF, 50 oC, 2 h
DBU (2.0 eq)
NC
t
t
80 oC, 10 h
CO2 Bu
t
CO2 Bu
CO2 Bu
CH3CN
4
Entry
Product
Yielda (%)
Entry
Product
Yielda (%)
46 (44)c
F
Br
Me
NHBoc
Me
NHBoc
N
1 (3)
49 (45)b
6 (8i)
EtO2C
EtO2C
H2N
N
N
N
H2N
t
t
CO2 Bu
CO2 Bu
Me
Cl
Cl
2 (8e)
43
7 (8j)
36
EtO2C
EtO2C
Me
N
N
N
N
Me
H2N
H2N
t
t
CO2 Bu
CO2 Bu
MeO
MeO2C
3 (8f)
65
8 (8k)d
31
EtO2C
H2N
EtO2C
N
N
N
CO2Et
N
O
H2N
F
t
t
CO2 Bu
CO2 Bu
Cl
4 (8g)
64
9
de
EtO2C
H2N
N
EtO2C
H2N
Me
N
N
N
NBoc
NMe2
t
CO2 Bu
t
CO2 Bu
F3C
OMe
5 (8h)
35
EtO2C
H2N
N
N
t
CO2 Bu
a
Isolated yield.
Yield of step-by-step method.
Reaction was performed at 20 mmol scale.
HCl (1.2 equiv) salt and 3.1 equiv of DBU were used.
Complex mixture was given in the third reaction (C).
b
c
d
e
system with pre-packed SiO2 columns. Visualization was done by
UV light (254 nm). 1H NMR spectra at 400 MHz and 13C NMR
spectra at 100 MHz were recorded on a Brucker AVANCE 400
MPA100. Each compound form was based on appearance, micro-
scopic observations and melting points. Measurement of purity of
compounds was done by Ultra Fluent Liquid chromatography
(UFLC) with Shim-pack XR-ODC 75 mmꢁ3.0. Samples were dis-
solved in MeOH/0.1%TFA and the eluent volume was 1.0 ml/min
with 10 min-gradient (from 10%B to 90%B), where solvent A is H2O/
0.1%TFA and solvent B is CH3CN/0.1%TFA. Purity of compounds was
determined by UFLC and averaged 95%.
spectrometer with all chemical shift (d) values referenced to CDCl3
as an internal standard and reported as shift (proton count, mul-
tiplicity, coupling constant (J)). Proton assignments were based on
COSY, and Carbon assignments were based on HMQC and/or HMBC.
IR spectra were recorded on a JEOL JIR-SPX60 spectrometer as ATR.
High-resolution mass spectra (HRMS) were recorded on a Thermo
Fischer Scientific LTQ Orbitrap Discovery MS equipment. Melting
points were determined on a Stanford Research Systems OptiMelt
6.1.1. General procedure. To a solution of tert-butyl 2-cyano-3,3-bis
(methylthio) acrylate (4) (245 mg; 1.0 mmol) in CH3CN (3.0 ml) was

Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
3129
CH2Ph), 4.49(1H, s,NHBoc), 7.25e7.38(5H, m,Ph).13CNMR(100 MHz,
CDCl3) :20.6(CH2, CH2NCH2CH2CH2),24.2(CH3, C(NHBoc)(Me)), 28.1
d
(CH3, C(CH3)3), 28.4 (CH3, C(CH3)3), 35.9 (CH2, CH2NCH2CH2CH2), 49.5
(CH2 CH2, CH2NCH2CH2CH2, CH2NCH2CH2CH2), 51.5 (CH2, CH2Ph),
56.3 (C, C(NHBoc)(Me)), 79.7 (CH2, CH2Ph), 121 (C), 127.3 (CH, Ph),
127.7 (CH, Ph),128.7 (CH, Ph),137 (C, Ph),155.3 (C),168.2 (C),168.8 (C).
HRMS (ESIþ): m/z 471.2955 (calcd m/z 471.2966 for C26H38N4O4þH).
Mp 80e88 ꢀC.
Scheme 2. Effect of the tert-butyl ester on the selectivity.
6.1.4. tert-Butyl 3-[benzy(2-ethoxy-2-oxoethyl)lamino]-3-{(3R)-3-
[(tert-butoxycarbonyl)amino]-3-methylpiperidine-1-yl}-2-cyano-
prop-2-enoate (7). The product was obtained as a yellow amor-
phous solid.
1H NMR (400 MHz, CDCl3)
d
: 1.0e1.70 (27H, m), 2.1e2.7 (1H, m),
3.0e4.0 (4H, m), 4.0e4.4 (5H, m), 4.81 (1H, s), 7.18e7.23 (1H, m),
7.27e7.40 (4H, m). IR (ATR): 3318, 2975, 2192, 1789, 1688 cmꢂ1
.
HRMS (ESIþ): m/z 557.3324 (calcd m/z 557.3334 for
C30H44N4O6þH). Mp 83e89 ꢀC.
Scheme 3. Effect of lithium on the selectivity.
6.1.5. 4-tert-Butyl 2-ethyl 3-amino-1-benzyl-5-{(3R)-3-[(tert-butox-
ycarbonyl)amino]-3-methylpiperidin-1-yl}-1H-pyrrole-2,4-dicarbox-
ylate(3). The product was obtained as a pale-yellow amorphous
solid (270 mg, 49%).
added R1R2NH (1.0 mmol), and the mixture was stirred at 50 ꢀC for
1 h. DBU (0.3 ml; 2.0 mmol) and R3-PhCH2NH2 (1.2 mmol) were
then added to the mixture, and the new mixture was stirred for
10 h at 80 ꢀC. The mixture was next diluted with EtOAc, washed
with H2O, 1 N HCl aq, satd NaHCO3 aq and brine, and dried over
Na2SO4, and the filtrate was concentrated in vacuo. To the residue in
DMF (3.0 ml) was added K2CO3 (415 mg; 3.0 mmol) and then ethyl
bromoacetate (0.13 ml; 1.3 mmol) dropwise, and the reaction
mixture was stirred for 2 h at 50 ꢀC. The resulting slurry was diluted
with EtOAc, washed with satd NH4Cl aq and brine and dried over
Na2SO4, and the filtrate was concentrated in vacuo. To tert-butanol
(1.5 ml) was added LiNH2 (58 mg; 2.5 mmol) and the mixture was
stirred for 10 min at 80 ꢀC and then cooled to room temperature,
and CH3CN (2.0 ml) was added. To the prepared slurry was added
dropwise the alkylated intermediate in toluene (1.0 ml), and the
resulting mixture was stirred for 2 h at 30 ꢀC. The slurry was diluted
with EtOAc, washed with satd NH4Cl aq, and brine and dried over
Na2SO4, and the filtrate was concentrated in vacuo. Finally, the
residue was purified by column chromatography (hexane/
EtOAc¼8/1 to 3/1).
1H NMR (400 MHz, CDCl3)
d: 1.16 (3H, t, J¼6.8 Hz, OCH2CH3),
1.25 (3H, s, C(NHBoc)(Me)), 1.41 (9H, s, C(CH3)3), 1.60 (9H, s, C
(CH3)3), 1.40e1.60 (3H, m, CH2NCH2CH2CH2), 2.19 (1H, s,
CH2NCH2CH2CH2), 2.49 (1H, s, CH2NCH2CH2), 2.72 (1H, s,
CH2NCH2CH2), 3.14 (1H, t, J¼11 Hz, CH2NCH2CH2CH2), 3.33 (1H, d,
J¼12 Hz, CH2NCH2CH2), 4.16 (2H, q, J¼7.0 Hz, OCH2CH3), 4.56 (1H, s,
NHBoc), 5.54e5.57 (2H, m, CH2Ph), 6.95 (2H, d, J¼7.0 Hz, H-20, and
H-60), 7.15e7.31 (3H, m, H-30, H-40, and H-50). 13C NMR (100 MHz,
CDCl3) d: 14.3 (CH3, OCH2CH3), 21.5 (CH2, CH2NCH2CH2CH2), 25.0
(CH3, C(NHBoc)(Me)), 28.5 (CH3, C(CH3)3), 28.9 (CH3, C(CH3)3), 32.8
(CH2, CH2NCH2CH2CH2), 47.2 (CH2, CH2Ph), 49.6 (CH2,
CH2NCH2CH2), 51.1 (CH2, CH2NCH2CH2), 58.8 (C, C(Me)(NHBoc)),
59.2 (CH2, OCH2CH3), 78.6 (C, C(CH3)3), 80.8 (C, C(CH3)3), 98.5 (C),
100.7 (C), 125.3 (CH, 20, and 60-Ph), 126.7 (CH, 40-Ph), 128.5 (CH, 30,
and 50-Ph), 139.1 (C, Ph), 145.9 (C), 147.6 (C), 154.5 (CO), 161.6 (CO),
164 (CO). IR (ATR): 3506, 3372, 2973, 2931,1677 cmꢂ1. HRMS (ESIþ):
m/z 557.3322 (calcd m/z 557.3334 for C30H44N4O6þH). Mp
61e72 ꢀC.
6.1.2. tert-Butyl 3-{(3R)-3-[(tert-butoxycarbonyl)amino]-3-methyl-
piperidine-1-yl}-2-cyano-3-(methylthio)acrylate (5). The product
was obtained as a white amorphous solid.
6.1.6. 4-tert-Butyl 2-ethyl 3-amino-1-benzyl-5-(piperidin-1-yl)-1H-
pyrrole-2,4-dicarboxylate (8a). The product was obtained as
a white solid (235 mg, 55%).
1H NMR (400 MHz, CDCl3)
d: 1.35 (3H, s, C(NHBoc)(Me)), 1.43
1H NMR (400 MHz, CDCl3)
d
: 1.16 (3H, t, J¼7.1 Hz, OCH2CH3), 1.47
(9H, s, C(CH3)3), 1.49 (9H, s, C(CH3)3), 1.50e1.60 (2H, m,
CH2NCH2CH2CH2), 1.60e1.72 (1H, m, CH2NCH2CH2CH2), 1.73e1.88
(1H, m, CH2NCH2CH2CH2), 2.59 (3H, s, SMe), 3.35e3.48 (2H, m,
CH2NCH2CH2CH2), 3.70 (1H, br s, CH2NCH2CH2CH2), 4.10 (1H, br s,
CH2NCH2CH2CH2), 4.55 (1H, br s, NHBoc). 13C NMR (100 MHz,
(6H, m, NCH2(CH2)3), 1.61 (9H, s, C(CH3)3), 2.50e3.50 (4H, m, NCH2),
4.16 (2H, q, J¼7.1 Hz, OCH2CH3), 5.46 (2H, s, CH2Ph), 6.97 (2H, d,
J¼7.2 Hz, H-20, and H-60), 7.15e7.26 (3H, m, H-30, H-40, and H-50). 13C
NMR (100 MHz, CDCl3)
d: 14.4 (CH3, OCH2CH3), 23.8 (CH2,
NCH2(CH2)3), 26.3 (CH2, NCH2(CH2)3), 28.9 (CH3, C(CH3)3), 47.3
(CH2, CH2Ph), 50.2 (CH2 NCH2), 59.0 (CH2, OCH2CH3), 80.6 (C, C
(CH3)3), 97.7 (C), 100.4 (C), 125.8 (CH, 20, and 60-Ph), 126.4 (CH, 40-
Ph), 128.2 (CH, 30, and 50-Ph), 139.5 (C, Ph), 146.2 (C), 149.4 (C), 161.7
CDCl3) d: 18.5 (CH3, SMe), 21.7 (CH2, CH2NCH2CH2CH2), 23.7 (CH3, C
(NHBoc)(Me)), 28.3 (CH3, C(CH3)3), 28.4 (CH3, C(CH3)3), 35.5 (CH2,
CH2NCH2CH2CH2), 52.1 (C, C(NHBoc)(Me)), 54.5 (CH2,
CH2NCH2CH2CH2), 61.1 (CH2, CH2NCH2CH2CH2), 76.2 (C), 79.6 (C, C
(CH3)3), 80.6 (C, C(CH3)3), 119.9 (C), 154.3 (C), 163.4 (C), 178.9 (C).
HRMS (ESIþ): m/z 412.2259 (calcd m/z 412.2265 for
C20H33N4O3SþH). Mp 128e137 ꢀC.
(CO), 164.3 (CO). IR (ATR): 3482, 3367, 2937, 2848, 1675, 1643 cmꢂ1
.
HRMS (ESIþ): m/z 428.2538 (calcd m/z 428.2544 for
C24H33N3O4þH). Mp 97e100 ꢀC.
6.1.7. 4-tert-Butyl 2-ethyl 3-amino-1-benzyl-5-(pyrrolidin-1-yl)-1H-
pyrrole-2,4-dicarboxylate (8b). The product was obtained as a pale-
yellow oil (201 mg, 48%).
6.1.3. tert-Butyl 3-(benzylamino)-3-{(3R)-3-[(tert-butoxycarbonyl)
amino]-3-methylpiperidine-1-yl}-2-cyanoprop-2-enoate
(6). The
product was obtained as a white amorphous solid.
1H NMR (400 MHz, CDCl3)
d: 1.16 (3H, t, J¼6.9 Hz, OCH2CH3),1.57
1H NMR (400 MHz, CDCl3)
d: 11.29 (3H, s, C(NHBoc)(Me)),1.37 (9H,
(9H, s, C(CH3)3), 1.85e1.89 (4H, m, NCH2(CH2)2), 3.10 (4H, s, NCH2),
4.15 (2H, q, J¼7.1 Hz, OCH2CH3), 5.41 (2H, s, CH2Ph), 6.96 (2H, d,
J¼7.1 Hz, H-20, and H-60), 7.17e7.26 (3H, m, H-30, H-40, and H-50). 13C
s, C(CH3)3), 1.48 (9H, s, C(CH3)3), 1.40e1.50 (2H, m, CH2NCH2CH2CH2),
1.55e1.68 (2H, m, CH2NCH2CH2CH2),1.88 (2H, br s, CH2NCH2CH2CH2),
2.98 (2H, br s, CH2NCH2CH2CH2), 3.47 (1H, br s, NHCH2Ph), 4.39 (2H, s,

3130
Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
NMR (100 MHz, CDCl3)
d
:
14.4 (CH3, OCH2CH3), 25.6 (CH2,
J¼8.7 Hz, H-30, and H-50), 6.90 (2H, d, J¼8.6 Hz, H-20, and H-60). 13C
NCH2(CH2)2), 28.7 (CH3, C(CH3)3), 47.4 (CH2, CH2Ph), 51.0 (CH2,
NCH2), 59.0 (CH2, OCH2CH3), 80.2 (C, C(CH3)3), 97.2 (C), 100.4 (C),
125.8 (CH, 20, and 60-Ph), 126.4 (CH, 40-Ph), 128.2 (CH, 30, and 50-Ph),
139.6 (C, Ph), 146.3 (C), 147.1 (C), 161.6 (CO), 164.0 (CO). IR (ATR):
3506, 3372, 2973, 2867, 1675 cmꢂ1. HRMS (ESIþ): m/z 414.2390
(calcd m/z 414.2387 for C23H31N3O4þH).
NMR (100 MHz, CDCl3) d: 14.1 (CH3, OCH2CH3), 14.4 (CH3,
OCH2CH3), 28.8 (CH3, CH2, C(CH3)3, NCH2CH2CH), 40.9 (CH,
NCH2CH2CH), 46.6 (CH2, CH2Ph), 48.8 (CH2, NCH2CH2CH), 55.1 (CH3,
OMe), 59.0 (CH2, OCH2CH3), 60.3 (CH2, OCH2CH3), 80.5 (C, C(CH3)3),
97.8 (C), 100.5 (C), 113.5 (CH, 30, and 50-Ph), 126.9 (CH, 20, and 60-Ph),
131.3 (C, Ph), 145.9 (C), 148.3 (C), 158.2 (C, Ph), 161.6 (CO), 164 (CO),
175 (CO). IR (ATR): 3506, 3374, 2975, 1729, 1675 cmꢂ1. HRMS (ESIþ):
m/z 530.2846 (calcd m/z 530.2861 for C28H39N3O7þH).
6.1.8. 4-tert-Butyl 2-ethyl 3-amino-1-benzyl-5-(azepan-1-yl)-1H-
pyrrole-2,4-dicarboxylate (8c). The product was obtained as a yel-
low oil (302 mg, 69%).
6.1.12. 4-tert-Butyl 2-ethyl 3-amino-5-[4-(tert-butoxycarbonyl)pi-
peradin-1-yl]-1-(2-chlorobenzyl)-1H-pyrrole-2,4-dicarboxylate
(8g). The product was obtained as a pale-yellow oil (362 mg, 64%).
1H NMR (400 MHz, CDCl3)
d
: 1.12 (3H, t, J¼7.0 Hz, OCH2CH3),
1.44e1.60 (8H, m, NCH2(CH2)4), 1.60 (9H, s, C(CH3)3), 2.80e3.50
(4H, m, NCH2), 4.11 (2H, q, J¼7.1 Hz, OCH2CH3), 5.52 (2H, s, CH2Ph),
6.90 (2H, d, J¼7.1 Hz, H-20, and H-60), 7.14e7.26 (3H, m, H-30, H-40,
1H NMR (400 MHz, CDCl3)
d
: 1.20 (3H, t, J¼7.1 Hz, OCH2CH3), 1.43
(9H, s, C(CH3)3), 1.58 (9H, s, C(CH3)3), 2.41e2.60 (2H, br s,
NCH2CH2NBoc), 2.73 (2H, br s, NCH2CH2NBoc), 3.43 (2H, br s,
NCH2CH2NBoc), 3.94 (2H, br s, NCH2CH2NBoc), 4.20 (2H, q, J¼7.1 Hz,
OCH2CH3), 5.50 (2H, s, CH2Ph), 6.84 (1H, apparent d, J¼6.6 Hz, H-60),
6.98 (1H, s, H-30), 7.17e7.21 (2H, m, H-40, and 50). 13C NMR (100 MHz,
and H-50). 13C NMR (100 MHz, CDCl3)
d: 14.4 (CH3, OCH2CH3), 27.3
(CH2, NCH2(CH2)4), 28.8 (CH3, C(CH3)3), 30.1 (CH2, NCH2(CH2)4),
46.9 (CH2, CH2Ph), 53.8 (CH2, NCH2), 58.9 (CH2, OCH2CH3), 80.2 (C,
C(CH3)3), 96.6 (C), 99.9 (C), 124.9 (CH, 20, and 60-Ph), 126.3 (CH, 40-
Ph), 128.1 (CH, 30, and 50-Ph), 139.6 (C, Ph), 146.3 (C), 150.9 (C),
161.5 (CO), 164.3 (CO). IR (ATR): 3488, 3375, 2927, 2852,
1675 cmꢂ1. HRMS (ESIþ): m/z 442.2700 (calcd m/z 442.2700 for
C25H35N3O4þH).
CDCl3) d: 14.3 (CH3, OCH2CH3), 28.3 (CH3, C(CH3)3), 28.7 (CH3, C
(CH3)3), 43.4 (CH2, NCH2CH2NBoc), 44.5 (CH2, NCH2CH2NBoc), 46.7
(CH2, CH2Ph), 48.7 (CH2, CH2, NCH2CH2NBoc), 59.3 (CH2, OCH2CH3),
79.6 (C, C(CH3)3), 81.1 (C, C(CH3)3), 98.4 (C), 100.6 (C), 123.8 (C, Ph),
125.8 (CH, 60-Ph), 126.9 (CH, 30-Ph), 129.6 (CH, Ph), 134.2 (CH, Ph),
141.4 (C, Ph), 145.9 (C), 146.9 (C), 154.3 (CO), 161.5 (CO), 163.9 (CO). IR
(ATR): 3506, 3376, 2975, 2931, 1675 cmꢂ1. HRMS (ESIþ): m/z
563.2623 (calcd m/z 563.2631 for C28H39ClN4O6þH).
6.1.9. 4-tert-Butyl 2-ethyl 3-amino-1-benzyl-5-[benzyl(methyl)amino]-
1H-pyrrole-2,4-dicarboxylate (8d). The product was obtained as
a pale-yellow oil (294 mg, 63%).
1H NMR (400 MHz, CDCl3)
d
: 1.12 (3H, t, J¼7.0 Hz, OCH2CH3),1.67
6.1.13. 4-tert-Butyl 2-ethyl 3-amino-5-[(2S)-2-(methoxymethyl)pyr-
rolidine-1-yl]-1-[3-(trifluoromethyl)benzyl]-1H-pyrrole-2,4-di-
carboxylate (8h). The product was obtained as a pale-yellow oil
(181 mg, 35%).
(9H, s, C(CH3)3), 2.60 (3H, s, NMe), 4.13 (2H, q, J¼7.1 Hz, OCH2CH3),
4.19 (2H, br s, MeNCH2Ph), 5.49 (2H, s, CH2Ph), 6.92 (2H, d, J¼7.3 Hz,
H-20, and H-60), 7.10e7.30 (8H, m, 2Ph). 13C NMR (100 MHz, CDCl3)
d: 14.3 (CH3, OCH2CH3), 28.8 (CH3, C(CH3)3), 39.8 (CH3, NMe), 47.2
1H NMR (400 MHz, CDCl3)
d
: 1.11 (3H, t, J¼6.6 Hz, OCH2CH3),1.58
(CH2, CH2Ph), 59.1 (CH2, MeNCH2Ph), 59.2 (CH2, OCH2CH3), 80.7 (C,
C(CH3)3), 97.8 (C), 100.3 (C), 125.4 (CH, 60-Ph), 126.4 (CH, Ph), 127.1
(CH, Ph), 128.3 (CH,CH, Ph), 128.8 (CH, Ph), 138.5 (C), Ph, 139.3 (C,
Ph), 146.2 (C), 149.3 (C), 161.6 (CO), 164.2 (CO). IR (ATR): 3506, 3372,
2975, 2931, 1675 cmꢂ1. HRMS (ESIþ): m/z 464.2534 (calcd m/z
464.2544 for C27H33N3O4þH).
(9H, s, C(CH3)3), 1.70e1.90 (3H, m, NCH2CH2CH2), 2.10e2.19 (1H, s,
NCH2CH2CH2), 2.77 (1H, br s, NCH2), 3.05e3.18 (3H, m, CH2NCH
(CH2OMe)), 3.17 (3H, s, OMe), 3.79e3.84 (1H, m, NCH), 4.08e4.20
(2H, m, OCH2CH3), 5.45e5.60 (2H, m, CH2Ph), 7.12 (1H, d, J¼7.7 Hz,
H-20), 7.32e7.46 (3H, m, H-40, H-50, and H-60). 13C NMR (100 MHz,
CDCl3) d: 14.2 (CH3, OCH2CH3), 24.7 (CH2, NCH2CH2), 28.7 (CH3, C
(CH3)3), 46.8 (CH2, CH2Ph), 53.1 (CH2, NCH2CH2), 58.6 (CH3, OMe),
59.1 (CH2, OCH2CH3), 61.4 (CH2, CH2OMe), 75.9 (CH, NCH), 80.5 (C, C
(CH3)3), 97.4 (C), 100.6 (C), 122.8 (3J(C,F)¼4.0 Hz) (CH, 20-Ph), 123.3
(3J(C,F)¼3.7 Hz) (CH, 40-Ph), 124.1 (C, 1J(C,F)¼270 Hz) (C, CF3), 128.7
(CH, Ph), 129.1 (CH, Ph), 130.4 (2J(C,F)¼32 Hz) (C, 30-Ph), 140.9 (C,
Ph), 146 (C), 146.9 (C), 161.4 (CO), 163.7 (CO). IR (ATR): 3507, 3376,
2975, 2871, 1675 cmꢂ1. HRMS (ESIþ): m/z 526.2513 (calcd m/z
526.2523 for C26H34F3N3O5þH).
6.1.10. 4-tert-Butyl 2-ethyl 3-amino-1-(2-methylbenzyl)-5-[methyl
(propyl)amino]-1H-pyrrole-2,4-dicarboxylate (8e). The product was
obtained as a pale-yellow oil (184 mg, 43%).
1H NMR (400 MHz, CDCl3)
d
: 0.72 (3H, t, J¼7.4 Hz, OCH2CH3),1.02
(3H, s, MeNCH2CH2CH3), 1.25e1.40 (2H, m, MeNCH2CH2CH3), 1.60
(9H, s, C(CH3)3), 2.34 (3H, s, Me), 2.63 (3H, s, NMe), 2.93 (2H, t,
J¼7.2 Hz, MeNCH2CH2CH3), 4.07 (2H, q, J¼7.1 Hz, OCH2CH3), 5.40
(2H, s, CH2Ph), 6.39 (1H, d, J¼7.4 Hz, H-60), 6.90e7.13 (3H, m, H-30, H-
40, and H-50). 13C NMR (100 MHz, CDCl3)
d: 11.3 (CH3,
6.1.14. 4-tert-Butyl 2-ethyl 3-amino-1-(2-bromo-5-fluorobenzyl)-
5-{(3R)-3-[(tert-butoxycarbonyl)amino]-3-methylpiperidin-1-yl}-
1H-pyrrole-2,4-dicarboxylate(8i). The product was obtained as
a pale-yellow amorphous solid (301 mg, 46%).
MeNCH2CH2CH3), 14.1 (CH3, OCH2CH3), 18.9 (CH3, Me), 21.8 (CH2,
MeNCH2CH2CH), 28.7 (CH3, C(CH3)3), 40.2 (CH3, NMe), 45.3 (CH2,
CH2Ph), 57.1 (CH2, MeNCH2CH2CH3), 58.9 (CH2, OCH2CH3), 80.4 (C, C
(CH3)3), 97.3 (C), 100.3 (C), 124.2 (CH, Ph), 125.9 (CH, Ph), 126.0 (CH,
Ph), 129.5 (CH, Ph), 133.5 (C, Ph), 137.7 (C, Ph), 146.2 (C), 149.6 (C),
1H NMR (400 MHz, CDCl3)
d: 1.10 (3H, t, J¼7.1 Hz, OCH2CH3), 1.26
(3H, s, C(NHBoc)(Me)), 1.39 (9H, s, C(CH3)3), 1.40e1.60 (3H, m,
CH2NCH2CH2CH2), 1.62 (9H, s, C(CH3)3), 2.27 (1H, br s,
CH2NCH2CH2CH2), 2.58 (1H, br s, CH2NCH2CH2), 2.80 (1H, s,
CH2NCH2CH2), 3.08 (1H, br s, CH2NCH2CH2), 3.33 (1H, br s,
CH2NCH2CH2), 4.13 (2H, q, J¼7.1 Hz, OCH2CH3), 5.34e5.60 (2H, m,
CH2Ph), 6.22 (1H, d, J¼8.0 Hz, H-60), 6.83 (1H, td, J¼8.2, 2.9 Hz, H-30),
161.5 (CO), 164.2 (CO). IR (ATR): 3486, 3372, 2971, 2871, 1677 cmꢂ1
.
HRMS (ESIþ): m/z 430.2690 (calcd m/z 430.2700 for C24H35N3O4þH).
6.1.11. 4-tert-Butyl 2-ethyl 3-amino-5-[4-(ethoxycarbonyl)piperidin-
1-yl]-1-(4-methoxybenzyl)-1H-pyrrole-2,4-dicarboxylate (8f). The
product was obtained as a pale-yellow oil (344 mg, 65%).
7.51 (1H, dd, J¼8.9, 3.6 Hz, H-40). 13C NMR (100 MHz, CDCl3)
d: 14.1
1H NMR (400 MHz, CDCl3)
d
: 1.20 (3H, t, J¼7.1 Hz, OCH2CH3),1.24
(CH3, OCH2CH3), 21.6 (CH2, CH2NCH2CH2CH2), 25 (CH3, C(NHBoc)
(Me)), 28.4 (CH3, C(CH3)3), 28.8 (CH3, C(CH3)3), 32.8 (CH2,
CH2NCH2CH2CH2), 48.0 (CH2, PhCH2), 50.2 (CH2, CH2NCH2CH2CH2),
51.1 (CH2, CH2NCH2CH2CH2), 59.2 (CH2, C, OCH2CH3, C(Me)(NHBoc)),
78.7 (C, C(CH3)3), 81.1 (C, C(CH3)3), 98.5 (C), 100.2 (C), 113.7 (2J(C,F)¼
24 Hz) (CH, Ph),114.6 (C, Ph), 115.3 (2J(C,F)¼22 Hz), (CH, Ph), 133.8 (3J
(3H, t, J¼7.1 Hz, OCH2CH3), 1.59 (9H, s, C(CH3)3), 1.50e1.70 (2H, m,
NCH2CH2CH), 1.80e1.90 (2H, m, NCH2CH2CH), 2.34 (1H, br s,
NCH2CH2CH), 2.74 (2H, br s, NCH2CH2CH), 3.35 (2H, br s,
NCH2CH2CH), 3.75 (3H, s, OMe), 4.12 (2H, q, J¼7.1 Hz, OCH2CH3),
4.18 (2H, q, J¼7.1 Hz, OCH2CH3), 5.39 (2H, s, CH2Ph), 6.77 (2H, d,

Y. Nishio et al. / Tetrahedron 67 (2011) 3124e3131
3131
(C,F)¼7.0 Hz) (CH, 30-Ph), 140.9 (C, Ph), 146 (C), 148 (C), 154.5 (CO),
6.1.19. Ethyl
1-benzyl-5-{(3R)-3-[(tert-butoxycarbonyl)amino]-3-
161.3 (CO), 162.4 (1J(C,F)¼245 Hz) (C, 50-Ph), 163.8 (CO). IR (ATR):
3496, 3371, 2973, 2921, 1679 cmꢂ1. HRMS (ESIþ): m/z 653.2344
(calcd m/z 653.2345 for C30H42BrFN4O6þH). Mp 74e84 ꢀC.
methylpiperidine-1-yl}-4-cyano-3-hydroxy-1H-pyrrole-2-carboxyl-
ate (11). The product was obtained as a pale-yellow amorphous
solid.
1H NMR (400 MHz, CDCl3)
d: 1.18 (3H, t, J¼7.1 Hz, OCH2CH3),
6.1.15. 4-tert-Butyl
2-ethyl
3-amino-5-(azepan-1-yl)-1-(2,6-di-
1.30e1.40 (1H, m, CH2NCH2CH2CH2), 1.33 (3H, s, C(Me)(NHBoc)),
1.39 (9H, s, C(CH3)3), 1.50e1.70 (2H, m, CH2NCH2CH2CH2), 1.97 (1H,
apparent d, J¼13 Hz, CH2NCH2CH2CH2), 2.92e3.00 (2H, m,
CH2NCH2CH2CH2), 3.10 (1H, d, J¼12 Hz, CH2NCH2CH2CH2), 3.28 (1H,
d, J¼12 Hz, CH2NCH2CH2CH2), 4.23 (2H, q, J¼7.12 Hz, OCH2CH3),
4.53 (1H, s, OH), 5.31 (2H, s, CH2Ph), 6.94 (2H, d, J¼7.1 Hz, H-20, and
H-60), 7.20e7.40 (3H, m, H-30, H-40, and H-50). 13C NMR (100 MHz,
chlorobenzyl)-1H-pyrrole-2,4-dicarboxylate (8j). The product was
obtained as a yellow solid (184 mg, 36%).
1H NMR (400 MHz, CDCl3)
d
: 1.08 (3H, t, J¼7.0 Hz, OCH2CH3),
1.59 (9H, s, C(CH3)3), 1.61 (8H, br s, NCH2(CH2)4), 2.98 (2H, br s,
NCH2), 3.35 (2H, br s, NCH2), 4.07 (2H, q, J¼7.1 Hz, OCH2CH3), 5.65
(2H, s, CH2Ph), 7.06 (1H, t, J¼8.0 Hz, H-40), 7.22 (2H, d, J¼8.0 Hz, H-
30, and H-50). 13C NMR (100 MHz, CDCl3)
d: 14.4 (CH3, OCH2CH3),
CDCl3) d: 14.2 (CH3, OCH2CH3), 21.6 (CH2, CH2NCH2CH2CH2), 24.1
27.5 (CH2, NCH2(CH2)4), 28.8 (CH3, C(CH3)3), 30.2 (CH2,
NCH2(CH2)4), 44.5 (CH2, PhCH2), 53.5 (CH2, NCH2), 58.8 (CH2,
OCH2CH3), 80.1 (C, C(CH3)3), 96.4 (C), 100.4 (C), 127.8 (CH, 40-Ph),
128.8 (CH, 30, and 50-Ph), 133.2 (C, Ph), 134.6 (C, 20, and 60-Ph), 146.9
(C), 151.9 (C), 161.6 (CO), 164.2 (CO). IR (ATR): 3488, 3372, 2927,
2852, 1675 cmꢂ1. HRMS (ESIþ): m/z 510.1911 (calcd m/z 510.1921 for
C25H33Cl2N3O4þH). Mp 100e106 ꢀC.
(CH3, C(Me)(NHBoc)), 28.4 (CH3, C(CH3)3), 34.2 (CH2,
CH2NCH2CH2CH2), 48.0 (CH2, CH2Ph), 51.1 (CH2, CH2NCH2CH2CH2),
52.1 (CH2, CH2NCH2CH2CH2), 60.2 (C, C(Me)(NHBoc)), 60.7 (CH2,
OCH2CH3), 79.2 (C, C(CH3)3), 101.9 (C), 113.4 (C), 125.6 (CH, 20, and
60-Ph), 127.4 (CH, 40-Ph), 128.7 (CH, 30, and 50-Ph), 137.4 (C, Ph),
149.7 (C), 154.5 (C), 156.5 (CO), 162.0 (CO). IR (ATR): 3417, 2975,
2221, 1704, 1648 cmꢂ1. HRMS (ESIþ): m/z 483.2601 (calcd m/z
483.2602 for C26H34N4O5þH). Mp 44e53 ꢀC.
6.1.16. 4-tert-Butyl 2-ethyl 3-amino-1-[4-(methoxycarbonyl)benzyl]-
5-(morpholin-4-yl)-1H-pyrrole-2,4-dicarboxylate(8k). The product
was obtained as a yellow oil (137 mg, 31%).
Acknowledgements
1H NMR (400 MHz, CDCl3)
d
: 1.17 (3H, t, J¼7.0 Hz, OCH2CH3),1.62
We are thankful to Ms. M. Honma for recording high MS spectra.
(9H, s, C(CH3)3), 3.57 (8H, br s, NCH2CH2O), 3.89 (3H, s, OMe), 4.17
(2H, q, J¼7.1 Hz, OCH2CH3), 5.59 (2H, s, CH2Ph), 7.03 (2H, d,
J¼8.4 Hz, H-20, and H-60), 7.94 (2H, d, J¼8.3 Hz, H-30, and H-50). 13C
Supplementary data
NMR (100 MHz, CDCl3) d: 14.3 (CH3, OCH2CH3), 28.8 (CH3, C(CH3)3),
47.1 (CH2, CH2Ph), 49.1 (CH2, NCH2CH2O), 52.0 (CH2, NCH2CH2O),
59.3 (CH2, OCH2CH3), 67.2 (CH3, OMe), 81.2 (C, C(CH3)3), 98.4 (C),
100.7 (C), 125.5 (CH, 30, and 50-Ph), 128.6 (C, Ph), 129.7 (CH, 20, and
60-Ph), 144.6 (C, Ph), 145.9 (C), 146.9 (C), 161.5 (CO), 164 (CO), 166.7
(CO). IR (ATR): 3504, 3374, 2975, 2854, 1720, 1675 cmꢂ1. HRMS
(ESIþ): m/z 488.2391 (calcd m/z 488.2386 for C25H33N3O7þH).
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.071.
References and notes
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Kieffer, T. J.; McIntosh, C. H.; Pederson, T. A. Endocrinology 1995, 136, 3585 For
reviews, see; (c) Deacon, C. F. Horm. Metab. Res. 2004, 36, 761.
4. (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey,
G. J.; Kowalchick, J. E.; Leiting, B.; Lynos, K.; Marsilio, F.; McCann, M. E.; Patel, R.
A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang,
B. B.; Zhu, L.; Thronberry, N. A.; Weber, A. E. J. Med. Chem. 2005, 48, 141; (b)
Miller, S. A.; St. Onge, E. L. Ann. Pharmacother. 2006, 40, 1336.
5. Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.; Dunning, B. E.; Prasad,
K.; Mangold, B. L.; Russell, M. E.; Hughes, T. E. J. Med. Chem. 2003, 46, 2774.
6. Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson,
J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.;
Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.;
Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. J. Med. Chem.
2005, 48, 5025.
7. (a) Gwaltney, S. L.; Aertgeerts, K.; Feng, J.; Kaldor, S. W.; Kassel, D. B.; Manuel,
M.; Navre, M.; Prasad, G. S.; Shi, L.; Skene, R. J.; Stafford, J. A.; Wallace, M.; Wu,
R.; Ye, S.; Zhang, Z. Abstracts of Papers, 231st Meeting of the American Chemical
Society, Atlanta, GA, 2006; American Chemical Society: Washington, DC, 2006;
MEDI 018. (b) Feng, J.; Zhang, Z.; Wallace, M. B.; Sttaford, J. A.; Kaldor, S. W.;
Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi, K.; Xu, R.;
Webb, D. R.; Gwaltney, S. L. J. Med. Chem. 2007, 50, 2297.
8. (a) Nakahira, H.; Kimura, H.; Hochigai, H. World Patent 2006068163, 2006. (b)
Nakahira H.; Nishio, Y.; Kimura, H.; World Patent 2009084497, 2009. (c) Nishio,
Y.; Kimura, H.; Tosaki, S.; Sugaru, E.; Sakai, M.; Horiguchi, M.; Masui, Y.; Ono,
M.; Nakagawa, T.; Nakahira, H. Bioorg. Med. Chem. Lett. 2010, 20, 7246.
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10. Kidwai, M.; Singhal, K.; Rastogi, S. J. Heterocycl. Chem. 2006, 43, 1231.
11. (a) Tsuge, O.; Hatta, T.; Tashiro, H.; Kakura, Y.; Maeda, H.; Kakehi, A. Tetrahedron
2000, 56, 7723; (b) Zaytsev, A. V.; Anderson, R. J.; Meth-Cohn, O.; Groundwater,
P. W. Tetrahedron 2005, 61, 5831.
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(b) Castellote, I.; Vaquero, J. J.; Fernandes-Gadea, J.; Alvarez-Bullia, J. J. Org.
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6.1.17. Methyl 3-[benzy(2-ethoxy-2-oxoethyl)lamino]-3-{(3R)-3-[(tert-
butoxycarbonyl)amino]-3-methylpiperidine-1-yl}-2-cyanoprop-2-
enoate (9). The product was obtained as a yellow amorphous solid.
1H NMR (400 MHz, CDCl3)
d: 1.0e1.70 (21H, m), 3.0e3.3 (1H, m),
3.5e3.8 (4H, m), 4.0e4.4 (6H, m), 4.81 (1H, s), 7.18e7.23 (1H, m),
7.27e7.40 (4H, m). IR (ATR): 3330, 2975, 2192,1737,1685 cmꢂ1. HRMS
(ESIþ): m/z 515.2860 (calcd m/z 515.2864 for C27H38N4O6þH). Mp
78e87 ꢀC.
6.1.18. 2-Ethyl 4-methyl 3-amino-1-benzyl-5-{(3R)-3-[(tert-butox-
ycarbonyl)amino]-3-methylpiperidine-1-yl}-1H-pyrrole-2,4-dicarbo-
xylate (10). The product was obtained a pale-yellow amorphous
solid.
1H NMR (400 MHz, CDCl3)
d: 1.16 (3H, t, J¼7.0 Hz, OCH2CH3), 1.25
(3H, s, C(NHBoc)(Me)), 1.42 (9H, s, C(CH3)3), 1.20e1.40 (3H, m,
CH2NCH2CH2CH2), 2.17 (1H, br s, CH2NCH2CH2CH2), 2.49 (1H, br s,
CH2NCH2CH2), 2.80 (1H, br s, CH2NCH2CH2), 3.10 (1H, t, J¼9.7 Hz,
CH2NCH2CH2), 3.22 (1H, d, J¼12 Hz, CH2NCH2CH2), 3.86 (3H, s, OMe),
4.16 (2H, q, J¼8.2 Hz, OCH2CH3), 4.56 (1H, s, NHBoc), 5.44e5.67 (2H,
m, CH2Ph), 5.92 (2H, s, NH2), 6.95 (2H, d, J¼6.8 Hz, H-20, and H-60),
7.17e7.28 (3H, m, H-30, H-40, and H-50). 13C NMR (100 MHz, CDCl3)
d:
14.4 (CH3, OCH2CH3), 21.5 (CH2, CH2NCH2CH2CH2), 25.0 (CH3, C(Me)
(NHBoc)), 28.5 (CH3, C(CH3)3), 33.4 (CH2, CH2NCH2CH2CH2), 47.3
(CH2, CH2Ph), 49.8 (CH2, CH2NCH2CH2), 50.8 (CH3, OMe), 51.1 (CH2,
CH2NCH2CH2), 59.0 (C, C(Me)(NHBoc)), 59.3 (CH2, OCH2CH3), 78.7 (C,
C(CH3)3), 96.8 (C), 100.8 (C), 125.3 (CH, 20, and 60-Ph), 126.8 (CH, 40-
Ph), 128.5 (CH, 30, and 50-Ph), 139 (C, Ph), 145.7 (C), 148.4 (C), 154.6
(CO), 161.6 (CO), 164.7 (CO). IR (ATR): 3506, 3376, 2975, 2935,
1681 cmꢂ1. HRMS (ESIþ): m/z 515.2857 (calcd m/z 515.2864 for
C27H38N4O6þH). Mp 43e58 ꢀC.
13. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Ananthan, S.; Ullas, G. V. Tetrahedron
Lett. 1984, 55, 1291.