One-pot synthesis of 5-amino 4-cyano pyrrole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.080

One-pot synthesis of 5-amino 4-cyano pyrrole derivatives is herein disclosed. The described method consists of four steps and gives new pyrrole derivatives in moderate to good yields. This synthesis can be used for a large scale preparation.

Full text of DOI:10.1016/j.tetlet.2011.03.080

Tetrahedron Letters 52 (2011) 2767–2770
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 5-amino 4-cyano pyrrole derivatives
Yukihiro Nishio a, , Hidenori Kimura a, Katsuya Uchiyama b, Yoshihiro Horiuchi a, Hiroyuki Nakahira a
⇑
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:
One-pot synthesis of 5-amino 4-cyano pyrrole derivatives is herein disclosed. The described method con-
sists of four steps and gives new pyrrole derivatives in moderate to good yields. This synthesis can be
used for a large scale preparation.
Received 24 January 2011
Revised 13 March 2011
Accepted 20 March 2011
Available online 11 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
5-Amino 4-cyano pyrrole
One-pot synthesis
1. Introduction
strongacids, whichlimitthe selectionof protectinggroups and other
substituents. In addition, a long process with additional steps is not
Dipeptidyl peptidase IV (DPP-4) inhibitors have recently been
the focus for a new treatment for type 2 diabetes.1 DPP-4 is an
ubiquitous serine protease that modulates the biological activity
of various peptides. One of the peptides cleaved by DPP-4 is gluca-
gon-like peptide 1, which plays an important role in maintaining
normal blood glucose level.2,3 DPP-4 inhibitors avert cleavage of
GLP-1 and prolong its lifetime in the blood. Based on this mecha-
nism of action, a number of DPP-4 inhibitors have already been ap-
proved for the treatment of type 2 diabetes, while other promising
candidates are undergoing clinical or preclinical development.4–7
We have previously reported novel DPP-4 inhibitors, such as the
pyrolo[3,2-d]pyrimidines 1 and deazahypoxanthines 2 (X = H).8
Subsequently, Novartis researchers have shown that structures
similar to 1 and 2 (X = ester, amide or nitrile) with an electron
withdrawing group (EWG) at position 7 also have strong inhibitory
activity against DPP-4.9
suitable for preparing a wide variety of compounds or a large scale
synthesis. As for the synthetic route described by Novartis research-
ers, the desired compounds are obtained by a microwave reaction,
which can be difficult to apply to a large scale synthesis and requires
special equipment.
Based on these findings, we were interested in expanding our
previous work by constructing 5-amino 4-cyano pyrrole deriva-
tives (4) that can conveniently afford various 7-cyano compounds.
An extensive effort led to a new synthetic method that can give un-
ique pyrrole derivatives having amino substituents at
a-position,
which are difficult to synthesize by traditional ways. In addition,
it can be carried out as a one-pot reaction suitable for collecting
a wide range of SAR information and a large scale synthesis. Here,
we disclose the scope and limitations of this new method (Fig. 1).
2. Results and discussion
Synthetic methods for preparing a series of pyrrole structures
substituted by amines at position 5 have rarely been reported.10–12
In our synthesis of the previously reported DPP-4 inhibitors, we
constructed a novel synthetic method for preparation of 5-amino
4-tert-butyl ester pyrrole derivatives (3) as main intermediates.8
The pyrrole structure of 3 is suitable for preparation of the unsubsti-
tuted, 7-ester and amide substituted structures 1 and 2 (X = H, ester
and amide). However, for preparation of 7-cyano structures, 1 and 2
(X = CN), compound 3 is inappropriate as intermediate because
transformation of the tert-butyl ester into a nitrile requires addi-
tional steps with harsh reaction conditions, including the use of
First, we examined the conditions of our previous work
(Scheme 1). In the first step (A) for R1R2N, the tert-butyl [(R)-3-
piperidine-3-yl]carbamate was selected due to its strong inhibitory
activity against DPP-4.8,9 On the other hand, in the second step (B)
for R3, 2-chloro benzylamine was used because this substituent
showed good DPP-4 inhibitory activity among all our compounds.
In our experiments, we found that cyclization proceeded to a cer-
tain extent under the third conditions (C), K2CO3 in DMF at 50 °C.
Based on this finding, we assumed that it was possible to carry
out one-pot reaction, and accordingly investigated its conditions.
As the first step (A) proceeded smoothly in various solvents,
such as toluene, CH3CN, and THF, without any base, the conditions
of the second step (B) were investigated. Preliminary research
⇑
Corresponding author. Tel.: +81 6 6466 5223; fax: +81 6 6466 5287.
E-mail address: yukihiro-nishio@ds-pharma.co.jp (Y. Nishio).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.080

2768
Y. Nishio et al. / Tetrahedron Letters 52 (2011) 2767–2770
R3
O
N
O
R1
R2
R1
R2
EtO2C
R1
R2
N
MeS
NC
N
N
N
N
N
SMe
N
N
O
N
H2N
A
A
X
X
t
1
2
3
A = CO2 Bu( )
A = CN (4)
Figure 1. 5-Amino pyrrole based DPP-4 inhibitors.
Cl
N
NHBoc
NHBoc
HN
MeS
NC
MeS
NC
(A)
(B)
(C)
SMe
CN
N
NC
CN
CN
7
5
6
Cl
N
Cl
NHBoc
NHBoc
EtO2C
EtO2C
H2N
N
N
(D)
N
NC
CN
CN
8
9
Scheme 1. Synthesis of compound 9. Reagents and conditions: (A) tert-butyl [(R)-3-piperidine-3-yl]carbamate (1.0 equiv), toluene, 60 °C, 4 h; (B) benzylamine (1.2 equiv),
1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) (2.0 equiv), CH3CN, 80 °C, 5 h; (C) ethyl bromoacetate (1.1 equiv), K2CO3 (1.2 equiv), DMF, 50 °C, 1 h; (D) LiNH2 (2.0 equiv), t-BuOH
(20 equiv), CH3CN, heptane, rt, 1 h.
indicated that a base is required in the second step (B). Accord-
ingly, we focused on K2CO3, which is used in the third reaction con-
ditions (C) (Table 1). The reaction did not finish in toluene at 80 °C
(entry 1). The reason for this seems to be toluene’s inability to dis-
solve inorganic bases. In addition, the more polar solvent DMF was
not appropriate for this step because the reaction gave a complex
mixture (entry 2). It was assumed that DMF was unstable under
basic conditions and heat. Therefore, other solvents were investi-
gated, and n-BuCN was proved to be a good choice (entry 3). The
use of K2CO3 in n-BuCN gave better results than the use of 1,8-
diazabicyclo[5,4,0]undeca-7-ene (DBU) in CH3CN. However,
1.2 equiv of K2CO3 did not finish the reaction, and 1.5 equiv was
necessary for reaction completion (entries 3 and 4). As for the tem-
perature, the reaction at 130 °C afforded slightly less yields, and
2.0 equiv of K2CO3 at 130 °C did not show any improvement (en-
tries 5 and 6).
As all reaction conditions in the table above could be applied to
the next alkylation step (C), the reaction conditions of entry 3 were
selected. However, the first/second (A/B) step did not proceed to
completion under these conditions. Therefore, the conditions of
entries 5 and 6 were examined, and found to be both suitable for
the smooth progression of the first/second step.
The preliminary research described above suggested that alkyl-
ation and cyclization (C/D) under K2CO3 in DMF can proceed at
once, however, under K2CO3 in n-BuCN even the alkylation (C)
did not finish. This is probably due to the low polarity of n-BuCN
as compared to DMF. DMF on the other hand was inappropriate
for the second step (B). Based on these findings, a combination of
solvents was used in the third/fourth step (C/D). As N-methyl pyr-
rolidinone (NMP) was more stable than DMF under basic condi-
tions and heat, the combination, NMP and n-BuCN, was selected
as solvent. The most important factor for these two steps was
found to be the temperature as alkylation/cyclization (C/D) pro-
ceeded smoothly at 110 °C with additional 2.0 equiv of potassium
carbonate and a catalytic amount of water, which seemed to help
dissolve K2CO3. Next, we explored the limitations of this one-pot
reaction13 (Table 2).
Table 1
Reaction conditions for the second step (B)
To examine the limitations of this reaction under harsh condi-
tions, the conditions of entry 6 in Table 2 were selected for the sec-
ond step (B). When 2,6-dimethyl piperidine was used in the first
step (A), the reaction did not proceed (entry 1). Steric hindrance
around NH seems to have a big impact on the progression of the
first step. The use of 2-methyl piperidine in the first step and 1-phe-
nyl ethylamine or cyclohexylamine in the second step did not allow
the second reaction to proceed to completion (entries 2–4). In addi-
tion, when aniline was used instead of benzylamine, the reaction
did not proceed (entry 5). As the use of cyclohexanemethylamine
Entry
Base
Solvent
Temp (°C)
Yielda (%)
1
2
3
4
5
6
K2CO3 (1.5 equiv)
K2CO3 (1.5 equiv)
K2CO3 (1.5 equiv)
K2CO3 (1.2 equiv)
K2CO3 (1.5 equiv)
K2CO3 (2.0 equiv)
Toluene
DMF
n-BuCN
n-BuCN
n-BuCN
n-BuCN
80
80
80
80
130
130
42b
––
75 (59)c
20b
68
69
a
b
c
Isolated yield.
Uncompleted reaction.
Yield of the previous conditions (2.0 equiv of DBU, CH3CN, 80 °C, 10 h).

Y. Nishio et al. / Tetrahedron Letters 52 (2011) 2767–2770
2769
Table 2
Limitations of this reaction
O
R1
H2N R4
(1.2 eq)
K2CO3 (2.0 eq)
Br
(A)
(B)
H N
(C/D)
EtO
O
R4
R2
(1.0 eq)
(1.5 eq)
R1
R2
MeS
NC
N
EtO
H2N
K2CO3 (2.0 eq)
SMe
N
130 oC, 5 h
110 oC, 4 h
50 oC, 1 h
CN
CN
n-BuCN
n-BuCN / NMP
5
H2O (cat)
Entry
1
R1R2NH
R4-NH2
(A)
(B)
––
(C/D)
––
Yielda (%)
H2N
HN
HN
HN
Not proceed
––
2
3
?
?
?
Not finish
––
––
––
––
––
––
H2N
H2N
Not finish
Not finish
HN
HN
HN
4
5
H2N
?
?
Not proceed
––
––
60
H2N
H2N
6
?
?
a
Isolated yield.
Table 3
Applications of the one-pot synthesis
R3
R3
O
R1
H2N
(B)
Br
(1.5 eq)
(A)
H N
(C/D)
EtO
O
R2
(1.0 eq)
(1.2 eq)
R1
MeS
NC
N
K2CO3 (1.5 eq)
EtO
H2N
K2CO3 (2.0 eq)
SMe
N
R2
130 oC, 5 h
110 oC, 4 h
50 oC, 1 h
CN
CN
n-BuCN
n-BuCN / NMP
5
H2O (cat)
Entry
R1R2NH
R3-BnNH2
Yielda (%)
66 (54)b
NHBoc
Cl
1 (914
)
H2N
H2N
HN
HN
2 (10a15
)
58
HN
c
3 (10b)
41 (54)
H2N
MeO
c
4 (10c)
5 (10d)
6 (10e)
HN
HN
59
H2N
Br
F
c
55
H2N
HN
c
28
H2N
(continued on next page)

2770
Y. Nishio et al. / Tetrahedron Letters 52 (2011) 2767–2770
Table 3 (continued)
Entry
R1R2NH
R3-BnNH2
Yielda (%)
77
Me
Cl
HN
NBoc
CO2Et
7 (10f)
8 (10g)
H2N
c
41 (60)
H2N
HN
a
Isolated yield.
Reaction performed at 25 mmol scale.
2.0 equiv of K2CO3 was used in the second step (B).
b
c
3. (a) Mentlein, R.; Ballwitz, B.; Schmidt, W. E. Eur. J. Biochem. 1993, 214, 829–835;
(b) Kieffer, T. J.; McIntosh, C. H.; Pederson, T. A. Endocrinology 1995, 136, 3585–
3596; For reviews, see (c) Deacon, C. F. Horm. Metab. Res. 2004, 36, 761–765.
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, 141–151;
(b) Miller, S. A.; St. Onge, E. L. Ann. Pharmcother. 2006, 40, 1336–1343.
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,
2774–2789.
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, 5025–5037.
7. Feng, J.; Zhang, Z.; Wallace, M. B.; Sttaford, J. A.; Kaldor, S. W.; Kassel, D. B.;
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Gwaltney, S. L. J. Med. Chem. 2007, 50, 2297–2300.
8. (a) 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–
7249; (b) Nishio, Y.; Uchiyama, K.; Kito, M.; Nakahira, H. Tetrahedron 2011, 67,
3124–3131.
was accepted in this synthetic method (entry 6), it is assumed that
the basicity of NH2 and steric hindrance caused by R1R2 or R4 are
important in the second step. Based on these findings, it is believed
that a series of dialkylamines is suitable for R1R2NH, and benzylam-
ines and some kinds of alkylamines are appropriate for R4-NH2. As
our aim was to prepare proper pyrrole derivatives for DPP-4 inhib-
itors synthesis, we investigated the applications of this one-pot
reaction, while focusing on a combination of dialkylaminnes and
benzylamies (Table 3).
The above-mentioned one-pot reaction gave the target pyrrole
9 in good yield, but large-scale experiment resulted in a slight de-
crease in the yield (entry 1). As a magnetic stirrer was used in the
large-scale experiment, the discrepancy in yield is thought to be
related to stirring and/or heat efficiency. As shown in Table 1,
although other primary amines were inappropriate for this reac-
tion, other ways to remove benzyl protection have already been re-
ported.8 Therefore, other structures will be synthesized from these
pyrrole derivatives (entry 2). While a series of carbamate was ac-
cepted as R1R2 (entries 1 and 7), some R1R2NH having an amine
substituent, such as NMe2, could not be used (data not shown).
The use of amine substituted reagents in the first step finally gave
complex mixtures, and the reason is thought that a series of amine
substituents are capable of reacting with ethyl bromoacetate. Es-
ter, which can easily be changed to other substituents, such as
alcohol or amide (entry 8), was also accepted in the first step. As
for R3, a wide variety of substituents were allowed (entries 4–8).
Bromo or chloro substituted benzylamines gave moderate to good
yields and were useful in introducing various other substituents
(entries 1, 5, and 8). In some cases, the use of 2.0 equiv of potas-
sium carbonate in the second step (B) was considered as suitable
(entries 4–6 and 8).
9. Baeschlin, D. K.; Clark, D.E.; dunsdon, S. J.; Fenton, G.; Fillmore, A.; Harris, N.V.;
Higges, C.; Hurley, C.A.; Krintel, S. L.; Mackenzie, R.E.; Osterman, N.; Sirockin, F.;
Sutton, J. M. WO2007071738.
10. Kidwai, M.; Singhal, K.; Rastogi, S. J. Heterocycl. Chem. 2006, 43, 1231–1237.
11. (a) Tsuge, O.; Hatta, T.; Tashiro, H.; Kakura, Y.; Maeda, H.; Kakehi, A.
Tetrahedron 2000, 56, 7723–7735; (b) Zaytsev, A. V.; Anderson, R. J.; Meth-
Cohn, O.; Groundwater, P. W. Tetrahedron 2005, 61, 5831–5836.
12. (a) Castellote, I.; Vaquero, J. J.; Alvarez-Bullia, J. Tetrahedron Lett. 2004, 45, 769–
772; (b) Castellote, I.; Vaquero, J. J.; Fernandes-Gadea, J.; Alvarez-Bullia, J. J. Org.
Chem. 2004, 69, 8668–8675.
13. General procedure: to a solution of 3 (1.0 mmol) in n-BuCN (1.0 ml), R1R2NH
(1.0 equiv) was added, and then the resulting solution was stirred at 50 °C for
1 h. K2CO3 (2.0 equiv) and R3-BnNH2 (1.2 equiv) were added to the solution,
and the mixture was stirred for 5 h at 130 °C. After cooling to room
temperature, K2CO3 (2.0 equiv), NMP (1.0 ml), ethyl bromoacetate
(1.5 equiv), and H2O (10 ll) were added. The resulting mixture was stirred
for 4 h at 110 °C. The slurry was filtered through Celite, then filtrate was
concentrated, and the residue was purified by SiO2 in a column chromatgraphy
(hexane/EtOAc = 8:1–3:1).
In conclusion, we herein report a one-pot synthesis of 5-amino
4-cyano pyrrole derivatives and show its limitations and possible
scale up. This new synthetic method could easily give unique com-
pounds that are difficult to synthesize by conventional methods.
14. Analytical data of ethyl ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)
amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (9):
1H NMR (400 MHz, CDCl3) d: 1.07 (3H, t, J = 6.9 Hz), 1.36–1.43 (1H, m), 1.50–
1.70 (2H, m), 1.75–1.83 (1H, m), 2.80–3.00 (3H, m), 3.36(1H, dd, J = 11.2,
3.3 Hz), 3.71 (1H, s), 4.12 (2H, q, J = 7.1 Hz), 4.56 (1H, s), 5.33–5.43 (2H, m),
6.53 (1H, d, J = 6.8 Hz), 7.18–7.20 (2H, m), 7.32–7.40 (1H, m). 13C NMR
(100 MHz, CDCl3) d: 14.0, 23.0, 28.2, 29.4, 46.2, 52.3, 56.5, 59.6, 75.3, 79.3, 101,
114, 126, 127, 128, 129, 131, 136, 146, 150, 155, 161, 171. HR-MS (ESI+): m/z
502.2213 (calcd m/z 502.2216 for C25H32ClN5O4+H).
15. Analytical data of ethyl 3-amino-1-benzyl-4-cyano-5-(piperidin-1-yl)-1H-pyrrole-
2-carboxylate (10a): 1H NMR (400 MHz, DMSO) d: 1.10 (3H, t, J = 7.1 Hz), 1.45–
1.57 (6H, m), 3.00–3.10 (4H, m), 4.07 (2H, q, J = 7.1 Hz), 5.21 (2H, s), 5.83 (2H,
s), 6.97 (2H, d, J = 7.7 Hz), 7.18–7.24 (1H, m), 7.25–7.32 (2H, m). 13C NMR
(100 MHz, CDCl3) d: 14.3, 23.6, 28.9, 48.4, 52.7, 59.4, 74.3, 101, 115, 126, 127,
128, 138, 146, 152, 161. HR-MS (ESI+): m/z 353.1973 (calcd m/z 353.1972 for
Acknowledgment
We are thankful to Ms. M. Honma for recording high MS
spectra.
References and notes
1. For a review, see Havale, S. H.; Pal, Manojit Bioorg. Med. Chem. 2009, 17, 1783–
1802.
C
20H24N4O2+H).
2. For some references, see (a) Holst, J. J. Curr. Opin. Endocrin. Diabetes 2005, 12,
56–62; (b) Knudsen, L. B. J. Med. Chem. 2004, 47, 4128–4134.